Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4: Azlactones and Oxazolidin-5-ones [4] 9781774911587

Citation preview

AMINO ACIDS Insights and Roles in Heterocyclic Chemistry Volume 4 Azlactones and Oxazolidin-5-ones

Amino Acids: Insights and Roles in Heterocyclic Chemistry, 4-volume set ISBN: 978-1-77491-150-1 (hbk) ISBN: 978-1-77491-151-8 (pbk) ISBN: 978-1-00333-019-6 (ebk) Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 1: Protecting Groups ISBN: 978-1-77491-152-5 (hbk) ISBN: 978-1-77491-153-2 (pbk) ISBN: 978-1-00332-979-4 (ebk) Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 2: Hydantoins, Thiohydantoins, and 2,5-Diketopiperazines ISBN: 978-1-77491-154-9 (hbk) ISBN: 978-1-77491-155-6 (pbk) ISBN: 978-1-00332-983-1 (ebk) Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 3: N-Carboxyanhydrides, N-Thiocarboxyanhydrides, Sydnones, and Sydnonimines ISBN: 978-1-77491-156-3 (hbk) ISBN: 978-1-77491-157-0 (pbk) ISBN: 978-1-00332-987-9 (ebk) Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4: Azlactones and Oxazolidin-5-ones ISBN: 978-1-77491-158-7 (hbk) ISBN: 978-1-77491-159-4 (pbk) ISBN: 978-1-00333-015-8 (ebk)

AMINO ACIDS Insights and Roles in Heterocyclic Chemistry Volume 4 Azlactones and Oxazolidin-5-ones

Zerong Wang, PhD

First edition published 2023 Apple Academic Press Inc. 1265 Goldenrod Circle, NE, Palm Bay, FL 32905 USA 760 Laurentian Drive, Unit 19, Burlington, ON L7N 0A4, CANADA

CRC Press 6000 Broken Sound Parkway NW, Suite 300, Boca Raton, FL 33487-2742 USA 4 Park Square, Milton Park, Abingdon, Oxon, OX14 4RN UK

© 2023 by Apple Academic Press, Inc. Apple Academic Press exclusively co-publishes with CRC Press, an imprint of Taylor & Francis Group, LLC Reasonable efforts have been made to publish reliable data and information, but the authors, editors, and publisher cannot assume responsibility for the validity of all materials or the consequences of their use. The authors, editors, and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged, please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, access www.copyright.com or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. For works that are not available on CCC please contact [email protected] Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. Library and Archives Canada Cataloguing in Publication Title: Amino acids : insights and roles in heterocyclic chemistry, Volume 4, Azlactones and Oxazolidin-5-ones / Zerong Wang, PhD. Names: Wang, Zerong (Daniel Zerong), author. Description: First edition. | Includes bibliographical references and indexes. | Contents: Volume 4: Azlactones and Oxazolidin5-Ones. Identifiers: Canadiana (print) 20220276242 | Canadiana (ebook) 20220276269 | ISBN 9781774911501 (set) | ISBN 9781774911587 (v. 4 ; hardcover) | ISBN 9781774911594 (v. 4 ; softcover) | ISBN 9781003330158 (v. 4 ; ebook) Subjects: LCSH: Heterocyclic compounds. | LCSH: Amino acids. Classification: LCC QD400 .W36 2023 | DDC 547/.59—dc23 Library of Congress Cataloging‑in‑Publication Data Names: Wang, Zerong (Daniel Zerong), author. Title: Amino acids : insights and roles in heterocyclic chemistry / Zerong Wang, PhD. Description: First edition. | Palm Bay, FL : Apple Academic Press, 2023- | Includes bibliographical references and index. | Contents: Volume 1. Protecting groups -- Volume 2. Hydantoins, Thiohydantoins, and 2,5-Diketopiperazines -- Volume 3. N-Carboxyanhydrides, N-Thiocarboxyanhydrides, and Sydnones -- Volume 4. Azlactones and Oxazolidin-5-ones. | Summary: “This first-of-its-kind four-volume book series, Amino Acids: Insights and Roles in Heterocyclic Chemistry, provides readers with up-to-date information on alpha-amino acids, the potential challenges in working with alphaamino acids, the protecting groups for the carboxyl, amino and side chain groups of the amino acids, and the most popular heterocyclic compounds that are originating from alpha-amino acids. These heterocyclic compounds include hydantoins, thiohydantoins (including 2-thiohydantoins, 4-thiohydantoins, 2,4-dithiohydantoins), 2,5-diketopiperazines, N-carboxyanhydrides, N-thiocarboxyanhydrides, sydnones, sydnonimines, azlactones, pseudoazlactones, and oxazolidin5-ones. This is the first resource to comprehensively collect all the heterocycles that can be directly prepared from alphaamino acids. In addition, almost all kinds of synthetic methods for a particular type of heterocycles from alpha-amino acids are include, along with the detailed mechanistic discussions and experimental procedures. In Volume 2: Hydantoins, Thiohydantoins, and 2,5-Diketopiperazines, the author has compiled the three IUPAC accepted nomenclature systems for heterocyclic compounds, which will be very useful for readers working in heterocyclic chemistry for giving synthesized molecules their correct names. In addition, three groups of heterocyclic compounds, i.e., hydantoins, thiohydantoins (including 2-thiohydantoin, 4-thiohydantoin and 2,4-dithiohydantoin), and 2,5-diketopiperazines, have been organized with updated literature information. Particularly, all three groups of heterocyclic compounds have demonstrated many important biological activities, particularly anticancer and antibacterial activities. On the other hand, these three groups of heterocycles can be applied as substrates to make other chemical derivatives, particularly novel unnatural amino acids. All their reactivities have been compiled and updated. These will be very valuable for the readers who have been working in this area or have interest in this area”-- Provided by publisher. Identifiers: LCCN 2022033373 (print) | LCCN 2022033374 (ebook) | ISBN 9781774911501 (set ; hardback) | ISBN 9781774911518 (set ; paperback) | ISBN 9781774911525 (volume 1 ; hardback) | ISBN 9781774911532 (volume 1; paperback) | ISBN 9781774911549 (volume 2 ; hardback) | ISBN 9781774911556 (volume 2 ; paperback) | ISBN 9781774911563 (volume 3 ; hardback) | ISBN 9781774911570 (volume 3 ; paperback) | ISBN 9781774911587 (volume 4 ; hardback) | ISBN 9781774911594 (volume 4 ; paperback) | ISBN 9781003330196 (set ; ebook) | ISBN 9781003329794 (volume 1 ; ebook) | ISBN 9781003329831 (volume 2 ; ebook) | ISBN 9781003329879 (volume 3 ; ebook) | ISBN 9781003330158 (volume 4 ; ebook) Subjects: LCSH: Amino acids. | Heterocyclic compounds. Classification: LCC QD431 .W36 2023 (print) | LCC QD431 (ebook) | DDC 547/.7--dc23/eng20220917 LC record available at https://lccn.loc.gov/2022033373 LC ebook record available at https://lccn.loc.gov/2022033374 ISBN: 978-1-77491-158-7 (hbk) ISBN: 978-1-77491-159-4 (pbk) ISBN: 978-1-00333-015-8 (ebk)

About the Editors

Zerong Wang, PhD Professor of Chemistry, College of Science and Engineering, University of Houston–Clear Lake, Houston, Texas Zerong Wang, PhD, is a full Professor at the University of Houston-Clear Lake, Texas. Prior to that, he worked at the Institute for Biological Sciences of the National Research Council of Canada for several years. Through his career, the author has gained specific training and expertise in organic chemistry, particularly in physical organic chemistry and other subdisciplines that include photochemistry, spectroscopies, carbohydrate chemistry, sulfur chemistry, nucleosides and heterocycles, material science, reaction methodology, computational chemistry, among other. Dr. Wang has developed research projects relating to sulfur chemistry, computational chemistry, nucleoside analogs, heterocycle chemistry, materials science, and macromolecules (pillarene, calix[n]arene, and melamine-based dendrimers, etc.) and has received 22 research grants, including from NSF-MRI, NSFSTEM, Welch Research Grant, Welch Departmental Research Grant, and University of Houston-Clear Lake’s Faculty Research and Support Fund (FRSF) Grants. The author has developed two compendiums in organic chemistry: Comprehensive Organic Named Reactions, with Detailed Mechanism Discussions and Updated Experimental Procedures (3 volumes) (Wiley, 2009) and Encyclopedia of Physical Organic Chemistry (6 volumes) (Wiley, 2017), the PROSE Award winner in 2018. While conducting research activities, the author also teaches courses for both graduate and undergraduate students. To date, the author has taught courses on General Chemistry, General Chemistry Laboratory, Analytical Chemistry, Quantitative Chemical Analysis, Forensic Chemistry, Organic Chemistry, Organic Chemistry Laboratory, Advanced Organic Chemistry, Physical Organic Chemistry, Synthetic Organic Chemistry, Organometallic Chemistry, Biochemistry, Biochemistry Laboratory, Polymer Chemistry, Introduction to Chemical Engineering, Nutrition and Diet Chemistry, Green Chemistry, Introduction to NMR Spectroscopy, Chemistry Seminar, Graduate Research, and Chemistry for Non-Science Majors.

vi

About the Editors

Dr. Wang earned his BS degree in Chemistry from Lanzhou University, PR China, and earned his MS and PhD degrees from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences. He conducted his postdoctoral research at the Department of Chemistry, University of California Berkeley and York University (Canada).

Contents

Abbreviations.......................................................................................................................................ix Acknowledgments..............................................................................................................................xi Preface.................................................................................................................................................xiii Preface for Amino Acids: Insights and Roles in Heterocyclic Chemistry................xvii

1.

Azlactones...............................................................................................................................1

2.

Oxazolidin-5-ones.......................................................................................................... 259

Index .................................................................................................................... 395

Abbreviations

ATRP atom transfer radical polymerization BPEI branched polyethyleneimine BQ 1,4-benzoquinone CaHPO4 calcium hydrogen phosphate CDMT 2-chloro-4,6-dimethoxy-1,3,5-triazine CIDR crystallization-induced dynamic resolution CLSI Clinical and Laboratory Standards Institute CNS central nervous system CPME cyclopentyl methyl ether CRE cAMP response element CSA camphorsulfonic acid CTA chain transfer agent DABCO 1,4-diazabicyclo[2.2.2]octane DAST diethylaminosulphur trifluoride DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC dicyclohexylcarbodiimide DIPEA diisopropylethylamine DKP 2,5-diketopiperazine DMAP 4-N,N-dimethylaminopyridine DMV 4,4-dimethyl-2-vinyloxazol-5(4H)-one DTBP di-tert-butyl peroxide FeCl3 ferric chloride FVP flash vacuum pyrolysis GAP group-assisted purification GBL γ-butyrolactone HEMA 2-hydroxyethyl methacrylate HLE human leukocyte elastase HMPA hexamethylphosphoramide IEDHDA inverse-electron-demand hetero-Diels–Alder reaction KOAc potassium acetate linear polyethyleneimine LPEI MAA methacrylic acid MDC monodansylcadaverine MDR multidrug resistant

x Abbreviations

MIC minimum inhibitory concentrations multiple response element MRE MRSA methicillin-resistant Staphylococcus aureus methyl tert-butyl ether MTBE NBS N-bromosuccinimide NEM N-ethyl morpholine NMM N-methylmorpholine NMO N-methylmorpholine-N-oxide NMP nitroxide-mediated polymerization PDI polydispersity index PDMV poly(2-vinyl-4,4’-dimethylazlactone) PEG poly(ethylene glycol) PEI poly(ethyleneimine) PFPA pentafluorophenyl acrylate PGMA poly(glycidyl methacrylate) PKS polyketide synthase PLE pig liver esterase POCl3 phosphoryl chloride PPA polyphosphoric acid PPh3 triphenylphosphine PPTS pyridinium p-toluenesulfonate PTSA para-toluenesulfonic acid RAFT reversible addition-fragmentation transfer RAGP reactive azlactone graphene platform ROMP ring-opening metathesis polymerization ROS reactive oxygen species SMM supplemented minimal medium SOD superoxide dismutase TBD 1,5,7-triazabicyclo[4.4.0]dec-5-ene TBTU tetramethyl-aminium tetrafluoroborate TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy TMG tetramethylguanidine TMPTMA trimethylolpropane trimethacrylate TMSCl trimethylsilyl chloride TPA tungstophosphoric acid TXL taxol vinyl dimethyl azlactone VDM VRE vancomycin-resistant Entrococcus faecium ZnO zinc oxide

Acknowledgments

Writing this book series was harder than I expected, even though I had already been through this process for my three-volume book, Comprehensive Organic Named Reactions, with Detailed Mechanism Discussions and Updated Experimental Procedures (2009, ISBN: 978-0-471-70450-8), as well as in editing the six-volume set, Encyclopedia of Physical Organic Chemistry (2017, ISBN: 978-1-118-47045-9), winner of 2018 PROSE Award for Multivolume Reference/Science. I’m eternally grateful to my wife, Xi Liu, and my daughter, Izellah, who have taken care of me so that I could focus on this book series in my spare time. It would not have been possible to complete these five books without their long-time support. A very special thanks to our librarians in the Newman Library of the University of Houston-Clear Lake, who helped me locate necessary references in a timely manner. Finally, I thank my colleagues and friends who have provided me with endless guidance.

Preface

This is the fourth book in the monograph series regarding α-amino acids and their simple heterocyclic derivatives. In general, four types of heterocyclic compounds can be formed from α-amino acids: ones with the heterocyclic ring formed from both the amino and carboxyl groups of amino acids, ones with the heterocyclic ring containing both the side chain functional group and either the carboxyl or amino group, ones with the heterocyclic rings arising from either the amino group or carboxyl group of amino acid, and lastly the heterocycles with the ring being generated from the side chain functional group only. This book series will be focused on the first type. The two chapters included in this book detail heterocyclic compounds of azlactones and oxazolidin-5-ones, which while very closely related have distinctive differences as well. Chapter 1 covers azlactones, also known as oxazolones. Azlactones are five-membered heterocyclic compounds formed from the condensation of N-acyl α-amino acids in the presence of dehydrating agents under basic conditions, or under acidic conditions with aldehydes (to form unsaturated azlactones in most cases). While these simple heterocycles have not demonstrated much biological activities, they have been explored for a variety of chemical reactivities. For example, the saturated azlactones can undergo alkylation, allylation, benzylation, arylation, acylation, alkynylation, Aldol condensation, Mannich reaction, Michael reaction, Ene reaction, as well as addition to alkynes, diazo compounds, and allenes at the C4 position. The reactivity of saturated azlactones at the C5 position includes the nucleophilic attacks from amines, alcohols, thiols, etc., to open the azlactone rings, forming the corresponding amides, ester, and thioester, respectively. In addition, when azlactones are deprotonated with base, the resulting conjugated systems have been extensively explored for 1,3-dipolar cycloaddition, [4+2] cycloaddition and [8+2] cycloaddition. Compared to the saturated azlactones, the unsaturated azlactones have been investigated for vinylogous arylation, nucleophilic addition by benzimidamide, carbon nucleophiles at the exocyclic double bond, and nucleophilic addition at C5 by water, amines, azide, alcohols, thiols, etc. The reactivity involving the exocyclic double bond of the unsaturated azlactones has also been greatly explored in

xiv Preface

1,3-dipolar cycloaddition, [4+2] cycloaddition, as well as cyclopropanation and photo-dimerization. Some products of these reactions would be very difficult to make from other alternative methods. Due to such diversified reactivity, azlactones have been applied to material science, providing potential for post-modification of polymers containing azlactone moiety in addition to forming polypeptides directly from the reaction of azlactones. With azlactone as the side chain of polymers, different drug-like molecules can be mounted to polymers by means of “Click Chemistry.” In addition, opening of the azlactone rings with amine or water allows the creation of pH responsive material. At the end of this chapter, pseudoazlactones have been briefly discussed because their reactivity is largely waited to be explored in the future. Pseudoazlactones can also be formed from α-amino acids but under different reaction conditions. Chapter 2 is devoted to oxazolidin-5-ones, which are also formed from the condensation of N-acyl amino acid with aldehydes or ketones in the presence of dehydrating agents. These compounds are considered as lactones as well as N,O-acetals (or N,O-ketals). Unlike azlactones, oxazolidin-5-ones have demonstrated many important biological activities, primarily represented by a group of antibiotics known as Jadomycins. According to the different amino acid and sugar sources provided by cell culture conditions, different Jadomycins can be obtained in variation of the components of the attached sugar as well as the oxazolidin-5-one moieties. These antibiotics have demonstrated activities against both gram-positive and gram-negative bacteria, as well as great potentials in cleavage of DNA, cancer treatment and being applied as signal molecules. According to the aldehydes and ketones used during their preparations, a total of nine groups of oxazolidin-5-ones have been summarized in this chapter, including the ones prepared from paraformaldehyde, acetaldehyde, benzaldehyde, pivalaldehyde, acetone, hexafluoroacetone, etc. In addition to their preparations, the reactivities of oxazolidin-5-ones have been explored at C4 and C5 positions; the former is nucleophilic after deprotonation while C5 is generally electrophilic. Therefore, the enolates generated from oxazolidin-5-ones have been commonly applied in alkylation to make α,α-disubstituted amino acids, or in addition onto other electrondeficient species. Reduction of oxazolidin-5-ones often gives the N-methyl α-amino acids or N-hydroxymethyl-amino acids which are used to make peptides against proteolytic enzymes. Furthermore, nucleophilic addition at C5 by amino acids allows the preparation of peptides without potential racemization issue. Decarboxylation from oxazolidin-5-one yields azomethine for 1,3-dipolar cycloaddition. In addition, the formation of oxazolidin-5-one

Preface xv

essentially protects both α-amino and carboxyl groups, providing a way of modifying amino acid side chains, and opens the door to synthesize other chiral molecules from α-amino acids. More importantly, the fact that proline has been commonly applied as an organic catalyst in Aldol reaction, Aldol condensation, and others has been rationalized in this chapter by means of parasitic equilibrium between the oxazolidin-5-one and enamine species. Still, there are many reactivities of oxazolidin-5-ones to be explored in the future.

Preface for Amino Acids: Insights and Roles in Heterocyclic Chemistry

α-Amino acids are a group of organic molecules with very important

biological roles, essentially forming the constitutional units of proteins and enzymes. In addition, α-amino acids are enriched with functional groups, and the majority of amino acids have at least one chiral center. This property makes amino acids de novo synthons in organic synthesis. A particular application for α-amino acids is the formation of heterocyclic compounds in pharmaceutical and medicinal chemistry. The heterocyclic compounds collected in this book series include hydantoins, thiohydantoins (including 2-thiohydantoins, 4-thiohydantoins, and 2,4-dithiohydantoins), 2,5-diketopiperazines (DKPs), N-carboxyanhydrides (NCAs), N-thiocarboxyanhydrides (NTAs), sydnones, sydnonimines, azlactones, pseudoazlactones, and oxazolidin-5-ones. The adjacent amino and carboxyl groups of α-amino acids not only synergistically strengthen their acidity but also ionize individually depending on the pH, leading to amino acids of different ionic states or the formation of inner salts and resulting in low solubility of amino acids in common organic solvents. Due to the opposite reactivity between the carboxyl and amino groups, they often interfere with each other in the transformation of amino acids into their derivatives, particularly for peptides and proteins. The protection of one group and activation of the other is a common practice in protein chemistry. Therefore, it is necessary to introduce the protecting group to either the amino or carboxyl group, as well as to the side-chain group (on various occasions) to temporarily cap these groups and avoid the formation of ionic species. The resulting amino acid derivatives of enhanced solubility in organic solvents can be smoothly transformed into the expected products. Based on what has been said above, this book series has been split into four volumes, where Volume 1 deals with the introduction of amino acids and their protecting groups, Volume 2 contains a general introduction of heterocyclic compounds and three types of heterocycles (hydantoin, thiohydantoins, and 2,5-diketopiperazines), Volume 3 comprises four types of heterocycles (NCAs, NTAs, sydnones, and sydnonimines), and Volume 4 describes the last two types of heterocycles (azlactones and oxazolidin-5-ones).

xviii

Preface for Amino Acids: Insights and Roles in Heterocyclic Chemistry

Specifically, Volume 1 introduces carboxylic acids, amines, amino acids, and their relevant physical properties. A collection of 260 protecting groups for the carboxyl, amino, or side-chain functional groups are arranged into three chapters, respectively. The carboxyl protecting groups have been organized into 12 categories, whereas the amino protecting groups have been categorized into five groups. Volume 1 also provides experimental procedures to introduce and remove these protecting groups. Volume 2 begins with a brief introduction of heterocyclic compounds, the three IUPAC accepted nomenclature methods for heterocycles and a compilation of book series for heterocyclic chemistry. Chapter 2 focuses on hydantoins, collecting 32 synthetic approaches of hydantoins as well as their biological activities. Chapter 3 covers the preparative methods for 2-thiohydantoins, 4-thiohydantoins, and 2,4-dithiohydantoins, with key experimental procedures. It also includes the reactions of 2-thiohydantoins and 4-thiohydantoins, including the formation of 5-arylidene-2-thiohydantoins, N- or S-alkylated 2-thiohydantoins, participation of 2-thiohydantoins in DielsAlder reactions, Mannich reactions, etc. Chapter 4 details DKPs, the widely existing natural cyclic dipeptides. More than 200 tryptophan, phenylalanine, or tyrosine-containing DKPs with associated biological activities have been organized in tables within this chapter. In addition, different preparation methods for DKPs, as well as individual chemical reactivities at the 1,4-, 2,5- and 3,6-positions have been summarized along with additional reactions for arylidene/alkylidene-DKPs. Volume 3 contains only two chapters. Chapter 1 contains different preparative methods for NCAs and NTAs, which are often used in ring-opening polymerization to give polypeptides and polypeptoids. Both polypeptides and polypeptoids have found wide applications in drug delivery, tissue engineering, and functional materials, among others. Different initiation methods for the ring-opening polymerization of NCAs and NTAs have been gathered in this book, particularly for the creation of living polypeptides and polypeptoids. General information on polymer characterizations has also been compiled. Particularly, the calculation of protein/polypeptide molecular weight based on modern mass spectrometry (e.g., ESI-TOF, MALTI-TOF), which is rarely available in mainstream literature, has been provided. Chapter 2 primarily focuses on sydnones, with a small section for sydnonimines. Both sydnones and sydnonimines are mesoionic compounds that cannot be represented by a fixed chemical structure. Sydnones have demonstrated a variety of biological activities, such as anti-inflammatory and analgesic activity, anti-HIV activity, and anticancer activity, just to name

Preface for Amino Acids: Insights and Roles in Heterocyclic Chemistry xix

a few. Several sydnonimines have already been applied as stimulants and other medicines in the actual treatment of diseases. All activities compiled here reflect the most up-to-date information. The different chemical transformations involving sydnones, including lithiation, alkylation, halogenation, 1,3-dipolar cycloaddition, etc., have also been compiled. Likewise, Volume 4 comprises two chapters, one for azlactones (also known as oxazolones), and the other for oxazolidin-5-ones. Azlactones have been explored for a variety of chemical reactivities. Saturated azlactones can undergo alkylation, allylation, benzylation, arylation, acylation, alkynylation, Aldol condensation, Mannich reaction, Michael reaction, Ene reaction, as well as the addition to alkynes, diazo compounds, and allenes at the C4 position. Deprotonated azlactones have been extensively explored for 1,3-dipolar cycloaddition, [4+2] cycloaddition, and [8+2] cycloaddition. Unsaturated azlactones have been investigated for vinylogous arylation, nucleophilic addition by benzimidamide, carbon nucleophiles at the exocyclic double bond, as well as different cycloadditions, and nucleophilic addition at C5 by water, amines, azide, alcohols, thiols, etc. In addition, azlactones have been applied in material science for the direct formation of polypeptides and post-modification of polymers containing azlactone moiety as a side group. Chapter 2 is devoted to oxazolidin-5-ones, which have demonstrated many important biological activities, primarily represented by a group of antibiotics known as Jadomycins. According to amino acid and sugar sources provided during cell culture, different Jadomycins can be obtained. These antibiotics have demonstrated activities against both gram-positive and gram-negative bacteria, as well as great potentials in the cleavage of DNA, cancer treatment, etc. Based on the aldehydes and ketones used, a total of nine groups of oxazolidin-5-ones have been summarized in this chapter, including the ones prepared from paraformaldehyde, acetaldehyde, benzaldehyde, pivalaldehyde, acetone, hexafluoroacetone, etc. The reactivities of oxazolidin-5-ones have been explored at C4 and C5 positions. The enolates generated from oxazolidin-5-ones have been commonly applied in alkylation to make α,α-disubstituted amino acids, or in addition reaction to electron-deficient species. Reduction of oxazolidin-5-ones often gives the N-methyl α-amino acids or N-hydroxymethyl-amino acids which are used to make peptides against proteolytic enzymes. Furthermore, nucleophilic addition at C5 by amino acids allows the preparation of peptides without potential racemization issues. Decarboxylation from oxazolidin-5-one yields azomethine for 1,3-dipolar cycloaddition. More importantly, the fact that proline has been commonly applied as an organic catalyst in Aldol reaction

xx

Preface for Amino Acids: Insights and Roles in Heterocyclic Chemistry

and others has been rationalized in this chapter using parasitic equilibrium between the oxazolidin-5-one and enamine species. The author sincerely wishes that readers will find this book series useful for their research in the areas of heterocycles, pharmaceutical/medicinal chemistry, physical organic chemistry, organic synthesis, and protein/peptide synthesis.

CHAPTER 1

Azlactones

1.1 INTRODUCTION Azlactone, also known as oxazol-5(4H)-one [1–4], oxazole-5-(4H)-one [5], oxazolone [6, 7], or 2-oxazolin-5-one [8–10], represents a particular group of heterocyclic compounds. It is generally known that a cyclic ester is called a lactone; whereas an organic compound in which a carbon atom is replaced by a nitrogen atom is known as an “aza-compound.” Therefore, when one of its carbon atoms is replaced by a nitrogen atom, the resulting lactone can be named aza-lactone. However, in the literature, azlactones stand for any five-membered aza-lactones arising from the dehydration of N-acyl α-amino acids, as shown in Figure 1.1. Depending on the preparation conditions, either saturated (1) or unsaturated azlactones (2) can be synthesized. R1

R1 O

4 5 1O

1

3

N 2

O

4 5 1O

R2 2

O

3

N 2

R1

R2

N

R2

O 3

FIGURE 1.1 The general structure of saturated and unsaturated azlactones and initially proposed structure.

In fact, the unsaturated azlactone has been synthesized earlier than the saturated azlactone, and the first unsaturated azlactone was prepared by Plöchl in 1883 [11], by means of the condensation of benzaldehyde with N-benzoyl glycine (hippuric acid) in the presence of acetic anhydride (Scheme 1.1), even though its structure was determined by Erlenmeyer 10 years later [12], who further extended this protocol to make several other unsaturated azlactones [13–19]. As a result, the reaction between an aldehyde and hippuric acid to form an unsaturated azlactone is generally referred to as the Erlenmeyer azlactone synthesis [20–22], Erlenmeyer-Plöchl azlactone

2

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

synthesis [23], Erlenmeyer-Plöchl reaction [8, 24], or simply Erlenmeyer synthesis [25]. O H N

O OH

O

O

Ac2O

+

N O

SCHEME 1.1 The initial preparation of unsaturated azlactone.

The difficulty to make saturated azlactones in the early days is probably due to the ignorance of the quick hydrolysis of saturated azlactones, as they can be considered as the anhydride of N-acyl α-amino acids (different from N-carboxyanhydrides). Only until 1908, the preparation of saturated azlactone has been realized by Mohr et al. by the treatment of N-acyl α-amino acids with acetic anhydride [26–32]. In addition to the well-recognized structures (1 and 2, Figure 1.1) for azlactones, several other structures have been proposed, of which only the three-membered lactimide (3) has been seriously considered. This particular lactimide structure has once been accepted by Erlenmeyer in 1893 [12], who suddenly abandoned this structure in 1900 [33]. The solid evidence for the actual structure of azlactone is probably its X-ray crystal structure, as shown by the azlactone of N-acetyl-(S)-isovalyl-(S)-isovaline, i.e., N-((S)-2-((R)-4ethyl-4-methyl-5-oxo-4,5-dihydrooxazol-2-yl)butan-2-yl)acetamide [34]. Since then, azlactone has been the general name for this type of five-membered heterocyclic compound, after being coined by Erlenmeyer in 1904 [35]. Occasionally, “lactimone” has also been used for this type of molecule [26, 36]. It should be pointed out that a few six-membered aza-lactones have also been classified as azlactones, such as the morpholin-2-ones fused to 1,2-position of indole, known as indole-fused azlactones. These molecules are prepared from the reaction between 1H-indole-2-carboxylic acids and 3-bromoprop-1-yne (propargyl bromide) in DMF in the presence of K2CO3 (Scheme 1.2) [37]. However, all azlactones mentioned in this book are the ones arising from α-amino acids. R

R

O N H

+ OH

R = H, F, Br, Me, MeO

Br

K2CO3 DMF,

O N

O

74 - 92 %

SCHEME 1.2 The preparation of indole-fused azlactone (note: this structure is actually not an azlactone).

Azlactones 3

1.2 BIOLOGICAL ACTIVITIES Due to the fact that azlactones resemble some properties and reactivities of anhydrides, there have not many reports about the biological activities of azlactones. In fact, many azlactones have been converted into alternative derivatives for a variety of biological purposes. Nevertheless, a few azlactones have been tested or screened for certain biological activities. For example, (R)-4-methyl-4-((R,E)-3-oxo-1,5-diphenylpent-4-en-1-yl)-2-phenyloxazol5(4H)-one (4, Figure 1.2) has been tested as a potential inhibitor for Trypanosoma cruzi. Screening with epimastigotes indicates that this compound is 14.1 times more potent against intracellular amastigotes (IC50 = 2.34 µM). Also, treatment of the infected Vero cells for 72 hours with this azlactone results in a dose-dependent decrease in the number of trypomastigotes and amastigotes released in the supernatant, whereas the ratio of amastigote over trypomastigote remains the same. This result implies that the growth of amastigote has been disturbed by this azlactone, but cell differentiation has not been affected yet [38]. Three piperazine containing azlactones, including (E)-4-(4-hydroxybenzylidene)-2-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl) oxazol-5(4H)-one (5), (E)-2-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl)4-(4-nitrobenzylidene)oxazol-5(4H)-one (6), and (E)-4-(4-hydroxy3-methoxybenzylidene)-2-(4-(4-methylpiperazin-1-yl)-3-nitrophenyl) oxazol-5(4H)-one (7), have demonstrated biological activities against Gramnegative bacterial Salmonella typhi and Escherichia coli, particularly for the azlactone 5 and 7. In addition, azlactone 7 has also demonstrated maximum inhibition against Gram-positive bacteria Staphylococcus aureus [20]. Also, (E)-2-acetoxy-5-((2-methyl-5-oxooxazol-4(5H)-ylidene)methyl)benzyl acetate (8) and (E)-2-acetoxy-5-((5-oxo-2-phenyloxazol-4(5H)-ylidene) methyl)benzyl acetate (9) have displayed some activities in the central nervous system (CNS), such as the anti-tremorine effect as determined with male albino mice of the Charles River strain, 8 has other effects in CNS depression and writhing movements [39]. Even though only a few direct biological activities have been reported from a few azlactones, azlactones have been largely mounted to the surface of polymers from which other important biological molecules and scaffolds can be mounted to the surface of polymers, as outlined in the application section of this chapter.

4

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

HO

O2N O

O

O

O O

NO2

N

N

N

O

O

N

5

4

O

N N

O

HO

NO2

N

NO2

O

O N

N

N

6 O

OAc

N

O

O

N OAc

7

OAc

8

OAc 9

FIGURE 1.2 The list of azlactones of biological activities.

1.3 PREPARATIVE METHODS 1.3.1 PREPARATION OF UNSATURATED AZLACTONES 1.3.1.1 ERLENMEYER AZLACTONE SYNTHESIS 1.3.1.1.1 Erlenmeyer Azlactone Synthesis Under Basic Conditions In coincidence with the history of the exploration of azlactones, most of the current syntheses of azlactones are focused on the unsaturated azlactones, particularly following the original procedure of Erlenmeyer, i.e., treatment of the N-acyl α-amino acids with sodium acetate in an excess amount of acetic anhydride in the presence of an aldehyde. As an example, the reaction of N-acyl glycine or N-benzoyl glycine (hippuric acid) with a series of benzaldehydes with an electron-donating group (e.g., OH, OMe) at the meta or para position in acetic anhydride in the presence of sodium acetate affords 10 unsaturated azlactone derivatives. Upon reduction with magnesium in methanol and pure L-tyrosine and L-dopa were obtained by means of crystallization induced asymmetric transformation [25]. Similarly, the reaction of p-fluorobenzaldehyde with hippuric acid is treated with potassium acetate (KOAc) in acetic anhydride to yield 4-(p-fluorobenzylidene)2-phenyloxazol-5(4H)-one [22]. Likewise, refluxing of an equimolar mixture (0.05 mol) of 4-(dimethylamino)benzaldehyde, hippuric acid and sodium acetate in 14 mL of acetic anhydride for 2 hours leads to 65% of 4-(4-(dimethylamino)benzylidene)-2-phenyloxazol-5(4H)-one. The product

Azlactones 5

is then purified by recrystallization in ethanol [40]. Another example of using an equal amount of N-acyl amino acid, aldehyde, and sodium acetate can be found in the preparation of 4-benzylidene-2-(4-(4-methylpiperazin1-yl)-3-nitrophenyl)oxazol-5(4H)-one [20]. Moreover, the reaction of 3-formylchromone and hippuric acid in acetic anhydride in the presence of sodium acetate yields the corresponding 4-((4-oxo-4H-chromen-3-yl) methylene)-2-phenyloxazol-5(4H)-one (be careful about this literature) [41]. It should be pointed out that in all these cases, the configuration of the unsaturated double bond has not been specified. Also, while the combined sodium acetate and acetic anhydride function as both condensation and dehydrating agents, the formation of azlactone might be complicated with side reactions, such as the Perkin reaction to form α,β-unsaturated carboxylic acid arising from the condensation between aldehyde and acetic anhydride in the presence of sodium acetate, as well as the acyl transformation to convert the N-acyl α-amino acid into alternative N-acetyl α-amino acid, from which different azlactone is formed instead, as illustrated in Scheme 1.3. It sounds like the base (e.g., sodium acetate) to promote the formation of unsaturated azlactone is not necessarily stoichiometric [42]. For example, the same reaction of 3-formylchromone (0.01 mol) and hippuric acid (0.01 mol) in 15 mL of acetic anhydride when treated with 0.5 g of sodium acetate (0.0061 mol) afford 88% of 4-((4-oxo-4H-chromen-3-yl)methylene)-2-phenyloxazol5(4H)-one after crystallization from alcohol-acetone (m.p. 195–197°C) [43]. In another example, the reaction of hippuric acid and meta-methoxybenzaldehyde in acetic anhydride in the presence of a catalytic amount of sodium acetate at 95°C yields 4-(3-methoxybenzylidene)-2-phenyloxazol-5(4H)-one, with an overall yield of 30% for the consecutive conversion of ethyl glycinate hydrochloride to ethyl N-benzoyl glycinate, formation of hippuric acid and final azlactonization [24]. In a practical scale preparation of azlactone, a mixture of 58.5 g of N-acetyl glycine (0.5 mol), 30 g of anhydrous sodium acetate (0.37 mol), 79 g of freshly distilled benzaldehyde (0.74 mol), and 134 g of 95% acetic anhydride (1.25 mol) leads to 69–72 g of 4-benzylidene-2-methyloxazol5(4H)-one, corresponding to 74–77% of yield. When an equivalent of glycine instead of N-acetyl glycine is used in this preparation, and the amount of acetic anhydride is increased to three equivalents, only 45–50% of 4-benzylidene-2methyloxazol-5(4H)-one can be obtained [44]. Under the mechanochemical conditions, high yields of unsaturated azlactones can be obtained by direct grinding the mixture of amino acid, aromatic aldehyde, benzoyl chloride and fused sodium acetate in a porcelain mortar in the presence of a few drops of acetic anhydride. This method has demonstrated several advantages over the conventional method, such as a facile work-up process, solvent-free condition,

6

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

high yield economy and environmental friendliness [45]. Other preparations of unsaturated azlactones in the presence of sodium acetate can be found in alternative literature [46–48]. While in most cases, the unsaturated azlactones of Z-configuration have been formed under this condition, a recent one-pot synthesis of an azlactone-based dye bearing an isoxazole moiety as a donor group displays the azlactone in E-configuration. Specifically, (E)-4-((3-(4-methoxyphenyl) isoxazol-5-yl)methylene)-2-phenyloxazol-5(4H)-one was prepared from 3-(4-methoxyphenyl)isoxazole-5-carbaldehyde and hippuric acid in Ac2O in the presence of NaOAc at 60°C for 3 hours. The aldehyde was prepared from 1,3-dipolar cycloaddition between (E)-4-methoxybenzaldehyde oxime and propargyl alcohol in CHCl3 at room temperature in the presence of NaOCl and Et3N followed by PCC oxidation. The final compound displays fluorescence emission both in solution and solid-state [49]. 2

2

2

1D2$F $F2+

2

2

2

2

5

+

2

2

1D2$F

2 2

5

2 2

2 +

+ 1

2 2

5

$F2+$F2

2$F

1D2$F $F2+

2

2

5

2

2 1

2+

2

$F2

2

2 2

1D2$F

2

2 2

2 1

2 2 3K

2

+1

$F2+

2 2 5

+

2+ 2

5

2

2

2

2

+1

$F2

2

2

2

2

2

+ 1

2

2

1

+ 2

1

2 2

$F2 $F2+

1

2

2

2 2

2

2

2

1

2

1

$F2+

5 1

2

SCHEME 1.3 The mechanism for the formation of unsaturated azlactone.

Azlactones 7

In many cases, sodium acetate can be replaced by other bases. For example, in the reaction of hippuric acid with methyl (1S,4aR,5S)-5-(2-(2-formylfuran-3-yl)ethyl)-1,4a-dimethyl-6methylenedecahydronaphthalene-1-carboxylate in acetic anhydride in the presence of 1 equivalent of sodium acetate, 61% of methyl (1S,4aR,5S)1,4a-dimethyl-6-methylene-5-(2-(2-((Z)-(5-oxo-2-phenyloxazol-4(5H)ylidene)methyl)furan-3-yl)ethyl)decahydronaphthalene-1-carboxylate was obtained after column chromatography on aluminum oxide using petroleum ether-diethyl ether (4: 1) as eluent. In contrast, when the same reaction mixture was treated with potassium carbonate, 76% of the product was obtained after crystallization from petroleum ether-diethyl ether (2:1) (Scheme 1.4) [2]. In another example, KOAc is applied to promote the formation of azlactone, in which methyl 3-formylbenzoate or methyl 5-formyl-2-hydroxybenzoate reacts with an equivalent amount of N-acetyl glycine and KOAc in acetic anhydride to afford methyl (Z)-3-((2-methyl5-oxooxazol-4(5H)-ylidene)methyl)benzoate or methyl (Z)-2-hydroxy5-((2-methyl-5-oxooxazol-4(5H)-ylidene)methyl)benzoate, in yield of 45% and 60%, respectively [50]. Likewise, calcium acetate [Ca(OAc)2] has been applied to promote the condensation between hippuric acid and several benzaldehydes under a solvent-free condition with microwave irradiation to afford 4-arylidene-2-phenyl-5(4H)-oxazolones, where the aryl group = Ph, 4-MeOC6H4, 4-MeC6H4, 4-ClC6H4, 3,4-(MeO)2C6H3, 2-O2NC6H4, 3-O2NC6H4, and PhCH=CH [51]. This method has been repeated with substituted hippuric acids and benzaldehydes in Ac2O under microwave irradiation in the presence of Ca(OAc)2 and 4Å zeolite. Among the prepared azlactones, (Z)-4-(4-methoxybenzylidene)-2-phenyloxazol5(4H)-one (shown as in E-configuration in the chapter) demonstrated potent antibacterial and antifungal activity even at lower concentrations [52]. Alternative metal acetates that have been applied for the preparation of unsaturated azlactones are Bi(OAc)3 [53], and Pb(OAc)2 [54, 55]. Other simple inorganic bases applied for the preparation of unsaturated azlactones include alumina supported potassium fluoride (KF/Al2O3) [56, 57], alumina supported magnesium oxide (MgO/Al2O3) [58], diammonium hydrogen phosphate [(NH4)2HPO4, under solvent-free condition] [59], zinc oxide (ZnO) [60], and calcium hydrogen phosphate (CaHPO4) [61].

8

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O

O

CHO N

O

O

H N

+

OH

K2CO3 Ac2O

O

O CO2Me CO2Me

SCHEME 1.4  Preparation of an unsaturated azlactone from N-benzoyl glycine and a furan aldehyde in the presence of K2CO3 and Ac2O.

For the case of using CaHPO4 to catalyze the azlactonization between benzaldehyde and hippuric acid in acetic anhydride under microwave irradiation, the optimal amount of catalyst is about 20%, and the yield of the azlactone is 93% after 5-minute irradiation under the microwave. Recycled CaHPO4 can be used for this transformation again, with inferior efficiency for the yield of azlactone, e.g., 93, 87, 85, and 82% after each cycle of azlactonization. For comparison, the same catalyzed reaction refluxed in CHCl3, THF, and DMF for 100 minutes yield only 38%, 45% and 61% of azlactone, respectively. More than 18 different aldehydes have been tested for this condition, all within 10 minutes, yielding very good yields of the corresponding azlactones. Interestingly, when 4,4’,4”-((1,3,5-triazine-2,4,6-triyl)tris(oxy))tribenzaldehyde is treated with 3 equivalents of hippuric acid under the same condition, only two equivalents of the hippuric acid have reacted, even under extended reaction time, yielding 90% of dipodal azlactone, i.e., 4-((4,6-bis(4-((Z)-(5-oxo-2-phenyloxazol-4(5H)ylidene)methyl)phenoxy)-1,3,5-triazin-2-yl)oxy)benzaldehyde, as shown in Scheme 1.5 [61]. The combination of MgO and Al2O3 also catalyzes the formation of unsaturated azlactones under microwave irradiation, showing the features of low toxicity, low cost, ease of handling and high activity. In addition, such a combined catalyst can be recovered by simple filtration which has been reused for the generation of the unsaturated azlactones five times without considerable loss of its catalytic activity [58]. O O CHO N

H N

3 O

O OH

+ OHC

N

O N

O N

CaHPO4 Ac2O, MW OHC

O

N

O N

N O

CHO

O

N

O O

SCHEME 1.5  CaHPO4 catalyzed synthesis of unsaturated azlactone under microwave irradiation.

Azlactones 9

Zeolites as complicated inorganic compounds are also effective in the formation of unsaturated azlactones [62]. Hydrous calcium aluminum silicate is known as scolecite zeolite (CaAl2Si3O10·3H2O), which has been found to catalyze the azlactonization of hippuric acid with a series of aldehydes at even lower temperature in acetic anhydride within a shorter reaction time, in comparison with the same reaction without such catalyst. For example, in the reaction of hippuric acid with 4-chlorobenzaldehyde (5 mmol each) in 15 mmol of acetic anhydride, only 10% of scolecite zeolite (200 mg) is already good enough to promote the azlactonization at 70°C in 50 minutes to afford 96% of 4-(4-chlorobenzylidene)-2-phenyloxazol-5(4H)-one. The corresponding reaction in the absence of scolecite zeolite takes 3 hours to yield only 35% of the corresponding azlactone, respectively. This catalyst works for a series of benzaldehydes, as well as furfural and even nonaromatic aldehydes, e.g., crotonaldehyde ((E)-but-2-enal). In addition, the catalyst retains most of its activity after being used four times [63]. Similar to scolecite zeolite, zeolite NaY also catalyzes the azlactonization of hippuric acid with a variety of aldehydes and ketones in the presence of acetic anhydride under microwave irradiation. For a typical procedure, the mixture of 1.0 mmol of aldehyde (or ketone), 1.1 mmol of hippuric acid and 0.1 g of zeolite NaY in 1.0 mL of acetic anhydride is irradiated under microwave for 10 to 15 minutes. The reaction works well for aldehydes but yields azlactones from the corresponding ketones in low yields (< 50%). When benzaldehyde is used, the yield of 4-benzylidene-2-phenyloxazol-5(4H)-one is 87%, 86%, 83% and 82% for the four consecutive uses of the catalyst, respectively [64]. Besides the inorganic bases, organic bases are also suitable for the preparation of unsaturated azlactones. Compared to the application of NaOAc, the formation of azlactone is faster in the presence of an organic base, although some side products have also been observed. In this case, the substituents on the aldehydes play an important role [42]. For example, under microwave irradiation and solvent-free condition, an organic base such as 2-aminopyridine supported on nano-sphere silica has been approved to be a proficient, environmentally benign, mild, and solid catalyst of good stability for the Erlenmeyer azlactone synthesis. For a typical preparation of nanosphere SiO2, 1.0 gram of polyethylene glycol (MW 6000) is dispersed in a mixture of 100 mL ethanol and 20 mL de-ionized water by ultrasonication. Then, 2.5 mL 25% aqueous ammonia and 2.0 mL tetraethyl orthosilicate are added. The resulting dispersion is refluxed for 24 hours under stirring. After that, the white precipitate is separated from the reaction medium by

10

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

centrifugation at 4000 rpm for 10 minutes, washed with hot ethanol and de-ionized water, and vacuum dried at 70°C to afford the nano-sphere SiO2. In order to load 2-aminopyridine to the surface of the nano-sphere, the prepared SiO2 is dispersed in a mixture of 100 mL dry toluene and 2.0 mL of 3-chloropropyl-trimethoxysilane by ultrasonication. This mixture is then stirred at 60°C for 24 hours, separated by centrifugation, washed with toluene, and dried under vacuum at 70°C. After the modification on the surface of nano-sphere SiO2, 1.0 g of such solid is dispersed in 20 mL dry toluene by ultrasonication, followed by the addition of 1.2 g of 2-aminopyridine and 0.5 mL of triethylamine. After refluxing this mixture for 24 hours, the nano-sphere SiO2 loaded with 2-aminopyridine is separated by centrifugation and washed with chloroform. This catalyst retains most of its catalytic activity after 6 cycles, and works best for aromatic aldehydes, but is inferior to cyclic ketones (e.g., cyclohexanone, and cyclopentanone) [65]. Also, an organic base such as triphenylphosphine (PPh3) is effective in promoting the formation of unsaturated azlactones, such as the treatment of a mixture of hippuric acid, aromatic aldehyde and two equivalents of acetic anhydride with 10 mol% of PPh3 at 130°C without additional solvent. This methodology is also effective for the synthesis of unsaturated azlactones from (5-(2,6-dichlorophenyl)-3-methylisoxazole-4-carbonyl)amino acetic acid that demonstrates several advantages such as solvent-free condition, excellent yield, simple procedure, mild condition, and reduced environmental consequence [66]. In addition, organic base 1,8-diazabicyclo[5.4.0]undec7-ene (DBU) is useful in the conversion of 4-unsubstituted azlactone into the corresponding unsaturated azlactone with an aldehyde [67]. Other organic bases that have been applied in the preparation of unsaturated azlactones include but are not limited to pyridine, triethylamine [68], 3-methylpyridine (and its analogs, e.g., picoline) [69], and dicyclohexylcarbodiimide (DCC) in dimethylacetamide under microwave irradiation [70]. Finally, several organic-inorganic hybrid polyoxometalates have been proved to be efficient, heterogeneous, and reusable catalysts for the synthesis of unsaturated azlactones. These hybrid polyoxometalates include the combination of 1-butyl-3-methylimidazolium (abbreviated as [bmim]+) with polyanions (W10O32)4– (i.e., [bmim]4W10O32) or (PW12O40)3– (i.e., [bmim]3PW12O40) (under solvent-free condition) [71], di[1,6-bis(3-methylimidazolium-1-yl) hexane] decatungstate dihydrate ([C6(MIm)2]2W10O32·2H2O) (under ultrasound irradiation) [72], and [(C14H24N4)2W10O32]-[bmim]NO3 (one-pot fashion under solvent-free condition) [73]. On the other hand, ionic liquids have also been developed for the preparation of unsaturated azlactones, such

Azlactones 11

as the application of [bmim]OH [74], and 1-benzyl-3-methylimidazolium dihydrogen phosphate ([bnmim]H2PO4) (under ultrasound) [75]. Another organic-inorganic hybrid catalyst is prepared by loading 2-aminopyridine into nano-sphere SiO2 through the prior treatment with triethoxysilylpropyl chloride. This heterogeneous catalyst is then applied to make various unsaturated azlactone derivatives from hippuric acid and aldehydes or ketones under microwave irradiation using Ac2O as a condensing agent under solvent-free conditions. High yields, recyclable catalyst, short reaction times and simple work-up have been claimed as the advantages of this approach [65]. For the alkaline hydrolysis of p-nitrophenyl hippurate, it involves two steps, i.e.: (a) the general base-catalyzed formation of 2-phenyloxazolin5-one and release of p-nitrophenol; and (b) hydrolysis of 2-phenyloxazolin5-one to hippuric acid. However, it has been found that the treatment of p-nitrophenyl esters of formyl-, acetyl-, and cinnamoyl-glycine yielded the corresponding oxazolinone intermediates, whereas the same treatment of benzyloxycarbonylglycine p-nitrophenyl ester would not yield the oxazolin5-one. In addition, the oxazolin-5-one intermediates are formed from a number of activated esters of hippuric acid but not from stable esters such as methyl hippurate [76]. 1.3.1.1.2 Erlenmeyer Azlactone Synthesis Under Neutral Conditions The unsaturated azlactones can also be formed from the condensation of simple azlactone with aldehyde under neutral conditions, such as the one between 2-phenyl-5(4H)-oxazolone and several aliphatic aldehydes upon adsorption on neutral alumina and irradiation with microwaves, which afford good yields (62–78%) of 4-alkylidene azlactones. The alkyl group in these 4-alkylidene azlactones are ethyl, n-propyl, isopropyl, isobutyl, n-hexyl, and (2,2,3-trimethylcyclopent-3-en-1-yl)methyl. This method expands the classical Erlenmeyer Synthesis to make 4-alkylidene azlactones, for which poor results have often been obtained with aliphatic aldehydes [77]. It is found that even at room temperature without microwave irradiation, the reaction between 2-phenyl-5(4H)-oxazolone and aldehyde in dichloromethane can take place instantly when alumina is used as a catalyst, affording the corresponding unsaturated azlactones in reasonably good yields [78].

12

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

In a separate preparation of alkylidene azlactones, when hippuric acid was treated with ethyl chloroformate in benzene in the presence of Et3N, the resulting 2-phenyloxazol-5(4H)-one was treated with aldehydes under microwave irradiation for only 2 minutes, and the corresponding alkylidene azlactones were obtained. It should be pointed out that pure Z-alkylidene azlactones were obtained in most cases, for the special case in reaction with cinnamaldehyde, (E)-2-phenyl-4-((E)-3-phenylallylidene)oxazol-5(4H)-one was obtained. This compound is thermolabile and can be isomerized to its cis-isomer when it is further irradiated for 4 more minutes, i.e., (Z)-2-phenyl4-((E)-3-phenylallylidene)oxazol-5(4H)-one [79]. 1.3.1.1.3 Erlenmeyer Azlactone Synthesis Under Acidic Conditions In addition to the use of bases, such as sodium acetate, potassium carbonate, etc., to promote the azlactonization of N-acyl α-amino acids in acetic anhydride, some acids, including Brønsted acids, Lewis acids, polyacids, acid chlorides, anhydride, as well as solid-supported acids and cationic resins, have been tested for the formation of unsaturated azlactones. For example, guided by the general principle of “Green Chemistry”, ethyl glycinate hydrochloride has been acylated with meta-methylbenzoyl chloride in methylene chloride at room temperature, in the presence of Et3N. The resulting ethyl (3-methylbenzoyl)glycinate is then hydrolyzed in aqueous methanol in the presence of NaOH. The condensation between (3-methylbenzoyl)glycine and meta-chlorobenzaldehyde in acetic anhydride in a catalytic amount of Lewis acid Bi(OAc)3 at 95°C affords (Z)-4-(3-chlorobenzylidene)-2-(mtolyl)oxazol-5(4H)-one, with an overall yield of 26% [24]. Reasonably good yields of unsaturated azlactones have been obtained in another report using Bi(OAc)3 as the catalyst [53]. Other examples of Lewis acids that have been tested for the preparation of unsaturated azlactones are Bi(NO3)3, Bi(TFA)3, Bi(OTf)3 [80], Yb(OTf)3 [81], and ZnCl2 [82]. In addition, tin(IV) chloride (SnCl4) has been proved to be a catalyst in the conversion of the trimethylsilyl enolate of 2-phenyloxazol-5(4H)-one, i.e., 2-phenyl-5-((trimethylsilyl) oxy)oxazole, into the corresponding unsaturated azlactone in the presence of a aldehyde or ketone (particularly, acetone, and cyclohexanone) in CH2Cl2 [83]. Some Brønsted acids have also been applied for the Erlenmeyer azlactone synthesis. For example, the addition of perchloric acid (70% strength) to a mixture of acetic anhydride and N-acyl α-amino acids, e.g.,

Azlactones 13

hippuric acid, below 30°C results in the formation of 5-oxo-2-substituted4,5-dihydrooxazol-3-ium perchlorate which usually crystallizes during the addition of perchloric acid. For the case of hippuric acid, 89% of 5-oxo2-phenyl-2-oxazolinium perchlorate has been obtained (Scheme 1.6), which is stable when kept dry in a desiccator for 2 years without deterioration, but rapidly hydrolyzes to hippuric acid with cold water. Similarly, treatment of 5-oxo-2-substituted-4,5-dihydrooxazol-3-ium perchlorate with MeOH, aqueous NH3, PhNH2, PhCH2NH2, or H2NCH2CO2Na leads to the formation of hippuramide, hippuranilide, N-(benzylcarbamoylmethyl)benzamide, and benzoylglycylglycine, respectively. However, condensation of 5-oxo2-substituted-4,5-dihydrooxazol-3-ium perchlorate with benzaldehyde in refluxing acetonitrile yields a low yield of (E)-4-benzylidene-5-oxo2-phenyl-4,5-dihydrooxazol-3-ium perchlorate (8.5%). Similar results were obtained when the condensation was carried out in acetic acid or acetic anhydride [84]. O O H N O

O

PhCHO

HN HClO4 OH Ac2O, < 30 °C

O ClO4

O

N H ClO 4

CH3CN, O

H N

O H2N

ONa

N H

O OH

O

SCHEME 1.6  Conversion of N-benzoyl glycine and benzaldehyde into the unsaturated azlactone in the presence of HClO4.

Similarly, treatment of N-acyl α-amino acids in concentrated sulfuric acid also forms 5-oxo-2-substituted-4,5-dihydrooxazol-3-ium hydrosulfate, which further condenses with an aldehyde to yield the unsaturated azlactone. For example, the van’t Hoff factor is an indicator for the degree of ionization of polyfunctional molecules in sulfuric acid. Measurement of the van’t Hoff factor of glycine in sulfuric acid yields a value of 2.2, indicating that the second ionization is only about 20% complete, whereas the corresponding van’t Hoff factors for hippuric acid and benzoyl sarcosine (i.e., N-methyl hippuric acid) are measured at 3.6 and 3.8, respectively [85, 86]. These values strongly indicate the cyclization of N-acyl α-amino acids into the corresponding oxazolonium ions as displayed in Scheme 1.6. When benzaldehyde is allowed to react with the sulfuric acid solution of hippuric acid, 35% of

14

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

(E)-4-benzylidene-2-phenyloxazol-5(4H)-one is obtained after further treatment of the reaction mixture with pyridine at room temperature. The ideal reaction condition requires one equivalent of benzaldehyde, one equivalent of hippuric acid, two equivalents of sulfuric acid and three equivalents of acetic anhydride at room temperature, affording 85–86% of (E)-4-benzylidene-2-phenyloxazol-5(4H)-one, with a melting point at 163.5–164.5°C [85]. There should be some (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one formed as well. Moreover, polyphosphoric acid (PPA) could be a good medium for the generation of unsaturated azlactones, particularly for the azlactones in E-configuration. For example, aromatic aldehydes have been condensed with hippuric acid in PPA at 80–100°C to give 80–90% of unsaturated azlactones in E-configuration. Compared to the normal preparation of unsaturated azlactones under basic conditions (e.g., in the presence of anhydrous K2CO3), the reaction in PPA has demonstrated some advantages. For example, acetophenone, and substituted acetophenones do not condense with hippuric acid in the presence of K2CO3, but the corresponding unsaturated azlactones in E-configuration could be obtained in good yield in the PPA medium, although benzophenone does not react under this condition either. Examination of the reaction detail indicates that in the PPA medium, hippuric acid is not converted into 2-phenyloxazol-5(4H)-one which then condenses with benzaldehyde to afford 4-benzylidene-2-phenyloxazol-5(4H)-ones; instead hippuric acid is directly condensed with benzaldehyde to form both Z- and E-isomers of 2-benzamidocinnamic acids, which then are converted into the 4-benzylidene-2-phenyloxazol-5(4H)-ones (Scheme 1.7) [87]. Possibly, the azlactone in E-configuration is the favored product. For a specific preparation of unsaturated azlactone, a mixture of 2,4-difluorobenzaldehyde and hippuric acid (0.05 mol each) and 60 g of PPA is heated at 90°C for 2 hours with occasional stirring. After that, the reaction mixture is poured into 250 mL of water, filtered, washed several times with water, and dried to give unsaturated azlactone in 90% yield. Fractional crystallization in CCl4 yields 0.015 mol of the (Z)-4-(2,4-difluorobenzylidene)2-phenyloxazol-5(4H)-one first as fine yellow crystals with a melting point at 187–189°C. Concentration of the mother liquid followed by cooling in a refrigerator, results in the crystallization of the (E)-4-(2,4difluorobenzylidene)-2-phenyloxazol-5(4H)-one, which is further purified by recrystallization from a benzene/n-hexane (1:2) mixture as yellow needle-like crystals, with a melting point at 127–128°C. Only 0.0074 mol

Azlactones 15

of the E-isomer is obtained. The corresponding Rf values for the Z- and E-isomers are measured at 0.56 and 0.35 (silica gel 60 and benzene/nhexane (1:1) as eluent), respectively. This particular preparation still indicates that the Z-isomer is the major product, accounting for 67% of the total products [88]. However, the preparation under basic conditions almost yields the Z-isomer as the sole product.

H N

Ph

O OH

+ ArCHO

O

Ph

O

HN

(OP(O)OH)nOH

PPA

O

Ar

O

O

HN

(OP(O)OH)nOH

Ar

PPA

PPA O

O

Ph

O

Ar

O N E-isomer

Ph

N

Ar

Z-isomer

SCHEME 1.7  Mechanism for the generation of unsaturated azlactone isomers in the PPA medium.

While strong acids such as sulfuric acid, and perchloric acid as well as not so strong acids like PPA have been successfully applied to the preparation of unsaturated azlactones, the acidic heterogeneous preparations of azlactones have demonstrated some unique features, particularly for their mild reaction conditions and easy recovery of products. However, the low solubility of some substrates in PPA has made such a procedure less attractive. One of the heterogeneous conditions uses a 1:1 mixture of Al2O3 and boric acid (H3BO3) in the presence of a stoichiometric quantity of acetic anhydride in refluxing toluene or benzene solution for the cyclodehydration/condensation of hippuric acid and aryl aldehydes ArCHO (Ar = Ph, 4-ClC6H4, 4-O2NC6H4, etc.), affording the expected azlactones in good yields. This procedure is also suitable for the preparation of 4-alkylidene azlactones. For this reaction condition, the cyclodehydration does not occur in the absence of any one of alumina, boric acid and acetic anhydride, although each one can be a good dehydrating agent. In addition, the resulting azlactones can be easily isolated by simple filtration to remove Al2O3-H3BO3 followed by removal of solvent, in about 80–90% of yields. Cyclohexanone and crotonaldehyde also participate under this condition, whereas acetone and acetaldehyde fail to

16

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

give the desired products due to their boiling points being lower than that of the solvent (benzene or toluene) [89]. Similarly, polynuclear complexes such as silica-alumina supported molybdophosphoric acid or tungstophosphoric acid (TPA) that are obtained by the sol-gel method have been used as the catalysts for the syntheses of unsaturated azlactones. These hetero-polyatomic structures, mainly constituted by molybdenum, tungsten, or vanadium as polyatoms (M), and phosphorus, silicon, or germanium as central atom or heteroatom (X), have a central tetrahedron XO4 surrounded by 12 octahedra MO6 and could be strong acids with an acid strength higher than that of classical acids. When the solid-supported molybdophosphoric or TPA is applied as the catalyst, only less than 1 mol% is needed. After the mixture of an equal amount of hippuric acid and aldehyde is headed in toluene in the presence of < 1 mol% of acid catalyst for 5 minutes, a stoichiometric amount of acetic anhydride is added as the dehydrating reagent. When the reaction completes, the cooled mixture is filtered to recycle the catalyst, the solvent is removed in a vacuum, and the product can be further purified by recrystallization from 95% ethanol. It is believed that a predominant reaction mechanism involves the protonation of hippuric acid to generate its enol form which undergoes Aldol reaction with the protonated aldehyde, followed by intramolecular cyclization to afford the final product, analogous to the one outlined in Scheme 1.7. The simple work-up process, excellent yield, and the reusability of the catalysts are noteworthy advantages of this particular method [90]. A model reaction between 1 mmol of thiophene-2-carbaldehyde and 1.1 mmol of hippuric acid in acetic anhydride under solvent-free conditions has been tested for 15 minutes at various temperatures and different amounts of TPA supported on nano-silica, so-called TPA@nano-SiO2. At 80°C, the yield of 2-phenyl-4-(thiophen-2-ylmethylene)oxazol-5(4H)one is 93% or 94% when 100 and 150 mg of TPA@nano-SiO2 are used, respectively. In contrast, only 15% of azlactone is formed in the absence of such catalyst even after 24 hours of reaction. The heterogeneous catalyst can be recycled and used several times without a dramatic decrease in its catalytical activity [91]. Alum [KAl(SO4)2·12H2O] is acidic because aqueous hydrolysis of this solid leads to the formation of Al(OH)3, resulting in the generation of the proton. This compound has been demonstrated to catalyze the azlactonization of hippuric acid in acetic anhydride with different aldehydes, at room temperature under ultrasound vibration. There is not much difference in catalytic efficiency when more than 10 mol% of alum is used for the

Azlactones 17

azlactonization. This condition particularly works for aromatic aldehydes, conjugated aldehydes (e.g., crotonaldehyde) and ketones (e.g., cyclohexanone, and acetophenone), but is not good for aliphatic aldehydes (e.g., butyraldehyde) [92]. Also, treatment of hippuric acid with aromatic (or aliphatic) aldehydes in acetic anhydride in the presence of a catalytic amount of cadmium chloride under microwave irradiation also gives the corresponding azlactones in excellent yields [93]. Recently, cellulose sulfuric acid as a biodegradable and recyclable polymer has shown catalytic activity for the Erlenmeyer azlactone synthesis. For example, when 0.5 g of cellulose sulfuric acid is applied for the reaction between hippuric acid and 4-chlorobenzaldehyde (5 mmol each) in the presence of 1.42 mL acetic anhydride (15 mmol) at 70°C for 40 minutes, 96% of 4-(4-chlorobenzylidene)-2-phenyloxazol-5(4H)-one can be obtained after filtration of the catalyst, which has shown nearly the same catalytic activity after being used for four times. For comparison, in the absence of such a catalyst, the same reaction only affords 39% of azlactone after an extended reaction for 160 minutes [94]. In addition to the above catalysts for the Erlenmeyer azlactone synthesis, several ionic liquids have been developed and used for the azlactonization of hippuric acid. For example, 10 mol% of 1-benzyl-3-methylimidazolium dihydrogen phosphate ([bnmim]H2PO4) catalyzes the ultrasound promoted azlactonization of hippuric acid with different aldehydes at 5 mmol scales at room temperature, affording 84% ~ 92% of the corresponding azlactones within 1 hour. Only slightly reduced catalytical activity has been observed for the ionic liquid catalyst recycled after five times. In this practice, other ionic liquids such as [hdmim]H2PO4, [hmim]H2PO4, and [bmim]H2PO4 have also been tested, which show inferior catalytic activity due to the lower yields of 4-benzylidene-2-phenyloxazol-5-one even with extended reaction times. However, the actual structures of these three ionic liquids have not been specified in this work [75]. In addition to the use of Brønsted acids, Lewis acids as well as biphasic polynuclear complexes as the catalysts for the syntheses of unsaturated azlactones, several acid halides have also been applied for such purpose. For example, a one-pot procedure for the synthesis of 4-arylidene2-phenyl-5(4H)oxazolones in good to excellent yields has been developed by means of the treatment of a mixture of aromatic aldehyde bisulfite adduct and hippuric acid with two equivalents of phosphoryl chloride (POCl3) in CH3CN in the absence of acetic anhydride. Under this condition, various substituted aromatic aldehyde bisulfite adducts carrying

18

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

either electron-donating or electron-withdrawing substituents have been successfully converted into the corresponding azlactones in good to excellent yields, whereas aromatic aldehydes themselves react sluggishly to afford the expected products of very low yields. It should be pointed out that aliphatic aldehyde bisulfites are inert toward POCl3 during this transformation, as indicated by the failure in the treatment of 2-phenylethanal bisulfite. In addition, this unique approach is highly chemoselective. For example, in a binary mixture of aromatic aldehyde bisulfite adduct and aromatic aldehyde or other protected forms of an aldehyde such as acetal or acylal, only the aldehyde bisulfite adduct is quantitatively converted into azlactone while the aldehyde, its acetal or acylal form remains intact in the presence of POCl3 [95]. Also, the combination of toluenesulfonyl chloride (i.e., 4-methylbenzenesulfonyl chloride, p-TsCl) and DMF is also an efficient condensation reagent in the absence of solvents under microwave irradiation for the synthesis of azlactones from hippuric acid and benzaldehyde or thiophene-2-carbaldehyde [96]. Moreover, ethyl carbonochloridate (ClCO2Et) is also effective in the conversion of N-acyl glycines (e.g., acetyl glycine, hippuric acid, and cinnamoyl glycine) into the corresponding azlactones (e.g., 2-methyloxazol-5(4H)-one, 2-phenyloxazol-5(4H)-one, and (E)-2styryloxazol-5(4H)-one) in the presence of Et3N in dry benzene via 2-acetamidoacetic (ethyl carbonic) anhydride or analogous intermediate. After the resulting 5-oxazolones are gently heated with imine or aldehyde for about 10 minutes, the 4-alkylidene azlactones are obtained in moderate to good yields. In some cases, 2-acylamino-2-alkeneilides are obtained in very low yields. The condensation between azlactone and cyclohexanone is ineffective even after a heating period of about 20 hours, but a somewhat better yield could be obtained when p-toluenesulfonic acid is used as a catalyst. Acetophenone does not react under any of these conditions, whereas its N-phenylimine reacts readily to give the expected product. A representative preparation of unsaturated azlactone under this condition is illustrated in Scheme 1.8 [97]. Likewise, treatment of the above N-acetyl glycines with ClCO2Et in benzene containing Et3N and then with an aldehyde (e.g., benzaldehyde, 2-nitrobenzaldehyde, 4-hydroxy-3methoxybenzaldehyde and cinnamaldehyde) in refluxing benzene afford the corresponding unsaturated azlactones [98].

Azlactones 19

H N

R1

O

O OH

+ Cl

O

OEt

Et3N benzene

H N

R1

O

O OEt

O

O

EtOH, CO2

R1 = Me, Ph, Ph-CH=CH R2

N R1

O

R2CHO or R2CH=NPh O

benzene,

N R1

O

O

SCHEME 1.8  Conversion of N-acyl glycine into unsaturated azlactones with ClCO2Et.

Although sulfur trioxide is not an acid halide, the addition of liquid SO3 to DMF at 0–5°C results in an SO3/DMF complex containing about 30% of SO3, with which unsaturated azlactones can be prepared in good to excellent yields by condensation of an equal amount of aldehyde and hippuric acid on a steam bath for 15–20 minutes. The following aldehydes or ketone successfully react under this condition, including PhCHO (77%), 4-MeC6H4CHO (85%), 4-MeOC6H4CHO (74%), 2-HOC6H4CHO (60%), 2-ClC6H4CHO (61%), 4-ClC6H4CHO (90%), 4-O2NC6H4CHO (81%), 2,4-Cl2C6H3CHO (90%), 3,4-Cl2C6H3CHO (98%), 3,4-MeO(HO)C6H3CHO (66%), 3,4-(MeO)2C6H3CHO (67%), cinnamaldehyde (65%), and 9H-fluoren-9-one (66%) [99]. Likewise, treatment of 6.65 g of pyridine-3-carboxaldehyde and 11.2 g of hippuric acid with 52 mL SO3/DMF complex heated for 1 hour affords 58% of the complex of SO3 with unsaturated azlactone, which melts at 248°C. Upon neutralization by shaking this complex with 20 mL saturated sodium acetate yield 55% of 2-phenyl-4-(pyridin-3-ylmethylene) oxazol-5(4H)-one (m.p. 163°C after recrystallization from 95% EtOH). The reaction with pyridine-4-carboxaldehyde gives 76% of 2-phenyl-4-(pyridin4-ylmethylene)-oxazol-5(4H)-one (m.p. 168°C) [100]. Similarly, neutral trimethylsilyl chloride (TMSCl) has once been used in combination with acetic anhydride in DMF for the preparation of unsaturated azlactones, from the condensation between hippuric acid and cyclohexanone or aromatic aldehydes (ArCHO, where Ar = Ph, 4-O2NC6H4, 3-O2NC6H4, 4-Me2NC6H4) [101]. Also, cationic ion-exchange resin Duolite 368 A PR has been applied in the condensation between hippuric acid and aromatic aldehydes RCHO, where R = 4-HOC6H4, 3,4-MeO(HO)C6H3, 2-thienyl, 5-nitro-2-thienyl, 2-furyl, 5-nitro-2-furyl, to afford 35–77% of the corresponding azlactones.

20

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

This condition is slightly inferior to the traditional method in the presence of fused NaOAc [102]. Similar to the formation of oxazolin-5-one during the alkaline hydrolysis of p-nitrophenyl hippurate [76], it is reported that the oxazolin-5-one core also forms during the coupling of peptide in the presence of DCC, which is considered as an acidic condition. For example, the coupling of Boc-Leu3Aib-OH (Aib = NHCMe2CO) with H-Leu3-OBn using DCC as a coupling reagent proceeded via the conversion of the 2-amino-2-methylpropanoic acid residue into its oxazolin-5-one form, followed by a slow aminolysis to give Boc-Leu3-Aib-Leu3-OBn. Particularly, treatment of Boc-Leu3-Aib-OH with DCC in the presence of p-nitrophenol did not produce a p-nitrophenyl ester, but the same oxazolin-5-one derivative in high yield within 20 minutes, due to the restriction of the backbone dihedral angles ϕ and ψ of Aib residue. This oxazolin-5-one terminus reacted faster with HOSu than H-Leu3-OBn, followed by a slow aminolysis of the succinimide ester produced to give larger peptide. While HOBt did not react with the terminal oxazolin-5-one functionality, it strongly catalyzed the aminolysis of the oxazolin-5-one in dichloromethane to form peptide bonds in nearly quantitative yields. The presence of acetic acid also demonstrated a little catalytic effect on the aminolysis of oxazolin-5-one [103]. 1.3.1.2 ALTERNATIVE METHODS FOR THE PREPARATION OF UNSATURATED AZLACTONES Despite the vast amounts of examples for the preparation of unsaturated azlactones by the Erlenmeyer azlactone synthesis, there are a few alternative methods as well. One of such methods is to separate the one-step reaction into two steps, i.e., the cyclization of N-acyl α-amino acids into simple azlactones with mild condensation agent, such as DCC, and the subsequent Aldol condensation between the azlactone and aldehyde (or ketone). A special preparation of unsaturated azlactone takes the advantage of α-amino acids with a β-hydroxyl group. For example, 2-((S)-2-((tert-butoxycarbonyl)amino)-4-methylpentanamido)-3-hydroxy-3-(pyridin-3-yl) propanoic acid, that is prepared from 2-amino-3-hydroxy-3-(pyridin-3-yl) propanoic acid and Boc-Leu-OSu in a 1:1 mixture of 10% NaHCO3 and 1,2-dimethoxyethane, once treated with sodium acetate in acetic anhydride, is converted into tert-butyl (S,Z)-(3-methyl-1-(5-oxo-4-(pyridin-3ylmethylene)-4,5-dihydrooxazol-2-yl)butyl)carbamate, as shown in Scheme 1.9 [104]. For the case of threonine, even if the hydroxyl group is protected

Azlactones 21

by a methyl group, the resulting methoxy group can be eliminated to form the unsaturated exocyclic double bond. For example, N-benzoyl-O-methylDL-allothreonine, upon treatment with Ac2O at 100°C, is converted into 30~35% of (Z)-4-ethylidene-2-phenyloxazol-5(4H)-one (e.g., benzoylα-aminocrotonic acid azlactone, m.p., 144–145°C). The configuration of the exocyclic double bond has been verified by hydrolysis of this azlactone with HCl to N-benzoyl-α-aminocrotonic acid. This azlactone is rapidly converted into a mixture of isomers when heated at 100°C or above, melting at 83–88°C, but will be completely converted into its isomer once treated with pyridine at room temperature for 15 minutes. Alternatively, when 5.9 g of N-benzoyl-O-methyl-DL-allothreonine is treated with 2.1 g of sodium acetate and 30 mL of acetic anhydride in 50 mL of water at 40–45°C, 80% of the azlactone isomers are obtained, whereas only 4–6% of azlactone can be formed in the absence of sodium acetate (Scheme 1.10) [105].

N

N

Boc

H N

OH

O N H

CO2H

NaOAc Ac2O Boc

H N

N

O O

SCHEME 1.9  Conversion of N-acyl amino acid with a β-hydroxyl group into unsaturated azlactone.

O

O N H

O

OH O

Ac2O

O

O

0.5 N HCl N

or NaOAc, AcOH Ac2O

OH O

O

pyridine NaOAc, Ac2O H 2O

N H

O N

SCHEME 1.10  Conversion of N-acyl amino acid with a β-methoxy group into unsaturated azlactone.

Other examples of converting N-acyl α-amino acid derivatives that contain a β-hydroxyl or protected hydroxyl group include: (a) generation of α,β-unsaturated azlactone in nearly quantitative yield from equimolar

22

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

quantities of N-benzoyl-dl-allothreonine and benzoyl chloride in pyridine at –5°C in the presence of benzoyl chloride, or in good yields from the treatment of N-benzoyl-O-methyl-dl-allothreonine or N-benzoyl-O-acetyldl-allothreonine in pyridine solution with benzoyl chloride [106]; (b) conversion of 2-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)3-hydroxy-3-phenylpropanoic acid and 2-((S)-2-((tert-butoxycarbonyl) amino)-3-phenylpropanamido)-3-hydroxy-3-phenylpropanoic acid into tert-butyl (S,Z)-2-(4-benzylidene-5-oxo-4,5-dihydrooxazol-2-yl)pyrrolidine-1-carboxylate (95% yield) and tert-butyl (S,Z)-(1-(4-benzylidene5-oxo-4,5-dihydrooxazol-2-yl)-2-phenylethyl)carbamate (75% yield) in the presence of Ac2O/NaOAc at room temperature, respectively [107]; (c) transformation of (E)-2-(2-acetamido-3-phenylacrylamido)-3-hydroxy3-phenylpropanoic acid into N-((E)-1-(4-benzylidene-5-oxo-4,5-dihydrooxazol-2-yl)-2-phenylvinyl)acetamide with Ac2O at room temperature in the presence of small amount of NaOAc [108]; and d) azlactonization of benzoyl-dl-O-methylphenylserines [109]. It should be pointed out that the configuration of the b-hydroxyl group in these amino acid derivatives plays an important role in the formation of unsaturated azlactones. For example, different from the treatment of N-benzoyl-dl-allothreonine with benzoyl chloride in pyridine, the reaction of an equimolar amount of N-benzoyl-dl-threonine and benzoyl chloride in pyridine affords the unsaturated azlactone of lower yield [106]. Likewise, an NMR study on the reaction of N-acyl-3-phenylserine methyl (or ethyl) ester (or N-acyl-3-(p-nitrophenyl)serine methyl (or ethyl) ester) with thionyl chloride (SOCl2) indicates that the erythro-isomers rapidly cyclize to transoxazoline hydrochlorides which open (more slowly) to erythro-β-chloroβ-arylalaninates, whereas the threo-phenylserinates give the threo-β-chloro derivatives without the intervention of oxazolines. However, the threo-pnitrophenyl serine methyl (or ethyl) ester slowly forms cis-oxazoline which does not open under the same conditions [110]. Another method to synthesize the unsaturated azlactones involves the halogenation of saturated azlactones with the alkyl group at position 4 and subsequent elimination of hydrogen halide. For example, treatment of amino acids with trifluoroacetic anhydride gives the said “pseudo” azlactones, which are then brominated α to the azomethine position. Subsequent treatment of the brominated azlactone with an equal molar quantity of Et3N yields the corresponding unsaturated azlactone, as demonstrated in Scheme 1.11 for the preparation of (E)-4-benzylidene-2-(trifluoromethyl)oxazol-5(4H)-one [111].

Azlactones 23

O OH

N

(CF3CO)2O

CF3 O

O

NH2 Br CF3 O

N

Et3N

N

CF3 O

O

O

SCHEME 1.11  Synthesis of (E)-4-benzylidene-2-(trifluoromethyl)oxazol-5(4H)-one from phenylalanine.

Similarly, N-benzoyl phenylalanine is converted into 4-benzyl-2phenyloxazol-5(4H)-one with DCC, which is then halogenated in CCl4 with a halogenating agent in the presence of K2CO3 to give (Z)-4-benzylidene-2phenyloxazol-5(4H)-one in a reasonably good yield. The halogenation agent can be bromine, N-bromosuccinimide (NBS), 2-pyrrolidinone hydrotribromide, trichloroisocyanuric acid, isopropylidene 2-bromo-2-methylmalonate, 1,3-dibromo-5,5-dimethylhydantoin (i.e., dibromantin) 1,3,5-trichloro-1,3,5triazinane-2,4,6-trione, or sulfuryl chloride. In addition, the conversion of 4-benzyl-2-phenyloxazol-5(4H)-one into (Z)-4-benzylidene-2-phenyloxazol5(4H)-one can also be achieved in the presence of an oxidizing agent, such as SeO2/Ac2O, PhSeCl/H2O2, t-BuOCl/K2CO3, Pd(OAc)2 or DDQ/collidine, although the yield of unsaturated azlactone has not been greatly improved compared to the halogenation method. However, treatment of 4-benzyl-2phenyloxazol-5(4H)-one with base in the presence of TMSCl affords 4-benzyl2-phenyl-5-((trimethylsilyl)oxy)oxazole, which can be transformed into (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one with Br2/K2CO3 (62% yield), or with the best yield of 75% under DDQ oxidation (Scheme 1.12) [112]. Br2/CCl4/K2CO3 (52%) O

O t-BuOCl/K2CO3/ (66%)

O

O

DCC N H

OH

O

N

N

O TMSCl base

OTMS O

DDQ (75%)

N

SCHEME 1.12  Conversion of N-benzoyl phenylalanine based azlactone into the unsaturated azlactone.

24

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Different from the traditional methods that form 4-arylidene azlactones from the existing azlactone moiety, an unusual approach to making 4-arylidene azlactones starts from the creation of the 4-arylidene moiety, from which the azlactone core is then built, as illustrated by the multi-step preparation of (Z)-2-(4-chlorophenyl)-4-(3,4-dimethoxybenzylidene)oxazol-5(4H)-one from 3,4-dimethoxybenzaldehyde (Scheme 1.13) [113]. In this approach, ethyl 2-azidoacetate is initially treated with sodium ethoxide in ethanol in the presence of 3,4-dimethoxybenzaldehyde at –5°C and subsequently, the reaction is allowed to proceed at room temperature for 17 hours to yield 60% of ethyl (Z)-2-azido-3-(3,4-dimethoxyphenyl)acrylate. The dichloromethane solution of this compound is then added to a solution of PPh3 in CH2Cl2 to form ethyl (Z)-3-(3,4-dimethoxyphenyl)-2-((triphenyl-λ5-phosphaneylidene) amino)acrylate. The toluene solution of this iminophosphorane at 0°C is then mixed with para-chlorobenzoyl chloride and the resulting mixture is refluxed for 8 hours to give the desired azlactone. This reaction is believed to proceed via the formation of ethyl (Z)-2-(((E)-chloro(4-chlorophenyl) methylene)amino)-3-(3,4-dimethoxyphenyl)acrylate after the addition of para-chlorobenzoyl chloride to the toluene solution of iminophosphorane, from which the oxygen atom on the ethoxy group adds to the imino group followed by the elimination of chloride to yield (Z)-2-(4-chlorophenyl)-4(3,4-dimethoxybenzylidene)-1-ethyl-5-oxo-4,5-dihydro-1H-oxazol-1-ium chloride. The nucleophilic substitution at the ethyl group with chloride results in the formation of the final 4-arylidene azlactone [113]. This approach of synthesizing 4-arylidene azlactone has been extended to convert ethyl (Z)-3(thiophen-2-yl)-2-((triphenyl-λ5-phosphaneylidene)amino)acrylate, ethyl (Z)-3-(furan-2-yl)-2-((triphenyl-λ5-phosphaneylidene)amino)acrylate and ethyl (Z)-3-(thiophen-3-yl)-2-((triphenyl-λ5-phosphaneylidene)amino)acrylate into the corresponding arylidene-azlactones with either benzoyl chloride, para-chlorobenzoyl chloride or 4-methylbenzoyl chloride, respectively [114]. MeO MeO

O

N3CH2CO2Et NaOEt, EtOH, 0 °C

MeO MeO

CO2Et N3

PPh3 CH2Cl2, r.t.

MeO

CO2Et N

MeO

PPh3

p-Cl-C6H4-COCl toluene, O

O

MeO MeO

MeO N

O MeO

N

MeO

O Cl

MeO

CO2Et Cl

N Cl

Cl

Cl

SCHEME 1.13  Synthesis of (Z)-2-(4-chlorophenyl)-4-(3,4-dimethoxybenzylidene)oxazol5(4H)-one from 3,4-dimethoxybenzaldehyde.

Azlactones 25

In a few cases, the generation of the exocyclic double and the formation of azlactone moiety may be combined in one reaction. For example, treatment of (E)-(4-bromobut-2-enoyl)phenylalanine (also known as γ-bromocrotonylDL-phenylalanine in a mixture of acetic anhydride and pyridine at room temperature for five minutes yields 47% of 4-((Z)-benzylidene)-2-((E)prop-1-en-1-yl)oxazol-5(4H)-one. Likewise, treatment of N-bromoacetyl or N-iodoacetyl-DL-phenylalanine under a similar condition also yields the corresponding (Z)-4-benzylidene-2-ethyloxazol-5(4H)-one. In addition, the mixture of (2-acetoxy-2-phenylethyl)phenylalanine, acetic anhydride and pyridine at room temperature gives (Z)-2-benzyl-4-benzylideneoxazol5(4H)-one within an hour in 78% yield. Interestingly, treatment of N-trichloroacetyl-DL-phenylalanine with a mixture of acetic anhydride and 2,6-lutidine for 2 hours at room temperature affords 36% of (Z)-4-benzylidene2-(dichloromethyl)oxazol-5(4H)-one, but no reaction occurs in the presence of acetic anhydride and pyridine. On the other hand, in the absence of pyridine, heating the mixture of N-trichloroacetyl-DL-phenylalanine with Ac2O for 45 minutes or the mixture of N-dichloroacetyl-DL-phenylalanine with acetic anhydride for 70 minutes at 100°C results in the recovery of 94% and 90% of the starting materials, respectively; whilst treatment of N-chloroacetyl-DL-phenylalanine with acetic anhydride at 100°C readily forms the unsaturated azlactone in five minutes [115]. An example is shown in Scheme 1.14 for the treatment of N-iodoacetyl-DL-phenylalanine with Ac2O and pyridine. It should be pointed out that the role of acetate in this mechanism can be substituted with pyridine or vice versa. This mechanism also explains that only the saturated azlactone can form from N-acetyl phenylalanine which lacks the α-halo group or acetoxy group that can be easily removed in the presence of pyridine. This approach is known as the Bergmann rearrangement [115]. Similar Bergmann rearrangement has been found for the conversion of (2-chloroacetyl)-L-tryptophan into (Z)-4-((1Hindol-3-yl)methylene)-2-methyloxazol-5(4H)-one in a mixture of acetic anhydride and pyridine in 92% crude yield and 56% isolated yield [116]. Another synthetic method for the unsaturated azlactone takes advantage of the equilibrium between an unsaturated azlactone and its isomeric pseudo-azlactone, the latter can easily be generated from the treatment of an N-(α-haloacyl)amino acid with a mixture of acetic anhydride and pyridine followed by elimination of hydrogen halide and oxidation of the CH-NH bond to the imine function (Scheme 1.15(a)). In addition, the position of the equilibrium between the unsaturated azlactone and pseudo-azlactone depends on the substituents R1 and R2 and the yield of the unsaturated

26

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

azlactone is a function of the starting amino acid. Likewise, treatment of an N-α,β-dihaloacylamino acid under a similar condition affords a pseudoazlactone intermediate which undergoes double dehydrohalogenation to form the unsaturated azlactone, avoiding the equilibrium step (Scheme 1.15(b)). For an example, when N-(erythro-DL-α,β-dibromo-α-methylbutyroyl)-DLphenylalanine is treated with a warm mixture of acetic anhydride and pyridine, 4-((Z)-benzylidene)-2-((E)-but-2-en-2-yl)oxazol-5(4H)-one is obtained in 93% yield (Scheme 1.15(c)). In comparison, the classical Erlenmeyer azlactone synthesis from N-tigloly glycine (i.e., (E)-(2-methylbut-2-enoyl) glycine) and benzaldehyde in the presence of Ac2O/NaOAc only affords 26% of the same azlactone [117]. Similar reaction has been demonstrated in the reaction of DL-tryptophan with chloroacetyl chloride/NaOH to yield 70% of (2-chloroacetyl)-DL-tryptophan, which is then converted into 4-((1H-indol3-yl)methylene)-2-methyloxazol-5(4H)-one in 92% yield [116]. O Ac2O/pyridine

O I

N H

O 50 %

OH

N O

O AcOH, AcO

O

Ph N H

AcO H

OAc

O I

N H

OH

O O

O

I

Ac2O/pyridine

H N

OAc

Ph O

O O

I

N H O Py

OH

I AcO PyH+

O

Ac2O pyridine

O OH

N O

AcO PyH+

O I

O

OAc

N

SCHEME 1.14  The reaction mechanism for the conversion of (2-iodoacetyl)phenylalanine into (Z)-4-benzylidene-2-methyloxazol-5(4H)-one.

Finally, treatment of hippuric acid with either phenoxyformyl chloride or p-nitrophenoxyformyl chloride (or styrenoxyformyl chloride) in the presence of Et3N leads to 2-phenyloxazol-5(4H)-one. Subsequently, 2-phenyloxazol-5(4H)-one is transformed into (Z)-4-(1-(dimethylamino)2-phenylethylidene)-2-phenyloxazol-5(4H)-one in reacting with

Azlactones 27

N,N-dimethyl-2-phenylethyn-1-amine. Alternatively, 2-phenyloxazol5(4H)-one can be converted into 4-(diphenylmethylene)-2-phenyloxazol5(4H)-one or (E)-2-phenyl-4-((phenylamino)methylene)oxazol-5(4H)-one by the treatment with N-methyl-1,1-diphenylmethanimine or trimethyl orthoformate, respectively, as shown in Scheme 1.16 [67]. O X HN

(a)

R2 CO2H

R1

Ac2O pyridine

X

R2

N

O

R1

R2 N

N

O

R1

O

H

R2 O

R1

O

O

X O

X

HN

(b) R1

X R2

X CO2H

Ac2O pyridine

N R1

O

Ac2O/pyridine N

Br CO2H

Ph

R1

O O

Br

HN

(c)

N

O H

O

R2

R2

O

93%

Ph O

SCHEME 1.15  Preparation of unsaturated azlactones by shifting pseudo-azlactones into azlactones. Me2N

Ph

N

33 %

O

O NMe2 Ph

H N

O

R OH

Ph

N

O

Ph

N

Cl O Et3N

O

O

Ph

Ph

N O

O R = Ph, 4-NO2-C6H4 or Ph-CH

78 %

O

CH

Ph HC(OMe)3 PhNH2

NH N O

O

66 %

SCHEME 1.16  Synthesis of unsaturated azlactones from the reaction of N-benzoyl glycine and phenoxyformyl chloride.

28

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

1.3.1.3 CONFIGURATION OF THE EXOCYCLIC DOUBLE BOND IN UNSATURATED AZLACTONES As indicated in Scheme 1.1 and structure 2 in Figure 1.1, there are two possible unsaturated azlactones based on the Z- and E-configurations of the exocyclic double bonds. However, in many of the cited literature, the actual configurations of unsaturated azlactones have not been specified. In some other situations, the configurations are assumed to be the default ones based on the Erlenmeyer azlactone synthesis. Since both Z- and E-configurations are possible, it is conceivable that both unsaturated azlactones might have formed in most of the reported preparations, but at different ratios. However, almost always, the unsaturated azlactones in Z-configurations are formed in the presence of fused sodium acetate or other alternative bases, at least the E-isomers are not mentioned or characterized. Only in a few cases, the unsaturated azlactones in E-configurations have been prepared or reported. Due to this potential possibility of generating azlactones in either configuration, some unsaturated azlactones, e.g., 4-benzylidene2-phenyloxazol-5(4H)-one, under the condition of Erlenmeyer azlactone synthesis have initially been assigned to the E-isomers [118], but are re-assigned to their Z-isomers [87]. A detailed discussion on this issue has been provided in a review [119]. Facing the challenge of forming the unsaturated azlactones in E-configuration, a few methods have been developed to convert the Z-azlactones into their E-isomers, such as the isomerization of Z-azlactones in saturated hydrobromic acid to yield the E-azlactones. For example, the Z-azlactones are converted into their E-isomers with 48% HBr followed by saturation with HBr [118]. In a detailed experiment for the isomerization of E- and Z-isomers, treatment of 5.0 g of (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one with 90 mL of 40% HBr on ice overnight affords (E)-4-benzylidene-2-phenyloxazol-5(4H)-one crystals which are further recrystallized from benzene (m.p., 146–148°C). In comparison, heating 0.3 g of the E-isomer in pyridine and cooling yield crystals in needles with a melting point of 164–165°C, which does not depress the melting point of the Z-isomer. In contrast, shaking 0.5 g of the E-isomer in a mixture of 15 mL EtOH and 10 mL 0.5 N NaOH leads to the decomposed compound which is then acidified with HCl. The HCl salt of this compound once heated with five times of Ac2O in volume is converted to the E-azlactone again (m.p., 145–147°C) [120]. This experiment indicates the isomerization between the Eand Z-azlactones and the preferred configuration of the exocyclic double bond under either acidic or basic conditions. In addition, the isomerization of the decomposed product, i.e., 2-benzamido-3-phenylacrylic acid, has not occurred

Azlactones 29

in the presence of base as the azlactone of the same configuration is obtained once retreated with Ac2O. Another common practice to form the E-unsaturated azlactones is the well-known photochemical E- and Z-isomerization of alkenes. For example, ultraviolet spectroscopy of (E)-4-benzylidene-2-phenyloxazol5(4H)-one demonstrates several maximum absorptions at λ = 259 nm (ε = 26,500), 346 nm (ε = 32,000), 361 nm (ε = 42,000) and 381 nm (ε = 30,000), respectively. Irradiation of this compound in degassed isopropyl alcohol with a light at 365 nm leads to diminution of the long-wavelength maximum, along with the appearance of isosbestic points at 345, 355, 364, and 377 nm, respectively. After a rapid change of the UV spectra, no further changes have been observed even after prolonged irradiation. The only components of the reaction mixture under photo-irradiation are (E)-4-benzylidene-2-phenyloxazol-5(4H)-one and its geometrical Z-isomer. Likewise, irradiation of (Z)-4-benzylidene2-phenyloxazol-5(4H)-one in isopropanol at 365 nm also yields the same photo-stationary mixture, indicating the formation of equilibrium between the Z- and E-isomers (Scheme 1.17) [121, 122]. Likewise, photo-isomerization of (Z)-4-(2-acetoxybenzylidene)-2-phenyloxazolin-5-one (i.e., (Z)-2-((5-oxo-2phenyloxazol-4(5H)-ylidene)methyl)-phenylacetate) also gives its E-isomer [123].

N O

O

h ( = 365 Å) i-PrOH

Me Me H Ph H N OH O O

i-PrOH

H BzHN O

Ph H Ph H BzHN H Me + Me O O Me O Me 17 %

N O

O

SCHEME 1.17  Photo-isomerization between (E)- and (Z)-4-benzylidene-2-phenyloxazol5(4H)-one in isopropanol and subsequent reaction.

Based on the preparations of unsaturated azlactones in the presence of perchloric acid, concentrated sulfuric acid or PPA, where E-azlactones have been obtained, either as single products or by fractional crystallization as described above, it is reasonable to conclude that the E-azlactones are formed under acidic conditions, potentially along with their Z-isomers; whereas the

30

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Z-azlactones are the predominating products under basic conditions. There might be an equilibrium between the Z- and E-azlactones, but the presence of acid will protonate the nitrogen atom on the azlactone core and inhibit further isomerization. One experimental evidence is the complete racemization of N-benzoyl D-alanine in Ac2O solution at room temperature in less than 10 hours, whereas an appreciable amount of N-benzoyl D-alanine remains in Ac2O solution containing sulfuric acid even after 24 hours, and nearly one-third of N-benzoyl D-alanine remains intact in 100% sulfuric acid after one week. It is possible that the formation of the azlactone ring is fast, and the presence of acid would inhibit the racemization of the optically active azlactone. Most likely, the presence of acid would inhibit the mutarotation of the intermediate condensation product of benzaldehyde and hippuric acid. In comparison, the racemization of many optically active azlactones in acetic anhydride has been further enhanced in the presence of a basic catalyst like NaOAc [85]. In another example, treatment of hippuric acid with perchloric acid yields 5-oxo2-phenyl-4,5-dihydrooxazol-3-ium perchlorate, which is then converted into the “labile” (E)-4-benzylidene-2-phenyloxazol-5(4H)-one in reaction with benzaldehyde. This E-isomer can be quantitatively converted into its Z-isomer in cold pyridine [84]. Therefore, a mixed mechanism is proposed by the author of this book in Scheme 1.18 to illustrate the formation of unsaturated azlactone from hippuric acid and benzaldehyde under either acidic or basic conditions. In this mechanism, the intermediate 2-phenyloxazol-5(4H)-one once formed under basic conditions will be further deprotonated with acetate, and the carbonyl oxygen atom in the resulting 5-oxo-2-phenyl-4,5-dihydrooxazol-4-ide anion should carry some character of negative charge due to the potential resonance. Therefore, when this anionic species approaches benzaldehyde from either above or below the aldehyde, benzaldehyde should be oriented in such a way that the oxygen atom in the aldehyde should be far away from the negative charge due to charge-charge repulsion. As a result, a pair of Aldol addition products with (RS or SR) diastereoselectivity are formed, which can be quickly esterified with the existing acetic anhydride. Then the E2 elimination of acetic acid from these intermediates affords the final product of (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one. In comparison, hippuric acid in the presence of an acid, such as perchloric acid, will be protonated to generate its enol form structure. The Aldol addition of the enol with protonated benzaldehyde from either direction, i.e., above the aldehyde or below the aldehyde, gives two diastereomers with RR or SS configuration. In this case, the protonated benzaldehyde will be oriented differently in comparison to the situation under basic conditions, due to the potential hydrogen bond. Dehydration of the Aldol addition intermediates

Azlactones 31

leads to the formation of (E)-2-benzamido-3-phenylacrylic acid. Cyclization under the acidic condition yields the final product of (E)-4-benzylidene2-phenyloxazol-5(4H)-one. While this mechanism might not be the perfect one, it is the best mechanism to rationalize the generation of either E- or Z-azlactones under acidic or basic conditions, respectively. 2

+ 1

3K

3K

1D2$F

2+

2

+1

3K

$F2+$F2

SDWKD DERYH3K&+2

3K

3K

2

+ 1

$F2+ 2

2 1

2

2 1

+1

1

3K

3K

SDWKE 2

$F2 3K ( HOLPLQDWLRQ

2$F

2+

+ 1

3K

2

2

1 3K

2+

3K&+2

2 2+

+ 1

2+

2 + 3K

2+ +

+ + 1

EHORZ3K&+2 3K

1

SDWKD +

+ + 3K

+ &O2

3K

3K

3K

DERYH3K&+2 3K

2+

2

2

2

2$F

+ +

2+

2 + +

1

1 +

$F2

2

3K

2+

+ 1

3K 2

2+

2

3K

$F2

2

2

2

3K

$F2

3K&+2

2

$F2 2

$F2

1 +

1

+ + 3K

2

3K

3K

$F2

2

2

2

+ + 3K

+&O2

2+

+ 1

$F2

1

3K

SDWKE EHORZ3K&+2

2

2

3K

2

2

2

2 2

2

2+

2+

+ 1

3K

2+

2

3K

2+

+ 2 +2 3K 2

2+ 2+ 3K

3K

2 1 +

2+ 2

+ 3K

+ 2

3K

2 1

2 3K

SCHEME 1.18  The mechanism for the generation of unsaturated azlactones of E- and Z-configurations.

32

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

1.3.2 PREPARATION OF SATURATED AZLACTONES As mentioned previously, saturated azlactones are much more difficult to make than their unsaturated counterparts, possibly due to the stability of unsaturated azlactones with extended conjugation systems. In addition, saturated azlactones can be easily hydrolyzed in the presence of water and acid, as azlactones essentially can be considered carboxylic acid anhydrides. Nevertheless, a few methods have been developed to form saturated azlactones. The most common method for saturated azlactones is the application of a mild dehydration agent (e.g., carbodiimide) to N-acyl amino acid derivatives, such as DCC. For example, N-(tert-butoxycarbonyl)-Lalanyl-DL-phenylalanine (Boc-L-Ala-dl-Phe) once dehydrated with either DCC or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride in CH2Cl2, is converted into tert-butyl ((1S)-1-(4-benzyl-5-oxo-4,5dihydrooxazol-2-yl)ethyl)carbamate, as shown in Scheme 1.19 [124]. In another preparation, N-(tert-butoxycarbonyl)-L-leucyl-L-phenylalanine in THF is treated with DCC to afford tert-butyl ((1S)-1-(4-benzyl-5-oxo-4,5dihydrooxazol-2-yl)-3-methylbutyl)carbamate. This saturated azlactone is then oxidized with DDQ in 1,2-dimethoxyethane to yield the corresponding unsaturated azlactone, i.e., tert-butyl (S,Z)-(1-(4-benzylidene-5-oxo-4,5dihydrooxazol-2-yl)-3-methylbutyl)carbamate, as shown in Scheme 1.20 [125]. Interestingly, when (1R,2S)-1-acetamido-2-vinylcyclopropane-1carboxylic acid in acetonitrile is treated with DCC, the resulting (1S,3R)5-methyl-1-vinyl-6-oxa-4-azaspiro[2.4]hept-4-en-7-one changes into its diastereoisomer, i.e., (1S,3S)-5-methyl-1-vinyl-6-oxa-4-azaspiro[2.4]hept4-en-7-one, as shown in Scheme 1.21. When the acetyl group in the starting material is replaced with a trifluoroacetyl group, the corresponding (1S,3R)-5-(trifluoromethyl)-1-vinyl-6-oxa-4-azaspiro[2.4]hept-4-en-7-one racemizes at an even faster rate. The racemization of the azlactone is possibly due to the presence of the highly strained three-member ring, which cleaves homolytically to generate a diradical intermediate. The combination of diradical leads to the original azlactone or stereochemically inverted azlactone [126].

N

O BocHN

N H

OH O

DCC or N C CH2Cl2

O

NH Cl

O BocHN

N Ph

SCHEME 1.19  Conversion of N-acyl amino acid derivatives into saturated azlactone with DCC.

Azlactones 33

O H N

O O

O N H

DCC THF

OH

O

O

O

O

O DDQ

N

O

O

O

N H

O

O

N

N H

SCHEME 1.20  Conversion of N-acyl amino acid derivatives into unsaturated azlactone with DCC and subsequent oxidation by DDQ.

O

O NH

HO

O DCC CH3CN

O

N

O

N

O

O

N

O

O HO

O

CF3

CF3 NH

O DCC CH3CN

CF3 O

N

fast

O

N

O CF3 O

N

O

SCHEME 1.21  The mechanisms for the racemization of (1S,3R)-5-methyl-1-vinyl-6-oxa-4azaspiro[2.4]hept-4-en-7-one and (1S,3R)-5-(trifluoromethyl)-1-vinyl-6-oxa-4-azaspiro[2.4]hept-4-en-7-one.

In order to make (R)- and (S)-α-methyl(alkyl)serine-containing peptides, the racemic alanine, phenylalanine, valine, and leucine with their α-amino groups protected with benzoyl groups are treated with DCC in CH2Cl2 at 0°C to room temperature to afford the corresponding azlactones, which are then deprotonated with NaH in DMF/THF and treated with CH2I2 (Scheme 1.22). Using (S)-phenylalanine cyclohexylamide (i.e., (S)-2-amino-N-cyclohexyl-3-phenylpropanamide) as chiral auxiliary, the optically pure (R)- and (S)-azlactones are converted into N-((S)-1(cyclohexylamino)-1-oxo-3-phenylpropan-2-yl)-4-methyl-2-phenyl4,5-dihydrooxazole-4-carboxamide, 4-benzyl-N-((S)-1-(cyclohexylamino)1-oxo-3-phenylpropan-2-yl)-2-phenyl-4,5-dihydrooxazole-4-carboxamide, N-((S)-1-(cyclohexylamino)-1-oxo-3-phenylpropan-2-yl)-4-isopropyl-2-

34

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

phenyl-4,5-dihydrooxazole-4-carboxamide, and N-((S)-1-(cyclohexylamino)1-oxo-3-phenylpropan-2-yl)-4-isobutyl-2-phenyl-4,5-dihydrooxazole-4carboxamide, via a novel azlactone/ oxazoline interconversion reaction, respectively [4]. R1

O N H

I

R1 OH O

DCC CH2Cl2, r.t.

N Ph

O

NaH, CH2I2 O DMF/THF

R1

N Ph

O

O

R1 = Me, Bn, i-Pr, i-Bu

SCHEME 1.22  Conversion of N-benzoyl alanine (phenylalanine, valine and leucine) into the corresponding azlactones with DCC and subsequent iodomethylation at C-4.

In addition to the application of DCC, other carbodiimides have been used for the dehydration of N-acyl α-amino acids. For example, when N-benzoyl alanylglycine or N-benzoyl leucylglycine is treated with N-(3dimethylaminopropyl)-N’-ethyl carbodiimide hydrochloride (EDC) in CH2Cl2 at 0°C for 1 hour, the corresponding azlactone, i.e., N-(1-(5-oxo4,5-dihydrooxazol-2-yl)ethyl)benzamide or N-(3-methyl-1-(5-oxo-4,5dihydrooxazol-2-yl)butyl)benzamide is formed in 75 and 85% yield, respectively [6]. Recent study in combination of theoretical and experimental approaches using EDC as the condensation agent during the formation of azlactone indicates that N-acyl amino acids (with either aromatic acyl or aliphatic acyl group) can be easily converted into the corresponding azlactones, whereas the N-(alkoxycarbonyl) amino acids are hardly transformed into the corresponding 2-alkoxy azlactones [127], even though a few 2-alkoxy-azlactones, such as 2-(benzyloxy)-8-oxo-7,7,9,9-tetramethyl3-oxa-1,8-diazaspiro[4.5]dec-1-en-4-one and 2-((9H-fluoren-9-yl)methoxy)8-oxo-7,7,9,9-tetramethyl-3-oxa-1,8-diazaspiro[4.5]dec-1-en-4-one (radicals) have been reported [128]. It should be pointed out that the fast formation of a 5(4H)-oxazolone intermediate from peptide in the presence of a strong activating agent like EDC suppresses the generation of 2,5-diketopiperazine (DKP), as the formation of DKP requires the rotation of the peptide bond from the predominant trans-conformation into the cis-isomer prior to the ring closure. Thus, the formation of DKP is no longer a drawback for the C-terminus elongation of peptides [129]. A convenient condition superior to DCC has been reported by the treatment of N-acyl amino acid with an acyl chloride in benzene. For example, treatment of hippuric acid in acetic anhydride at 70°C yielded 48.3% of

Azlactones 35

2-phenyloxazolin-5-one, whereas the treatment of hippuric acid with ethyl chloroformate in benzene at 40°C afforded 77.5% of 2-phenyloxazolin5-one. This condition would avoid the formation of dicyclohexylurea [130]. Moreover, acyl chloride such as ethyl chloroformate (i.e., ethyl carbonochloridate) has also been applied for the azlactonization of N-acyl α-amino acids, as demonstrated in the preparation of tert-butyl (S)-4-benzyl2-methyl-5-oxo-4,5-dihydrooxazole-4-carboxylate. In this protocol, (R)-2-acetamido-2-benzyl-3-(tert-butoxy)-3-oxopropanoic acid in dry THF at –10°C is mixed with 1.5 equivalents of N-methyl morpholine (NMM) and ethyl chloroformate sequentially. After 15 minutes, NMM hydrochloride is filtered, and all volatiles are removed under reduced pressure to afford tert-butyl (S)-4-benzyl-2-methyl-5-oxo-4,5-dihydrooxazole-4-carboxylate. However, this compound has very low stability and must be used as soon as it is formed [131]. A special case for the generation of azlactone should be mentioned, in which 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in combination with NMM promotes a rapid formation of the peptide bond in a one-pot manner without significant loss of configuration. For example, when NMM is added to the mixture of N-acetyl-L-leucine, ethyl (R)-2-amino-4-phenylbutanoate hydrochloride and CDMT in acetonitrile, the dipeptide of ethyl (R)-2-((S)2-acetamido-4-methylpentanamido)-4-phenylbutanoate is formed in 1 hour, with a trace amount of (S)-4-isobutyl-2-methyloxazol-5(4H)-one identified. The isolated dipeptide demonstrates a ratio of 94:6 for the syn- and anti-diastereomers. However, when this one-pot procedure is performed in two steps, by mixing N-acetyl-L-leucine, CDMT, and NMM in acetonitrile for 1 hour, then ethyl (R)-2-amino-4-phenylbutanoate hydrochloride is added, the resulting dipeptide shows a ratio of 44:56 for the syn- and anti-diastereomers, due to the formation of (S)-4-isobutyl-2-methyloxazol-5(4H)-one that racemizes before the coupling with the subsequent amino acid (Scheme 1.23) [132]. A few years ago, a uniquely scalable and safe process for the preparation of α,α-dialkyl amino acid (e.g., 2-aminoadamantane-2-carboxylic acid) has been reported by means of the azlactone intermediate in a manner of flow-based synthesis, as displayed in Scheme 1.24 [133]. In this practice, 2-adamantanone in THF is treated with a solution of ethynyl magnesium bromide to yield 2-ethynyl adamantan-2-ol. The subsequent Ritter reaction is performed under a strong acidic conditions so that the tertiary alcohol is protonated to generate a tertiary carbocation which is then nucleophilically attacked by the nitrogen atom of nitrile to form an amide product. The following 5-exo-dig cyclization has been performed by treatment of the solution of

36

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

2-ethynyl 2-acetylamino adamantane or 2-ethynyl 2-benzamido adamantane in EtOH with potassium hydroxide to yield 2-methyl-4-(adamantane-2’spiro)-5-methylidene oxazoline or 2-phenyl-4-(adamantane-2’-spiro)5-methylidene oxazoline, respectively. Under the flow-based synthesis condition, the Ritter reaction and subsequent 5-exo-dig cyclization can be combined into a single process. The solution of the corresponding oxazoline in acetonitrile is then ozonolyzed and reduced by passing through a cartridge containing polymer-fixed thiourea to yield the respective azlactone. Under batch reaction conditions, the ozonide can be reduced by dimethylsulfide or zinc, instead of thiourea. Ph

Cl N O

O

N

OH N

O N H

Cl

O

O , H3N CH3CN

CO2Et , NMM

O

H N

N H

OEt

O

Ph CDMT NMM CH3CN

Ph

N O H3N

O

Cl

CO2Et

SCHEME 1.23  CDMT and NMM promoted formation of dipeptide from N-acetyl-L-leucine and amino acid ethyl ester.

HC C O

HO

5-exo-dig cyclization

RCN Ritter R Reaction

N

NH O

1) O3 2)

H N

H2 N S

N

O

O HCl, AcOH H 2O

O

R

H 3N

CO2H Cl

R

SCHEME 1.24  Flow-based synthesis of α-amino acid from 2-adamantanone.

Finally, it should be mentioned for a general method for the 4,4-disubstituted azlactones as displayed in Scheme 1.25, involving the Rh2(OAc)4-catalyzed one-pot cyclopropanation of nitriles with α-diazo carboxylic acid esters, yielding 5-methoxy-2,4-disubstituted oxazoles. Subsequently, in the

Azlactones 37

presence of a catalytic amount of iodide (e.g., NaI), the 5-methoxy-2,4disubstituted oxazoles react with allyl iodide or other active alkyl iodides, such as methyl iodide, methyl 2-(iodomethyl)acrylate, methyl 2-iodoacetate, iodoacetophenone, etc., to generate the corresponding azlactones with the alkyl group of the iodide introduced at position 4 of the azlactones [134].

R1CN +

N2 R2

R2

R3

N R1

O

R2

cat. Rh2(OAc)4 CHCl3, CO2Me

OMe

CO2Me N

R1

R2

I

R3

N

NaI (10 mol%) Na2CO3, acetone,

R1

O

O

SCHEME 1.25  Preparation of 4,4-disubstituted azlactones from nitrile and α-diazo carboxylic acid esters.

1.3.3 MECHANISMS FOR THE FORMATION OF AZLACTONES While there have been many illustrations in the literature for the generation of azlactones from N-acyl α-amino acids, particularly from the treatment of hippuric acid with acetic anhydride in the presence of sodium acetate, it is still necessary to discuss the mechanism here. Similar to the Erlenmeyer azlactone synthesis, the treatment of α-amino acids with carboxylic acid anhydride and pyridine leads to the formation of N-acyl-α-aminoketone and carbon dioxide, known as the Dakin-West reaction as shown in Scheme 1.26, for the case of acetic anhydride [135]. For this particular reaction, several mechanisms have been proposed, one of the mechanisms involves the formation of azlactone and two equivalent of acetic acid from the treatment of N-acyl amino acid with acetic anhydride [136]. Based on the known experimental data, one mechanism for the conversion of N-benzoylalanine with acetic anhydride to (S)-4-methyl-2-phenyloxazol-5(4H)-one is proposed by the author of this book in Scheme 1.27. O O R

OH + Ac2O

pyridine

R

CH3

HN

NH2 O

SCHEME 1.26  The Dakin-West reaction.

+ CO2

38

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O H N

O

O

O

O

O

H N

OH

O

O

O

O

H N

OH

O

AcOH

O

H

OAc

O

O

H N

O

O

H N

HN

O O O

O

O

O O

O O

O

O

H N OAc

O

N

O

O AcOH

SCHEME 1.27  The mechanism for the conversion of N-benzoyl alanine into azlactone with acetic anhydride.

1.4 REACTIONS 1.4.1 CHEMICAL REACTIVITIES OF SATURATED AZLACTONES Saturated azlactones have three reactive sites at the C2, C4, and C5 positions, where both C2 and C5 are double-bonded to the electronegative elements (N and O) so that they are electron-deficient and electrophilic. Often, nucleophilic attack at C5 results in a ring-opening reaction, particularly when amine, alcohol, and thiol are used as the nucleophiles. Especially, when an amino acid is applied as the nucleophile, the corresponding ring-opening reaction leads to the formation of a peptide. However, due to potential racemization at C4, often this reaction is performed by means of dynamic kinetic resolution to form the expected peptides. Particularly, this ring-opening reaction has largely been applied for the modification of polymer when azlactone is mounted to the polymer as a pendant. On the other hand, C4 is at the α-position of the electron-withdrawing carbonyl group, naturally, the hydrogen atom at C4 is more acidic and can be removed by a strong base, thus C4 is nucleophilic. C4 can be converted into carbanion, enol or enolate carbon that undergoes the typical reactions a normal enolate (or enol) takes place, such as alkylation, allylation, Michael addition, Aldol condensation, Mannich reaction, etc. In addition, the enolate form of azlactone naturally

Azlactones 39

contains extended conjugated double bonds that then potentially participate in a series of cycloadditions, such as [2+3], [2+4] and even [2+8] as shown below. Therefore, the reactivities of saturated azlactones are grouped into several sections: reactions at C2, reactions at C4, reactions at C5 and reactions involving more than one atom on the azlactone ring. 1.4.1.1 REACTIONS AT C2 OF AZLACTONES Although C2 of azlactone is electrophilic, C4 is even more electrophilic. As a result, the nucleophilic addition to azlactones often occurs at C4 rather than C2. Consequently, the reactions occurring at C2 have not been well explored yet. Still, under a special condition, C2 can be converted into nucleophilic, when a supramolecular catalyst (10, Figure 1.3) formed from chiral P-spiro-triaminoiminophosphorane, i.e., (2S,7S)-2,7-diisopropyl-1,6dimethyl-3,3,8,8-tetraphenyl-1,4,6,9-tetraaza-5λ5-phosphaspiro[4.4]non5(9)-ene (11, Figure 1.3) and three equivalents of phenol via hydrogen bonds is applied [137]. Under this condition, when azlactone such as 4-isopropyloxazol-5(4H)-one is added, the phenoxide in hydrogen-bond assisted charge-separated catalyst 10 promotes the deprotonation of C4 in the azlactone to generate a 4-isopropyloxazol-5-olate that replaces the position of phenoxide in the supramolecular structure, yielding a new supramolecular cluster as represented by 12 in Figure 1.3. Upon the addition of cinnamoyl benzotriazole, i.e., (E)-1-(1H-benzo[d][1,2,3]triazol-1-yl)-3-phenylprop-2en-1-one, the supramolecular clustered oxazol-5-olate undergoes Michael addition with the cinnamoyl benzotriazole, affording 2-((R)-3-(1H-benzo[d] [1,2,3]triazol-1-yl)-3-oxo-1-phenylpropyl)-4-isopropyloxazol-5(2H)-one (Scheme 1.28). N N Ph Ph

N P

N H

N H

O Ar

Ar O H

H O Ar 10

Ph Ph

Ph Ph

N Ph Ph

N N 11

N H

N H

Ph Ph

Ph Ph

CF3 S

O Ar

Ar O

P N H

N P

H

H

F3C

HN

O 13 O N 12

FIGURE 1.3  The chiral catalysts and hydrogen bonding complex with azlactone.

N H

N

40

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

N Ph Ph

N P

N H

N H

O Ar

Ar O

O N N N

+ 12

Ph Ph

H

O

H

O O

O

N

N N N

O N

O N N N

SCHEME 1.28  The Michael addition of azlactone to cinnamoyl benzotriazole via a supramolecular complex intermediate.

For this reaction in toluene at –60°C, the number of equivalents of phenol plays an important role in the enantioselectivity. It is found that when one, two, and three equivalents of phenol are used to form the charge-separated complex with 4-isopropyloxazol-5(4H)-one, the corresponding enantioselectivity of the Michael addition product with (E)-1-(1H-benzo[d][1,2,3]triazol1-yl)-3-phenylprop-2-en-1-one, i.e., 2-((R)-3-(1H-benzo[d][1,2,3]triazol1-yl)-3-oxo-1-phenylpropyl)-4-isopropyloxazol-5(2H)-one, has been measured at 67%, 89%, and 90% ee, respectively. For comparison, in the absence of phenol, i.e., 11 in Figure 1.3 is used as the catalyst instead, the enantioselectivity is only 51% ee [137]. The yield of the Michael addition product is similar when a different amount of phenol is used. Further study on this reaction with different Michael reaction acceptors also indicates that a lower asymmetric induction (34% ee) is reached in the absence of two phenol moieties. In addition, chlorine-substituted phenols, in particular 3,5-dichlorophenol, can further enhance the enantioselectivity, possibly due to the electron-withdrawing nature of chlorine that makes the phenol form phenoxide easily. Also, high catalyst loading and decreased solvent volume further improve the enantioselectivity. Moreover, both electron-donating and electron-withdrawing groups on the aryl component of the α,β-unsaturated acylbenzotriazoles can be tolerated [138]. The Michael addition of azlactone at position C2 has been applied to extend the hydrocarbon chain of carboxylic acid by three carbon atoms, by means of the Michael addition with acrylonitrile and subsequent hydrolysis under either basic (1.0 M NaOH) or acidic (0.1 M HCl) condition [139].

Azlactones 41

In this way, the carboxylic acid is converted into acyl chloride with SOCl2, which then reacts with DL-valine and the resulting N-acyl valine is converted into the corresponding azlactone. In the presence of Et3N, the Michael addition with acrylonitrile occurs at the C2 position. The reaction between 4-isopropyl-2-phenyloxazol-5(4H)-one and N-phenylmaleimide in the presence of Et3N also occurs with complete C2-regioselectivity. Particularly, in the presence of 10 mol% 1-(3,5bis(trifluoromethyl)-phenyl)-3-((1S,2S)-2-(dimethylamino cyclohexyl)thiourea (13, Figure 1.3) in toluene at temperature from –20°C to room temperature, the azlactone has been 100% converted into (S)-3-((R) 4-isopropyl-5-oxo-2phenyl-2,5-dihydrooxazol-2-yl)-1-phenylpyrrolidine 2,5-dione with up to 25:1 of diastereoselectivity and 94:4 of enantioselectivity. However, this reaction does not occur in ethanol and DMF. Further extension of this reaction to 4-(tert-butyl)-2-phenyloxazol-5(4H)-one, 4-(tert-butyl)-2(fluorophenyl)oxazol-5(4H)-one or 4-(tert-butyl)-2-(2,4 difluorophenyl) oxazol-5(4H)-one with one of the N-arylmaleimides (aryl = Ph, 4-MeOC6H4, 3-Cl-C6H4, 4-CF3-C6H4, 6-Cl-C6H4) in the presence of 10 mol% of 13 in toluene at 4°C, leads to the expected C2-Michael adducts in yields from 62% to 99%, and excellent diastereoselectivity (> 25:1) as well as enantioselectivity (up to 99.5% ee) [140]. Extension of the Michael reaction at C2 allows the preparation of a-diketones. For example, treatment of valine with trifluoroacetic anhydride yielded 4-isopropyl-2-(trifluoromethyl)oxazol-5(4H)-one. In the presence of Et3N in CH2Cl2, the hydrogen atom at C-4 was abstracted by Et3N and the Michael addition with t-butyl acrylate occurred at the C2 position, giving pseudo-azlactone tert-butyl 3-(4-isopropyl-5-oxo-2-(trifluoromethyl)2,5-dihydrooxazol-2-yl)propanoate. Subsequent Grignard reaction with PhMgBr afforded 63% of tert-butyl 3-(5-hydroxy-4-isopropyl-5-phenyl2-(trifluoromethyl)-2,5-dihydrooxazol-2-yl)propanoate, which decomposed under acidic condition to give 77% of 3-methyl-1-phenylbutane-1,2-dione (Scheme 1.29) [141]. Likewise, isoleucine, methionine, etc., have been converted into the corresponding azlactones, and subject to the subsequent Michael reaction and Grignard reaction. In the latter step, alkyl lithium can be used instead of the Grignard reagent.

42

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

OH NH2

O

O

O N

(CF3CO)2O

O OBut

O

Et3N, CH2Cl2

HO Ph

O

O HCO2H

O N

O CF3

O CF3

CF3

PhMgBr

O N

Ph

r.t., 12 hrs. O

O

SCHEME 1.29  Conversion of valine into 3-methyl-1-phenylbutane-1,2-dione via the Michael addition of the corresponding azlactone of valine and subsequent Grignard reaction.

1.4.1.2 REACTIONS AT C4 OF AZLACTONES The reactivity of azlactone at C4 is probably the most diversified, due to the nucleophilicity of C4. This is because the hydrogen at C4 is pretty acidic, with a pKa of around 9 [7, 142–144]. Nevertheless, once C4 is deprotonated or the azlactone is converted into its enolate or enol form, C4 will undergo two types of reactions, i.e., nucleophilic substitution and nucleophilic additions. The nucleophilic substitutions include alkylation, allylic alkylation, arylation, carboxylation, and propargylation. The nucleophilic additions include the addition of nucleophilic C4 to double bonds or triple bonds that are connected to an electron-withdrawing group, such as Michael addition, and addition to an electron-deficient double bond, such as Aldol reaction, Mannich reaction, addition to allene, diazo compounds and even to alkenes and alkynes. After the functionalization at C4, the resulting 4,4-disubstituted azlactones can be converted into α,α-disubstituted amino acids, or other useful molecules. 1.4.1.2.1 Alkylation of Azlactones The C4-alkylation can be stereoselectively controlled to afford the 4,4-dialkyl-azlactone, such as the alkylation in the presence of a catalytic amount of an optically pure D2-symmetric tetraaminophosphonium salt as a phase-transfer catalyst in an organic-aqueous binary system. For example, when a bulky chiral P-spiro-tetraaminophosphorane, i.e., (2R,3R,7R,8R)-1,4,6,9-tetrakis(3,5-bis(tert-butyldimethylsilyl)benzyl)-

Azlactones 43

2,3,7,8-tetraphenyl-1,4,6,9-tetraaza-5-phosphaspiro[4.4]nonan-5-ium chloride is applied as the catalyst to a biphasic system between K3PO4 saturated aqueous solution and an organic solvent (e.g., toluene, Et2O, tert-butyl methyl ether or cyclopentyl methyl ether (CPME)), the reaction between tert-butyl ((1S)-1-(4-benzyl-5-oxo-4,5-dihydrooxazol-2-yl)ethyl)carbamate and allyl bromide below room temperature afford a reasonably good yield of tert-butyl ((S)-1-((R)-4-allyl-4-benzyl-5-oxo-4,5-dihydrooxazol-2-yl)ethyl) carbamate with an excellent diastereoselectivity (> 94: 6% for the S/R and S/S diastereomers), as shown in Scheme 1.30 [124]. It is found that this biphasic alkylation system is compatible with ethereal solvents, for which CPME is the solvent of choice. While a subtle temperature effect on the stereoselectivity has been observed, the reaction at –15°C is recommended to suppress the self-acylation for the purpose of higher chemical yield. Furthermore, the dialkylated diastereomerically enriched azlactone can be used directly as an acyl donor for the subsequent ligation with another amino acid (or peptide), as demonstrated in the stereoselective synthesis of a tetrapeptide with two non-adjacent chiral quaternary α-amino acid residues. This biphasic system provides an approach to introduce α,α-dialkyl α-amino acids of significant conformational constraint to probe the molecular structure of receptors or enhance the biological activity of peptides due to the preorganized optimal conformation for binding or inhibiting metabolic degradation [124]. O

O

O BocHN

sat. K3PO4, cat.

+ Br N

CPME, -25 °C to r.t.

Ph

N

N

cat. =

Ph

Ph Ar =

P Ph

N

Ar

Ar Ph

O BocHN

N

N Cl

Ph

Si

Si

Ar Ar CPME = cyclopentyl methyl ether

SCHEME 1.30  Asymmetric C4-allylation of azlactone.

While α-bromo carbonyl compounds are good alkylating agents, the α-hydrogen is even more acidic than the corresponding carbonyl compound due to the presence of an additional electron-withdrawing bromo group. Consequently, the chiral α-bromo carbonyl compounds often undergo racemization in the presence of a base. For α-bromo carboxylic acid ester, the enantiomeric mixture can be enriched for a particular enantiomer by

44

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

means of crystallization-induced dynamic resolution (CIDR) mediated via L-threonine. Subsequently, the bromo is stereoselectively substituted using azlactone as the nucleophile that takes place at its C4 position to afford 4,4-disubstituted azlactone of high diastereoselectivity. Further treatment of this azlactone with TMSCl in methanol decomposes the azlactone moiety and yields 2,3-disubstituted succinic acid methyl ester, as illustrated in Scheme 1.31. Isopropyl N-benzoyl-O-((R)-2-bromo-2-phenylacetyl)L-threoninate can epimerize at the bromo position, but upon the CIDR, one of the diastereomers is enriched as solid, which is then treated with a phenylalanine-derived azlactone (i.e., 4-benzyl-2-phenyloxazol-5(4H)-one) in the presence of diethylamine in DMF at room temperature for 1 hour to afford 95% of the product as a mixture of four diastereomers. Subsequent treatment of these diastereomers with TMSCl in methanol followed by the removal of chiral auxiliary with Et3N in methanol, afford dimethyl asparate derivative with a 91:9 diastereomeric ratio. The enhanced diastereomeric ratio is attributed to the rate difference in the removal of the chiral auxiliary of the intermediates [145]. Even in the absence of a halide alkylating agent, the azlactone has been successfully alkylated at C4 with an imidazole ketone in the presence of an oxidizing agent, by means of a catalytically oxidative cross-enolate coupling reaction via a transient homocoupling dimer. In this case, azlactone can be converted into the corresponding enolate, and the oxidative coupling of enolate leads to an unstable homocoupling dimer of the azlactone with contiguous tetra-substituted carbon centers, which then decomposes and couples with another possible enolate if available under this condition. As an example, in the presence of a catalytic amount of ferric chloride (FeCl3) and DMAP (10 mol% each) and 1.6 equivalents of di-tert-butyl peroxide (DTBP) as the competing oxidant, 2-(4-methoxyphenyl)-4-phenyloxazol-5(4H)-one is converted into 2,2’-bis(4-methoxyphenyl)-4,4’-diphenyl-[4,4’-bioxazole]-5,5’(4H,4’H)dione in 96% of yield with a diastereomeric ratio of 3:1. Under the same reaction condition but with a double quantity of catalyst and oxidizing agent, this azlactone dimer cleaves and reacts with 1-(1-methyl-1Himidazol-2-yl)ethan-1-one to afford 71% of 2-(4-methoxyphenyl)-4-(2(1-methyl-1H-imidazol-2-yl)-2-oxoethyl)-4-phenyloxazol-5(4H)-one (Scheme 1.32). In contrast, under the standard reaction condition with 10 mol% of FeCl3 and DMAP as well as 1.6 equivalent of DTBP, the direct coupling between 2-(4-methoxyphenyl)-4-phenyloxazol5(4H)-one and 1-(1-methyl-1H-imidazol-2-yl) ketone gives 74% of

Azlactones 45

2-(4-methoxyphenyl)-4-(2-(1-methyl-1H-imidazol-2-yl)-2-oxoethyl)-4phenyloxazol-5(4H)-one. A variety of 1H-imidazol-2-yl ketones have been successfully coupled with azlactone in good yields [146]. 2

;F 2 %U

2

2 2

3K

2L3U 1+%]

&,'5

%U

%U

1 3K 3K 2L3U ',($\LHOG 1+%]

3K

!GUVROLG 2 2

2 2

3K

2

2

HSLPHUL]DWLRQ LQVROXWLRQ 2

2

2L3U 1+%]

3K  2

2 3K

;F

1

3K

2

%Q 2

1

%Q 2

2

;F

1

3K

3K  2

%Q 2

2 ;F

3K 

3K

1

%Q 2 ;F

3K 

706&O0H2+ 0H2& %]+1

%Q 2

20H 3K GUHU

0H2+ (W1

0H2&

%Q 2

%]+1

;F 3K

SCHEME 1.31  L-Threonine mediated crystallization-induced dynamic resolution and subsequent nucleophilic substitution.

Similarly, 2-(4-methoxyphenyl)-4-phenyloxazol-5(4H)-one undergoes a catalytic dehydrogenative cross-coupling with toluene, ethyl benzene, n-propylbenzene, and n-butylbenzene, in the presence of an equal amount of Pd(OAc)2 in 1,4-dioxane at 90°C, all occurring at the terminal methyl sites rather than the more commonly observed arylation, in yield of 72%, 65%, 62% and 46%, respectively (Scheme 1.33). It is believed that in the presence of an oxidizing agent, e.g., Pd(OAc)2, 2-(4-methoxyphenyl)-4-phenyloxazol5(4H)-one dimerizes. In addition, this dimer forms a metal complex with Pd(TFA)2 at 60°C. Treatment of this metal complex with toluene at elevated temperature (95°C) affords 37% of 4-benzyl-2-(4-methoxyphenyl)-4phenyloxazol-5(4H)-one. Isotopic study with both toluene and toluene-d8 indicates an isotopic effect of 3.55, whereas the competition between

46

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

toluene and toluene-2,3,4,5,6-d5 with 2-(4-methoxyphenyl)-4-phenyloxazol5(4H)-one shows an isotopic effect of 1.09. In contrast, when only a catalytic amount of Pd(OAc)2 (e.g., 20 mol%) is used, the dehydrogenative crosscoupling between 2-(4-methoxyphenyl)-4-phenyloxazol-5(4H)-one and ethylbenzene in the presence of two equivalents of t-butyl peroxide afford both 2-(4-methoxyphenyl)-4-phenyl-4-(1-phenylethyl)oxazol-5(4H)-one and 2-(4-methoxyphenyl)-4-phenethyl-4-phenyloxazol-5(4H)-one at 125°C, whereas only 2-(4-methoxyphenyl)-4-phenyl-4-(1-phenylethyl)oxazol5(4H)-one is observed in the absence of Pd(OAc)2 [147]. O Ph O

O

N

N N MeO

FeCl3 (20 mol%) DMAP (20 mol%) DTBP (3.3 eq.) MS 4Å, PhCl 60 °C, 2 h 71 % OMe

O N N O O

Ph N

O

FeCl3 (10 mol%) DMAP (10 mol%) DTBP (1.6 eq.) MS 4Å, PhCl 60 °C, 2 h 96 %

MeO

Ph

O N

N O

Ph O

MeO

dr = 3:1 O O

O

Ph N

N

+ N

MeO

O

FeCl3 (10 mol%) DMAP (10 mol%) DTBP (1.6 eq.) MS 4Å, PhCl 60 °C, 2 h 74 %

Ph O

O

N

N N MeO

SCHEME 1.32  C4-Alkylation of azlactone with an imidazole ketone in the presence of oxidizing agent.

A unique method to make C4-alkylated azlactones, as shown in Scheme 1.25, takes advantage of iodide catalyzed cleavage of the methyl group on the 5-methoxy-2,4-disubstituted-oxazoles in the presence of an alkylating agent by means of in situ generated 2,4-disubstituted-oxazol5-olate. These 5-methoxy-2,4-disubstituted-oxazoles can be easily prepared from Rh2(OAc)4 catalyzed reaction between nitriles and 2-diazo esters [134].

Azlactones 47

O O

O Ph

1.0 eq. Pd(OAc)2

+

N

CH3 n

N

1,4-dioxane 90 °C

n = 0, 1, 2, 3

MeO

Ph n

O Ph

MeO O

when n = 1 0.2 eq. Pd(OAc)2

2.0 eq. (t-BuO)2 ° 125 C

O

2.0 eq. (t-BuO)2 ° 125 C O MeO Ph Ph

O Ph

O N

Ph

O Ph +

Ph

N

MeO

N

MeO

SCHEME 1.33  Pd(OAc)2 catalyzed C4-alkylation of azlactone.

1.4.1.2.2 Allylic Alkylation of Azlactones It is generally known that allyl ester such as allyl acetate can be applied as a donor of the allyl group in the presence of a palladium catalyst derived from π-allylpalladium chloride dimer and bis-2-diphenylphosphinobenzamide of R,R-1,2-diaminocyclohexane ligands. Using azlactone as the nucleophile, and a variety of allyl esters as the alkylating agents, catalytic asymmetric synthesis of quaternary amino acids has been developed. Particularly, a variety of α-alkylated aspartic acids with the α-alkyl group arising from differently substituted azlactones can be easily obtained once the double bond of the allylic moiety is oxidatively cleaved, and the azlactone ring is hydrolyzed, as illustrated in Scheme 1.34. In this practice, it is found that the 4-allylated azlactones have low to moderate ee% from the highly symmetrical allylating agents such as allyl acetate and 2-methylallyl acetate, whereas the respective azlactones of > 90% ee could be formed from 1-monosubstituted and 1,1-disubstituted allylic systems [148]. Such allylation condition also demonstrates a facial selectivity with respect to the azlactone when different allylating agents and ligands are used. For example, prenylation gives 99% ee derived from an attack on the si face of the azlactone in the presence of an R,R-ligand, whereas the corresponding cinnamylation affords a 90% ee of the product derived from the attack on the reface with the same ligand. The facial selectivity has been shown in Figure 1.4.

48

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O

O NH HN

Ph2P PPh2 (7.5 mol%) [ 3-C3H5PdCl]2 (2.5 mol%)

O O

+

N

OAc

O O

PhCH3, EtN(i-Pr)2

N

Ph

TMSCl MeOH

Ph O

O OMe O3, NaOH, MeOH Ph CH2Cl2 HN

MeO2C

O

OMe 6 N HCl Ph HN

HO O

OH NH3 Cl

O

O

SCHEME 1.34  C4-Prenylation of 4-methyl-2-phenyloxazol-5(4H)-one and subsequent conversion into (S)-2-amino-2-methylsuccinic acid.

OAc Ph

OAc OAc

OAc

SiMe3 OAc

Ph

OAc

N O

R O

OAc

FIGURE 1.4  Facial selectivity of allylic alkylation of azlactone.

Extension of this strategy using a gem-diacetate of allyl alcohol (i.e., (E)-4-((tert-butyldiphenylsilyl)oxy)but-2-ene-1,1-diyl diacetate) as the carbonyl surrogate in reaction with 4-methyl-2-phenyloxazol-5(4H)-one, in the presence of only 0.2 mol% of Pd(η3-C3H5)2Cl2 and 0.6 mol% of N,N’((1R,2R)-cyclohexane-1,2-diyl)bis(2-(diphenylphosphaneyl)benzamide) compounded with 4-methyl-2-phenyloxazol-5(4H)-one (1:1) yields 70% of (R,E)-4-((tert-butyldiphenylsilyl)oxy)-1-((S)-4-methyl-5-oxo-2-phenyl-4,5dihydrooxazol-4-yl)but-2-en-1-yl acetate, with 87% ee, whereas the yield of its corresponding diastereomer, i.e., (R,E)-4-((tert-butyldiphenylsilyl)

Azlactones 49

oxy)-1-((R)-4-methyl-5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)but-2-en1-yl acetate is only 6%, in 89% ee. Brønsted acid catalyzed esterification of the RS diastereomer (the major product) affords methyl (2S,3R,E)-3acetoxy-2-benzamido-6-((tert-butyldiphenylsilyl)oxy)-2-methylhex-4enoate. OsO4 catalyzed asymmetric dihydroxylation of this compound generates (3S,4S)-4-benzamido-2-((S)-2-((tert-butyldiphenylsilyl)oxy)-1hydroxyethyl)-4-methyl-5-oxotetrahydrofuran-3-yl acetate, which upon a series of consecutive treatments, the important intermediate of (3aS,6R,6aR)6-((S,E)-3-iodo-1-((4-methoxybenzyl)oxy)allyl)-3a-methyl-2-phenyl6,6a-dihydrofuro[3,4-d]oxazol-4(3aH)-one is obtained. Hydroboration of 2-(hex-5-en-1-yl)-2-hexyl-1,3-dioxolane with 9-BBN following coupling with the previous intermediate yields (3aS,6R,6aR)-6-((S,E)-9-(2-hexyl1,3-dioxolan-2-yl)-1-((4-methoxybenzyl)oxy)-non-2-en-1-yl)-3a-methyl2-phenyl-6,6a-dihydrofuro[3,4-d]oxazol-4(3aH)-one. Final treatment of this compound gives (2S,3R,4R,5S,E)-2-amino-3,4,5-trihydroxy-2-methyl14-oxoicos-6-enoic acid, so-called Sphingofungin F (Scheme 1.35). Similar synthetic route allows the preparation of Sphingofungin E, i.e., (2S,3R,4R,5S,E)-2-amino-3,4,5-trihydroxy-2-(hydroxymethyl)-14-oxoicos6-enoic acid [149]. An alternative synthesis of Sphingofungin E has been reported 10 years later [150]. Further extension of this approach leads to the preparation of “branched” chiral α-amino acids with vicinal tertiary and quaternary stereocenters of high yields and excellent stereoselectivities from the reaction of azlactones (e.g., 4-methyl-2-phenyloxazol-5(4H)-one, 4-benzyl-2-phenyloxazol-5(4H)-one and 4-ethyl-2-phenyloxazol-5(4H)-one) and (E)-4-styryl-1,3-dioxolan2-one (or other (E)-4-arylvinyl-1,3-dioxolan-2-ones), as shown in Scheme 1.36. Mechanistic studies reveal that the excellent regioselectivity is due to the formation of a hydrogen bond between the Pd-allylic complex and the enolate form of azlactone, rather than the possible π-π interaction between the phenyl ring of the Pd-allylic complex and the unsaturated bond or phenyl ring of the azlactone [151]. In addition, when sodium tetrakis[3,5bis(trifluoromethyl)phenyl]borate [NaB(ArF)4] is used as an additive, similar catalytic behavior but increased reaction activity has been observed due to the large non-coordinating counterion [B(ArF)4]–. The resulting product can be further transformed into a chiral azetidine.

3K

2

2 %%1

6SKLQJRIXQJLQ)

2

2+

2+

2

1

3K

2+

2+ 2+

2+

1+ 6SKLQJRIXQJLQ(

2

+ 2

1+

2

2

&2+

2

30%

&2+

2

W%X 2 3K 6L 3K

$F2 + 2 W%X 7V2+ 2 2 0H2+ 3K 6L 1 3K 3K HH 3K 2+ 2$F 30% 2 2 1+&23K + 1 , 2 2 2 2 

SCHEME 1.35  Total synthesis of Sphingofungin F starting from 4-methyl-2-phenyloxazol-5(4H)-one.

2

2+

 GSSI 3G&O3K$V &V&2'0)7+)+2UW

2

2V2DT 102&+&O

W%X 2 6L 3K 3K

1+&23K

&20H

2$F

$F2 +

 $F2

 Q&+

W%X 2 3K 6L 3K

1

2

1+ +1

3K3 33K PRO > &+3G&O@PRO ƒ 7+)&

2

50 Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Azlactones 51

Ph O P N O Ph O O Ph

O +

N

O

3-C

1) [Pd( 3H5)Cl]2, NaB(ArF)4 Et3N, PhMe, 0 °C

O 2) NaOMe, MeOH

O MeO

NHCOPh OH

SCHEME 1.36  Synthesis of methyl (2R,3R,E)-2-benzamido-6-hydroxy-2,3-dimethylhex4-enoate from 4-methyl-2-phenyloxazol-5(4H)-one.

Several types of organic molecules of high enantioselectivity and diastereoselectivity can be obtained by means of the coupling between azlactones and (1R,4S)-2-oxabicyclo[2.2.0]hexan-3-one, the latter can be easily achieved by photochemical electrocyclic reaction in quantitative yield. Stock solutions of this compound in diethyl ether at a concentration of 0.1 to 0.2 M could be stored and routinely handled without special precautions. Naturally, (1R,4S)-2-oxabicyclo[2.2.0]hexan-3-one offers several structural features: a highly unstable oxetan-2-one that can be easily opened upon exposure to nucleophile; a stereochemically fused cyclobutene moiety of which the double bond can be cleaved by the Grubbs’ catalyst, epoxidized or dihydroxylated like other normal alkenes; strained allylic lactone moiety that would respond productively to palladium catalysis. Very interestingly, a palladium-catalyzed reaction between azlactone and (1R,4S)-2-oxabicyclo[2.2.0]hexan-3-one affords an unexpectedly rearranged product rather than the alkylated azlactone (Scheme 1.37). In addition, this reaction demonstrates a very high double diastereoselectivity, even when 5 mol% of Pd(PPh3)4 is applied as the catalyst in the absence of a chiral ligand [152]. Moreover, the aromatic portion of azlactone plays a significant role, where the yield of final lactam is enhanced from azlactone with a phenyl ring containing an electron-donating group (e.g., OMe) to the phenyl ring of an electron-withdrawing group (e.g., CF3, NO2).

52

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O

O O

O

h O

[Pd( O

N

Ph

N

Ph

O

O

3-C

3H5)Cl]2, 5 mol% Et3N, THF, 0°C 15 mol% Ligand

CO2H CO2H O N Ph O

O Ligand =

O NH HN Ph2P PPh2

SCHEME 1.37  Unexpected rearrangement in the allylation of azlactone with (1R,4S)-2oxabicyclo[2.2.0]hex-5-en-3-one.

Further extension of this reaction with azlactones containing different group at C4 and commercially available phosphoramidite ligand (11bS)N,N-bis((R)-1-phenylethyl)dinaphtho[2,1-d:1’,2’-f][1,3,2]dioxaphosphepin4-amine indicates unaffected enantioselectivity upon modification of the substituent borne by the azlactone moiety [153]. Remarkably, this transformation brings together racemic (1R,4S)-2-oxabicyclo[2.2.0]hexan-3-one and nucleophilic azlactone to generate one out of four possible stereoisomers with high levels of selectivity, an approach that combines catalyst-controlled enantioselectivity and powerful double diastereoselectivity. Besides allyl halides and alkyl esters, simple allyl alcohols can be used as allylic donors in the presence of a Brønsted acid. For example, in the presence of benzoic acid or trifluoroacetic acid, the azlactones prepared from amino acids (e.g., alanine, phenylalanine, valine, leucine, isoleucine, (4-trifluoromethyl) phenylalanine, and 2-amino-2-cyclohexylacetic acid) and benzoic acid (or 4-methyl benzoic acid, 2- or 4-chlorobenzoic acid), are alkylated with (E)-3phenylprop-2-en-1-ol in toluene in the presence of Pd2(dba)3 using N,N’((1R,2R)-cyclohexane-1,2-diyl)bis(2-(diphenylphosphaneyl)benzamide) as the ligand, affording (S)-4-cinnamyl-4-methyl-2-phenyloxazol-5(4H)-ones in 80~98% of yields, with > 77% of enantioselectivity. While several other chiral ligands have been tested for this condition, N,N’-((1R,2R)-cyclohexane-1,2diyl)bis(2-(diphenylphosphaneyl)benzamide) is the choice of ligand. Water is the by-product of this reaction so 5Å molecular sieves have been added to absorb water and promote the reaction. This mild reaction condition provides

Azlactones 53

a facile access to quaternary allylic amino acids that is scalable to a magnitude of one gram [154]. Even neutral alkenes can be used as allylic donors to react with azlactones. It is found that when (E)-1,4-dienes are applied as the allylic donors, asymmetric allylic C−H alkylation of 1,4-dienes with azlactones in the presence of 2 mol% of ligand (11bR)-N-(naphthalen-1-yl)-2,6-bis(4nitrophenyl)-N-((perfluorophenyl)methyl)dinaphtho[2,1-d:1’,2’-f ][1,3,2] dioxaphosphepin-4-amine and 2 mol% of catalyst Pd(dba)2 as well as 1.1 equivalent of 2,5-dimethylbenzoquinone (2,5-DMBQ) in toluene at 25°C, affords C4-branched azlactones with an unusual dienyl component of Z-configuration. For this mild allylation, fine-tuning of the amine moiety in the phosphoramidite ligands reveals the above-mentioned ligand with a pentafluorophenyl and 1-naphthyl groups works the best among the eight tested ligands, leading to 99% of yield and 99% ee, together with excellent regio- and Z-selectivity. On the other hand, various primary and secondary alkyl-substituted 1,4-dienes are suitable for this reaction to make the branched products in excellent yields and high levels of enantioselectivity. Also, azlactones bearing either a para- or meta-substituted phenyl group at the C2 and different alkyl groups at C4 smoothly undergo this asymmetric allylic C−H alkylation in high yields and excellent regio- and stereoselectivities, regardless of the electronic nature of the group on the C2-phenyl group. A particular reaction of this type between 4-(3-(benzyloxy)propyl)-2(4-methoxyphenyl)oxazol-5(4H)-one and (E)-2-(hepta-3,6-dien-1-yl)-2hexyl-1,3-dioxolane or (E)-2-butyl-2-(hepta-3,6-dien-1-yl)-1,3-dioxolane, yields (S)-4-(3-(benzyloxy)propyl)-4-((R,Z)-1-(2-hexyl-1,3-dioxolan-2-yl) hepta-4,6-dien-3-yl)-2-(4-methoxyphenyl)oxazol-5(4H)-one or (S)-4(3-(benzyloxy)propyl)-4-((R,Z)-1-(2-butyl-1,3-dioxolan-2-yl)hepta-4,6dien-3-yl)-2-(4-methoxyphenyl)oxazol-5(4H)-one, in yield of 92 or 95%, respectively. Both compounds have enantioselectivity of 96% ee, with > 20:1 of diastereoselectivity and > 20:1 of Z/E selectivity, as shown in Scheme 1.38. These two compounds are further converted into marine alkaloids of lepadiformine A and lepadiformine B [155].

54

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

2 0H2

2 2%Q

1

5



2 2

PROOLJDQG 3GGED PRO '0%4HT WROXHQHUW

5 Q&+RUQ&+ 2

2 5

2 2

1

1 0H2

2%Q HHGU!=(!

+2

5

/HSDGLIRUPLQH$5 Q&+ /HSDGLIRUPLQH%5 Q&+ 12

/LJDQG

2 2

&) 3

1

12

SCHEME 1.38  C4-Allylation of 4-(3-(benzyloxy)propyl)-2-(4-methoxyphenyl)oxazol5(4H)-one.

Another C4-allylation proceeds by means of Pd2(dba)3 catalyzed rearrangement of allyl (2,4-disubstituted-oxazol-5-yl) carbonates in the presence of ligand 1,2-bis(diphenylphosphino)ethane (dppe). The allyl oxazole carbonates can be easily prepared by conversion of azlactones into the corresponding enolates which are trapped with allyl chloroformate, as illustrated by the conversion of 4-benzyl-2-phenyloxazol-5(4H)-one into allyl (4-benzyl-2-phenyloxazol-5-yl) carbonate and further transformation of allyl (4-benzyl-2-phenyloxazol-5-yl) carbonate into 4-allyl-4-benzyl2-phenyloxazol-5(4H)-one (Scheme 1.39) [156]. This approach has been extensively scrutinized for the selection of palladium catalyst, the choice of ligand and solvent. For example, N,N’-((1R,2R)-cyclohexane-1,2-diyl) bis(2-(diphenylphosphaneyl)benzamide) has been the ligand of choice

Azlactones 55

among the 14 tested ligands (Figure 1.5), including (S)-4-(tert-butyl)2-(2-(diphenylphosphaneyl)phenyl)-4,5-dihydrooxazole (14), (S)-2-(2(diphenylphosphaneyl)phenyl)-4-isobutyl-4,5-dihydrooxazole(15),(S)-4-(tertbutyl)-2-(2-(di-o-tolylphosphaneyl)phenyl)-4,5-dihydrooxazole (16), (S)-2(2-(diphenylphosphaneyl)phenyl)-4-phenyl-4,5-dihydrooxazole (17), ((2R,4R)-pentane-2,4-diyl)bis(diphenylphosphane) (18), (S)-1[(Sp)-2-(dicyclohexylphosphino)ferrocenyl]ethyldiphenylphosphine ((S)-(R)-Josiphos, (19), (Rp)-1-dicyclohexylphosphino-2-[(R)-α(dimethylamino)-2-(dicyclohexylphosphino)benzyl]ferrocene (Taniaphos SL-T002-1, (20), Mandiphos-SL-M001-1 (21), N,N’-((1R,2R)cyclohexane-1,2-diyl)bis(2-(diphenylphosphaneyl)-1-naphthamide), 2-(diphenyl-phosphaneyl)-N-((11R,12R)-12-(2-(diphenylphosphaneyl) benzamido)-9,10-dihydro-9,10-ethanoanthracen-11-yl)benzamide (22), N,N’((1R,2R)-cyclohexane-1,2-diyl)dipicolinamide (23), (S)-2,2’-bis (diphenylphosphaneyl)-1,1’-binaphthalene (24), and 2,6-bis((S)-4-isopropyl4,5-dihydrooxazol-2-yl)pyridine (25). The ligand of choice leads to excellent yield of product at certain level of enantioselectivity, depending on the reaction conditions. Among the screened solvents, such as THF, Et2O, CH2Cl2, toluene, DMSO, acetonitrile, 1,4-dioxane, 1,2-dimethoxyethane and methanol, three solvents are recommended which are THF, Et2O and acetonitrile, whereas no product is observed in methanol. In the presence of the ligand of choice, Pd2(dba)3, PdCl2, [(cinnamyl)PdCl]2, Pd(OAc)2 and [(η3-C3H5)PdCl]2 have been examined. Although all catalysts work very well, affording the C4-allylated azlactones in excellent yields, Pd(OAc)2 leads to completely racemic product, whereas other catalysts provide certain level of enantioselectivity [157]. O O N

Cl

O O

O Et3N

Pd2(dba)3 CHCl3

THF, 0 C

°

O

O

dppe =

THF, dppe

N

O

N

O

O

P

P

SCHEME 1.39  C4-Allylation of 4-benzyl-2-phenyloxazol-5(4H)-one with allyl chloroformate.

56

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O

O

P

N

N

P

N

O

15

14

O

P

N

P

16

17

PCy2 Cy2P Fe

PPh2

Ph2P

PPh2 Me2N

Fe

PCy2

Ph

Ph2P Fe

Me2N Ph

18

O

19

N H

N H

Ph2P PPh2 22

20

O

21

O

O

PPh2

NH HN

PPh2

N

N

23

NMe2 PPh2

24

O

O

N N

N

25

FIGURE 1.5  Chiral ligands used in asymmetric C4-allylation of azlactones.

Recently, an organometallic compound catalyzed reaction of azlactone occurring at the C4 position in the presence of a chiral ligand has been reported, affording chiral amides with very high yield and enantioselectivity. One of such reactions is illustrated by the reaction between (E)-7,8-dimethyl-4-(prop-1-en-1-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin2-one and 2-phenyloxazol-5(4H)-one in the presence of 5 mol% of Pd2dba3·CHCl3 in 1,2-dichloroethane, affording N-((3R,4S)-7,8-dimethyl2-oxo-4-((E)-prop-1-en-1-yl)-1,2,3,4-tetrahydroquinolin-3-yl)benzamide in nearly quantitative yield and 88% ee (Scheme 1.40) [158]. For this reaction, N-((1S,2R)-2-((4-bromophenyl)thio)-1,2-diphenylethyl)-N(cyclohexylmethyl)-2,6-di(naphthalen-2-yl)-3,5-dihydro-4H-dinaphtho[2,1c:1’,2’-e]phosphepin-4-amine has been applied as chiral ligand in 12 mol% amount, among several other chiral ligands. It is assumed that the presence of a vinyl group at position 4 of 1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one is very critical, as it allows the formation of temporary allylic cation during the catalytic decarboxylation. The resulting amide is a strong base that deprotonates one hydrogen at the C4-position, making the C4 position nucleophilic that then attacks the allylic cation which is stabilized by the catalyst, affording the intermediate of (R)-4-((S,E)-1-(2-amino-3,4-dimethylphenyl) but-2-en-1-yl)-2-phenyloxazol-5(4H)-one while releasing the catalyst for the

Azlactones 57

subsequent reactions. Then, intramolecular aminolysis opens the azlactone ring and yields the final product as demonstrated in Scheme 1.41. O +

O N H

O

N

O

Pd2dba3 CHCl3 (5 mol%) Ligand (12 mol%) ClCH2CH2Cl, 30 °C, 10 hrs.

H N N H

Ph

O

O

> 99% yield 88% ee Ph Ligand =

Ph

P N

Br

S

SCHEME 1.40  Catalyzed C4-allylation of 2-phenyloxazol-5(4H)-one. Ph

CO2

N

O

[PdII]

O N H

[PdII] O

Pd2dba3/Ligand

H

NH

O

N

O

N H

O

H

Ph Pd catalyst

H N

Ph

N

N

O N H

O

O

N H2

O

O

NH2 O

SCHEME 1.41  A plausible mechanism for the C4-allylation of 2-phenyloxazol-5(4H)-one.

1.4.1.2.3 Benzylation of Azlactones Similar to the allylic group, a benzylic group can also be introduced at the nucleophilic C4 of azlactone. Thus, asymmetric benzylation of prochiral azlactone enables a catalytic introduction of the benzyl group, providing a tool for the synthesis of α,α-disubstituted amino acids, such

58

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

as 2-amino-2-alkyl-3-phenylpropanoic acid. However, the C4-benzylation has been found to be more complicated than the corresponding allylation, as a good leaving group on the benzylic electrophile is necessary in order to form the benzylic ion. In this practice, [(η3-C3H5)PdCp] is used as a palladium catalyst, and a group of chiral bis(diphenylphosphinobenzoyl) diamine (dppba) ligands are tested to induce high levels of enantioselectivity, of which N,N’-((1S,2S)-1,2-diphenylethane-1,2-diyl) bis(2-(diphenylphosphaneyl)benzamide) and its enantiomer are the choices of ligands. Two types of benzylic electrophiles have been explored, arylmethyl diphenylphosphates and arylmethyl methyl carbonates. Careful examination of the influence of leaving group indicates that two different mechanisms are involved in such benzylation. For example, when carbonate is the leaving group and the corresponding aryl group (e.g., naphthalene or five-membered heterocycle) for which the loss of aromaticity is less energetically unfavored, a mechanism of π-coordination of the aryl ring to Pd(0) followed by ionization to directly form the η3-benzyl structure may be involved. However, when the aryl ring is a simple substituted phenyl group, direct oxidative addition of the benzyl-oxygen bond to Pd(0) occurs first with inversion, leading to an η1-benzyl structure, which then relaxes to the η3-complex prior to alkylation. In addition, the arylmethyl methyl carbonates do not require an additional base as the carbonate itself may be basic enough to promote the reaction, whereas arylmethyl phosphates need a stoichiometric amount of base, possibly because the phosphate is neutral under this condition and not basic enough to promote the reaction. The need for the presence of base has been clearly demonstrated for the poor yield when benzyl diethylphosphate is applied as the electrophile, where only 6%, 11%, 24% and 34% of products have been obtained when 1.2 eq. of KHCO3, 1.2 eq. of CsHCO3, 0.6 eq. of K2CO3 and 0.6 eq. of Na2CO3 are used, respectively. When 1.2 eq. of triethylamine or diisopropylethylamine (DIPEA) is used, the yield has been increased to 38 and 36% correspondingly. Particularly, for arylmethyl phosphate, simple benzyl or p-methylbenzyl diphenylphosphate only lead to benzylated azlactones of poor yields, whereas the benzyl group of a strong electrondonating group generally affords the product of good yield [159]. Nevertheless, excellent enantioselectivity has been reached in the presence of ligand N,N’-((1S,2S)-1,2-diphenylethane-1,2-diyl)bis(2(diphenylphosphaneyl)benzamide) or its enantiomer. A general diagram for this benzylation is illustrated in Scheme 1.42.

Azlactones 59

O

O

R

O

+ Ar

N

OCO2Me

[(

3-C

R

3H5)PdCp],

(S,S)-L t-BuOH, CH2Cl2, 25°C

O Ar

Ph

N Ph

O R

O

O

+

Ar

O [( 3-C3H5)PdCp], (R,R)-L P OEt O Cs 2CO3, t-BuOH, CH2Cl2, 25°C OEt

Ph

Ph2P PPh2

R O Ar

O

N Ph O

O N

+

Ar

O [( 3-C3H5)PdCp], (R,R)-L P OPh Et3N, t-BuOH, dioxane, 50°C O OPh

Ph

O NH HN

O

N

R

(S,S)-L =

(R,R)-L =

R O Ar

N Ph

O

O NH HN Ph2P PPh2

SCHEME 1.42  Catalytic C4-benzylation of azlactone with benzyl esters.

1.4.1.2.4 Arylation of Azlactones Two approaches have been developed for the synthesis of α-aryl-α-alkyl amino acid derivatives from azlactones. The first approach utilizes a palladium catalyst and adamantyl phosphine ligand to couple aryl bromide with azlactones prepared from alanine, valine, phenylalanine, phenyl glycine, and leucine in the presence of a base. When Pd(OAc)2 is applied as the catalyst, the yield of the coupled azlactone is generally 10% higher than that when Pd(dba)2 is used as the catalyst. Such difference in reactivity is even more evident for azlactones prepared from phenylalanine and phenylglycine. Mechanistic study of this reaction indicates that a stable complex containing a ligand formed by the reaction of dibenzylidene acetone (dba) with azlactone creates a new inhibiting effect of dba, which is absent when Pd(OAc)2 is used [160]. Another approach might take the advantage of the nucleophilic C4 of azlactone in reaction with highly electron-deficient aromatic compounds, such as perfluorobenzene, perfluorotoluene, etc. In the presence of a base, the azlactone is converted into its enolate form, which then couples with the highly fluorinated (hetero)arenes involving an addition-elimination mechanism to afford C4-arylated azlactones. In this reaction, an excess amount of tetramethylguanidine (TMG) or DIPEA is applied as the base. The resulting products have been further converted into N-benzoyl arylglycinates, N-benzoyl arylglycines, and even arylmethylamines. The latter are assumed to form by means of a Schiff-base decarboxylation [161]. A special case of using electron-deficient aromatic compounds is exemplified in the reaction of quinoline 1-oxides or quinoline 2-oxides with

60

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

either 2-methyl-oxazolin-5(4H)-one or 2-phenyl-oxazolin-5(4H)-one in acetic anhydride under heating (90°C). In this case, the reaction of quinoline 1-oxide with 2-methylazlactone gives 49% of 2-methyl-4-(quinolin-2-yl) oxazol-5(4H)-one while the same reaction with 2-phenylazlactone yields 86% of 2-phenyl-4-(quinolin-2-yl)oxazol-5(4H)-one, as shown in Scheme 1.43. In contrast, the reactions of quinoline 2-oxide with these two azlactones give the respective products of similar yields, i.e., 64% of 4-(isoquinolin1-yl)-2-methyloxazol-5(4H)-one (solid of yellow prisms) and 77% of 4-(isoquinolin-1-yl)-2-phenyloxazol-5(4H)-one (solid of orange needles), respectively (Scheme 1.43) [162]. Substituted quinoline 1-oxides all react with 2-methylazlactone or 2-phenylazlactone as expected, and the structures of the corresponding azlactones have been further elucidated by means of oxidation with H2O2, hydrolysis with HCl refluxing, and aminolysis with aniline, in addition to normal IR and NMR characterizations. However, the mechanism of this reaction has not been provided yet. O N

O +

O

O

Ac2O

R

N

+ O isoquinoline 2-oxide N

R

N

N quinoline 1-oxide

O

R = Me, 49% R = Ph, 86%

O

O N

N R

Ac2O O

N O

R R = Me, 64% R = Ph, 77%

SCHEME 1.43  C4-Arylation of azlactone with quinoline 1-oxide and isoquinoline 2-oxide.

In contrast to the case of pyridine oxide or quinoline oxides, where the arylation of azlactone occurs at the position ortho to nitrogen atom inside the electron-deficient aromatic core, the reaction of azlactone with N-acylpyridinium ion (e.g., 1-acetylpyridin-1-ium) occurs at the paraposition of the nitrogen atom. This is illustrated by the reaction between 4-methyloxazol-5(4H)-one and 1-acetylpyridin-1-ium that gives 2-(1-acetyl1,4-dihydropyridin-4-yl)-4-methyloxazol-5(2H)-one. It should be pointed out that the position of the double bond within the original azlactone rearranges to give pseudoxazolone, and this heterocyclic ring can withstand the

Azlactones 61

hydrogenation of the 1,4-dihydropyridine ring, as shown in Scheme 1.44 [163]. It is unspecified whether the change of azlactone core really occurs or not. O N

O + N

N

O

O

H2, Rh/Al2O3 EtOAc

N

O

O

O

N COCH3

N COCH3

SCHEME 1.44  The reaction between 4-methyloxazol-5(4H)-one and 1-acetylpyridin1-ium, affording pseudoxazolone.

1.4.1.2.5 Carboxylation of Azlactones, the Steglich Rearrangement This transformation is similar to the allyl (2,4-disubstituted-oxazol-5-yl) carbonates based C4-allylation of azlactones, but occurs in the presence of an organic base, instead of a palladium catalyst. It was initially reported by Steglich in 1970, for the general conversion of 2,4-disubstituted-oxazol-5-yl esters into either 2-acyl-2,4-disubstituted oxazol-5(2H)-ones or 4-acyl2,4-disubstituted oxazol-5(4H)-ones in the presence of pyridine or substituted pyridine (e.g., N,N-dimethylpyridin-4-amine, DMAP), as shown in Scheme 1.45 [164]. Similarly, this transformation can be easily extended to make C4-carboxylated azlactones from 2,4-disubstituted-oxazol-5-yl carbonates. O R2

O O R2

R’

R3 +

N

N

R’

R1

O R1

O

N

R2 N

O R1

O

N COR3

R3 O

R2 N

COR3 O O R1

SCHEME 1.45  Pyridine facilitated rearrangement of 2,4-disubstituted oxazol-5-yl esters to 4-acyl azlactones.

Extension of this inceptive approach by the formation of 2,4-disubstitutedoxazol-5-yl carbonates and subsequent organic base promoted rearrangement

62

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

provides a general method for the preparation of 2,4-disubstituted 5-oxo-4,5dihydrooxazole-4-carboxylates, particularly in the presence of chiral organic bases. For example, isothioureas, including (S)-2-phenyl-3,4-dihydro-2Hbenzo[4,5]thiazolo[3,2-a]pyrimidine (26, Figure 1.6), (2S,3R)-3-isopropyl2-phenyl-3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimidine (27, Figure 1.6) and (R)-2-isopropyl-3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-a] pyrimidine (28, Figure 1.6), all effectively catalyze the conversion of 4-benzyl2-(4-methoxyphenyl)oxazol-5-yl phenyl carbonate into phenyl (R)-4benzyl-2-(4-methoxyphenyl)-5-oxo-4,5-dihydrooxazole-4-carboxylate in excellent yields (> 92%) and reasonably good enantioselectivity (> 80% ee) [165]. It should be pointed out that catalyst 28 is less effective than 26 and 27 in this transformation, and quite possibly the configuration of 4-benzyl2-(4-methoxyphenyl)-5-oxo-4,5-dihydrooxazole-4-carboxylate is S in the presence of catalyst 28. In addition to these three chiral isothioureas, a group of ADMAP-N-oxides featuring an α-amino acid as the chiral source have been developed for the asymmetric Steglich rearrangement [166]. These ADMAP-N-oxides include (S)-3-(2-((2,6-diethylphenyl)carbamoyl)pyrrolidin-1-yl)-4-(pyrrolidin1-yl)pyridine 1-oxide, (S)-3-(2-(phenylcarbamoyl)pyrrolidin-1-yl)-4(pyrrolidin-1-yl)pyridine 1-oxide, (S)-3-(2-((3,5-bis(trifluoromethyl)phenyl) carbamoyl)pyrrolidin-1-yl)-4-(pyrrolidin-1-yl)pyridine 1-oxide, (S)-3-(2(methyl(phenyl)carbamoyl)pyrrolidin-1-yl)-4-(pyrrolidin-1-yl)pyridine 1-oxide, (S)-3-(2-((2,6-diisopropylphenyl)carbamoyl)pyrrolidin-1-yl)-4(dimethylamino)pyridine 1-oxide, and (S)-3-(2-((2,6-diisopropylphenyl) carbamoyl)pyrrolidin-1-yl)-4-(pyrrolidin-1-yl)pyridine 1-oxide.Among these ADMAP-N-oxides, (S)-3-(2-((2,6-diisopropylphenyl)carbamoyl)-pyrrolidin-1-yl)-4-(pyrrolidin-1-yl)pyridine 1-oxide (29, Figure 1.6) is especially effective in conversion of a series of benzyl (4-X-2-(4-methoxyphenyl) oxazol-5-yl) carbonates (where X = Me, Et, Bn, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, allyl, CH2CH2SMe, Ph, 4-BnOC6H4CH2, 4-BnO2COC6H4CH2) into the corresponding benzyl (R)-4-X-2-(4-methoxyphenyl)-5-oxo4,5-dihydrooxazole-4-carboxylates in high yields (up to 96%) and excellent enantioselectivities (up to 96% ee). Interestingly, a certain level of crossover products have been achieved when two of such carbonates, e.g., benzyl (4-benzyl-2-(4-methoxyphenyl)oxazol-5-yl) carbonate and 2-(4-methoxyphenyl)-4-methyloxazol-5-yl(1,1,1-trichloro-2-methylpropan2-yl) carbonate, are treated with a catalytic amount of 29, where the crossover products, i.e., 1,1,1-trichloro-2-methylpropan-2-yl (R)-4-benzyl2-(4-methoxyphenyl)-5-oxo-4,5-dihydrooxazole-4-carboxylate and benzyl

Azlactones 63

(R)-2-(4-methoxyphenyl)-4-methyl-5-oxo-4,5-dihydrooxazole-4-carboxylate have been obtained in 16 and 14% yields, respectively, in addition to the expected products [166]. In addition, a group of chiral 4-N,N-dimethylaminopyridine (DMAP) derivatives have been developed and applied to the Steglich rearrangement, yielding chiral azlactones of high enantioselectivity. These chiral DMAP derivatives include: (a) a sandwiched cobalt metallocene containing 1-(4-((2R,5R)-2,5-dimethylpyrrolidin-1-yl)pyridin-3-yl)cyclopenta-2,4-dien1-ide and 1,2,3,4-tetraphenylcyclobuta-1,3-diene components (30, Figure 1.6) [167]; (b) an iron metallocene containing 4-(pyrrolidin-1-yl)-7H-cyclopenta[b] pyridin-7-ide and 1,2,3,4,5-pentamethylcyclopenta-2,4-dien-1-ide components (31, Figure 1.6) [168]; (c) an iron metallocene containing 4-(dimethylamino)7H-cyclopenta[b]pyridin-7-ide and 1,2,3,4,5-pentamethylcyclopenta-2,4-dien1-ide components (32, Figure 1.6) [169]; and (d) (S)-1-(4-(dimethylamino) pyridin-3-yl)-2,2,2-triphenylethyl acetate (33, Figure 1.6) [170, 171]. In addition, a chiral phosphorus compound, i.e., (1R,3S,3aS,6aR)-1-(3,5-di-tertbutylphenyl)-3,6,6-trimethyloctahydrocyclopenta[b]phosphole (34, Figure 1.6), is also suitable for such chiral transformation for the purpose of kinetic resolution [171]. Moreover, the Steglich rearrangement has been performed in a tandem manner, to make azlactone C4-carboxylates, in the presence of N-heterocyclic carbenes. For example, treatment of N-p-anisoyl phenylalanine with DCC in THF followed by filtration of byproduct dicyclohexylurea, and sequential addition of 5 mol% 2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4] triazol-2-ium tetrafluoroborate (35, Figure 1.6), 1.5 equivalents of Et3N and 1.3 equivalents of phenyl chloroformate directly to the filtrate afford good yield (71%) of phenyl (R)-4-benzyl-2-(4-methoxyphenyl)-5-oxo-4,5dihydrooxazole-4-carboxylate after chromatography (Scheme 1.46). In this case, Et3N deprotonates the freshly formed azlactone and the resulting enolate is immediately trapped by phenyl chloroformate to yield 4-benzyl2-(4-methoxyphenyl)oxazol-5-yl phenyl carbonate. Meanwhile, a little excess of Et3N also converts 2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4] triazol-2-ium tetrafluoroborate into its carbene form, which then catalyzes the O- to C-carboxyl transfer, yielding the expected phenyl (R)-4-benzyl-2(4-methoxyphenyl)-5-oxo-4,5-dihydrooxazole-4-carboxylate. Furthermore, this tandem process has been modified to a one-pot fashion by the addition of 3.0 equivalents of phenyl chloroformate to a THF solution containing N-p-anisoyl norleucine, 3.5 equivalents of Et3N, and 5 mol% of 2-phenyl-6,7dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate, affording

64

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

75% of (±)-phenyl 4-butyl-2-(4-methoxyphenyl)-5-oxo-4,5-dihydrooxazole4-carboxylate within 10 minutes after chromatography (Scheme 1.46). In this one-pot protocol, excess of phenyl chloroformate also functions as a dehydration agent to convert the N-acyl amino acid into the corresponding azlactone [172].

N Ph

N Ph

N

N

S 26

N

S 28

iPr N N H

N

iPr

N O

Fe N

Ph 30

H CPh3 H OAc Me 33

N

Ph Co Ph

Me2N N

N

N

29

32

N

S 27

O

N

N

Fe

Ph 31 Me Me H

t-Bu N

P N t-Bu 34

N BF4 35

FIGURE 1.6  Organic bases used in the Steglich rearrangement.

1.4.1.2.6 Acylation of Azlactones This transformation is very similar to the C4-carboxylation of azlactone. For the purpose of introducing an acyl group at C4 of azlactone, the azlactone is first treated with base to yield the corresponding enolate which is then captured with carboxylic acid anhydride instead of phenyl chloroformate to yield 2,4-disubstituted oxazol-5-yl ester. Further treatment of the ester results in the O- to C-acyl transfer, also known as the Steglich rearrangement, to yield the C4-acyl azlactone. When acetic anhydride is applied under this condition, C4-acetyl azlactone will be obtained. Decomposition of the resulting C4-acetyl azlactone and subsequent β-decarboxylation afford α-acetamido methylketone. This whole process is known as the Dakin-West reaction

Azlactones 65

as shown in Scheme 1.26. The first enantioselective Dakin-West reaction, yielding α-acetamido methylketones in good yields with up to 58% ee, has recently been reported, which uses methylimidazole-containing oligopeptides (e.g., methyl Nα-((1S,3R,5R,7S)-3-((S)-2-((tert-butoxycarbonyl)-amino)-3cyclohexylpropanamido)adamantane-1-carbonyl)-Nπ-methyl-L-histidinate) to catalyze both the acetylation of azlactone intermediate and the terminal enantioselective decarboxylative protonation, as shown in Scheme 1.47 [173].

O Ar

N H

OH

DCC THF

O Ar

O

N Ph N BF4 (5 mol%) N

O

N

O

1.5 eq. Et3N 1.3 eq. PhOCOCl THF, r.t.

O

OPh

O Ar

N

Ar = O

N

N Ph N Ar

N

O

O O

O

N Ph N BF4 (5 mol%) N

O

O N H

O

OH

3.5 eq. Et3N 3.0 eq. PhOCOCl THF, r.t.

O

OPh N

O

O O

SCHEME 1.46  2-Phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate catalyzed C4-carboxylation of azlactones.

It should be pointed out that on the one hand, azlactone is a unique type of anhydride that naturally can be applied as the acylating agent, whereas on the other hand the azlactone can be treated as a nucleophile once being treated with base. This concept has been nicely elaborated by the diastereoselective dimerization of azlactones using trichloroacetate salt as a base in acetonitrile, which provides straightforward access to azlactone dimer in good to excellent yield and good diastereoselectivity (up to > 19:1 dr), as illustrated by the dimerization of 4-methyl-2-phenyloxazol-5(4H)-one to yield N-((3S,5S)-1benzoyl-3,5-dimethyl-2,4-dioxopyrrolidin-3-yl)benzamide (Scheme 1.48) [174].

66

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O

H N

OH

O

Ph

1) 1.7 eq. DCC, 1.5 eq. Ac2O 10 mol% catalyst Toluene, r.t. 1-3 days 2) 1.3 eq. AcOH r.t., 2-4 days

O

Ph

O

H N HN

O

H N

OMe

O O

cat. =

N

N

NH

O

O

SCHEME 1.47  The enantioselective Dakin-West reaction.

O N

O Ph

O

Cl3CCO2

O

Cl3CCO2H

O

N

O

O

O

Ph

N

O

Ph

Ph

N

O

N Ph

O

O Ph

N

N

O O

Ph

Cl3CCO2H

Cl3CCO2

H N

Ph

O

O N

Ph

O O

SCHEME 1.48  Diastereoselective dimerization of 4-methyl-2-phenyloxazol-5(4H)-one.

1.4.1.2.7 Alkynylation of Azlactones It is generally known that triple bonds can be easily converted into a variety of other functional groups, so that C4-alkynylated azlactones would be transformed into a variety of derivatives based on the modification of the newly introduced triple bond, in addition to the known transformations of the azlactone moiety. So far, there is only one report for the introduction of a C-C triple bond to the C4 position of azlactone. In this report, two types of stable and easy to handle electrophilic alkyne sources have

Azlactones 67

been used, which are alkynyl(phenyl)iodonium salts, (e.g., hex-1-yn-1yl(phenyl)iodonium tosylate (36), phenyl(phenylethynyl)iodonium tosylate (37) and, phenyl((trimethylsilyl)ethynyl)iodonium) tosylate (38)) and alkynyl-1,2-benziodoxol-3-(1H)-ones (e.g., 1-(hex-1-yn-1-yl)-1λ3-benzo[d] [1,2]iodaoxol-3(1H)-one (39), 1-(phenylethynyl)-1λ3-benzo[d][1,2] iodaoxol-3(1H)-one (40), and 1-((trimethylsilyl)ethynyl)-1λ3-benzo[d][1,2] iodaoxol-3(1H)-one(41)) (Figure 1.7) [175].

TsO

TsO

I+

I+ 36

I+ 38

37 O

O

O

O I 39

Si

TsO

O I

Si

40

O I 41

FIGURE 1.7  The alkynes used for the alkynylation of azlactones.

While it is assumed that this reaction involves a vinylidene carbene intermediate, the individual alkyne synthon has demonstrated different reaction behaviors, by means of an [1,2]-migration to the desired C4-alkyne azlactone or an [1,5]-insertion to the tertiary hydrogen of the leucine side chain to give the spirocyclic compounds, as shown in Scheme 1.49. Besides the azlactone arising from leucine, azlactones derived from aliphatic α-amino acids such as valine, alanine, norvaline, and norleucine all react smoothly with phenyl((trimethylsilyl)ethynyl)iodonium) tosylate to give the desired tetra-substituted azlactones in very high yields (90%-97%). In comparison, azlactones of steric hindrance such as the ones derived from tert-leucine and α-phenylglycine afford the corresponding azlactones in yields of 60% and 75%, respectively. Heteroatom-containing azlactones arising from methionine and lysine also work under this condition, whereas cysteine and serine based azlactones are not synthetically accessible from their protected amino acid precursors [175].

68

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

2 2 ,

6L 1 2

3K

2

',3($&+&OUW

1 2

3K

706 2

>@PLJUDWLRQ

1

2

2

3K

2 3K 1 2

3K

2

2 ,

',3($&+&OUW

1 2

3K

3K 2

3K

>@PLJUDWLRQ

1

1 2

3K

2



',3($&+&OUW

1 2

3K

Q%X 2

>@LQVHUWLRQ

3K

2 

5

2

3K

2

',3($&+&OUW 5 3K6L0H

7V2

1 2

3K

Q%X

,

1 2

2

2



1 3K

2

2



5

,

1

3K

Q%X  2

1

3K 2

1

>@LQVHUWLRQ

2 ,

7V2

3K

2

3K

2 Q%X

2

',3($&+&OUW

1 3K

2

5 2

>@PLJUDWLRQ

3K

1 2

2

Q%X 1D20H  Q%X LQVLWX 2 HVWHULILFDWLRQ %]+1 &20H %]+1 &20H 



SCHEME 1.49  C4-Alkynylation of 4-isobutyl-2-phenyloxazol-5(4H)-one with different alkyne sources.

1.4.1.2.8 Aldol Condensation of Azlactones Due to the nucleophilic nature of the C4 position, azlactone readily undergoes Aldol reaction with aldehydes to form 4-(1-hydroxyalkyl)-oxazol-5(4H)ones, like the one between ketone and aldehyde. In addition, the resulting 4-(1-hydroxyalkyl)-oxazol-5(4H)-ones arising from hippuric acid based azlactones can further dehydrate to afford 4-alkylideneoxazol-5(4H)-ones containing an α,β-unsaturated double bond. Recently, a fast one-pot protocol for the direct vinylation of azlactones for the purpose of making α-vinyl amino acids has been reported,

Azlactones 69

as α-vinyl amino acids have demonstrated irreversible inhibitory effects on a variety of pyridoxal phosphate-dependent enzymes and amino acid decarboxylases. This protocol involves the Aldol reaction of azlactone with 2-(phenylselenenyl)acetaldehyde and subsequent dehydroxyselenation, in which the in-situ generated 4-benzyl-4-(1-hydroxy-2-(phenylselanyl)ethyl)2-phenyloxazol-5(4H)-one is trapped with methanesulfonyl chloride as the corresponding methanesulfonate and further treated with triethylamine in the presence of tetrabutylammonium iodide. Among the tested solvents (CH2Cl2, 1,2-dichloroethane, acetonitrile, THF, and toluene), THF, and toluene work the best. In order to make the C4-vinylation enantioselective, a variety of chiral bases have been screened. The result indicates that the presence of Sharpless ligand 1,4-bis((1S)-(5-ethylquinuclidin-2-yl)(6-methoxyquinolin4-yl)methoxy)phthalazine [i.e., (DHQD)2PHAL] as the catalyst at the Aldol reaction stage allows the synthesis of enantiomerically enriched C4-vinyl azlactones (up to 86% ee), as shown in Scheme 1.50 [176]. Furthermore, the scaling up of the optimized synthetic protocol does not affect the overall chemical yields and respective enantioselectivity. Also, the vinyl group can be further extended by means of Heck reaction.

Bn N Ph

O

O Se O Et3N, toluene PhSe ° -10 C Ph

OH

Ph

MeSO2Cl Et3N

O N

Ph

N

O O O

PhSe

Ph

O N

(DHQD)2PHAL (0.1 eq.)

O Ph

N

N Ph

Ph

N

N N O H

H

(DHQD)2PHAL =

O O S O

O

O H

H O N

SCHEME 1.50  C4-Vinylation of 4-benzyl-2-phenyloxazol-5(4H)-one.

It should be pointed out that the reaction of 2-phenyloxazol-5(4H)-one with 1-phenylprop-2-yn-1-one in the presence of acetic anhydride yields N-(2oxo-6-phenyl-2H-pyran-3-yl)benzamide, instead of the unsaturated azlactone or Aldol condensation product. Under this condition, 2-phenyloxazol5(4H)-one does not react with other electrophiles such as ethyl propionate, dimethyl but-2-ynedioate and ethyl 3-phenylpropanoate [177].

70

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

1.4.1.2.9 Mannich Reaction The Mannich reaction is an alternative version of the Aldol reaction that takes place under mildly acidic conditions. There are several variants of the Mannich reactions, but all of them involve the reaction of a nucleophilic ketone with a primary or secondary ammonium ion (RN+H3 or R2N+H2) and an aldehyde, usually formaldehyde (CH2O). The Mannich reaction proceeds via an iminium ion (also known as aldimine in this case) formed from the reaction between an amine and aldehyde (RN+H=CH2 or R2N+=CH2), which is electrophilic and reacts with the enol form of the ketone to give a β-aminoketone. Similar to the Aldol reaction, the great feature of the Mannich reaction is to construct two consecutive chiral centers in the final products. Recently, the Mannich reaction has been often performed in the presence of a chiral catalyst to enhance both enantioselectivity and diastereoselectivity. The first type of Mannich reaction involving azlactone is the addition of azlactone in enol (or enolate) form to aldimine arising from 4-methylsulfonamide. For example, in the presence of only 3 mol% of commercially available (S)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate, [(S)-TRIP], the reaction between 4-methyl-2-phenyloxazol5(4H)-one and (E)-N-benzylidenemethanesulfonamide in toluene affords the desired Mannich adduct in good yield with excellent enantio- and diastereoselectivity (Scheme 1.51) [178]. It must be emphasized that acidic hydrolysis of the resulting azlactones leads to protected 1,2-anti-diamino acid derivatives in moderate to good yields with nearly perfect control of both diastereo- and enantioselectivity (up to >19:1 dr and >99:1 er). In comparison, the same reaction between 4-methyl-2-phenyloxazol-5(4H)-one and (E)-N-benzylidenemethanesulfonamide catalyzed with 3 mol% of (R)-xylyl-SDP(AuOBz)2 affords N-((R)-((R)-4-methyl-5-oxo-2-phenyl-4,5dihydrooxazol-4-yl)(phenyl)methyl)methanesulfonamide with 88% ee at room temperature. Optimization of this reaction condition reveals that the use of fluorobenzene as solvent is essential to obtain the Mannich adducts with high diastereo- and enantioselectivity. In addition, a bulkier group on the aldimine moiety also enables the highest level of both enantio- and diastereocontrol [179].

Azlactones 71

O

O S

N Ph

O NHSO2Me (S)-TRIP, 3 mol% O toluene, MS 4Å R N Ph r.t., 24 hours R (R = H, 2-Cl, 3-Cl, 4-Cl, 4-Br, 4-F, 4-CF3)

N

O + O

i-Pr i-Pr

(S)-TRIP = O

i-Pr

O P i-Pr HO O i-Pr i-Pr

SCHEME 1.51  The catalyzed Mannich 4-methyl-2-phenyloxazol-5(4H)-one.

reaction

at

the

C4

position

of

In addition to the (E)-N-benzylidenemethanesulfonamides, (E)-Nalkylidenesulfonamides are also suitable for the Mannich reaction, albeit they are not commonly applied. For example, the reaction between (E)-N-(3-phenylpropylidene)toluenesulfonamide and 4-butyl2-(naphthalen-2-yl)oxazol-5(4H)-one in THF at –40°C in the presence of 10 mol% of a newly designed bis(betaine)s, such as 3-((2R)-2((S)-hydroxy(6-methoxyquinolin-4-yl)methyl)-5-vinylquinuclidin1-ium-1-yl)-3’-((2S,4R,5S)-2-((S)-hydroxy(6-methoxyquinolin-4-yl) methyl)-5-vinylquinuclidin-1-ium-1-yl)-[1,1’-binaphthalene]-2,2’-bis(olate), produces 91% of N-((S)-1-((S)-4-butyl-2-(naphthalen-2-yl)-5-oxo-4,5dihydrooxazol-4-yl)-3-phenylpropyl)-4-methylbenzenesulfonamide, with 97% of enantioselectivity and a diastereoselectivity of 2.6:1. (Scheme 1.52) [180]. The addition of 10 mol% TFA principally converts the bis(betaine) into a mono-anionic catalyst, which downgrades both chemical yield and stereoselectivity. Very sensitively, the presence of 15 mol% of TFA completely deteriorates the expected reaction with no product obtained. This reaction has been extended to the combination of different (E)-Nalkylidene 4-isopropylbenzenesulfonamide and 4-alkyl-2-(naphthalen2-yl)oxazol-5(4H)-one under the same condition, all affording the expected product in very good yield and excellent enantioselectivity.

72

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O O S NH O

O O S O

N

O +

10 mol% cat. toluene, -40 °C 24 hrs.

N

O N

O

OH

HO

cat. = N

N N

O O

N

O

SCHEME 1.52  Enantioselective Mannich reaction between 4-butyl-2-(naphthalen-2-yl) oxazol-5(4H)-one and (E)-4-methyl-N-(3-phenylpropylidene)benzenesulfonamide.

It should be pointed out that when aliphatic aldimines are applied to the Mannich reaction, the aliphatic aldimines potentially isomerize into their tautomers, known as enamides, particularly for the aldimines prepared from acetaldehyde [181]. When N-vinylbenzamide is applied to the Mannich reaction with 2,4-diphenyloxazol-5(4H)-one in the presence of 5 mol% (2r,11bR)-2,6-di(anthracen-9-yl)-4-hydroxydinaphtho[2,1d:1’,2’-f][1,3,2]dioxaphosphepine 4-oxide, 18% of N-((S)-1-((S)-5-oxo2,4-diphenyl-4,5-dihydrooxazol-4-yl)ethyl)benzamide is obtained with an anti/syn ratio of 57:43 and enantioselectivity of 67% ee. In comparison, when 2,4-diphenylthiazol-5(4H)-one is applied to the same reaction with N-vinylbenzamide, the corresponding N-((S)-1-((S)-5-oxo-2,4-diphenyl4,5-dihydrothiazol-4-yl)ethyl)benzamide is obtained in a yield of 75%, with an enhanced anti/syn ratio of 98/2 and enantioselectivity of 96% ee. Extension of the reaction of N-vinylbenzamide to other nine 4-substituted2-phenylthiazol-5(4H)-ones affords N-((S)-1-((S)-4-substituted-5-oxo-2phenyl-4,5-dihydrothiazol-4-yl)ethyl)benzamides, with very good anti/syn selectivity as well as enantioselectivity [181]. A unique Mannich reaction condition involving azlactone must be mentioned, which adopts a concept of group-assisted purification (GAP) as represented in the reaction between (3aR,7aR)-2-(((E)benzylidene)amino)-1,3-diisopropyloctahydroisophosphindole 2-oxide and 4-methyl-2-phenyloxazol-5(4H)-one in dichloromethane at room temperature, affording (4S)-4-((1R)-(((3aR,7aR)-1,3-diisopropyl-2-

Azlactones 73

oxidooctahydroisophosphindol-2-yl)amino)(phenyl)methyl)-4-methyl2-phenyloxazol-5(4H)-one in 92% yield and > 20:1 syn:anti selectivity as well as > 12:1 of diastereomeric ratio for the syn-enantiomer (Scheme 1.53) [142]. The isolated yield of the product after the GAP is 83%, and the diastereomeric ratio for the syn-enantiomer has been improved to > 20:1. In this new GAP protocol, with the auxiliary group of (3aR,7aR)-1,3-diisopropyloctahydroisophosphindole-2-oxide attached, the resulting Mannich reaction products often can be obtained simply by washing the crude mixture with common solvents without recourse to chromatography or recrystallization. The GAP protocol intends to avoid classical purification processes, such as chromatography and recrystallization, by purposely introducing well-functionalized groups in the starting materials, which would be further transferred into final products. As a result, the liquid products might be converted into solid with such an auxiliary group, enabling their purification by a simple wash with common solvents. This protocol has been extended to 32 examples by changing the component in either azlactone or aldimine reaction partner in the absence of any bases, additives, or catalysts to achieve good up to excellent chemical yields and diastereoselectivity. In addition, the auxiliary group can be readily removed and used again after recycling.

O

i-Pr P O i-Pr

N

+

N

O Ph

Ph

CH2Cl2

i-Pr O P

r.t., 18 hrs i-Pr

NH

Ph

O O N

Ph

SCHEME 1.53  Example of Mannich reaction adopting the concept of group-assisted purification.

A special three-component one-pot Mannich reaction involving azlactone applies substituted pyridine 1-oxide as an alternative aldimine, in the presence of p-toluenesulfonyl chloride as the activating agent, and a nucleophile such as water, alcohol, primary (or secondary) amine, or N,Odialkylhydroxylamine (Scheme 1.54) [182]. This protocol allows the direct amidoalkylation of pyridine N-oxides, without the use of a precious metal catalyst to achieve a formal enolate arylation reaction.

74

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O + N O

O

N

1.1 eq. TsCl Et3N EtOAc, r.t.

O

N N

Ph

H2O, ROH, RNH2 RR’NH, or MeNH(OMe)

O Ph

N X R

H N O

1M HCl - CO2 O

N

H N

Ph O

X = O, N or NH

SCHEME 1.54  An example of three-component one-pot Mannich reaction.

More examples of the Mannich-type reactions involving aldimines and azlactones are: (a) reaction between 4-benzyl-2-(3,4,5-trimethoxyphenyl) oxazol-5(4H)-one and (E)-2,6-dimethyl-N-(3-phenylpropylidene)benzenesulfonamide in the presence of (2S,7S)-2,7-diisopropyl-1,6-dimethyl-3,3,8,8tetraphenyl-1,4,6,9-tetraaza-5-phosphaspiro[4.4]nonan-5-ium pivalate to give 99% of addition product with 97% ee [183]; (b) reaction between 4-isopropyl-2-phenyloxazol-5(4H)-one and (E)-N-benzylidene-4-methylbenzenesulfonamide in the presence of (1S,2S,4S,5R)-2-((R)-(6-methoxyquinolin-4-yl)((trimethylsilyl)oxy)methyl)-5-vinyl-quinuclidine to give 92% of N-((S)-((R)-4-isopropyl-5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl) (phenyl)methyl)-4-methylbenzenesulfonamide with 15:1 of diastereoselectivity and 94% ee [184]; (c) reaction of 4-methyl-2-phenyloxazol-5(4H)-one with (E)-N-benzylidene-4-methylbenzenesulfonamide in the presence of (((6r,11bR)-2,6-di(anthracen-9-yl)-4-oxidodinaphtho[2,1-d:1’,2’-f ][1,3,2] dioxa-phosphepin-4-yl)oxy)silver to afford 94% of 4-methyl-N-((S)-((R)4-methyl-5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)(phenyl)methyl)benzenesulfonamide with 15:1 of diastereoselectivity and 92% ee [185]; and (d) chiral thiourea catalyzed Mannich reactions [186]. In addition, thio-azlactone also undergoes the Mannich-type reaction to afford the corresponding addition product, as represented in a highly stereoselective reaction of 2-(benzyloxy)4-arylthiazol-5(4H)-ones (where aryl = Ph, 4-ClC6H4, PhCH2) with N-Boc aldimines RCH:NBoc (R = Ph, 4-FC6H4, 3-MeOC6H4, 2-naphthyl, 3-furyl, etc.), in the presence of (R)-3’-phenyl-3-(2’,4’,6’-triisopropyl-[1,1’biphenyl]-4-yl)-2’-((trimethylammonio)methyl)-[1,1’-binaphthalen]-2-olate [187].

Azlactones 75

1.4.1.2.10 Michael Reaction The Michael addition or Michael reaction was initially reported in 1887 [188]. It is a conjugate addition (also known as 1,4-addition) of a relatively stabilized carbanion to an electron-deficient alkene. Carbanion adjacent to at least one strongly electron-withdrawing group such as carbonyl, nitro, sulfonyl, sulfoxide, etc., can be stabilized to a certain level as the negative charge can be delocalized to the electron-withdrawing group, thus it can be easily generated in the presence of base due to the relatively high acidity of the α-proton adjacent to the electron-withdrawing group. On the other hand, an alkene is usually considered as an electron-enriched species, however, the alkene moiety directly connecting to a strong double-bonded electronwithdrawing group would be considered electron-deficient. As a result, the carbanion can add to the alkene moiety in a 1,4-addition (or conjugate addition) fashion, leading to the Michael addition product, as shown in Scheme 1.55, with an α,β-unsaturated ketone to represent the electron-deficient alkene. This reaction is thermodynamically controlled, and can be promoted by a catalytic amount of base. EWG R1

1. cat. base EWG 2. acid work-up R1

EWG + R2

EWG R2

B

R1

EWG

BH

O

BH R2

EWG

EWG

R

EWG

R

R2 + R 1

R1

B

R

R1

R2 O R2 O 1,4-addition thermodynamically favored

O R 1,2-addition

R1, R2 = H, alkyl, aryl O

O

O

EWG = R,

OR ,

NR’R” ,

C

N ,

O N

O ,

O S

O

O R,

S

R , etc.

SCHEME 1.55  General mechanism of the Michael reaction.

As indicated in Scheme 1.55, two contiguous chiral centers could be generated in the Michael addition, in a manner similar to the previously mentioned Aldol reaction and Mannich reaction. Possibly, quaternary

76

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

chiral centers could be formed should the β,β-disubstituted α,β-unsaturated compounds are applied as the Michael acceptors. In order to enhance the enantioselectivity as well as diastereoselectivity, a variety of chiral additives have been developed for the Michael addition. However, due to the nature of the Michael reaction that is often performed under basic conditions, the conjugate addition to α,β-unsaturated aldehydes and ketones might be well suited for iminium ion activation catalysis, whereas the conjugate addition to α,β-unsaturated carboxylic acids and their derivatives is not applicable. Thus, the most common activation mechanism of the Michael addition to the α,β-unsaturated carboxylic acids and their derivatives relies upon the coordination of the carbonyl group to a Lewis acid (metal catalysis) or a hydrogen bond donor species. To enhance such coordination, several two-point binding templates with an additional coordinating site in the heterocyclic ring or extrapolar functional group tethered to the α,β-unsaturated carboxylic acids have been developed. As one of such practices, α’-hydroxy enones have been screened for the Brønsted base-catalyzed asymmetric conjugate addition with a range of soft carbon nucleophiles, affording tetrasubstituted carbon stereocenters in very high enantioselectivity. In this case, the substrates can engage as either donor or acceptor of hydrogen-bond (or both) during activation by a bifunctional catalyst. A particular Michael addition between azlactones arising from N-benzoyl phenylalanine (or leucine, valine, and 2-amino-2-phenylacetic acid) and 4-methyl-4-((trimethylsilyl)oxy)pent-1en-3-one has been performed in CH2Cl2 at room temperature, in the presence of 20 mol% chiral catalyst of 3-((3,5-bis(trifluoromethyl)phenyl)amino)4-(((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl) methyl)amino)cyclobut-3-ene-1,2-dione or (S)-3-((3,5-bis(trifluoromethyl) phenyl)amino)-4-((3,3-dimethyl-1-(piperidin-1-yl)butan-2-yl)amino) cyclobut-3-ene-1,2-dione, as shown in Scheme 1.56 [189]. The Michael addition products have been worked up with aqueous acetic acid to yield (R)-4-substituted-4-(4-hydroxy-4-methyl-3-oxopentyl)-2-phenyloxazol5(4H)-ones, in good yields and excellent enantioselectivity. A Michael addition of racemic 2-phenylazlactone to (E)-4-phenylbut-3en-2-one by means of cooperative activation with a bis-palladacycle catalyst, a Brønsted acid (acetic or benzoic acid) and a Brønsted base (NaOAc) has been found to yield (R)-4-benzyl-4-((R)-3-oxo-1-phenylbutyl)-2-phenyloxazol5(4H)-one in a good to excellent chemical yield, as well as excellent diastereoselectivity and very good enantioselectivity (Scheme 1.57) [143]. AgOTf is used to activate the bis-palladacycle catalyst by removing the otherwise inert chloro bridges in the bis-metallic complex [190]. For comparison, the

Azlactones 77

corresponding planar chiral ruthenocene bis-palladacycle has demonstrated comparable cooperative bimetallic asymmetric catalysis, whilst the distance between the two cyclopentadienyl rings in the ruthenocene (3.58 Å) is slightly greater than that in the ferrocene counterpart (3.29 Å) [191]. O O TMSO

O

R

F3C

N R

CF3

CF3 cat. =

O OH

20 mol% cat. O + O N CH2Cl2, r.t., 20 hrs. then H2O, AcOH Ph Ph (R = Ph, Bn, i-Pr, i-Bu)

O

O

N H

N H

O

O

N H

N H

N or F C 3 N

t-Bu

N

MeO

SCHEME 1.56  Catalyzed enantioselective Michael addition of azlactone to 4-methyl-4((trimethylsilyl)oxy)pent-1-en-3-one. O R1 O

O +

N

R3

R2

Ph Ph

N Pd

Cl

Pd Ph

O

N

R1

O R3

N

R1 = Me, Et, n-Pr, Bn

2

Fe

Ts N

R2

O

Ph

Ts N

[FBIP-Cl]2 =

2 mol% [FBIP-Cl]2 8 mol% AgOTf 10 mol% NaOAc Ac2O/AcOH (3:7) ° 24 hrs. 30 C,

2

Cl

R2 = Ph, Me, n-Pr, i-Pr, 4-MeO-C6H4, 4-HO-C6H4, 4-Cl-C6H4, 2-Cl-C6H4, 4-Br-C6H4, 4-NO2-C6H4, 3,4-(MeO)2-C6H3, 2-furyl R3 = Me, Et, Ph

Ph

SCHEME 1.57  A Michael addition of 2-phenylazlactone to α,β-unsaturated ketones under the condition of cooperative activation.

Kinetic studies of the reaction protocol indicate that the azlactone is in rapid equilibrium with the corresponding acyclic mixed anhydride by ring-opening with acetic acid. Due to the remarkable robustness of the bis-palladacycle

78

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

catalyst towards acetic anhydride, this equilibrium could be developed to a tandem formation of azlactone and Michael addition process starting from racemic N-benzoyl α-amino acids. Further extension of this procedure could lead to a cascade sequence containing the direct N-amino acid acylation, cyclization to racemic azlactones, enolization, and the asymmetric addition to enones from the unprotected α-amino acids [143]. Due to the steric difference between 2-phenylazlactones and 2-methylazlactones prepared from N-benzoyl and N-acetyl α-amino acids respectively, the Michael addition of 2-phenylazlactones leads to only the C4-addition products whereas one of 2-methylazlactones might generate both C4- and C2-addition products. However, conversion of the unprotected amino acids into the corresponding 4-phenylazlactones requires an excess amount of benzoic anhydride (in combination with benzoic acid), which may complicate the purification process. Thus, it is advantageous to generate 4-phenylazlactone in situ starting from N-benzoyl α-amino acids with an excess of acetic anhydride, as acetic acid can be easily removed by means of distillation. For this reason, a pentaphenylferrocene monopalladacycle catalyzed multicomponent reaction has recently been reported, which involves regioselective Michael addition of in situ generated azlactone to enones (Scheme 1.58) [192]. Under this reaction condition, it sounds that the increase in the amount of catalyst from 3 mol% to 5 mol% may increase the chemical yield, but does not affect the diastereoselectivity as well as enantioselectivity (both > 99%). Regarding the solvents (e.g., acetone, diglyme, THF, toluene, hexane, and CH2Cl2) used for this reaction, CH2Cl2 should be the solvent of choice in terms of both chemical yield and stereoselectivity. What product might be for the Michael addition of hippuric acid based azlactone with substituted (1E,4E)-penta-1,4-dien-3-ones? In this case, 2-phenyloxazol-5(4H)-one formed from hippuric acid has no additional substituent at C4, so that C4 potentially can participate in two consecutive Michael addition. On the other hand, the (1E,4E)-penta-1,4-dien-3-ones have two Michael acceptor components. Therefore, spirocyclic azlactones could be formed from the cascade Michael addition between 2-phenyloxazol-5(4H)-one and (1E,4E)-penta-1,4-dien-3-one. It has been shown that the azlactone can be generated in situ in the presence of acetic anhydride, thus one-pot fashion of the cascade Michael addition is plausible from hippuric acid in the presence of the bis-palladacycle bimetallic catalyst, in order to achieve a certain level of enantioselectivity. For example, in the presence of 2 mol% of [FBIP-Cl]2, 8 mol% of AgOTf, up to 2 equivalents of NaOAc, as well as AcOH/Ac2O (7:3) in acetonitrile, the reaction between hippuric acid and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one produces a predominant

Azlactones 79

trans-product of (6S,10S)-2,6,10-triphenyl-3-oxa-1-azaspiro[4.5]dec-1ene-4,8-dione and a minor product of (5s,6R,10S)-2,6,10-triphenyl-3-oxa1-azaspiro[4.5]dec-1-ene-4,8-dione, due to the steric hindrance between the two phenyl groups on the six-membered ring (Scheme 1.59) [193]. It is found that the chemical yield increases as the amount of NaOAc grows, with a slight enhancement of the enantioselectivity of the trans-product as well, albeit the increase of the yield of the cis-product is more prominent than the corresponding trans-product. Extension of this model reaction to different (1E,4E)-penta-1,4-dien-3-ones indicates that the higher electrophilicity of dienones most likely allows for a faster monometallic reaction pathway, in which the dienone is not further activated by a Pd(II) center. While the respective products have not demonstrated good diastereoselectivity, the enantioselectivity is very good to excellent.

R1

O

CO2H + NH2

R3

R2

O O

N

O R3

R1

°

R2

3 mol% cat. 12 mol% AgOTf 25 mol% NaOAc Ac2O, AcOH, CH2Cl2 50 C, 20 hrs.

Ph

Ph

Ts N

N Pd

Cl

cat. = Fe

Ph

2

Ph Ph

Ph

R1 = Me, Et, n-Pr, n-Bu, i-Bu, Bn, CH2CH2CO2Me, (1H-indol-3-yl)methyl R2 = Me, n-Pr, i-Pr, 2-furyl, Ph, 4-MeO-C6H4, 4-Cl-C6H4, 2-Cl-C6H4, 4-Br-C6H4, 4-NO2-C6H4, 3,4-(MeO)2-C6H3 R3 = Me, Et, i-Pr

Ph

SCHEME 1.58  The Michael addition of the in situ generated azlactone to enones.

H N O

O

O OH

+

2 mol% [FBIP-Cl]2 8 mol% AgOTf 0.1 - 2.0 eq. NaOAc AcOH/Ac2O (7:3) ° 18 hrs. 30 C,

O

Ph O

O

N O major

Ph + Ph O Ph

N O

Ph Ph

minor

SCHEME 1.59  The double Michael addition of 2-phenyloxazol-5(4H)-one with (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one.

In addition to the organometallics catalyzed Michael addition of azlactones towards α,β-unsaturated ketones as described above, some asymmetric

80

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

organic molecules have also been found effective in catalyzing the Michael addition of azlactones. For example, 7 mol% of (±)-camphorsulfonic acid ((1S,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid, 42 in Figure 1.8) successfully catalyzes the reaction of azlactone arising from leucine, alanine or phenylalanine with (E)-4-phenylbut-3-en-2-one, (E)-chalcone, (E)-1-(4-fluorophenyl)-3-phenylprop-2-en-1-one or (1E,4E)1,5-diphenylpenta-1,4-dien-3-one in toluene, affording the expected Michael adducts in good yields with complete control of both regioselectivity and diastereoselectivity (dr > 20:1) [194]. Also, a variety of sulfonamides have been screened for the Michael reaction between 4-benzyl-2-phenyloxazol5(4H)-one and cyclohex-2-en-1-one in CH2Cl2 at room temperature, affording (R)-4-benzyl-4-(4-oxocyclohexyl)-2-phenyloxazol-5(4H)-one with very good diastereoselectivity and a certain level of enantioselectivity. L-Proline and 4-hydroxyproline based sulfonyl carboxamides, particularly (S)-N-((4-dodecylphenyl)sulfonyl)pyrrolidine-2-carboxamide (43, Figure 1.8) are effective for this reaction [195]. Scrutinization of solvents clearly indicates that dioxane and (trifluoromethyl)benzene are superior to other tested solvents that include THF, DMF, DMSO, 2-methyl-tetrahydrofuran, toluene, diethyl ether, methanol, and acetonitrile, in terms of chemical yield. When (trifluoromethyl)benzene is selected as the solvent, the addition of 10 mol% of additive (e.g., Et3N, K2CO3, benzoic acid, NH4Cl, H2O, NaCl, KCl, NaBr, NaI) all lead to decreased chemical yield except for H2O. Several quinine-derived catalysts, particularly 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)-(6-methoxyquinolin-4-yl)((1S,2S,4S,5R)-5-vinylquinuclidin2-yl)-methyl)thiourea (44, Figure 1.8), stimulates the reaction of azlactones prepared from phenylalanine (or alanine, leucine, methionine, and (S)-2aminopent-4-enoic acid) with (E)-1,1,1-trichloro-4-phenylbut-3-en-2-one (or (E)-1,1,1-trichloro-4-arylbut-3-en-2-ones, (E)-1,1,1-trichloropent-3-en2-one) in mesitylene at 0°C, affording (S)-4-benzyl-2-phenyl-4-((R)-4,4,4trichloro-3-oxo-1-phenylbutyl)oxazol-5(4H)-one and other Michael adducts depending on the structures of azlactone substrates and trichloroacetyl alkenes, with excellent diastereoselectivity and enantioselectivity [144]. Exploration of the Michael addition of azlactone (e.g., 4-methyl-2-phenyloxazol-5(4H)-one and 4-benzyl-2-phenyloxazol-5(4H)-one) to N-protected dehydroalanine derivatives (e.g., methyl 2-(1,3-dioxoisoindolin-2-yl)acrylate and methyl 2-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)acrylate) that leads to potential (2S,4S)-2,4-diamino-2-substituted-pentanedioic acids after decomposition of the azlactone moiety has been screened for a series of chiral thioureas as well as urea and diamine. The results show

Azlactones 81

that 1-(3,5-bis(trifluoromethyl)benzyl)-3-((1R,2R)-2-(dimethylamino) cyclohexyl)thiourea (45, Figure 1.8) is most effective in controlling the enantioselectivity. Thus, this particular thiourea has been further tested with a variety of solvents, including toluene, trifluoromethylbenzene, chlorobenzene, fluorobenzene, Et2O, THF, 1,2-dichloroethane, acetonitrile, etc., in which toluene works the best. Based on this result, a variety of azlactones prepared from phenylalanine, methionine, tyrosine, and leucine with substituted benzoyl groups have been applied to elaborate this reaction condition in toluene, and the expected Michael adducts have shown excellent diastereoselectivity and enantioselectivity, whilst some chemical yields are not so good [196]. Very interestingly, when 1-(3,5-bis(trifluoromethyl) benzyl)-3-((1S,2S)-2-(dimethylamino)cyclohexyl)thiourea (13, Figure 1.3), the enantiomer of compound 45, is applied to catalyze the Michael addition of 2-(2,4-difluorophenyl)-4-X-oxazol-5(4H)-ones (X = Me, i-Pr, i-Bu, t-Bu) to N-phenylmaleimide (also known as 1-phenyl-1H-pyrrole-2,5dione) in toluene at –20°C, the C2-instead of C4-addition occurs, yielding (S)-3-((R)-2-(2,4-difluorophenyl)-4-X-5-oxo-2,5-dihydrooxazol-2-yl)-1phenylpyrrolidine-2,5-diones in yield of 73–99%, with up to 99.5% ee and diastereoselectivity of > 25:1 [140]. For the particular Michael addition between racemic 4-benzyl2-phenyloxazol-5(4H)-one and (Z)-4-benzylidene-5-methyl-2-phenyl2,4-dihydro-3H-pyrazol-3-one in CH2Cl2 at room temperature, 12 chiral organic compounds have been tested as catalysts in 10 mol% amount, of which nine molecules are chiral thiourea derivatives. Among these organic catalysts, ethyl (4R,4aS,6aR,8S,9S,11aR,11bS)-8-(3-((1R,2R)-2(dimethylamino)cyclohexyl)-thioureido)-4,9,11b-trimethyltetradecahydro6a,9-methanocyclohepta[a]-naphthalene-4-carboxylate (46, Figure 1.8) is especially effective, in terms of enantioselectivity as well as chemical yield and the ratio of (R)-4-benzyl-4-((S)-(5-hydroxy-3-methyl-1-phenyl-1Hpyrazol-4-yl)(phenyl)methyl)-2-phenyloxazol-5(4H)-one over N-(5-benzyl3-methyl-6-oxo-1,4-diphenyl-1,4,5,6-tetrahydropyrano[2,3-c]pyrazol-5-yl) benzamide (Scheme 1.60) [197]. The second product is believed to form by the intramolecular attack of the hydroxyl group in the 3-methyl-1-phenyl1H-pyrazol-5-ol moiety to the carbonyl group of the azlactone component. Careful examination of the reaction conditions by changing the solvent (CH2Cl2, Et2O, toluene, chlorobenzene) as well as reaction temperature (-40°C, room temperature) reaches the optimal condition at –40°C in toluene. Then, a series of azlactones prepared from phenylalanine, leucine, valine, and methionine with N-benzoyl (or 4-fluorobenzoyl, 4-chlorobenzoyl, 4-methylbenzoyl, 3,3-dimethylbutanoyl) have been subject to the Michael

82

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

addition with (Z)-4-arylidene-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol3-ones, where the aryl is Ph, 4-MeC6H4, 4-MeOC6H4, 4-MeSC6H4, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 2,4-Cl2C6H3, or 2-naphthyl. In most cases, the yields of regular Michael adducts are very good (> 80%) with excellent enantioselectivity (> 90% ee) [197].

CF3

OMe N H

O

N H

H N

O S O O

SO3H 43

42

44 S

CF3 S

N

N H

H N H

N H

CF3

N H

N H

N

11

S

CF3

EtO

N H

N

H O

45

46

FIGURE 1.8  The chiral organic catalysts for the Michael reaction involving azlactones.

O O Ph

+ N

Ph

Ph

O Ph

N 10 mol% 46 N Ph CH2Cl2, r.t. O

O Ph

N

Bn

Ph

OH N Ph + N

N N Ph

O

Bn

Bz

N H O

SCHEME 1.60  Chiral thiourea catalyzed Michael addition of 4-benzyl-2-phenyloxazol5(4H)-one to (Z)-4-benzylidene-5-methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one.

Besides the traditional α,β-unsaturated ketones (or aldehydes), alkene conjugated to phosphate group can also be applied as the Michael acceptor. For example, tetraethyl ethene-1,1-diylbis(phosphonate), which contains two phosphate groups, has been used in the reaction with azlactone to form quaternary amino acids with a geminal bisphosphonate moiety. In this practice, azlactones prepared from N-benzoylphenylalanine, leucine, valine, alanine, methionine, and 2-amino-2-phenylacetic acid, all react with tetraethyl ethene-1,1-diylbis(phosphonate) in CH2Cl2 at room temperature in the presence of 20 mol% Et3N, affording tetraethyl (2-(4-X-5-oxo2-phenyl-4,5-dihydrooxazol-4-yl)ethane-1,1-diyl)bis(phosphonate)s (X = Me, Bn, i-Bu, i-Pr, Ph, CH2CH2SMe) in yields from 44% to 88% and excellent regioselectivity (> 20:1) in preference of C4-addition rather than

Azlactones 83

C2-addition, except for the azlactone from alanine. To make this Michael addition asymmetric, Et3N has been substituted with 20 mol% of five (1R)-(6-methoxyquinolin-4-yl)((1R,5S)-5-vinylquinuclidin-2-yl)methanol or (1S)-1-(6-methoxyquinolin-4-yl)-1-((1R,5S)-5-vinylquinuclidin-2-yl) methanamine based chiral organic molecules. Among these catalysts, (1R)-(6-methoxyquinolin-4-yl)((1R,5S)-5-vinylquinuclidin-2-yl)methanol and thiourea 44 (Figure 1.8) work reasonably well, producing the expected Michael adducts in 60% and 55% yields, respectively; and the corresponding enantioselectivities are 37% and 30% ee [198]. In addition to the Michael addition with normal α,β-unsaturated ketones (or aldehydes) that leads to the β-tetrasubstituted ketones (aldehydes), a few Michael additions involving azlactones also generate other types of cyclic molecules after the subsequent functionalization of the corresponding Michael adducts. For example, the ferrocene-based bis-palladacycle catalyzed Michael addition between the in-situ generated 2-phenylazlactone from N-benzoyl amino acid and (E)-4-phenylbut-3-en-2-one yields (R)-4benzyl-4-((R)-3-oxo-1-phenylbutyl)-2-phenyloxazol-5(4H)-one in good chemical yield, as well as excellent diastereoselectivity and very good enantioselectivity [143]. The same bis-palladacycle ([FBIP-Cl]2 in Scheme 1.57) catalyzed Michael addition between 4-methyl-2-phenyloxazol5(4H)-one (formed in situ from N-benzoyl alanine) and (E)-(2-nitrovinyl) benzene affords a mixture of regular Michael adduct (i.e., (R)-4-methyl4-((S)-2-nitro-1-phenylethyl)-2-phenyloxazol-5(4H)-one) with good enantioselectivity and succinimide (i.e., (3R,4R)-3-benzamido-3-methyl2,5-dioxo-4-phenylpyrrolidin-1-yl acetate also in good enantioselectivity) as shown in Scheme 1.61 [190]. The succinimide is believed to form from the further reaction of the regular Michael adduct. The reaction temperature and the presence of metal acetate greatly impact the ratio of these two products. For example, the regular Michael adduct is the major product at the reaction temperature of 23°C, whereas at 50°C, such Michael adduct predominates only in the presence of 2 equivalents of Ca(OAc)2, Zn(OAc)2 and Mn(OAc)2, but the succinimide becomes the major product in the presence of 2 equivalents of NaOAc, KOAc, and tetrabutylammonium acetate. Particularly, an increase in the amount of acetate additive leads to an increase in the yield of succinimide, as evidenced in the 91% and 95% of the succinimide in the presence of 4 equivalent of CsOAc and 5 equivalent of Mn(OAc)2, respectively [190]. These experimental facts can be rationalized as increased reaction temperature promotes the further decomposition of the azlactone ring caused by the attack of the nitrogen atom from the nitro group

84

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

after reacting with acetic anhydride and the higher concentration of acetate additive increases the ionic strength of reaction media that facilitates such attack as shown in Scheme 1.61. The optimized condition for the generation of succinimide has been extended to other N-benzoyl amino acids (e.g., benzoylalanine, 2-benzamido butanoic acid, 2-benzamidopentanoic acid, 2-benzamido-5-methoxy-5-oxopent anoic acid) in Michael addition with (E)-3-methyl-1-nitrobut-1-ene, (E)-1-nitropent-1-ene, (E)-(2-nitrovinyl) cyclohexane or one of the (E)-2-nitrovinylbenzenes (Ph, 4-MeC6H4, 4-MeOC6H4, 3-ClC6H4, 4-ClC6H4, 4-BrC6H4, 3-MeOC6H4), in the presence of 5 mol% of [FBIP-Cl]2, 20 mol% of AgOTf, Mn(OAc)2, Ac2O, AcOH in hexane at 50°C, all yield the expected succinimides in very good yields for the majority of reactions, with excellent diastereoselectivity (> 50:1) and very good enantioselectivity (78% to 96% ee). It should be pointed out that the succinimide product can be further converted into a bicyclic molecule by consecutive treatment of the succinimide with morpholine in CH2Cl2 followed by methanesulfonyl chloride and Et3N, as represented by the conversion of (3R,4R)-3-benzamido-3-butyl-2,5-dioxo-4-phenylpyrrolidin-1-yl acetate into (3aR,6aS)-3a-butyl-2,6a-diphenyl-3a,6a-dihydro-4H-pyrrolo[3,4-d] oxazole-4,6(5H)-dione. In contrast, for the Michael addition of azlactone with nitroalkene in the presence of bifunctional cinchona alkaloid thiourea organo-catalysts, only the phenylglycine-derived azlactones yield the C4-Michael addition products [199]. Another interesting Michael addition involving azlactones is a chiral organic base-catalyzed reaction with benzoquinone or naphthalene-1,4dione, for which the expected Michael adduct undergoes further cascade reactions including the aromatization, decomposition of the azlactone moiety, and cyclization, as represented by the preparation of (R)-N-(3-benzyl-5hydroxy-2-oxo-2,3-dihydronaphtho[1,2-b]furan-3-yl)benzamide from 4-benzyl-2-phenyloxazol-5(4H)-one and naphthalene-1,4-dione in Scheme 1.62 [200]. In this practice, the catalysts of organic bases applied include compound 44 and the enantiomer of 45 in Figure 1.8, as well as 1-((1S,2S)2-(dimethylamino)cyclohexyl)-3-(4-(trifluoromethyl)phenyl)thiourea (47), 1-((1S,2S)-2-(dimethylamino)cyclohexyl)-3-(4-methoxyphenyl) thiourea (48), 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((1S,2S)-2(dimethylamino)cyclohexyl)amino)cyclobut-3-ene-1,2-dione (49) and 3-((3,5-bis(trifluoro-methyl)phenyl)amino)-4-(((1S)-(6-methoxyquinolin4-yl)((2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)amino)cyclobut-3-ene1,2-dione (50) as demonstrated in Figure 1.9. Among these chiral organic

OAc

O N OAc

O O OAc N O OAc N Ph

N

O Ph

OH +

O

O

Ph

N

CsOAc N

Ph

AcO

O

O N OAc

AcOH

O Ph

O OAc N OAc

Ph

O

NO2

Ph

HN

O

O

Ph

N

N

AcOH O

H AcO

O

O

+

Ph

HN

NO2

O N OAc

O Ph

O Ph

Ac2O

O

O OAc N H OAc

AcOH Ph

2-5 mol% [FBIP-Cl]2 8-20 mol% AgOTf 0.5-5 eq. metal acetate Ac2O/AcOH, n-hexane 23 or 50 °C, 20 hrs.

Ph

O N

Ph

HN

O

O

O

O

Ph

N

O

O

N OAc

O

Bz NH O

Ph

SCHEME 1.61  Proposed mechanism for the reaction between benzoylalanine and (E)-(2-nitrovinyl)benzene to form the Michael addition product and unexpected succinimide derivative.

Ph

Ph

O

O

H N

O

Azlactones 85

86

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

catalysts, compound 50 is the most effective, affording the final product of 99% ee. When compound 50 is fixed as the catalyst, the model reaction in CH2Cl2, THF, Et2O, CHCl3, methyl tert-butyl ether (MTBE) and 1,2-dichloroethane all give the final product in more than 85% yield, whereas the same reaction in toluene only produces 40% of product, albeit the enantioselectivity in these reactions is 97% ee or above. The optimized reaction condition has been expanded to the reaction of naphthalene-1,4-dione with azlactones derived from N-benzoyl 2-amino-3-(4-(tert-butoxy)phenyl)propanoic acid, tryptophan, alanine, valine, methionine, N6-(tert-butoxycarbonyl)lysine, and 2-aminopent-4-enoic acid, as well as N-(X-benzoyl)phenylalanines (where X = 2-Me, 3-Cl, 4-Cl, 4-Br, 4-NO2, 4-Me, 4-Me), etc., most of the individual reactions afford the expected products of very good yield as well as excellent enantioselectivity [200].

Bn N

O +

SCHEME 1.62  The naphthalene-1,4-dione.

O 20 mol% cat. solvent, r.t. 2 days

Ph

reaction

Ph

OH

between

4-benzyl-2-phenyloxazol-5(4H)-one

O

OMe

S

H N Bn O

O

CF3

S

O

O

O

O

O

O

NH

N H

and

CF3

N

CF3

CF3

MeO N

N H

N H 47

N

N H

N H 48

N

N H

N H

CF3 N

49

50

FIGURE 1.9  Chiral catalysts for the reaction in Scheme 1.62.

A challenge exists for the Michael addition of azlactone to an extended conjugate system, i.e., which addition is favored, 1,4-addition, 1,6-addition or even 1,8-addition? To address this issue, both intermolecular and intramolecular competing experiments have been developed. For the sake of enhancing the diastereoselectivity as well as enantioselectivity of the Michael adducts, chiral organic base has been added to the reaction system. For example, the Michael addition between 4-benzyl-2-(2,6dimethoxyphenyl)oxazol-5(4H)-one and (2E,5E,7E)-nona-2,5,7-trien-4-one

Azlactones 87

has been performed in toluene at 0°C for 0.5 to 4 hours in the presence of 5 mol% chiral P-spiro iminophosphorane. This particular Michael addition can potentially create three possible addition products with (2E,5E,7E)nona-2,5,7-trien-4-one, which are (R)-4-benzyl-2-(2,6-dimethoxyphenyl)4-((S,3E,7E)-6-oxonona-3,7-dien-2-yl)oxazol-5(4H)-one (i.e., 1,6-addition product), (R)-4-benzyl-2-(2,6-dimethoxyphenyl)-4-((R,2E,7E)-6-oxonona2,7-dien-4-yl)oxazol-5(4H)-one (i.e., the 1,4-addition product from the long-hand side) and (R)-4-benzyl-2-(2,6-dimethoxyphenyl)-4-((S,5E,7E)4-oxonona-5,7-dien-2-yl)oxazol-5(4H)-one (i.e., the 1,4-addition product from the short-hand side), as illustrated in Scheme 1.63 [201]. The configurations of the adducts are guessed based on other experiments provided in this study. The chiral P-spiro iminophosphoranes tested in this study include (2S,7S)-1,2,6,7-tetramethyl-3,3,8,8-tetraphenyl-1,4,6,9-tetraaza-5λ5-phosphaspiro[4.4]non-5(9)-ene (51), (2S,7S)-2,7-diisobutyl-1,6-dimethyl-3,3,8,8tetraphenyl-1,4,6,9-tetraaza-5λ5-phosphaspiro[4.4]non-5(9)-ene (52), (2S,7S)-2,7-dibenzyl-1,6-dimethyl-3,3,8,8-tetraphenyl-1,4,6,9-tetraaza5λ5-phosphaspiro[4.4]non-5(9)-ene (53), (2S,7S)-2,7-di((S)-sec-butyl)1,6-dimethyl-3,3,8,8-tetraphenyl-1,4,6,9-tetraaza-5λ5-phosphaspiro[4.4] non-5(9)-ene (54), (2S,7S)-3,3,8,8-tetrakis(4-fluorophenyl)-2,7-diisobutyl-1,6-dimethyl-1,4,6,9-tetraaza-5λ 5-phosphaspiro[4.4]non-5(9)-ene (55), (2S,7S)-2,7-diisobutyl-3,3,8,8-tetrakis(4-methoxyphenyl)-1,6dimethyl-1,4,6,9-tetraaza-5λ5-phosphaspiro[4.4]non-5(9)-ene (56), (2S,7S)-3,3,8,8-tetrakis(3-fluorophenyl)-2,7-diisobutyl-1,6-dimethyl1,4,6,9-tetraaza-5λ5-phosphaspiro[4.4]-non-5(9)-ene (57) and (2S,7S)2,7-diisobutyl-3,3,8,8-tetrakis(3-methoxyphenyl)-1,6-dimethyl-1,4,6,9tetraaza-5λ5-phosphaspiro[4.4]non-5(9)-ene (58) in Figure 1.10 [201], as well as (2S,7S)-2,7-diisopropyl-1,6-dimethyl-3,3,8,8-tetraphenyl-1,4,6,9tetraaza-5λ5-phosphaspiro[4.4]non-5(9)-ene (11 in Figure 1.3) [137].

88

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O O OMe

O

+

O

O

MeO

5 mol% cat. toluene, 0 C

+

N

°

N

O

Ph

MeO

OMe (major)

O MeO

O

O

O

+

MeO

O

O N

N

Ph

Ph

OMe

OMe (minor)

(minor)

SCHEME 1.63  The preference of 1,6-addition over 1,4-addition between the reaction of 4-benzyl-2-(2,6-dimethoxyphenyl)oxazol-5(4H)-one and (2E,5E,7E)-nona-2,5,7-trien-4-one in the presence of P-spiro iminophosphorane catalyst.

N Ph Ph

N

N

P N H

Ph Ph

N

N P

Ph Ph

N H

51

N

Ph Ph Ph

Ph Ph

52

N

F

N H

N P

N H

N

Ph Ph

N

N H

N H

N

Ph Ph

OMe N

MeO

F

N

N P

OMe 56

55

N

MeO

N

N H

OMe N

P F

Ph Ph

N P

54

MeO

F

F

N

Ph

53

N P

N

P

N N H

F F

F 57

N N

MeO

OMe 58

FIGURE 1.10  The chiral P-spiro iminophosphorane catalysts for the reaction outlined in Scheme 1.63.

Azlactones 89

Except for the catalysts 54 and 58 (Figure 1.10), other chiral P-spiro iminophosphoranes tested all facilitate the 1,6-addition products, with regioselectivity of greater than 8:1 in preference of the 1,6-adducts, particularly prominent for compound 55. Therefore, 55 has been used as the catalyst to further elaborate this reaction with substituted (1E,4E,6E)-hepta-1,4,6trien-3-ones. Around 11 experiments tested all produce the expected 1,6-adducts in good to excellent yields (64%-99%), with more than 95% of regioselectivity, as well as excellent diastereoselectivity (> 20:1 dr) and enantioselectivity (> 90% ee) [201]. Further examples to demonstrate the ability of 55 to catalyze the extended Michael additions can be found in the 1,6-addition between 4-benzyl-2-(2,6-dimethoxyphenyl)oxazol-5(4H)-one and (2E,4E)-1-(1H-pyrrol-1-yl)octa-2,4-dien-1-one in toluene at 0°C to afford 94% of (R)-4-benzyl-2-(2,6-dimethoxyphenyl)-4-((S,E)-8-oxo-8(1H-pyrrol-1-yl)oct-5-en-4-yl)oxazol-5(4H)-one with greater than 20:1 of diastereoselectivity and 98% ee; and the 1,8-addition of 4-benzyl-2-(2,6dimethoxyphenyl)oxazol-5(4H)-one with (2E,4E,6E)-1-(1H-pyrrol-1-yl) octa-2,4,6-trien-1-one in toluene in the presence of molecular sieves 4Å to yield 89% of (R)-4-benzyl-2-(2,6-dimethoxyphenyl)-4-((S,3E,5E)-8-oxo8-(1H-pyrrol-1-yl)octa-3,5-dien-2-yl)oxazol-5(4H)-one with greater than 20:1 of selectivity for the 1,8-addition and less than 5% of 1,6-addition and 1,4-addition, where the corresponding 1,8-addition product has a greater than 20:1 of diastereoselectivity and 99% ee [202]. The regioselectivity has been further explored with the Michael addition of 2-(2,6-dimethoxyphenyl)-4-methyloxazol-5(4H)-one with (E)-1-(1H-pyrazol-1-yl)-pent-2-en-4-yn-1-one in the presence of different chiral organic catalyst. In this case, if the extended Michael addition (i.e., 1,6-addition) occurs, the addition would break the stronger triple bond rather than double bond as shown in Scheme 1.64. Then, several products such as 2-(2,6-dimethoxyphenyl)-4-methyl-4-(5-oxo-5-(1H-pyrazol-1-yl)pent1-yn-3-yl)oxazol-5(4H)-one (59), 2-(2,6-dimethoxyphenyl)-4-methyl-4(5-oxo-5-(1H-pyrazol-1-yl)penta-1,2-dien-1-yl)oxazol-5(4H)-one (60), 2-(2,6-dimethoxyphenyl)-4-methyl-4-((1E,3Z)-5-oxo-5-(1H-pyrazol-1-yl) penta-1,3-dien-1-yl)oxazol-5(4H)-one (61), 2-(2,6-dimethoxyphenyl)4-methyl-4-((1E,3E)-5-oxo-5-(1H-pyrazol-1-yl)penta-1,3-dien-1-yl) oxazol-5(4H)-one (62), 2-(2,6-dimethoxyphenyl)-4-methyl-4-((1Z,3E)-5oxo-5-(1H-pyrazol-1-yl)penta-1,3-dien-1-yl)oxazol-5(4H)-one (63) and 2-(2,6-dimethoxyphenyl)-4-methyl-4-((1Z,3Z)-5-oxo-5-(1H-pyrazol-1-yl) penta-1,3-dien-1-yl)oxazol-5(4H)-one (64) as well as their enantiomers can be generated, as illustrated in Scheme 1.64. For this reaction, KOBut, TMG,

90

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5,7-triazabicyclo[4.4.0] dec-5-ene (TBD), (-)-cinchonine, (+)-cinchonidine, chiral thiourea of 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)-quinolin-4-yl((1S,2S,4S,5R)5-vinylquinuclidin-2-yl)methyl)thiourea (65, Figure 1.11), (2S,7S)-2,7-diisobutyl-1,6-dimethyl-3,3,8,8-tetra-m-tolyl-1,4,6,9-tetraaza5λ5-phosphaspiro[4.4]non-5(9)-ene (66, Figure 1.11) as well as 11 (Figure 1.3) and 51, 54, 55, 57 (Figure 1.10), etc., have been examined as catalytic bases [203]. The results indicate that the cinchonidine-derived thiourea (65) catalyzes the 1,4-addition of prochiral azlactone enolates to (E)-1-(1Hpyrazol-1-yl)pent-2-en-4-yn-1-one to give stereochemically defined alkynes of excellent enantioselectivity (>96% ee) as well as diastereoselectivity (>20:1); whereas the chiral P-spiro triaminoiminophosphoranes as represented in Figure 1.10 facilitate the catalytical 1,6-addition and the consecutive γ-protonation of the vinylogous enolate intermediate to afford Z,E-conjugated dienes, particularly with compound 66 (Figure 1.11) as the catalyst. Under the optimized condition with 55 as the catalyst, the reaction between (E)-1-(1H-pyrazol-1-yl)pent-2-en-4-yn-1-one and a series of azlactones derived from N-(2,6-dimethoxybenzoyl) amino acids (e.g., alanine, 2-aminobutanoic acid, 2-aminohexanoic acid, 2-aminooctanoic acid, methionine, phenylalanine, valine, leucine, 2-amino-2-phenylacetic acid, 2-amino-3-(4-methoxyphenyl)propanoic acid, 2-amino-3-(4chlorophenyl)propanoic acid, 2-amino-3-(3,4-dimethoxyphenyl)propanoic acid, 2-amino-3-(2-fluorophenyl)prop anoic acid, etc.), all give the specific 1,6-addition product represented by 63 in Scheme 1.64, in yield of 88–99% and excellent enantioselectivity (>90% ee) [203]. Computations on the reaction with (E)-1-(1H-pyrrol-1-yl)penta-2,4-dien-1-one at the B3LYP-D3/6-31+G** level using (2S,7S)-1,2,3,3,6,7,8,8-octamethyl1,4,6,9-tetraaza-5λ5-phosphaspiro[4.4]non-5(9)-ene for the chiral catalyst and furan-2(3H)-one for the azlactone core indicate that the rate- and stereo-determining C−C bond formation proceeds through the formation of phosphonium-enolate ion-pair complexes. The Cα-protonation of the resulting enolate anion is energetically favored over the Cγ-protonation as the latter involves a high energy barrier and a reversible O-protonation. The high regio- and enantioselectivities for the 1,6-addition are attributed to the notable steric and electronic features of the catalyst and Michael acceptor, as well as the hydrogen bonds (NH−O and CH−O) and the attractive CH−π interaction. Similar results are obtained for the reaction with further extended conjugate system, such as (2E,4E)-1-(1H-pyrrol1-yl)hepta-2,4,6-trien-1-one, favoring the 1,8-addition [204].

Azlactones 91

2

0H2



2 0H2

1

+

0H2

1 1

1

2 0H2



2

2 1

2

20H

2

20H 

1



1



2

2

0H2

1 1

1



20H





2 0H2

2

2

20H 

1 1

&

PROFDW (W2&

1 1

20H

2

2

2

1

ƒ

2

2

2 1



20H

2

1

1

0H2

2

2

1

1 1

20H





SCHEME 1.64  The conjugate addition products from 2-(2,6-dimethoxyphenyl)-4methyloxazol-5(4H)-one and (E)-1-(1H-pyrazol-1-yl)pent-2-en-4-yn-1-one.

CF3

N

N F3C

N H

N H 65

N P

S

N H

N

N 66

FIGURE 1.11  The organic catalysts for the extended Michael addition between 2-(2,6-dimethoxyphenyl)-4-methyloxazol-5(4H)-one and (E)-1-(1H-pyrazol-1-yl) pent-2-en-4-yn-1-one.

Experimental evidence for the 1,8-addition involving azlactone can be found in the (2S)-2,6-di(anthracen-9-yl)-4-hydroxydinaphtho[2,1-d:1’,2’-f] [1,3,2]dioxaphosphepine 4-oxide catalyzed reaction between 4-(1-hydroxy1,3-diphenylprop-2-yn-1-yl)phenol and 2-(X-phenyl)-4-ethyloxazol-5(4H)one (where X = H, 4-F, 4-Cl, 4-Me, 4-MeO, 3-Cl, 3-Br, 3-Me, and 2-Br), affording (S)-2-(X-phenyl)-4-ethyl-4-((R)-3-(4-hydroxyphenyl)-1,3-diphenylpropa-1,2-dien-1-yl) oxazol-5(4H)-one in good yield (65–94%) and very good enantioselectivity (86–97% ee), as shown in Scheme 1.65 [205]. In the presence of a chiral phosphoric acid (CPA), protonation of 4-(1-hydroxy1,3-diphenylprop-2-yn-1-yl)phenol results in dehydration, yielding 4-(1,3-diphenylprop-2-yn-1-ylidene)cyclohexa-2,5-dien-1-one. Meanwhile, 2-(X-phenyl)-4-ethyloxazol-5(4H)-one undergoes tautomerization to afford

92

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

2-(X-phenyl)-4-ethyloxazol-5-ol. This reaction has been extended to other substituted 4-(1-hydroxy-1,3-arylprop-2-yn-1-yl)phenols, also affording the expected products in very good yields and enantioselectivities. Likewise, several 4-substituted-2-phenylthiazol-5(4H)-ones undergo similar reactions with 4-(1-hydroxy-1,3-diphenylprop-2-yn-1-yl)phenol, in the presence of (11bR)-2-(4,6-dihydropyren-1-yl)-4-hydroxy-6-(pyren-1-yl)dinaphtho[2,1d:1’,2’-f][1,3,2]di-oxaphosphepine 4-oxide in CH2Cl2 or (trifluoromethyl) benzene, affording the expected products in very good yields as well as enantioselectivities [205]. * O

P

H

O

H O O

O

X

N Ph

H 2O

Ph OH

CPA OH

O

+ HO Ph

N

O

1 mol% CPA CH2Cl2, r.t., 36 hrs.

C

X

N

Ph

O

O

X

CPA = O O P HO O

SCHEME 1.65  The 1,8-conjugate addition between 2-aryl-4-ethylazlactone and 4-(1-hydroxy-1,3-diphenylprop-2-yn-1-yl)phenol in the presence of a catalytic amount of chiral phosphoric acid.

Another extended conjugate system as the Michael acceptor is a substituted 2,6-di-tert-butyl-4-benzylidenecyclohexa-2,5-dien-1-one, which undergoes Michael addition in the presence of a chiral phosphoric acid (CPA, e.g., (2S)-4-hydroxy-2,6-bis(2,4,6-triisopropylphenyl)dinaphtho[2,1-d:1’,2’f][1,3,2]dioxaphosphepine 4-oxide) with azlactone (e.g., 4-ethyl2-(4-methoxyphenyl)oxazol-5(4H)-one) to afford (R)-4-((S)-(3,5-di-tert-

Azlactones 93

butyl-4-hydroxyphenyl)(X-phenyl)methyl)-4-ethyl-2-(4-methoxyphenyl) oxazol-5(4H)-one (X = 4-Me, 4-MeO, 4-F, 4-Cl, 4-Br, etc.), involving a 1,6-addition rather than the normal 1,4-addition, due to the re-aromatization of the quinone ring, as illustrated in Scheme 1.66. This reaction has been tested in CHCl3, CH2Cl2, CCl4, toluene, THF, and 1,2-dichloroethane, and the results indicate that the reaction in CCl4 yields a product of excellent diastereoselectivity (> 20:1) and enantioselectivity (> 99% ee). Therefore, additional reactions by changing the structures of quinones as well as azlactones have been performed in CCl4 in the presence of the ideal catalyst to generate the expected products [206]. In contrast, alkylidenecyclohexa2,5-dien-1-one, such as 2,6-di-tert-butyl-4-ethylidenecyclohexa-2,5-dien1-one does not function as well as its arylidene-counterpart, because only a trace amount of product (< 5%) has been obtained. OH

O

O t-Bu

Et

t-Bu

t-Bu N

t-Bu OMe

O 5 mol% cat. CCl4, r.t.

+

H

N O

MeO

OMe

i-Pr

O

i-Pr

cat. = i-Pr

MeO

O O P i-Pr HO O i-Pr

i-Pr

SCHEME 1.66  The extended conjugate addition between 4-ethyl-2-(4-methoxyphenyl) oxazol-5(4H)-one and 2,6-di-tert-butyl-4-(4-methoxybenzylidene)cyclohexa-2,5-dien-1-one in the presence of a catalytic amount of chiral phosphoric acid.

Extension of this work for 2-hydroxybenzylidenecyclohexa-2,5-dien1-one with substituted azlactone, as represented by the reaction between 2,6-di-tert-butyl-4-(2-hydroxybenzylidene)cyclohexa-2,5-dien-1-one and 4-benzyl-2-phenyl-oxazol-5(4H)-one), affords a product with a dihydrocoumarin moiety and hydroxyphenyl scaffold due to the re-aromatization of the cyclohexa-2,5-dien-1-one, e.g., N-((3R,4S)-3-benzyl4-(3,5-di-tert-butyl-4-hydroxyphenyl)-2-oxochroman-3-yl)benzamide, as illustrated in Scheme 1.67. In order to create an asymmetric environment for

94

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

this addition, different types of organic chiral molecules have been applied as catalysts, including 44 (Figure 1.8), 50 (Figure 1.9), (11bS)-4-hydroxy-2,6diaryldinaphtho[2,1-d:1’,2’-f][1,3,2]dioxaphosphepine 4-oxides, (11bS)4-hydroxy-2,6-diaryl-8,9,10,11,12,13,14,15-octahydrodinaphtho-[2,1d:1’,2’-f][1,3,2]dioxaphosphepine 4-oxides, N-((11bS)-2,6-di(anthracen9-yl)-4-oxidodinaphtho[2,1-d:1’,2’-f][1,3,2] dioxaphosphepin-4-yl)1,1,1-trifluoromethanesulfonamide, and 1,10-bis(3,5-bis(trifluoromethyl) phenyl)-12-hydroxy-4,5,6,7-tetra-hydrodiindeno[7,1-de:1’,7’-fg][1,3,2] dioxaphosphocine 12-oxide [207]. When this reaction is performed in toluene in the presence of one of these catalysts, the yield varies from 21% to 99%, but all with excellent diastereoselectivity (> 19:1). Extensive study on the solvent effect in the presence of the ideal catalyst shows the advantage of the fluorinated solvents ((trifluoromethyl)benzene and perfluorobenzene). Then, different Michael acceptors have been further examined under this condition, including 2,6-di-tert-butyl-4-(X-2-hydroxybenzylidene)cyclohexa-2,5-dien1-ones (X = 4-F, 4-Cl, 4-Br, 4-Me, 4-OMe, 3-OMe, 5-OMe, 6-OMe) and 2,6-di-tert-butyl-4-((3-hydroxynaphthalen-2-yl)methylene)cyclohexa-2,5dien-1-one. The expected products all have excellent diastereoselectivity (> 19:1) and enantioselectivity (89–98% ee) [207]. OH

O t-Bu

t-Bu

t-Bu

O Bn +

N

O

t-Bu

5-10 mol% cat. C6F6, r.t.

O Bn

Ph OH

O

cat. = F3C

O O P HO O CF3

N H O

Ph

CF3

F3C

SCHEME 1.67  The extended conjugate addition between 4-benzyl-2-phenyloxazol5(4H)-one and 2,6-di-tert-butyl-4-(2-hydroxybenzylidene)cyclohexa-2,5-dien-1-one.

This particular reaction has been considered to occur in two possible mechanisms, including: (a) Michael addition of the azlactone enolate with the quinone-methide (1,6-addition) followed by the nucleophilic attack of the 2-hydroxy group to the azlactone moiety of the adduct (path A); and (b) CPA catalyzed isomerization of 2,6-di-tert-butyl-4-(2-hydroxybenzylidene)

Azlactones 95

cyclohexa-2,5-dien-1-one into (E)-6-(3,5-di-tert-butyl-4-hydroxybenzylidene) cyclohexa-2,4-dien-1-one which complexes with CPA via hydrogen bond and undergoes a Diels-Alder cycloaddition with the newly generated enol form of azlactone (i.e., 4-benzyl-2-phenyloxazol-5-ol) to directly form the dihydrocoumarin motif followed by a ring-opening of (9S,9aR)-9a-benzyl-9-(3,5-ditert-butyl-4-hydroxyphenyl)-2-phenyl-9,9a-dihydro-3aH-chromeno[3,2-d] oxazol-3a-ol (path B), as illustrated in Scheme 1.68 [207]. While both mechanisms sound reasonable, based on the experimental evidence, path A is more plausible as the 1,6-addition has been known for arylidenecyclohexa-2,5-dien1-ones already, as demonstrated in Scheme 1.66 [206].

O

CPA

OH

t-Bu

t-Bu

t-Bu

O

O

t-Bu

t-Bu

Bn +

N

t-Bu

+

O Ph

OH

O path A

O

path B

CF3 Ph

CF3

O N CF3 Bn H O O O t-Bu P O O H O CF3 t-Bu

N

O H O O P O O H O

OH

Bn

t-Bu OH t-Bu

CF3 CF3 [4+2] cycloaddition

1,6-addition

OH

OH t-Bu

t-Bu

t-Bu

Ph

CF3 O

CF3

HO

H

N

t-Bu

t-Bu

O

O Bn

O Bn OH

N O

O H

OH t-Bu

t-Bu

t-Bu O

Bn N

Ph

Bn Ph

O

O OH

O

N H O

Ph

SCHEME 1.68  Two possible mechanisms for the reaction between 4-benzyl-2-phenyloxazol5(4H)-one and 2,6-di-tert-butyl-4-(2-hydroxybenzylidene)cyclohexa-2,5-dien-1-one.

1.4.1.2.11 Addition to Isolated Alkenes or Ene Reactions Individual alkene is considered an electron-enriched species, so it can be easily added by electrophilic agents, such as hydrochloric acid, hydrobromic acid, etc. Thus, the direct reaction between azlactone and a

96

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

non-conjugated alkene is not common. An exception is a palladium(II)catalyzed enantioselective carbo-Wacker α-alkylation of azlactone with a non-conjugated alkene in the presence of a chiral BINOL-derived phosphoric acid to induce asymmetry. A representative reaction is provided in Scheme 1.69 [208], for the reaction of 4-benzyl-2-(4-methoxyphenyl) oxazol-5(4H)-one and N-(quinolin-8-yl)but-3-enamide and subsequent decomposition of the azlactone moiety with NaOMe to yield the final product of methyl (S)-2-benzyl-2-(4-methoxybenzamido)-6-oxo-6(quinolin-8-ylamino)hexanoate. The catalyst is [Pd(PhCN)2]Cl2 and the stereo-induction chiral phosphoric acid is (6r,11bR)-4-hydroxy2,6-bis(2,4,6-tricyclohexylphenyl)dinaphtho[2,1-d:1’,2’-f][1,3,2]dioxaphosphepine 4-oxide. Further optimization of this reaction reveals that a non-polar solvent is critical for the induction of asymmetry, and the electronic property of the substituent on CPA to perturb the pKa of the acid does not significantly impact the stereo-induction, as the products obtained in the presence of CPA with either electron-donating or electronwithdrawing group have shown similar enantioselectivity. Presumably, such a group is too far from the phosphoric acid moiety. In addition, azlactone derived from N-benzoyl amino acid with an electron-donating group on the para-position of the benzoyl group affords the product of the highest yield and enantiomeric ratio, possibly due to the π-π stacking with the chiral phosphoric acid. On the other hand, azlactones prepared from substituted phenylalanines containing an electron-donating group (e.g., Me, MeO) or a weak electron-withdrawing group (Br, Cl, and F) lead to the final products of high yields and excellent enantioselectivity, whereas azlactones derived from substituted phenylalanine with strong electronwithdrawing groups (e.g., CF3 and NO2) afford products with slightly diminished yields and enantioselectivity, presumably due to an attenuated nucleophilicity. Further study using TRIP as a model CPA indicates that the enantioselectivity of the final product correlates very well with the %ee of the TRIP. DFT calculation shows that the (S)-nucleopalladation pathway has a lower activation barrier (10.3 Kcal/mol) than that of the (R)-pathway (11.2 Kcal/mol); and the CPA-assisted protodepalladation step to form the S-enantiomer has lower activation energy (13.5 Kcal/ mol) than the one to form the R-enantiomer (14.9 Kcal/mol). However, this reaction system is not suitable for an internal alkene [208]. Likewise, the model reaction between 2-(4-methoxyphenyl)-4phenyloxazol-5(4H)-one and 1-benzyl-3-vinyl-1H-indole has been tested

Azlactones 97

in toluene at 0°C in the presence of molecular sieves and a catalytic amount of (11bR)-2,6-di([1,1’-biphenyl]-4-yl)-4-hydroxydinaphtho[2,1-d:1’,2’-f] [1,3,2]dioxaphosphepine 4-oxide, (6r,11bR)-2,6-di(anthracen-9-yl)-4hydroxydinaphtho[2,1-d:1’,2’-f][1,3,2]dioxa-phosphepine 4-oxide or (6r,11bR)-4-hydroxy-2,6-bis(2,4,6-triisopropylphenyl)dinaphtho[2,1d:1’,2’-f][1,3,2]dioxaphosphepine 4-oxide, which yields a mixture of (S)-4-((S)-1-(1-benzyl-1H-indol-3-yl)ethyl)-2-(4-methoxyphenyl)-4phenyloxazol-5(4H)-one (syn-product) and (S)-4-((R)-1-(1-benzyl1H-indol-3-yl)ethyl)-2-(4-methoxyphenyl)-4-phenyloxazol-5(4H)-one (anti-product) at various ratios. The resulting products are further treated with 2.5 equivalents of sodium methoxide in methanol at room temperature to give the corresponding methyl (2S,3R)-3-(1-benzyl-1H-indol-3-yl)2-(4-methoxybenzamido)-2-phenylbutanoate and the anti-counterpart [209]. Analysis of these products indicates that chiral phosphoric acid (11bR)-2,6-di([1,1’-biphenyl]-4-yl)-4-hydroxydinaphtho[2,1-d:1’,2’-f] [1,3,2]dioxaphosphepine 4-oxide gives superior results in terms of chemical yields as well as the ratio of syn-product/anti-product and the enantioselectivity of the syn-product. Thus, this catalyst has been further examined to achieve the optimal reaction conditions (e.g., choice of solvent, type of molecular sieves and reaction temperature). Additional experiments with 1-benzyl-3-vinyl-1H-indoles of substituent at position 5 or 6 and 2-(4-methoxyphenyl)-4-aryloxazol-5(4H)-ones with substituent at ortho/meta/para position of the aryl moiety demonstrate that the electrondonating group on either reaction component (i.e., azlactone, and 3-vinyl1H-indole) surrenders better results. On the other hand, configuration of the vinyl moiety also affects the reaction outcome, as indicated in the reaction of 2-(4-methoxyphenyl)-4-phenyloxazol-5(4H)-one with either (E)-1-benzyl-3-(prop-1-en-1-yl)-1H-indole or (Z)-1-benzyl-3-(prop-1-en1-yl)-1H-indole, where the former leads to a better chemical yield (69%) and greater ratio of the syn-product/anti-product (86/14), as well as better enantioselectivity for the syn-product (74% ee). In contrast, the reaction of azlactone with (Z)-1-benzyl-3-(prop-1-en-1-yl)-1H-indole yields only 39% of product, with 59:41 ratio of methyl (2S,3S)-3-(1-benzyl1H-indol-3-yl)-2-(4-methoxybenzamido)-2-phenylpentanoate over methyl (2S,3R)-3-(1-benzyl-1H-indol-3-yl)-2-(4-methoxybenzamido)-2phenylpentanoate [209].

98

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O Ph

O

N

N H

N

a) 10 mol% [Pd(PhCN)2]Cl2 20 mol% CPA Benzene, 70 °C, 48 hrs. b) NaOMe, MeOH r.t. 3 hrs.

O

+

H N N

H N

O

O MeO2C Bn

OMe OMe

Cy

Cy

CPA = Cy

Cy

O O P Cy HO O Cy

Cy = cyclohexyl

SCHEME 1.69  Palladium catalyzed reaction between N-(quinolin-8-yl)but-3-enamide and 4-benzyl-2-(4-methoxyphenyl)oxazol-5(4H)-one.

Besides the above reactions, there are many examples of the reactions of azlactones with electron-rich alkenes (e.g., vinyl ethers) at the C4 position. For example, after leaving the stirred mixture of methyl 5-oxo-2-phenyl4,5-dihydrooxazole-4-carboxylate and 3,4-dihydro-2H-pyran-5-d in CH2Cl2 under nitrogen atmosphere in a flame dried flask for a certain time as monitored by TLC, CH2Cl2 was removed under vacuum and the flask was filled with methanol. The opening of the azlactone ring was also monitored by TLC. Removal of the solvent afforded 99% of dimethyl 2-benzamido-2((2S,3S)-tetrahydro-2H-pyran-2-yl-3-d)malonate as the single diastereomer (Scheme 1.70). Based on this result, it is believed that the azlactone undergoes intramolecular hydrogen shift to generate methyl 5-hydroxy-2-phenyloxazole-4-carboxylate in situ, which then undergoes Conia ene reaction with 3,4-dihydro-2H-pyran-5-d, affording the intermediate of methyl (R)-5-oxo2-phenyl-4-((2S,3S)-tetrahydro-2H-pyran-2-yl-3-d)-4,5-dihydrooxazole-4carboxylate. Alcoholysis of this azlactone in MeOH leads to the final product as the saturated azlactone is not so stable. The whole process is illustrated in Scheme 1.70. The reaction of the same azlactone with other enol ethers reveals that only electron-enriched enol ethers work under this condition, as vinyl acetate such as 2-methylprop-1-en-1-yl acetate does not react. On the other hand, the existence of an electron-withdrawing group (e.g., the ester group) at C4 is very crucial, replacement of the ester group by either phenyl or 1-naphthyl group from the same azlactone requires extended reaction time from 20 minutes to 8 hours or longer at high temperature (e.g., 110°C) instead of room temperature. Replacement of the ester group with methyl group leads to no reaction at all [210].

Azlactones 99

O O Ph

N

O

O H

O

D

Ph

+ CO2Me D

CH2Cl2, r.t.

N

CO2Me O

O

D Ph

N O MeO2C

Ph MeOH

HN

O

CO2Me CO2Me 99% O

D

O

SCHEME 1.70  The Conia ene reaction between methyl 5-oxo-2-phenyl-4,5-dihydrooxazole4-carboxylate and 3,4-dihydro-2H-pyran-5-d.

Further optimization of this initial reaction condition realized that when benzene was used as the solvent for the Conia ene reaction, reasonably good diastereoselectivity can be achieved, particularly when diphenylphosphoric acid was applied as the Bronsted acid catalyst (10 mol%). This has been illustrated in Scheme 1.71 for the reaction between methyl 5-oxo-2-phenyl-4,5-dihydrooxazole4-carboxylate and 2-methyl-2-(vinyloxy)propane in benzene at room temperature for 3 hours, and the resulting ene reaction product was further reduced by NaBH4 to afford diastereomer mixtures in 3:1 ratio, i.e., methyl (2R,3R)-2-benzamido3-(tert-butoxy)-2-(hydroxymethyl)butanoate and methyl (2S,3R)-2-benzamido3-(tert-butoxy)-2-(hydroxymethyl)butanoate, in total yield of 90%. Application of an even larger chiral catalyst, such as 4-hydroxydinaphtho[2,1-d:1’,2’-f][1,3,2] dioxaphosphepine 4-oxide, only lightly enhanced the diastereoselectivity, i.e., from 75:25 to 79:21. In comparison, when the 2-phenyl group is replaced by an alkyl group, such as an ethyl or even benzyl group, the diastereoselectivity is not so obvious, and the ethyl group sounds slightly favoring the corresponding (2S,3R)-diastereomer [211]. One of the major diastereomers, e.g., methyl (2R,3R)3-(tert-butoxy)-2-(hydroxymethyl)-2-(4-methoxybenzamido)butanoate has been applied as the key intermediate for the total synthesis of (±)-Salinosporamide A [212], which is a different approach from the one that Corey used, i.e., methyl (2R,3R)-2-((benzyloxy)methyl)-3-hydroxy-2-((4-methoxybenzyl)amino) butanoate, that was obtained from NaBH3CN reduction of methyl (4R,5R)4-((benzyloxy)methyl)-2-(4-methoxyphenyl)-5-methyl-4,5-dihydrooxazole4-carboxylate [213]. O O Ph

N

CO2Me

+

O

1) (PhO)2P(O)OH benzene, r.t. 2) NaBH4

Ph

O

Ph

O +

HN MeO

OH

O

O

HN MeO

O

OH O

90 % (3:1)

SCHEME 1.71  The reaction between methyl 5-oxo-2-phenyl-4,5-dihydrooxazole-4carboxylate and tert-butyl vinyl ether.

100

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

1.4.1.2.12 Addition to Alkynes Recently, a rhodium catalyst [Rh(COD)Cl]2 promoted a regioselective addition of azlactone to an internal alkyne (e.g., prop-1-yn-1-ylbenzene) in the presence of DPEphos ligand and 2,2-diphenylacetic acid has been reported, that predominantly yields a C2-alkylated product as well as the C4-alkylated one as the minor product. However, sophistical examination of the reaction mechanism indicates that treatment of prop-1-yn-1-ylbenzene with [Rh(COD) Cl]2 and the ligand (oxybis(2,1-phenylene))bis(diphenylphosphane) (DPEphos) generates an [η3-allyl-Rh] complex which is then nucleophilically attacked by the azlactone enol (i.e., 2,4-diphenyloxazol-5-ol) to afford 4-cinnamyl-2,4-diphenyloxazol-5(4H)-one and 2,4-diphenyl-4-(1-phenylallyl)oxazol-5(4H)-one. The latter undergoes aza-Cope [3,3]-rearrangement to give 2-cinnamyl-2,4-diphenyloxazol-5(2H)-one as the major product. In addition, this compound can further undergo thermal decarboxylation to yield 2,5,6-triphenyl-2,5-dihydropyridine, which upon oxidation leads to the formation of 2,3,6-triphenylpyridine, as illustrated in Scheme 1.72 [9]. This typical reaction can be extended to other azlactones as well as alternative alkynes (e.g., oct-2-yne), affording C2-allylated azlactone derivatives. Therefore, this reaction provides a general method for the preparation of 2,3,6-trisubstituted pyridines. In addition, this reaction can be performed in a manner of cascade reaction starting from N-acyl amino acid to generate the azlactone in situ, followed by the allylation of azlactone and conversion into 2,3,6-trisubstituted pyridines. A special reaction between azlactone and 4-yn-1-ols has been developed that has been co-catalyzed with a gold complex (e.g., methyl gold in complexation with di-tert-butyl(2’,4’,6’-triisopropyl-[1,1’-biphenyl]-2-yl) phosphane) and a chiral phosphoric acid (e.g., (11bS)-4-hydroxy-2,6-bis(2,4,6triisopropylphenyl)dinaphtho[2,1-d:1’,2’-f][1,3,2]dioxaphosphepine 4-oxide) that affords (R)-4-((R)-2-methyltetrahydrofuran-2-yl)-2,4disubstituted oxazol-5(4H)-ones with good to excellent chemical yields, as well as reasonably good diastereoselectivity and good to excellent enantioselectivity for the syn-products, as represented by the specific reaction between (1-(prop2-yn-1-yl)cyclohexyl)methanol and 4-phenyl-2-(3,4,5-trimethoxyphenyl) oxazol-5(4H)-one that yields 98% of (R)-4-((R)-3-methyl-2-oxaspiro[4.5] decan-3-yl)-4-phenyl-2-(3,4,5-trimethoxyphenyl)oxazol-5(4H)-one, as demonstrated in Scheme 1.73 [214]. This reaction is believed to proceed in two plausible pathways. In one of such pathways, a gold complex promotes the conversion of pent-4-yn-1-ol into 2-methylenetetrahydrofuran, which is further converted into 5-methyl-3,4-dihydro-2H-furan-1-ium by Lewis acid.

Azlactones 101

On the other hand, the azlactone is transformed into its enol form, which then undergoes the chiral phosphoric acid promoted addition to 5-methyl3,4-dihydro-2H-furan-1-ium, yielding the final product. Alternatively, 2-methylenetetrahydrofuran reacts with gold complex to form ((3,4-dihydro2H-furan-1-ium-5-yl)methyl)(phosphonooxy) gold, which then is attacked by the enol form of azlactone to give the final product. It is found that both gold complex and chiral phosphoric acid can promote the reaction, but chiral phosphoric acid is a better catalyst. For this particular reaction, a non-polar solvent, such as toluene and benzene, is suitable for this reaction; and a larger substituent at C4 of azlactone is beneficial to the stereoselectivity. On the other hand, the counter anion of the gold complex exerts a great impact on the reaction. Also, low reaction temperature and concentration can further enhance stereoselectivity [214]. 1.4.1.2.13 Addition to Diazo Compounds Besides the regular addition of azlactone (as nucleophile) to a variety of substrates containing a C-C multiple bond as described above, the addition of azlactone to a diazo compound has also been reported, as represented by the reaction between 4-isopropyl-2-phenyloxazol-5(4H)-one and diisopropyl (E)-diazene-1,2-dicarboxylate in the presence of a chiral organic base (e.g., chiral thiourea or amide), that yields diisopropyl (S)-1-(4-isopropyl5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl)hydrazine-1,2-dicarboxylate. Further treatment of this compound with (diazomethyl)trimethylsilane (i.e., trimethylsilyl diazomethane) in methanol at 0°C leads to the formation of 1,2-diisopropyl 3-methyl (S)-3-isopropyl-5-phenyl-1H-1,2,4-triazole1,2,3(3H)-tricarboxylate (Scheme 1.74) [3]. It is found that a series of chiral amides as single point H-bond donors are superior to the double H-bonded thioureas (e.g., the enantiomer of 44 in Figure 1.8) due to their dynamic rotational flexibility for a better substrate alignment in the transition state. Particularly, in the presence of N-((S)-((1S,2S,4S,5R)-5-ethylquinuclidin2-yl)(6-methoxyquinolin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide, 81% of diisopropyl (S)-1-(4-isopropyl-5-oxo-2-phenyl-4,5-dihydrooxazol4-yl)hydrazine-1,2-dicarboxylate has been obtained with 93% ee. For this reaction, various di-substituted azlactones are well tolerated with uniformly satisfactory yields and enantioselectivities of the expected products. Also, azlactone derived from N-benzoyl amino acids containing an electron-rich group on the benzoyl moiety generally displays a superior reactivity to its counterpart containing an electron-deficient group on the benzoyl moiety;

Ph

H[Rh]X

CH3

[Rh]X

[Rh]X

[Rh(COD)Cl]2

+

Ph

Ph

Ph

N

N

Ph

O

OH

Ph

O

O

Ph

O

O N

Ph Ph Ph

+ O

O

Ph

Ph

O

N

Ph2CHCO2H (10 mol%) ° 18 hrs. O ClCH2CH2Cl, 50 C,

[Rh(COD)Cl]2 (1 mol%) DPEphos (2 mol%)

Ph

Ph major

N

H

N

Ph

N

Ph

Ph

+

CO2

Ph

Ph

O

Ph

Ph

O

[O]

minor

N

Ph

Ph SCHEME 1.72  A plausible mechanism for the reaction between 2,4-diphenyloxazol-5(4H)-one and prop-1-yn-1-ylbenzene.

X[Rh]

H[Rh]X

Ph

Ph

Ph

Me

H

N

Ph

N

Ph

Ph

Ph

Ph

Ph

Ph

102 Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Azlactones 103

OMe

O

MeO OH +

O

MeO

O

N

5 mol% LAuMe 10 mol% CPA toluene, 0 °C

O

O Ph N OMe

Ph OMe MeO 98%, 87/13 dr, 90% ee i-Pr i-Pr L = i-Pr

i-Pr P(t-Bu)2

i-Pr

CPA = i-Pr

i-Pr

O O P i-Pr HO O

i-Pr

SCHEME 1.73  A gold complex catalyzed reaction between 4-phenyl-2-(3,4,5trimethoxyphenyl)oxazol-5(4H)-one and (1-(prop-2-yn-1-yl)cyclohexyl)methanol.

for which near or above 90% ee’s have been obtained in most cases regardless of the electronic pattern. However, azlactone contains a 2-aryl moiety with strong electron-withdrawing groups (e.g., 3,5-dinitrophenyl) or a severe sterically bulky alkyl group (e.g., tert-butyl) will diminish the reactivity. On the other hand, moderately reactive azodicarboxylates lead to the best yields and enantioselectivities, but the constraint of the azodicarboxylate would reduce the enantioselectivity. Upon the hydrolysis of the methyl ester in the presence of lithium iodide in ethyl acetate under refluxing, standard amide coupling with alkyl amines or amino esters facilitate the concurrent cyclization to generate [5,5] hetero bicyclic products except for 3,5-dimethoxyaniline, such as the one in coupling with methyl alaninate in the presence of peptide coupling reagents (EDCI, HOAT) in methylene chloride that affords isopropyl (S)-7a-isopropyl-6-((S)-1-methoxy-1-oxopropan-2-yl)5,7-dioxo-2-phenyl-5,6,7,7a-tetrahydro-3H-imidazo[1,5-b][1,2,4]triazole3-carboxylate in 85% yield and 92% of enantioselectivity [3]. In contrast, when simple 2-aryl azlactones are treated with 1-naphthyldiazonium chloride (i.e., naphthalene-1-diazonium chloride) in the presence of sodium acetate at low temperature, (Z)-4-(2-(naphthalen-1-yl) hydrazineylidene)-2-aryloxazol-5(4H)-ones are obtained in less than 50% yields. Further refluxing these azlactones in acetic acid in the presence of sodium acetate and substituted anilines, the azlactone cores are converted

104

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

into 1H-1,2,4-triazoles, and the corresponding 1-(naphthalen-1-yl)-N,5diaryl-1H-1,2,4-triazole-3-carboxamides are formed in good yields. Some of these derivatives have demonstrated anti-cancer activities [215]. CF3 N

O N

H N

H O

CF3 O

O

O O

O +

N

N

O

O

Ph

O

N MeOBut

Ph

N O

N

H N O

O O

O Ph TMSCHN2 MeOH, 0 °C

N

CO2-i-Pr N N CO2-i-Pr

Ph

N

O

HN N

O

O O

CO2Me

O -N

N+

Si

LiI/EtOAc

Ph

CO2-i-Pr CO2-i-Pr Ph N N O N N CO2-i-Pr methyl alaninate, EDCI N N HOAT, DIPEA, CH2Cl2 CO2Me N CO2H O

SCHEME 1.74  The addition of 4-isopropyl-2-phenyloxazol-5(4H)-one into the diazo compound of diisopropyl (E)-diazene-1,2-dicarboxylate and subsequent reactions.

1.4.1.2.14 Addition to Allenes Very recently, a unique reaction between 4-ethynyl-X-1-tosyl-1,4-dihydro2H-benzo[d][1,3]oxazin-2-one (where X = H, 5-F, 6-Me, 6-Cl, 6-Br, 7-Me, 7-CF3, 7-F, 7-Cl, 6,7-F2) and 4-benzyl-2-phenyloxazol-5(4H)-one to afford N-((3R,4R)-3-benzyl-4-ethynyl-X-2-oxo-1-tosyl-1,2,3,4-tetrahydroquinolin-3-yl)benzamide in very good yield in most cases and excellent enantioselectivity (> 90% ee) has been reported, which is cooperatively catalyzed by CuI in combination with 2,6-bis((S)-4-(tert-butyl)-4,5-dihydrooxazol-2-yl)pyridine as the ligand and bifunctional urea derived from (R,R)1,2-diaminocyclohexane (Takemoto urea) (it might be thiourea as mentioned in various occasions above), as shown in Scheme 1.75 [216]. While no allene

Azlactones 105

moiety is apparently noticeable in either the starting material or the product, it is believed that this reaction involves a CuI catalyzed decarboxylation of 4-ethynyl-X-1-tosyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one to yield an electrophilic Cu-allenylidene, to which 4-benzyl-2-phenyloxazol-5-olate derived from the Takemoto urea promoted enolization of 4-benzyl-2-phenyloxazol-5(4H)-one, adds nucleophilically. Subsequent decomposition of the azlactone moiety leads to the final product. This reaction has been further extended to different azlactones under the ideal reaction condition, all yielding the expected products in good to excellent yield as well as excellent enantioselectivity. Further treatment of the product with NBS/AgNO3 yields the corresponding (4aR,10bR)-4a-benzyl-1-(dibromo-methylene)-X-3phenyl-6-tosyl-6,10b-dihydro-1H-[1,3]oxazino[4,5-c]quinolin-5(4aH)-one without erosion of enantiomeric purity; likewise, treatment with NIS and 1-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(dimethylamino)ethyl)thiourea in chloroform leads to (4aR,10bR,E)-4a-benzyl-1-(iodomethylene)-X-3phenyl-6-tosyl-6,10b-dihydro-1H-[1,3]oxazino[4,5-c]quinolin-5(4aH)-one, also without reduction of enantioselectivity [216]. 1.4.1.2.15 Miscellaneous Reactions at C4 of Azlactones A unique reaction involving the C4 of azlactone is a chiral Pd(0) complex in combination with a chiral secondary amine catalyzed asymmetric [3+2] dipolar cycloaddition between vinylcyclopropane azlactone and an α,β-unsaturated aldehyde that affords spirocyclic azlactone in high yield and moderate diastereoselectivity as well as excellent enantioselectivity. A representative reaction is illustrated in Scheme 1.76, for a cooperatively catalyzed reaction between 5-phenyl-1-vinyl-6-oxa-4-azaspiro[2.4]hept-4-en-7-one and cinnamaldehyde using Pd2(dba)3 (5 mol%) and (S)-2-(diphenyl((trimethylsilyl) oxy)methyl)pyrrolidine ((S)-TMS-DPP, 20 mol%) in EtOAc [174]. For this particular reaction, (5S,6S,7S,8R)-4-oxo-2,6-diphenyl-8-vinyl-3-oxa1-azaspiro[4.4]non-1-ene-7-carbaldehyde has been isolated as the major product whereas its diastereomeric isomer (5R,6S,7S,8R)-4-oxo-2,6-diphenyl-8-vinyl-3-oxa-1-azaspiro[4.4]non-1-ene-7-carbaldehyde is a minor product. It is found that the chemical yield, as well as diastereoselectivity, and the enantioselectivity of individual diastereomers can be affected by the choice of the ligand. For example, in the presence of Joergensen’s ligand or the first generation of MacMillan’s ligand, no expected reaction has been observed, in contrast, in the presence of L-Proline, 20% of conversion has been achieved, with a diastereomeric ratio of 3:1 and only 11% of yield. In contrast, in the presence of (S)-2-(diphenyl((trimethylsilyl)oxy)methyl)

base CuI/L*

O

N Ts

CuX-L*

CO2

N Ts

O

O

N

O

Ph

Ph

Ph

O

O

t-Bu

O

base

N

N

base H+

Bn

+

N

N F3C

X N O Ts

Bn N * * O

Ph

CuI (10 mol%) ligand (12 mol%) Takemoto base (25 mol%) Toluene, -10°C

Takemoto base = N H

X

O

X

N Ts

NMe2

base

N H

O Ph

N Ts

O

N

Bn

base H+

N H O

Bn

O Ph

NIS

N

NBS/AgNO3

X

X

N H

I

S

Br

H

N H

H

O

O

Ph

N Bn O

Ph

CF3

N Bn O

CF3

N Ts

N Ts

Br

SCHEME 1.75  The mechanism for the reaction between 4-benzyl-2-phenyloxazol-5(4H)-one and substituted 4-ethynyl-1-tosyl-1,4-dihydro2H-benzo[d][1,3]oxazin-2-one in the presence of Takemoto base and CuI.

X

X

O

t-Bu

ligand =

CF3

106 Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Azlactones 107

pyrrolidine, the highest yield (71%) as well as excellent enantioselectivity (98% ee and 99% ee for the two diastereomers) have been observed. This ideal condition has also been performed in MeCN, THF, CH2Cl2, toluene, and MTBE, which all are inferior to EtOAc. Extension of this reaction to a variety of 5-aryl-1-vinyl-6-oxa-4-azaspiro[2.4]hept-4-en-7-ones as well as different α,β-unsaturated aldehydes provides the corresponding spirocyclic azlactones in good yield and excellent enantioselectivity [174]. O O

+ Ph N

O

Ph

Ph CHO

O

5 mol% Pd2(dba)3 20 mol% (S)-TMS-DPP EtOAc, r.t.

+

O

O N

N Ph

Ph CHO

O

Ph

SCHEME 1.76  A palladium catalyzed reaction between 5-phenyl-1-vinyl-6-oxa-4azaspiro[2.4]hept-4-en-7-one and cinnamaldehyde.

1.4.1.3 REACTIONS AT C5 OF AZLACTONES Generally speaking, C5 is electrophilic as it is a part of the carbonyl group and will behave like the normal carbonyl group in esters. As a result, the nucleophilic attack at C5 will always lead to the opening of the azlactone ring, yielding different derivatives depending on the actual nucleophiles. The most common nucleophiles are primary amines and amino acids and their derivatives (e.g., peptides). Alternatively, alcohols, thiols, oximes, and even water have been applied to react with azlactone cores as described in subsections. 1.4.1.3.1 Reactions with Amines The reaction between amines and azlactones is generally known as the aminolysis of azlactone. Two general reactions between azlactones and amines have been established, i.e., the reaction with amines to form: (a) amides or peptides; and (b) 4,5-dihydro-1H-imidazole or 3,5-dihydro4H-imidazol-4-one derivatives, where the one to yield amides or peptides is the common practice and has been wildly applied to the field of material science. It has been reported that the terminal 2-amino-2-methylpropanoic acid in Boc-Leu3-Aib-OH was converted into oxazolin-5-one core in the presence

108

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

of DCC, which was then coupled with Leu3-OBn, as detailed in the formation of azlactone under acidic condition [103]. However, the aminolysis of 5(4H)-oxazolones originated from N-benzoyl amino acids potentially causes asymmetric induction when amino acid esters are used as amine nucleophiles. It sounds like the asymmetric induction is common during the formation of the peptide bond by means of azlactone intermediate, as the L-L isomeric dipeptide was found to be the predominant form only when methyl L-alaninate was used as the amine nucleophile, while the D-L dipeptides were the major products in other cases. Particularly, the reaction between N-benzoyl-DL-tert-leucine based 5(4H)-oxazolone and methyl L-prolinate almost specifically produces the diastereomeric D-L isomer. Additional studies indicated that low temperature and solvent of low polarity favor the asymmetric induction, particularly for the aromatic solvent. For example, during the aminolysis of L-proline methyl ester with oxazolone of Bz-DLvaline, the percentage of D-Val-L-Pro was found to be 66% (DMF), 87% (toluene), 88% (m-xylene), 89% (o-xylene). A similar result was found for the aminolysis of oxazolone from Bz-DL-Ile with L-proline methyl ester: 79% (DMF), 92% (toluene, m-xylene, or o-xylene) [217]. Similarly, treatment of N-Boc-Val-OH with one equivalent of EtN=C=N(CH2)3NMe2 (EDC) in CH2Cl2 at 23°C gave symmetric anhydride of (Me3CO2C-Val)2O, as well as (S)-2-(tert-butoxy)-4-isopropyloxazol-5(4H)one in ≥ 50% yield. Likewise, (S)-2-(benzyloxy)-4-isobutyloxazol-5(4H)-one was obtained during the treatment of Z-Leu-OH with EDC. The additional reaction of the azlactone with N-acyl amino acid led to the formation of symmetric anhydride, whereas the reaction of azlactone with amino acid ester in the presence of salts afforded the optically pure peptides, although partial racemization occurred in the presence of a tertiary amine [218]. Other condition was also reported to obtain the symmetric anhydride, and a series of peptides with C-terminal azlactone moiety have been prepared to evaluate the racemization of amino acid [219]. This result is somewhat contradicting the asymmetric induction during the formation of peptides, where the isomerization from L-configuration to D-configuration has been largely identified. For example, the EDC promoted coupling of N-benzoylDL-amino acids with L-amino acid esters afforded the D-L-peptides that significantly exceeded 50% yield in some cases, particularly for the reaction between N-Benzoyl-DL-leucine and methyl L-prolinate, that almost exclusively afforded the D-L-peptide (up to 96% yield). This is claimed to be the most efficient dynamic kinetic resolution obtained in the field of amino acids [220].

Azlactones 109

To further study the racemization during the formation of peptides from the reaction of azlactone and amino acid ester, benzyl (S)-(2-(4-benzyl5-oxo-4,5-dihydrooxazol-2-yl)propan-2-yl)carbamate has been allowed to react with a number of amino acid esters in several solvents that are commonly used in peptide chemistry. The results indicated that racemization of azlactone is in a pseudo first-order kinetic when the rate of racemization is much larger than the rate of ring-opening. In contrast, the ring opening reaction always proceeds via 2nd-order kinetics. When the rates of racemization and ring-opening are comparable, azlactone racemization follows 2nd-order kinetics. In addition, chloride or phosphate ions accelerate the rate of racemization, apparently by increasing the ionic strength of the solution. Solvents that can accommodate charge separation by solvation (e.g., dioxane) give rise to much higher extents of azlactone racemization than solvents such as toluene [221]. A recent study on the reaction between azlactone and amino acid reveals some role of fatty acid. It is found that under buffered aqueous conditions, the reaction of (S)-4-(4-methoxybenzyl)-2-methyloxazol-5(4H)-one with (S)-2-amino-4-methylpentanamide, (S)-2-aminopropanamide, 2-aminoacetamide or L-leucine, yields a mixture of the corresponding dipeptide with racemization of the configuration originated from the azlactone core [222]. This result coincides with the aminolysis of azlactone with proline as mentioned previously [217]. However, in the presence of fatty acid, both the yield of dipeptide and the changes in stereoselectivity have been increased significantly when the concentration of the fatty acid exceeds its critical aggregation concentration (should be critical micelle concentration, cmc), forming supramolecular assemblies or vesicles. This result may suggest the dual role of fatty acid as enhancer for both: (a) peptide chemistry under prebiotic conditions that provide soft and hydrophobic organic domains through self-assembly; and (b) actively inducing catalysis at their interface with the aqueous environment. In addition to fatty acid in the aqueous environment, 5–10 mol% of Bronsted acid (e.g., (±)-camphorsulfonic acid) has been proven as an effective catalyst for the reaction between amino acid and azlactone to give dipeptides in CH2Cl2 at room temperature [223]. It has been reported that the coupling of dipeptides containing a C-terminal α,α-disubstituted α-amino acid (e.g., Aib-OH) and ethyl p-aminobenzoate using DCC as the coupling reagent proceeds via 4,4-disubstituted oxazol-5(4H)-one intermediate. However, there is a potential issue with the epimerization of the nonterminal amino acid in dipeptide substrates in the presence of DCC. The application of

110

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

camphorsulfonic acid as a catalyst for this coupling at 0°C has suppressed completely this troublesome side reaction [224]. Another example is the application of CDMT to convert (S)-1-(2-bromo3-methylbutanamido)cyclopentane-1-carboxylic acid in the presence of NMM in CH3CN into its azlactone, i.e., (S)-2-(1-bromo-2-methylpropyl)3-oxa-1-azaspiro[4.4]non-1-en-4-one, which then couples with ethyl (S)-2-amino-4-phenylbutanoate hydrochloride to afford a peptide of ethyl (S)-2-(1-((S)-2-bromo-3-methylbutanamido)cyclopentane-1-carboxamido)4-phenylbutanoate. In contrast, under the optimized condition, the peptide can be formed nearly quantitatively in a one-pot, one-step procedure in the presence of CDMT, which is a stable, crystalline compound of good solubility in organic solvents, and demonstrates several advantages over other peptide coupling agents. The formation of peptides via azlactone intermediate may lose certain configurational purity due to the relatively low stability of azlactone [132]. One more example of reaction between azlactone and amines is the treatment of methyl (1S,4aR,5S,8aR)-1,4a-dimethyl-6methylene-5-(2-(2-((Z)-(5-oxo-2-phenyloxazol-4(5H)-ylidene)methyl) furan-3-yl)ethyl)decahydronaphthalene-1-carboxylate with a primary amine (e.g., benzylamine), an amino acid ester (e.g., methyl L-isoleucinate or tert-butyl L-leucinate) or acid to yield methyl (1S,4aR,5S,8aR)-5-(2(2-((Z)-2-benzamido-3-(benzylamino)-3-oxoprop-1-en-1-yl)furan-3-yl) ethyl)-1,4a-dimethyl-6-methylenedecahydronaphthalene-1-carboxylate, methyl (1S,4aR,5S,8aR)-5-(2-(2-((Z)-2-benzamido-3-(((2S,3S)-1-methoxy3-methyl-1-oxopentan-2-yl)amino)-3-oxoprop-1-en-1-yl)furan-3-yl) ethyl)-1,4a-dimethyl-6-methylenedecahydronaphthalene-1-carboxylate (or methyl (1S,4aR,5S,8aR)-5-(2-(2-((Z)-2-benzamido-3-(((S)-1-(tert-butoxy)4-methyl-1-oxopentan-2-yl)amino)-3-oxoprop-1-en-1-yl)furan-3-yl) ethyl)-1,4a-dimethyl-6-methylenedecahydronaphthalene-1-carboxylate) or (Z)-2-benzamido-3-(3-(2-((1S,4aR,5S,8aR)-5-(methoxycarbonyl)-5,8adimethyl-2-methylenedecahydronaphthalen-1-yl)ethyl)furan-2-yl)acrylic acid, respectively (Scheme 1.77) [2]. The corresponding azlactone has been prepared from the condensation of 16-formyllambertianic acid methyl ester with hippuric acid in a 44% yield. In this series of reactions with amines, it is clear that the lowest yield of amide was obtained in the reaction with 3,5,6-trimethoxybenzylamine, whereas extension of the alkyl chain between phenyl and amino group increases the yield of the corresponding product. However, reactions of azlactone with the secondary amines (e.g., piperidine, and N-methylphenylmethanamine) require prolonged heating, due to the increased steric hindrance [2].

Azlactones 111

Likewise, benzoyl-L-alanylglycine or benzoyl-L-leucylglycine has been converted into the corresponding azlactone with carbodiimide, and the resulting azlactone is subsequently treated with a series of nucleophilic amines (octan-1-amine, benzylamine, and aniline) or alcohols (butan-1-ol, octan-1-ol, benzyl alcohol, and isopropanol) to afford the corresponding bisprotected amino acid derivatives in moderate to excellent yields [6]. Based on so many examples, it is clear that azlactone moiety can be considered as an activated ester functionality of reactivity different from traditional ester functionalities. Consequently, other functional groups can be introduced in a controlled manner. For example, the pentafluorophenyl group has been commonly applied to activate an ester group. Kinetic studies on the reaction of perfluorophenyl acrylate or 4,4-dimethyl-2-vinyloxazol-5(4H)-one (DMV) with benzylamine in DMSO or CH3CN indicate a much higher reactivity of perfluorophenyl acrylate over DMV. O

OH

O

O

O

NHCOPh

N O PhCONHCH2CO2H Ac2O, K2CO3

MeO

O

H O PhCH2NH2 ° benzene, 75 C H N

O

Ph

MeO

O

H+

H O

H O

MeO

methyl L-isoleucinate ° benzene, 75 C O

HN

NHCOPh

O

t-butyl L-leucinate ° benzene, 75 C

HN

NHCOPh

O

H O MeO

H O

O O-t-Bu

NHCOPh

O

MeO

O

OMe

O

MeO

H O

SCHEME 1.77  The reaction of methyl (1S,4aR,5S,8aR)-1,4a-dimethyl-6-methylene-5(2-(2-((Z)-(5-oxo-2-phenyloxazol-4(5H)-ylidene)methyl)furan-3-yl)ethyl)decahydronaphthalene-1-carboxylate with acid, primary amine and amino acid.

Poly(ethylene glycol)s (PEGs) as eco-friendly solvents of high polarity and high boiling point have been applied for the reaction between azlactones and diamines (e.g., propane-1,3-diamine or ethane-1,2-diamine) to afford diamides at room temperature, such as the reaction of (Z)-2-phenyl4-(thiophen-2-ylmethylene)oxazol-5(4H)-one with propane-1,3-diamine

112

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

to afford N,N’-((2Z,2’Z)-(propane-1,3-diylbis(azanediyl))bis(1-oxo-3(thiophen-2-yl)prop-2-ene-1,2-diyl))-dibenzamide as demonstrated in Scheme 1.78, where Ar = thiophen-2-yl [225]. Interestingly, it is reported that such diamides can be transformed back to the corresponding azlactone in excellent yield in 10 minutes in the presence of PdCl2 or Pd(OAc)2 in ethanol. It should be pointed out that the direct treatment of azlactone with ammonia in ethanol will afford N-acyl α-amino amide [226].

Ar N

O

+ H2 N

NH2

PEG-400 r.t.

N H Ar

NH

HN

Ph

Ph

Ar O O

O

O N

HN

O

Ph

Ar

O

O

O

NH

O + H2N

NH2

PEG-400 r.t.

Ar

N H

NH

HN

Ph

Ph

O

Ph PdCl2 or Pd(OAc)2

Ar O

EtOH Ar =

S

OMe MeO

Cl

Br

O2N

Cl

Cl

SCHEME 1.78  The reaction of (Z)-4-arylidene-2-phenyloxazol-5(4H)-one with ethane-1,2diamine or propane-1,3-diamine in PEG-400.

A particular reaction condition between azlactone and a tertiary amine such as dihydroisoquinoline or 1-substituted dihydroisoquinoline should be mentioned which undergoes an initial nucleophilic addition of the nitrogen atom to the C5-position of azlactone to open the azlactone moiety but followed by three distinctive pathways to afford midazoloisoquinolin3-one, benzo[a]quinolizine-4-one, and benzo[d]azocin-4-one, respectively [227]. Specifically, the reaction of 1-methyl-3,4-dihydroisoquinoline) with (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one yields (Z)-1-benzoyl-2benzylidene-10b-methyl-1,5,6,10b-tetrahydroimidazo[2,1-a]isoquinolin3(2H)-one, whereas the reaction of 1-unsubstituted 3,4-dihydroisoquinoline

Azlactones 113

such as 6,7-dimethoxy-3,4-dihydroisoquinoline with 2-phenyloxazol5(4H)-one gives 1-benzoyl-8,9-dimethoxy-1,5,6,10b-tetrahydroimidazo[2,1a]isoquinolin-3(2H)-one. On the other hand, refluxing of 6,7-dimethoxy1-methyl-3,4-dihydroisoquinoline with (Z)-4-benzylidene-2-phenyloxazol5(4H)-one in acetonitrile affords 89% of N-(9,10-dimethoxy-4-oxo-2-phenyl3,4,6,7-tetrahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)benzamide with a cis/ trans ratio of nearly 3:1. In contrast, the reaction between 6,7-dimethoxy1-methyl-3,4-dihydroisoquinoline and 2-phenyloxazol-5(4H)-one affords 56% of (E)-N-(8,9-dimethoxy-6-methyl-4-oxo-1,2,3,4-tetrahydrobenzo[d] azocin-5-yl)benzamide, as illustrated in Scheme 1.79 [227]. In addition to the above examples, more examples of the reactions between amines and azlactones have been found in the post-modification of polymers containing azlactones as the side chains, so that a variety of functional groups can be mounted to the polymers. Many of these azlactonecontaining polymers are prepared from the polymerization of vinyl dimethyl azlactone (VDM). For example, when statistical and block copolymers of VDM and pentafluorophenyl acrylate (PFPA), i.e., (p(VDM-stat-PFPA)) and (p(VDMblock-PFPA)), prepared by reversible addition-fragmentation transfer (RAFT) polymerization, are modified with a library of amines (e.g., N1,N1-diethylethane-1,2-diamine, 2-(1H-imidazol-4-yl)ethan-1-amine, 3-morpholinopropan-1-amine, 1-aminopropan-2-ol, and poly(ethylene glycol)-amine), macromolecules of bespoke functionality have been achieved [228]. Another example involving the reaction between azlactone and amine to form functional materials is to mount an azlactone-containing moiety to the surface of graphene to build a reactive azlactone graphene platform (RAGP) by means of the “Click Chemistry.” To do so, 2-amino-2-methylpropanoic acid is acylated with 4-(azidomethyl)benzoyl chloride to afford 2-(4-(azidomethyl) benzamido)-2-methylpropanoic acid, which is then dehydrated with ethyl carbonochloridate to generate 2-(4-(azidomethyl)phenyl)-4,4-dimethyloxazol5(4H)-one. On the other hand, propargyl alcohol is mounted to the surface of graphene via ether linkage, and the subsequent Cu(I) catalyzed 1,3-dipolar cycloaddition between the azido group of the azlactone component and the C-C triple bond of the graphene affords the azlactone functionalized graphene. The azlactone moiety of the RAGP is further treated with 3-(triethoxysilyl)propan1-amine or (2S,2’S)-5,5’-(((2S,2’S)-disulfanediylbis(3-((carboxymethyl) amino)-3-oxopropane-1,2-diyl))bis(azanediyl))bis(2-amino-5-oxopentanoic acid) (GSSG) for the purpose of the development of novel biosensors in the context of nanoscale detection of pathogens and other metabolites related to issues of human health [229].

114

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O O

N

O

+

N

N

Ph

Ph

CH3CN

N

Ph O

Ph O N

O

OMe

O

+

N

OMe

CH3CN

N

Ph

N O

OMe

Ph OMe MeO

O

OMe

O

+

N

OMe

N

Ph

N

MeO Ph

CH3CN H

Ph

MeO OMe N

NH

O

N

O

MeO

O

+ OMe

O O H Ph N H

CH3CN Ph

NH O Ph

SCHEME 1.79  The reactions of substituted 3,4-dihydroisoquinolines with azlactones.

In another example, the aminolysis of azlactone has been applied to postmodify the polymer side chain after ring-opening metathesis polymerization (ROMP) of a heterofunctional azlactone-based monomer, namely 2-((1S,4S)-bicyclo[2.2.1]hept-5-en-2-yl)-4,4-dimethyloxazol-5(4H)-one, which can be prepared from the Diels-Alder cycloaddition between 2-vinyl4,4-dimethyl-5-oxazolone and cyclopentadiene. In this approach, the ROMP of this monomer has been catalyzed by (1,3-bis-(2,4,6-trimethylphenyl)-2imidazolidinylidene) (phenylmethylene)bis(pyridine)ruthenium dichloride. The azlactone moiety of the resulting polymer side chain was then treated with 2-(2-(2-(3-azidopropoxy)ethoxy)ethoxy)ethan-1-amine alone or in the presence of 1-aminopropan-2-ol (the ratio can be varied), to introduce the azido functionality to the end of the polymer side chain. The azido functionality is well-known to undergo the “Click Chemistry” with the alkyne group by means of 1,3-dipolar cycloaddition, such as in the reaction with 3’,6’-dihydroxy-3-oxo-N-(prop-2-yn-1-yl)-3H-spiro[isobenzofuran1,9’-xanthene]-5-carboxamide. The concept of this approach is illustrated in Scheme 1.80 [230]. Many alternative examples can be found in the section of the application.

Azlactones 115

m

p

O N

n

ROMP cat.

O

O

N3

N

and/or OH NH2

O

O

HN

NH2

3

O

O HN

O

O NH

O

NH

3

HO

N3 HO

O

OH

HO N N N

O H N

OH

O O

O

O

3

O

O

HN HN

HN O

O O

NH O

OH

NH

N

N

O Cl Ru Cl p

m

cat. =

N

N

(n = m + p)

SCHEME 1.80  Side chain functionalization of 4,4-dimethyl-azlactone-containing polymers with primary amines.

In addition to the example of forming cyclized product as shown in Scheme 1.79, more examples to form the cyclized products from the reaction of azlactones and primary amines include: (a) the reaction of (Z)-4-((5-chloro-3-methyl-1phenyl-1H-pyrazol-4-yl)methylene)-2-phenyloxazol-5(4H)-one with o-phenyl enediamine in 50% acetic acid to yield (Z)-N-(1-(1H-benzo[d]imidazol-2-yl)-2(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)vinyl)benzamide [23]; (b) a series reactions between (Z)-4-((4-oxo-4H-chromen-3-yl)methylene)-2-phenyloxazol5(4H)-one and amines such as pyridin-2-amine in refluxing acetic acid in the presence of sodium acetate to generate 78% of (Z)-5-((4-oxo-4H-chromen-3-yl) methylene)-2-phenyl-3-(pyridin-2-yl)-3,5-dihydro-4H-imidazol-4-one as an orange red crystal [43]; (c) condensation between (Z)-4-((4-oxo-4H-chromen3-yl)methylene)-2-phenyloxazol-5(4H)-one and a series of aniline derivatives as well as amino acids, that affords (Z)-3-hydroxy-2-(5-oxo-4-((4-oxo-4Hchromen-3-yl)methylene)-2-phenyl-4,5-dihydro-1H-imidazol-1-yl)propanoic acid when serine is specifically chosen to react with the azlactone [41]; and (d) the reaction of (Z)-4-(4-(dimethylamino)benzylidene)-2-phenyloxazol-5(4H)one with p-toluidine in ethanol in the presence of zeolite to give

116

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

(Z)-5-(4-(dimethylamino)benzylidene)-2-phenyl-3-(p-tolyl)-3,5-dihydro-4Himidazol-4-one [40]. 1.4.1.3.2 Reactions with Alcohols Nucleophilic attack of azlactone by alcohol is known as alcoholysis of azlactone, which generally leads to N-acyl amino acid ester, as indicated in the reaction of butan-1-ol, octan-1-ol, benzyl alcohol, or isopropanol with N-(1-(5oxo-4,5-dihydrooxazol-2-yl)ethyl)benzamide or N-(3-methyl-1-(5-oxo-4,5dihydrooxazol-2-yl)butyl)benzamide [6]. However, due to the instability of azlactones and the high potential of racemization of azlactones derived from chiral amino acids, the reaction of azlactones with alcohols has often been applied to generate asymmetric N-acyl amino acid esters, a protocol generally known as the dynamic kinetic resolution in the ring-opening (de-racemization) of azlactone. For example, in the presence of 100% weight equivalent of enzyme and additive in methyl butyl ether, 4-(2-fluoro-2-methylpropyl)-2-phenyloxazol-5(4H)-one has been converted into ethyl (S)-2-benzamido-4-fluoro4-methylpentanoate, i.e., (S)-N-benzoyl ethyl γ-fluoro-leucinate with very good enantioselectivity. In this practice, the azlactone is prepared by a consecutive reaction of ethyl 2-((diphenylmethylene)amino)acetate with 1-bromo-2-fluoro2-methylpropane to give ethyl 4-fluoro-4-methyl-2-(diphenylmethyleneamino) pentanoate, hydrolysis, and benzoylation of the amino group lead to ethyl 2-benzamido-4-fluoro-4-methylpentanoate, and final conversion to azlactone with EDCI, as demonstrated in Scheme 1.81 [231].

3K

)

)

3K

D .2%XW'0) &2(W E %U )

1

) 3K&2&O 1D+&2 07%(+2

2 3K

1 +

2

3K

3K 3K

1

&2(W

)

&O +1

&2(W

)

1D2+ 07%(+

2 3K

(Q]\PHZWHTXLY (W2+HT 07%( $GGLWLYH

2 1

&2(W

1+&O 07%(

&2+

1 +

('&, &+&O

) 2 3K

1 +

&2(W

SCHEME 1.81  Preparation of 4-(2-fluoro-2-methylpropyl)-2-phenyloxazol-5(4H)-one and its enzymatic conversion into ethyl (S)-2-benzamido-4-fluoro-4-methylpentanoate.

Azlactones 117

Compared to the enzyme-promoted dynamic kinetic resolution of racemic azlactones, the application of a C2-symmetric squaramide-based catalyst for enantioselective azlactone dynamic kinetic resolution to generate orthogonally protected amino acids has been developed. Under this condition, the reaction of benzyl alcohol with isopropyl 2,3,4,5-tetrachloro-6-(4-substituted5-oxo-4,5-dihydrooxazol-2-yl)benzoate generates benzyl (S)-2-(4,5,6,7tetrachloro-1,3-dioxoisoindolin-2-yl)-substituted acetate with excellent enantioselectivity, such compound can be further converted into an orthogonally protected amino acid, e.g., N- or C-protected amino acid (Scheme 1.82) [232]. In this particular exercise, in the presence of a catalytic amount of 3,4-bis(((R)-(6-methoxyquinolin-4-yl)-((1S,2R,4S,5R)-5-vinylbicyclo[2.2.2] octan-2-yl)methyl)amino)cyclobut-3-ene-1,2-dione, isopropyl 2-(4-benzyl5-oxo-4,5-dihydrooxazol-2-yl)-3,4,5,6-tetrachloro-benzoate was treated with two equivalents of benzyl alcohol followed by base 1,4-diazabicyclo[2.2.2] octane (DABCO) to afford 99% of benzyl (S)-3-phenyl-2-(4,5,6,7-tetrachloro1,3-dioxoisoindolin-2-yl)propanoate with excellent enantio-selectivity (98% ee). Selective treatment of this molecule results in either N-protected or C-protected phenylalanines with excellent yields. Extension of this process using N-protected serines (e.g., methyl (tert-butoxycarbonyl)-L-seryl-L-alaninate at stoichiometric loadings) leads to a highly stereoselective ligation-type coupling of serines with racemic azlactones derived from either natural or abiotic amino acids. After deprotection, a base-mediated O→N acyl transfer occurs to form a tripeptide (Scheme 1.83) [232]. Based on this strategy, a simple model of dynamic kinetic resolution of azlactones in the presence of 10 mol% benzoic acid and 3 mol% N2,N6-diphenyl-4-(pyridin-4-yl)-4,5-dihydro-3H-dinaphtho[2,1-c:1’,2’-e] azepine-2,6-dicarboxamide has been developed. The reaction of a wide range of azlactones with 3 equivalents of isopropanol proceeds smoothly in the presence of this catalyst to provide α-amino acid derivatives with good to high enantiomeric ratios. Furthermore, such a reaction has been made to a multigram scale for the dynamic kinetic resolution of 2.5 g of 4-(naphthalen1-ylmethyl)-2-phenyloxazol-5(4H)-one into 91% of unnatural α-amino acid derivative, i.e., isopropyl (S)-2-benzamido-3-(naphthalen-1-yl)propanoate with 96:4 of enantioselectivity. Additional purification of this compound by recrystallization leads to increased enantioselectivity of > 99:1. Acidic hydrolysis of this amino acid derivative gives 43% of an unnatural amino acid (S)-2-amino-3-(naphthalen-1-yl)propanoic acid hydrochloride with 98% ee [233]. More examples of the dynamic kinetic resolution of azlactones with alcohols have been reported elsewhere [234].

118

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Cl

O

Cl

Ph N OH

Cl H

O

H H

1)

Ph Cl

MeO

OMe

Pd/C, H2 (1 atm) EtOAc/CH2Cl2 r.t., 20 min

H

H

Cl

O

Cl

Ph N

2.0 eq. PhCH2OH, CHCl3, -30 °C, 16 hrs 2) DABCO (40 mol%), r.t., 24 hrs

O Cl

(99%)

H N (10 mol%) H

O O

Cl

HN

H

N

Cl

NH

N

O

O

O

Cl

O

Cl

Ph

O O Cl 99%, 98% ee

O

H2 N

NH2 (2.0 eq.) THF, r.t., 24 hrs Ph H2N O O (91%)

Ph

SCHEME 1.82  Conversion of azlactone into N- or C-protected amino acid. +



3K &O

2

1

&O

2 2

&O &O

2

2 

2

2

2

+ +

1+

+1

+

0H2

1

2

+

+

&20H

20H

1+

1+

2

ƒ HT3K&+2+&+&O&KUV ƒ 1+%RF  '$%&2PRO &+&O&KUV

2+

2

3K 2

1

2

&O

&O &O

&O  7)$&+&OEDVLFZRUNXS  '0$3PRO &+&OUWGD\V

1+%RF

2 + 1 PRO +

&O

2 3K 1

&O &O

2

2 +2

&O

GU 2 1+ +1 2

GU

SCHEME 1.83  A base-mediated O→N acyl transfer to form a tripeptide.

2

Azlactones 119

A series of reactions between 2-phenyl-azlactones and nucleophiles (such as 1-octanol and octan-1-amine) in the presence of a catalytic amount of Brønsted acid (e.g., camphorsulfonic acid) in CH2Cl2 give 2-benzoylamino esters or amides in good to very high yields. The Brønsted acid facilitates the activation of the azlactone ring, and the azlactones studied include 2-phenyloxazol-5(4H)-one, 4-methyl-2-phenyloxazol-5(4H)-one, 4-isopropyl-2-phenyloxazol-5(4H)-one, 4-isobutyl-2-phenyloxazol-5(4H)one and 4-benzyl-2-phenyloxazol-5(4H)-one [235]. In addition to the camphorsulfonic acid that facilitates the activation of azlactone, a unique organic compound with a 1,3-keto-enol moiety, such as N-(1H-benzo[d]imidazol-2-yl)-8-bromo-4-hydroxy-2-oxo-1,9bdihydrodibenzo[b,d]furan-4a(2H)-carboxamide, functions as an acid catalyst with hydrolytic activity in the dynamic resolution of azlactones during alcoholysis. In addition, such compound has shown moderate enantioselectivity for the obtained esters from the alcoholysis (isopropanol or diphenylmethanol) of 4-methyl-2-phenyloxazol-5(4H)-one, 4-isopropyl2-phenyloxazol-5(4H)-one, etc. [236]. 1.4.1.3.3 Reactions with Thiols Thiols are often considered as superior nucleophiles than their corresponding alcohol counterparts, as well as better leaving groups in thioesters. Therefore, there is an obvious advantage to conduct the dynamic kinetic resolution of azlactones using thiols instead of alcohols. In fact, several practices have already been performed in this area. For example, when racemic 4-methyl-2-phenyloxazol-5(4H)-one was treated with three equivalents of cyclohexanethiol in CH2Cl2 at room temperature, in the presence of 5 mol% of 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1S)-((2S,4S,5S)-5ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methyl)urea (67, Figure 1.12), S-cyclohexyl (S)-2-benzamidopropanethioate was obtained in 98% yield with 50% ee, whilst the yield slightly decreased to 90% at –30°C, the enantioselectivity has been enhanced to 64% ee [237]. In comparison, when racemic 4-methyl-2-phenyloxazol-5(4H)-one was treated with three equivalents of (4-(tert-butyl)phenyl)methanethiol in the presence of 5 mol% 3,4-bis(((R)-(6-methoxyquinolin-4-yl)((1S,2R,4S,5R)-5-vinylbicyclo[2.2.2] octan-2-yl)methyl)amino)cyclobut-3-ene-1,2-dione (68, Figure 1.12) in CH2Cl2, S-(4-(tert-butyl)benzyl) (S)-2-benzamidopropanethioate was obtained in 99% yield, but with only 26% ee [238]. Likewise, treatment of

120

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

racemic 2-(furan-2-yl)-4-methyloxazol-5(4H)-one with two equivalents of (4-(tert-butyl)phenyl)methanethiol in CH2Cl2 in the presence of 10 mol% of 1-((R)-((1S,2R,4S,5S)-5-ethylbicyclo[2.2.2]octan-2-yl)(6-methoxyquinolin-4-yl)methyl)naphthalen-2-ol (69, Figure 1.12) led to 86% of 4-(tert-butyl) benzyl (R)-2-(furan-2-carboxamido)propanethioate with 73% ee. However, the reaction of analogous 2-(furan-2-yl)-4-isopropyloxazol-5(4H)-one afforded 82% of 4-(tert-butyl)benzyl (R)-2-(furan-2-carboxamido)-3methylbutanethioate, with only 23% ee [239]. Further development of chiral catalyst, such as 4-((R)-((1S,2S,4S,5R)-5-ethylquinuclidin-2-yl)(hydroxy) methyl)-6-methoxy-8-((E)-phenyldiazenyl)quinolin-5-ol (70, Figure 1.12) has led to improved enantioselectivity, as indicated in the treatment of a series of 4-substituted-2-(4-(trifluoromethyl)phenyl)oxazol-5(4H)-ones with four equivalents of (4-(tert-butyl)phenyl)methanethiol in CH2Cl2 at –70°C, with enantioselectivity greater than 84% ee. However, the chemical yields of the corresponding thioesters are only moderate [240]. H

H

H N

H MeO

H

H N

H N

CF3

NH

N

O

O

H

HN

H

OMe H

H

O MeO

H H

N

CF3

N

68

67 H H OH H MeO

H

N 69

OH N HO

N

MeO

N

N

Ph

70

FIGURE 1.12  Chiral catalysts for the reaction between azlactones and thiols.

Similar to the reaction between azlactone and a-chymotrypsin to form peptide where the azlactone is applied as the acylating agent, papain, a thiol protease, has also been proven to be capable of undergoing a similar reaction, using azlactones as the acyl donors in peptide segment condensations. The effectiveness of this methodology has been illustrated by the successful

Azlactones 121

coupling of oxidized insulin B chain (30 residues) to angiotensin III (7 residues) in 59% yield, as well as a series of short peptides (from dipeptides and beyond) [241]. 1.4.1.3.4 Reactions with Oximes Compared to alcohols, oximes represent a valuable class of oxygen nucleophiles with increased acidity and nucleophilicity [242]. When oximes are applied as the nucleophiles to react with azlactones, N-acyl amino acid oxime esters can be obtained, particularly the chiral amino acid oxime esters by means of the dynamic kinetic resolution of azlactones in the presence of a chiral catalyst. For this purpose, chiral bisguanidinium salts such as (S,E)-N-benzhydryl-2-(N,N’-dicyclohexylcarbamimidoyl)-1,2,3,4tetrahydroisoquinoline-3-carboxamide (71, Figure 1.13), (S,E)-N-benzhydryl1-(N,N’-dicyclohexylcarbamimidoyl)pyrrolidine-2-carboxamide (72), (1S,3aS,6aR)-N-benzhydryl-2-((E)-N,N’-dicyclohexylcarbamimidoyl) octahydrocyclopenta[c]pyrrole-1-carboxamide (73), (2S,2’S)-N,N’-((1S,2S)1,2-diphenylethane-1,2-diyl)bis(1-((E)-N,N’-dicyclohexylcarbamimidoyl) pyrrolidine-2-carboxamide) (74), (2S,2’S)-N,N’-((1S,2S)-1,2diphenylethane-1,2-diyl)bis(1-((E)-N,N’-dicyclohexylcarbamimidoyl) piperidine-2-carboxamide) (75) and (2S,2’S)-N,N’-(1,3-phenylene) bis(1-((E)-N,N’-dicyclohexylcarbamimidoyl)-piperidine-2-carbox-amide) (76) have been tested as the catalysts. Among these chiral catalysts, the bisguanidinium salt (75) of tetrakis(3,5-bis(trifluoromethyl)phenyl)λ4-borate (HBArF4) is especially effective, from which a variety of chiral N-acyl amino acid oxime esters have been generated in excellent enantiomeric excesses (up to 97%) and high yields (up to 99%). An example of the complex 75·HBArF4 catalyzed dynamic kinetic resolution of azlactone is the one between 4-isobutyl-2-phenyloxazol-5(4H)-one and (E)-4-methoxybenzaldehyde oxime that affords 97% of (R,E)-N-(1-(((4methoxybenzylidene)amino)oxy)-4-methyl-1-oxopentan-2-yl)benzamide with 94% ee (Scheme 1.84) [242]. The resulting active oxime esters could be used in dipeptide synthesis, as shown in the reaction between (R,E)-N(1-((benzylideneamino)oxy)-4-methyl-1-oxo-pentan-2-yl)benzamide and (S)-3-hydroxy-1-methoxy-1-oxopropan-2-aminium chloride (i.e., methyl L-serinate hydrochloride) to yield methyl N-benzoyl-D-leucyl-L-serinate in yield of 84% with 5:95 diastereoselectivity and 99% ee (Scheme 1.84) [242].

122

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O N

O

CHPh2

N

H

N Cy N

Cy

Cy N

H

Cy

Ph

Ph

N

Cy N

O

N

N

Ph

N H

Cy N

N Cy

O

O

O N

N

N

N

N

N Cy Cy

H

Cy H

73

H H

N

N

Cy Cy H

Ph N

H H

N

72

O

N

Cy N

H

H

Cy N

N Cy

N H

H

Cy

Cy

N

N

N

H

H

75

74

CHPh2 H

N

N

71

O

N

H

N

N

O

CHPh2

N Cy

76

FIGURE 1.13  The chiral catalysts for the reaction between azlactones and oximes.

O MeO

+ N OH

O

N

5 mol% 75 HB(ArF)4 toluene, -40 °C

O Ph

O

N H

N

O

Ph

OMe

97 % yield, 94% ee

O O Ph

N H

O O

+ N

Ph

HO Cl NH3

O

O

Et3N THF, 60 °C, 20 hrs

Ph

N H

H N O

O

OH O

84% yield, 5:95 dr, 99% ee

SCHEME 1.84  Preparation of methyl N-benzoyl-D-leucyl-L-serinate via dynamic kinetic resolution of azlactone.

1.4.1.3.5 Miscellaneous Reactions at C5 of Azlactones In addition to so many reactions involving azlactones as described above, alternative azlactone participating reactions do exist, depending on the actual reaction partners. For example, the reaction between (Z)-2-(4-chlorophenyl)4-(4-methoxybenzylidene)oxazol-5(4H)-one and anthranilic acid yields (Z)-4-chloro-N-(2-(4-methoxyphenyl)-1-(4-oxo-4H-benzo[d][1,3]

Azlactones 123

oxazin-2-yl)vinyl)benzamide, which is then treated with benzene-1,2-diamine to give (Z)-N-(1-(benzo[4,5]imidazo[1,2-c]quinazolin-6-yl)-2-(4-methoxyphenyl)vinyl)-4-chlorobenzamide. Further treatment of this compound with phenylhydrazine leads to the formation of 6-(3-(4-chlorophenyl)-6-(4methoxyphenyl)-1-phenyl-1,4,5,6-tetrahydro-1,2,4-triazin-5-yl)benzo[4,5] imidazo[1,2-c]quinazoline (Scheme 1.85) [243]. In another reaction, the nucleophilic attack of (Z)-4-(4-methoxybenzylidene)-2-phenyloxazol5(4H)-one with 6-aminopyrimidine-2,4(1H,3H)-dione affords N-(2-(4methoxyphenyl)-4,6,8-trioxo-1,3,4,6,7,8-hexahydro-2H-pyrimido[1,6-a] pyrimidin-3-yl)benzamide, which is then treated with acetic anhydride to yield 5-acetyl-4-(4-methoxyphenyl)-9-oxo-2-phenyl-5,9-dihydro-4H-furo[3,2-e] pyrimido-[1,6-a]-pyrimidin-7-yl acetate (Scheme 1.85) [243]. Similarly, the reaction of (Z)-4-(4-methoxybenzylidene)-2-phenyloxazol-5(4H)-one with 5-phenyl-1,3,4-thiadiazol-2-amine gives N-(7-(4-methoxyphenyl)-5-oxo-2phenyl-6,7-dihydro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-6-yl)benzamide, which is then treated with acetic anhydride to generate 5-(4-methoxyphenyl)2,7-diphenyl-3aH-oxazolo[4,5-e]-[1,3,4]thiadiazolo[3,2-a]pyrimidine (Scheme 1.85) [243]. Due to the high reactivity at the C5 (the carbonyl C) toward nucleophilic attack, oxazolin-5-ones have been applied as the substrates for a number of hydrolytic enzymes, where 2-phenyloxazolin-5-one and 4,4-dimethyl2-phenyloxazolin-5-one react rapidly with α-chymotrypsin, trypsin, and papain to form relatively stable acyl-enzymes [244]. While azlactone has not popularly been used for peptide synthesis, limited practice has already shed light on the potential of this approach, using α-chymotrypsin. α-Chymotrypsin is known to be an endopeptidase with a primary specificity for peptide substrates containing aromatic amino acids in the P1 position. In the presence of azlactone-containing peptide, α-chymotrypsin rapidly cleaved the azlactone ring of the peptide fragment bearing a large C-2 backbone to generate the acyl-enzyme, which was deacylated by the N-terminal group of the succeeding peptide fragment at rates faster than the competing hydrolysis of the acyl-enzyme intermediates. In addition, when the racemic amino acid based azlactone was applied as the acyl donor, the enzyme showed a preference for the azlactone of L-amino acid origin. Under this condition, the protection of the C-terminal carboxyl group is unnecessary. The validity of this approach has been confirmed by the preparation of several oligopeptides containing 8 to 24 amino acid residues in overall yields of 57–97% [245].

124

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O

Cl

O O

O N

OH

+

MeO

NH2

O

O

NH2

NH

N

NH2 Cl

O

Cl N O N N

N

PhNHNH2

NH

O O H2 N

MeO

H N

O

NH

+ N H

N

HN

O

Ph

O

O

O H2N

S

N

NH O

N O

Ph

N Ph

OAc

Ac2O

MeO

N N +

Ac N

O

MeO

O

Ph MeO

MeO

O

N

OMe

N N

Cl

OMe

N

N

HN

N

N N

HN

MeO Ph

O

N

S Ph

Ac2O

S N N

N

Ph

O

O Ph

SCHEME 1.85  Examples of the reactions at C5 of azlactones.

Due to the easy acylation of enzyme with azlactone, a series of azlactone-based heterofunctional linkers bearing two orthogonally clickable groups have been prepared, such as 2-(1-azidoethyl)-4,4-dimethyloxazol-5(4H)-one (77), 1-(4,4-dimethyl-5-oxo-4,5-dihydrooxazol-2-yl) ethyl hex-5-ynoate (78), 1-(4,4-dimethyl-5-oxo-4,5-dihydrooxazol-2-yl) ethyl propiolate (79), 1-(4,4-dimethyl-5-oxo-4,5-dihydrooxazol-2-yl)ethyl (2E,4E)-hexa-2,4-dienoate (80), 1-(4,4-dimethyl-5-oxo-4,5-dihydrooxazol2-yl)ethyl 3-(furan-2-yl)propanoate (81), 1-(4,4-dimethyl-5-oxo-4,5-dihydrooxazol-2-yl)ethyl 3-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)propanoate (82), 1-(4,4-dimethyl-5-oxo-4,5-dihydrooxazol-2-yl)ethyl (1r,4r)-4-((2,5dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexane-1-carboxylate (83), and 1-(4,4-dimethyl-5-oxo-4,5-dihydrooxazol-2-yl)ethyl 6-amino-6-oxohexanoate (84). The amino group in 84 is a (Z)-5,6-dihydrodibenzo[b,f]azocine moiety with the double bond substituted with a triple bond. All these structures are displayed in Figure 1.14 [246]. Another example of heterofunctional links contains the moieties of azlactone, triple, and double bonds, such as 4,4-diallyl2-(4-ethynylphenyl)oxazol-5(4H)-one [247].

Azlactones 125

These compounds can be prepared from the further substitution of 2-(1-bromoethyl)-4,4-dimethyloxazol-5(4H)-one with the corresponding nucleophiles, where 2-(1-bromoethyl)-4,4-dimethyloxazol-5(4H)-one is synthesized from the reaction between 2-amino-2-methylpropanoic acid (i.e., amino acid Aib) and 2-bromopropanoyl bromide and further treatment with ethyl carbonochloridate in the presence of Et3N. All these bifunctional linkers can quickly react with the amino group of lysozyme at the azlactone moiety in a biologically relevant medium without byproduct elimination, and the remaining functional groups further undergo facile and selective click reactions, such as thiol-ene coupling, Diels-Alder reaction, or azidealkyne cycloadditions [246]. O O

O

N

N3

N

O

O N

O

O O

O

O

O

77

N

O O

O

79

78

80 O

N3

O O

O

O

O

O

N

O

N

O

O O

O

81

82 O O

O

N

O

N

O

N

O O

O

N

O O

O 83

84

FIGURE 1.14  4,4-Dimethylazlactone-containing bifunctional linkers for the Click Chemistry.

Another unique reaction is the thermolysis of 2,4-disubstituted 4-acyl-2-oxazolin-5-ones and 2,4-disubstituted 2-acyl-3-oxazolin-5ones, which afford 2,4,5-trisubstituted oxazoles via cycloelimination of CO2. Particularly, for the case of 2,4-disubstituted 2-acyl-3-oxazolin5-ones, the substituents at C-2 and C-4 were interchanged. For example, thermolysis of 4-acetyl-4-methyl-2-phenyloxazol-5(4H)-one gives 87% of 4,5-dimethyl-2-phenyloxazole, whereas thermolysis of 2-benzoyl-4methyl-2-(trifluoromethyl)oxazol-5(2H)-one affords 94% of 2-methyl-5phenyl-4-(trifluoromethyl)oxazole, respectively. In contrast, thermolysis of 4-isopropyl-2-phenyloxazol-5-yl acetate in γ-picoline leads to a mixture

126

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

of 2-isopropyl-5-methyl-4-phenyloxazole and 4-acetyl-4-isopropyl2-phenyloxazol-5(4H)-one, as illustrated in Scheme 1.86 [248]. Another approach to convert the azlactones into oxazoles has been achieved under the Friedel-Crafts reaction condition, as represented by the conversion of 4-methyl-2-phenyloxazol-5(4H)-one into 78% of 5-(4-methoxyphenyl)4-methyl-2-phenyloxazole when the azlactone was treated with anisole in 1,2-dichloroethane in the presence of AlCl3 and TfOH (Scheme 1.87) [249]. It is believed that this reaction involves the ring-opening of azlactone in the presence of AlCl3, where the azlactone functions as the acylating reagent for the anisole, yielding N-(1-(4-methoxyphenyl)-1-oxopropan-2-yl)benzamide intermediate. In the presence of TfOH, the reaction intermediate undergoes cyclization to give 5-(4-methoxyphenyl)-4-methyl-2-phenyl-4,5-dihydrooxazol-5-ol. Dehydration of the latter intermediate leads to the final product. However, this reaction sounds to be sensitive to the reaction condition, as the model reaction tested with 2-phenylazlactone has been converted to the first intermediate in 85% yield in the presence of either AlCl3, AlCl3/ P2O5, or AlCl3/POCl3, in reaction with benzene, but no oxazole product has been formed. In the presence of other Lewis acid/dehydrating agents, such as TfOH, AlCl3/TFAA, TFAA, AlCl3/Tf2O, Tf2O, BF3·OEt2/TfOH, P2O5CH3SO3H/TfOH, etc., there is no reaction between benzene and azlactone. In contrast, in the coexistence of AlCl3 and TfOH, 2,5-diphenyloxazole was obtained in a 76% yield. The reaction works for electron-enriched aromatics, as the reaction with nitrobenzene gives no expected product. Interestingly, the reaction with naphthalene under a similar condition yields a mixture of two oxazoles in a 1.2:1 ratio, occurring from the acylation at the α and β positions of naphthalene (Scheme 1.87) [249]. O

CO2 O

N O

CO2

O N Ph

Ph

O O

O

F3C

87%

4-methylpyridine

Ph

O

Ph 94%

Ph

O

O

N

CF3

O

O

Ph N

N

N

+

N

O Ph

O O

SCHEME 1.86  Thermolysis of 4-acyl-azlactones into oxazole derivatives and thermal isomerization of oxazol-5-yl acetate back to 4-acetyl-azlactone in 4-methylpyridine.

Azlactones 127

OMe O O N

Anisole AlCl3/TfOH ClCH2CH2Cl

78%

O N H 2O

AlCl3 Anisole

OMe OMe

O Ph

HO TfOH

N H

O N

O

O Naphthalene AlCl3/TfOH

O N

O

ClCH2CH2Cl

+

O

N N 61% (1.2 : 1)

SCHEME 1.87  Conversion of azlactones into oxazole derivatives.

Another reaction is worthy of further comment that occurs between azlactone and benzoyl chloride in the presence of Et3N. Specifically, when an equimolar solution of 4-methyl-2-phenyloxazol-5(4H)-one and Et3N in tetrahydrofuran was treated with benzoyl chloride, 4-methyl-2phenyloxazol-5-yl benzoate (m.p., 115–117°C) was obtained in 63–70% yield after evaporation of solvent and partition of the residue between CHCl3 and dilute acid. When this benzoate was warmed in pyridine, it rearranged to 4-benzoyl-4-methyl-2-phenyloxazol-5(4H)-one (m.p., 81–84°C). When the new azlactone was left in methanol at 20°C, alcoholysis occurred to give methyl 2-benzamido-2-methyl-3-oxo-3-phenylpropanoate (m.p., 114–116°C) (Scheme 1.88). Subsequent reduction with NaBH4 or catalytic hydrogenation gave methyl 2-benzamido-3-hydroxy-2-methyl-3phenylpropanoate [250]. Similar compound has also been prepared from the Grignard reaction of ethyl 2,4-dimethyl-5-oxo-4,5-dihydrooxazole-4carboxylate with phenyl magnesium halide, affording ethyl 2-acetamido-2methyl-3-oxo-3-phenylpropanoate [251]. (The Grignard reaction may give more mess products as the Grignard reagent can also attack the carbonyl and ester groups).

128

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O N Ph

O

+

Cl

O

Et3N THF

O

N Ph

O

O O

Ph

O Ph

O O

Ph pyridine

N

MeOH Ph

Ph HN OMe

O O

SCHEME 1.88  Preparation of 4-benzoyl-4-methyl-2-phenyloxazol-5(4H)-one benzoyl chloride and 4-methyl-2-phenyloxazol-5(4H)-one.

from

1.4.1.4 CYCLOADDITIONS Regarding its potential participation in cycloaddition, azlactone can be converted into its enolate or enol form that then undergoes either [3+2]dipolar cycloaddition with dipolar compounds or normal Diels-Alder reaction with dienes. On the other hand, azlactone in the form of enolate or enol can provide 4 π-electrons in reaction with dienophiles in the Diels-Alder reaction as well. 1.4.1.4.1 1,3-Dipolar Cycloaddition The combination of nucleophilic C4 and electrophilic C2 in azlactone allows the generation of mesoionic azomethine ylides (münchnones) which smoothly undergoes a 1,3-dipolar cycloaddition reaction with alkenes. For example, the reaction between tert-butyl (E)-3-(2-ethoxy-2-oxoethylidene)2-oxoindoline-1-carboxylate and 4-benzyl-2-phenyloxazol-5(4H)-one has been sophistically screened in a variety of solvents in the presence of different chiral organic catalysts. A representative reaction in MTBE is illustrated in Scheme 1.89, with 1-((1S,2S)-2-(dimethylamino)cyclohexyl)3-(4-(trifluoromethyl)phenyl)thiourea (47, Figure 1.9) as the catalyst at room temperature, that affords 99% of 1’-(tert-butyl) 5-ethyl 4-methyl (1R,4S,5R)-4-benzyl-2’-oxo-2-phenylspiro[cyclopentane-1,3’-indolin]2-ene-1’,4,5-tricarboxylate, with a ratio of 9:1 for the diastereoselectivity and 94% ee of enantioselectivity. For this reaction, eight different chiral organic catalysts have been screened, and compound 47 works the best. Among the tested solvents [THF, CH2Cl2, CHCl3, toluene, CPME, and MTBE], MTBE surrenders the best yield of the expected product as well

Azlactones 129

as diastereoselectivity and enantioselectivity [1]. Based on this preliminary result, 23 reactions in a combination of different azlactones and (E)-3methylene-2-oxoindoline derivatives have been examined under the ideal reaction condition. Most of these reactions provide the desired products in good yields (70–95%) with good diastereoselectivity (d.r. = 75:25 to 93:7) and moderate to excellent enantioselectivity (47–98% ee). For the cases of (E)-3-(2-methoxy-2-oxoethylidene)-2-oxoindoline derivatives, regardless of the electronic nature, bulkiness, or position of substituents on the benzo-moiety, similar chemical yields, as well as diastereoselectivity and enantioselectivity for the expected products have been observed. In contrast, the reaction of azlactone with 3-benzylidene-2-oxoindoline gives the product of only moderate enantioselectivity. On the other hand, while azlactones with either alkyl or aryl substituent at the C2 position can participate in this reaction, decreased enantioselectivity has been observed for azlactones with alkyl or aryl group containing an electron-withdrawing substituent at the para-position. Furthermore, this 1,3-dipolar cycloaddition can be extended to generate amide in situ after the reaction mixture is treated with HOBt, benzylamine, and EDCI in CH2Cl2 at 0°C, affording the desired amidation product in excellent yield with excellent diastereoselectivity and enantioselectivity. This reaction provides a tool for making 3,3’-pyrrolidonyl spiro-oxindole scaffolds such as that in spirotryprostatin A and salacin [1]. O

EtO2C O +

N

O N Boc

O

1. 20 mol% 47 MTBE, r.t. 2. MeOH, TMSCHN2

O

N Ph O

TMSCHN2, MeOH O

N

O N

CO2Me

N Boc

O

N EtO2C

Bn EtO2C

Boc

EtO2C

O N

Boc

SCHEME 1.89  A 1,3-dipolar cycloaddition between 4-benzyl-2-phenyloxazol-5(4H)-one and tert-butyl (E)-3-(2-ethoxy-2-oxoethylidene)-2-oxoindoline-1-carboxylate.

130

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

The reaction between azlactone and (E)-3-methylene-2-oxoindoline derivative has been further improved using binaphthol-based chiral phosphoric acid as a catalyst. Around 14 screened chiral phosphoric acids all promote the 1,3-dipolar cycloaddition between 4-benzyl-2phenyloxazol-5(4H)-one and tert-butyl (E)-3-(2-ethoxy-2-oxoethylidene)2-oxoindoline-1-carboxylate in CH2Cl2, followed by subsequent esterification with (diazomethyl)trimethylsilane in methanol and deprotection to yield 4’-ethyl 5’-methyl (3R,4’S,5’R)-5’-benzyl2-oxo-2’-phenyl-4’,5’-dihydrospiro[indoline-3,3’-pyrrole]-4’,5’dicarboxylate, with more than 95% of conversion and greater than 20:1 of diastereoselectivity, but at various level of enantioselectivity. Particularly, (11bR)-2,6-bis(tert-butyldiphenylsilyl)-4-hydroxydinaphtho[2,1-d: 1’,2’-f][1,3,2]dioxaphosphepine 4-oxide (85, Figure 1.15) provides the superior results in terms of enantioselectivity, when the reaction is performed in a combined solvent of THF and CHCl3, with 95% ee. Based on the optimized condition, twenty-two 3,3’-pyrrolidonyl spiro-oxindoles have been obtained in good to excellent yields, as well as excellent diastereo- and enantioselectivities [252]. Several organometallic complexes have been demonstrated as effective catalysts for the 1,3-dipolar cycloadditions between azlactones and dipolarophiles. For example, dimeric gold complex of (S)-2,2’-bis(diphenylphosphaneyl)-1,1’-binaphthalene with trifluoroacetate as the counter anion (86, Figure 1.15), efficiently catalyzes the 1,3-dipolar cycloaddition between 2-phenyloxazol-5(4H)-one and 1-phenyl-1H-pyrrole2,5-dione (N-phenyl maleimide) in toluene in the presence of catalytic amount of triethylamine at room temperature, affording (1R,3aS,6aR)-4,6-dioxo3,5-diphenyl-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrrole-1-carboxylic acid which is subsequently converted into the corresponding methyl ester (i.e., methyl (1R,3aS,6aR)-4,6-dioxo-3,5-diphenyl-1,3a,4,5,6,6ahexahydropyrrolo[3,4-c]-pyrrole-1-carboxylate) by means of (diazomethyl) trimethylsilane in 90% yield with 99% ee (Scheme 1.90) [253]. For this particular reaction, toluene is the most appropriate solvent, and the presence of triethylamine as the base is crucial for this transformation, which ensures both high conversion and enantioselectivity. Other nitrogenous bases such as DBU and DIPEA do not improve the results. While a variety of N-substituted maleimides react with 2-phenyloxazol-5(4H)-one to afford the expected cycloadducts in very reasonably good yields and enantioselectivity, this reaction condition does not apply to other dipolarophiles such as fumarates, maleates, vinyl phenyl sulfone, trans-1,2-bis(phenylsulfonyl)ethylene, chalcone, crotonaldehyde, and cinnamaldehyde. While 4-substituted azlactones

Azlactones 131

show poor reactivity with N-phenyl maleimide under this reaction condition, 4-methyl-2-phenyloxazol-5(4H)-one reacts with tert-butyl acrylate smoothly at 25 and at 0°C, yielding 3-(tert-butyl) 2-methyl (2R,3R)-2-methyl-5-phenyl3,4-dihydro-2H-pyrrole-2,3-dicarboxylate in good yields and moderate to good enantioselectivity. DFT computation at M06/Lanl2dz//ONIOM(b3lyp/ Lanl2dz:UFF) level indicates such cycloaddition as a concerted but highly asynchronous cycloaddition, with a preferred exo-approach [253]. O

O O

+

N Ph

5 mol% 86 5 mol% Et3N toluene, 25 °C, 19-24 hrs.

HO2C N

MeO2C

O N Ph

TMSCHN2

N

O N Ph

N Ph

O

Ph

O

Ph O 90% yield, 99% ee

SCHEME 1.90  The catalyzed 1,3-dipolar cycloaddition between 2-phenyloxazol-5(4H)-one and 1-phenyl-1H-pyrrole-2,5-dione.

Similarly, the 1,3-dipolar cycloaddition between 4-methyl-2-phenyloxazol-5(4H)-one and N-phenylmaleimide has been performed in THF in the presence of a gold catalyst (2 mol%) followed by the esterification with diazomethane or (diazomethyl)trimethylsilane to afford methyl (1R,3aS,6aR)1-methyl-4,6-dioxo-3,5-diphenyl-1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c] pyrrole-1-carboxylate. While nine different gold complexes have been screened for this reaction, two catalysts behave reasonably well, which are (S)-5,5’-bis(dicyclohexylphosphaneyl)-4,4’-bibenzo[d][1,3]dioxole bis(benzoyloxy)gold (87, Figure 1.15) and (R)-5,5’-bis(bis(3,5-di-tertbutyl-4-methoxyphenyl)phosphaneyl)-4,4’-bibenzo[d][1,3]-dioxole bis(benzoyloxy)gold (88, Figure 1.15) [254]. Based on this preliminary result, the 1,3-dipolar cycloaddition between N-phenyl maleimide and nine 2,4-disubstituted oxazol-5(4H)-ones has been carefully examined in the presence of 79 in fluorobenzene at room temperature, affording the expected products with very good yields as well as excellent enantioselectivity in most of the cases. Also, this reaction has been extended to alternative electrondeficient alkenes, such as acrylonitrile, tert-butyl acrylate, ethyl acrylate and methyl acrylate, in reaction with 4-methyl-2-phenyloxazol-5(4H)-one, yielding methyl (2R,3R)-3-cyano-2-methyl-5-phenyl-3,4-dihydro-2Hpyrrole-2-carboxylate or 3-(tert-butyl) 2-methyl (2R,3R)-2-methyl5-phenyl-3,4-dihydro-2H-pyrrole-2,3-dicarboxylate, 3-ethyl 2-methyl (2R,3R)-2-methyl-5-phenyl-3,4-dihydro-2H-pyrrole-2,3-dicarboxylate or dimethyl (2R,3R)-2-methyl-5-phenyl-3,4-dihydro-2H-pyrrole-2,3-dicarbox-

132

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

ylate, respectively, in excellent enantioselectivity with reasonable to very good yields [254]. 2+

Ph Ph Ph Ph P Au P Si

O P HO O O

Si

2 CF3CO2

Au P P Ph Ph Ph Ph

85

86 O

O O

t-Bu

O

MeO O O O O

Cy Cy Au P P Cy

Au Cy

87

t-Bu

O

P

t-Bu

AuOBz BzOAu

Ph Ph

O O O

P

t-Bu

t-Bu

t-Bu

t-Bu OMe

MeO

OMe

t-Bu

88

FIGURE 1.15  The chiral catalysts used in the 1,3-dipolar cycloaddition of azlactones.

Different from the catalyst 86, PPh3 gold benzoate facilitates the reaction between 4-methyl-2-phenyloxazol-5(4H)-one and dimethyl fumarate, dimethyl maleate, or (2,2-di-tert-butyl-5-methyl-1,3,2-dioxasilinan-5-yl) methyl acrylate, affording the expected 1,3-dipolar cycloadducts. It should be pointed out that the reaction between 4-methyl-2-phenyloxazol-5(4H)-one and (E)-N-benzylidenemethanesulfonamide or (E)-N-benzylidene-2,4,6trimethylbenzene-sulfonamide may undergo two competing reaction pathways, i.e., the 1,3-dipolar cycloaddition and the normal Michael addition, where the Michael addition may surpass the 1,3-dipolar cycloaddition. For example, in the presence of catalyst 87 or 88, the reaction of 4-methyl-2-phenyloxazol5(4H)-one with (E)-N-benzylidenemethanesulfonamide in fluorobenzene yields 51% of N-((R)-((R)-4-methyl-5-oxo-2-phenyl-4,5-dihydrooxazol-4-yl) (phenyl)methyl)methanesulfon amide with diastereoselectivity of 4.6:1 (anti/ syn) and 82% ee [179]. It is reported that B-Raf protein kinase, a key signaling molecule in the RAS-RAF-MEK-ERK signaling pathway, is an important cancer therapeutic target for inhibition. Based on the study of structureactivity relationship, three imidazole intermediates have been developed and screened as potential DFG-out allosteric inhibitors of B-Raf V600E with very low IC50 values (0.3–0.4 nM). These candidates are

Azlactones 133

5-(4-fluorophenyl)-N-(4-methyl-3-((3-methyl-4-oxo-3,4-dihydroquinazolin6-yl)amino)phenyl)-2-(trifluoromethyl)-1H-imidazole-4-carboxamide (89 in Figure 1.16), 5-(3-fluoro-4-methylphenyl)-N-(4-methyl-3-((3-methyl-4-oxo3,4-dihydroquinazolin-6-yl)amino)phenyl)-2-(trifluoromethyl)-1H-imidazole-4-carboxamide (90 in Figure 1.16) and 5-(3,4-difluorophenyl)-N-(4-methyl-3-((3-methyl-4oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)-2-(trifluoromethyl)-1H-imidazole-4-carboxamide (91 in Figure 1.16), where the imidazole moiety functions as the selectivity site. These inhibitors can be easily prepared by means of 1,3-dipolar cycloaddition of azlactone with imine, followed by N-acyl transformation, as illustrated in Scheme 1.91 for the preparation of N-(4-methyl-3-((3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)amino)phenyl)5-phenyl-2-(trifluoro-methyl)-1H-imidazole-4-carboxamide from 2-amino2-phenylacetic acid, where the mechanism for 1,3-dipolar cycloaddition to yield benzyl 5-phenyl-2-(trifluoromethyl)-1H-imidazole-4-carboxylate is provided in the bracket [255]. F N N O

N

O N H

N H

NH N

N

O

N

N H

F

F

O

N H

O

N

N H

NH N

O

CF3

N H

NH N

CF3

89

F

CF3

90

91

FIGURE 1.16  The imidazole derivatives as potential DFG-out allosteric inhibitors of B-Raf V600E. O

O OH NH2

PBu3 (1.0 eq.) BnOC(O)CN (1.1 eq.) CF3 toluene, 8 hrs.

O N

TFAA (2.0 eq.), 2 hrs.

O BnO

NH N CF3

N N

N H

O

N

NH2

O

N

N H

O

N H

NH N CF3

O

O

O N

CF3 PBu3

O BnO

PBu3 CN

O N H

CF3

PBu3 OBn

O N H

N O

O

CF3 N PBu3

O OBn

O BnO CO2, PBu3

NH N CF3

SCHEME 1.91  Preparation of imidazole inhibitor of B-Raf V600E via 1,3-dipolar cycloaddition of azlactone and in situ generated imine followed by N-acyl transformation.

134

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Another group of 1,3-dipolar cycloaddition occurs between azlactones and substituted alkynes, where the alkynes function as dipolarophiles. It is said that the reaction pathway involves a cycloaddition to an azomethine ylide, affording an N-bridged intermediate that loses carbon dioxide and forms a heterocycle. The regioselectivity of the cycloaddition should be controlled by the asymmetry in the dipole frontier orbitals caused by the substituent groups [256], such as the use of unsymmetrically substituted acetylenes as the electron-deficient dipolarophiles, yielding single product. For example, treatment of ethyl propiolate and N-formylpipecolic acid (i.e., 1-formylpiperidine-2-carboxylic acid) (50:7 ratio) in Ac2O at 120°C for 2 hours yielded 82% of ethyl 5,6,7,8-tetrahydroindolizine-1-carboxylate as the single product, no isomer has been isolated (Scheme 1.92) [257]. Similarly, direct treatment of N-​formyl-​L-proline and ethyl propiolate in Ac2O under this condition gave 90% of ethyl 2,3-dihydro-1H-pyrrolizine-7-carboxylate [258]. Although in both cases, no azlactones have been used directly, it is believed that the corresponding azlactones are the reaction intermediates. Different from these cyclic N-acyl amino acids, the reaction of ethyl propiolate with acyclic N-acyl amino acids under a similar condition afforded the corresponding pyrrole derivatives of relatively low regioselectivity. For example, heating the mixture of N-acetyl-N-phenylglycine and ethyl propiolate (1:1.5) in Ac2O at 115°C for 3 hours, gave a mixture of ethyl 2-methyl-1-phenyl-1H-pyrrole3-carboxylate (32%) and ethyl 5-methyl-1-phenyl-1H-pyrrole-3-carboxylate (9%) in 3:1 ratio. Replacement of N-acetyl group by N-trifluoroacetyl group from the starting material, i.e., using N-phenyl-N-(2,2,2-trifluoroacetyl) glycine as the reactant, greatly enhanced the regioselectivity to favor ethyl 1-phenyl-5-(trifluoromethyl)-1H-pyrrole-3-carboxylate over ethyl 1-phenyl2-(trifluoromethyl)-1H-pyrrole-3-carboxylate, in a ratio of 9:1 when the reaction was carried out at 130°C. However, when the phenyl group on the nitrogen is replaced with a methyl group, no apparent regioselectivity has been observed from the reaction products, as shown by the reaction of ethyl propiolate with 2-(N-methylacetamido)-2-phenylacetic acid or N-acetyl-Nmethylphenylalanine, both gave a mixture of products in a 1:1 ratio [259]. O

N

CO2Et

O OH + O

OEt

Ac2O 120°C

N 82%

SCHEME 1.92  The reaction between 1-formylpiperidine-2-carboxylic acid and ethyl propiolate, affording ethyl 5,6,7,8-tetrahydroindolizine-1-carboxylate

Azlactones 135

Likewise, the reaction of azlactones with polarized asymmetric alkenes can also provide the cycloadducts of good regioselectivity. For example, the reaction of 2-chloroacrylonitrile with N-acyl α-amino acids in Ac2O afforded 3-cyanopyrroles after elimination of hydrogen chloride, via oxazolium 5-​ oxide intermediates, with an overall yield of ∼70%. A representative direct reaction between L-proline and 10 equivalents of 2-chloroacrylonitrile was carried out in Ac2O at 80°C for 24 hours, affording 65% of 5-methyl2,3-dihydro-1H-pyrrolizine-7-carbonitrile (m.p., 58–62°C) after evaporation of excess reagent and column chromatography. While no mechanism has been provided for this reaction in the original report, it is assumed that in the presence of Ac2O, L-proline is converted into azlactone (S)-3-methyl1-oxo-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-c]oxazol-4-ium, which upon deprotonation, yields a mesoionic intermediate of 3-methyl-1-oxo-6,7dihydro-1H-pyrrolo[1,2-c]oxazol-4(5H)-ium-7a-ide. It is this mesoionic compound which regioselectively undergoes the 1,3-dipolar cycloaddition with 2-chloroacrylonitrile, affording 1-chloro-3-methyl-8-oxotetrahydro1H,5H-3,7a-(epoxymethano)pyrrolizine-1-carbonitrile. Subsequent extrusion of CO2, elimination of HCl and 1,5-H shift lead to the final product as displayed in Scheme 1.93 [260]. The regioselectivity of cycloaddition between 2-chloroacrylonitrile and mesoionic oxazol-5(4H)-one has been studied using MNDO calculation [261]. Likewise, the treatment of N-formylpipecolic acid and 2-chloroacrylonitrile under the same condition yielded 77% of expected 5,6,7,8-tetrahydroindolizine-1-carbonitrile and 14% of the acetylated product of 2-acetyl-5,6,7,8-tetrahydroindolizine-1-carbonitrile (Scheme 1.94). Usually, the acetylation should occur at the position close to the nitrogen atom, i.e., giving 3-acetyl-5,6,7,8-tetrahydroindolizine1-carbonitrile. Although the characteristic NMR and IR data were provided, it is difficult to differentiate between these two isomers. O

O OH + NH

Ac2O 80°C

CN

N

O Cl CN

Cl CN N

H

CN

HCl N

H

Cl

Ac2O

OAc CN

O

AcOH

O O

N

CO2

Cl

OAc

CN O

N

N 70%

SCHEME 1.93  The mechanism for the reaction between L-proline and 2-chloroacrylonitrile in acetic anhydride that affords 5-methyl-2,3-dihydro-1H-pyrrolizine-7-carbonitrile.

136

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

CN O

N

CN

Cl OH O

+ CN

CN O

+

Ac2O 80°C

77%

SCHEME 1.94  The reaction between 2-chloroacrylonitrile in acetic anhydride.

N

N

N

14%

O not this one?

1-formylpiperidine-2-carboxylic

acid

and

Certainly, the use of symmetric alkynes would not cause the issue of regioselectivity, as shown in the 1,3-dipolar cycloaddition between dimethyl but-2-ynedioate and 2,4-diphenyloxazol-5(4H)-one in xylene at 100°C for 2 hours to afford 83% of dimethyl 2,5-diphenyl-1H-pyrrole-3,4-dicarboxylate. The reaction of dimethyl but-2-ynedioate with 4-methyl-2-phenyloxazol-5(4H)-one, 2-methyl4-phenyloxazol-5(4H)-one, 2-(2-nitrophenyl)-4-phenyloxazol-5(4H)-one and 4-(4-methoxyphenyl)-2-phenyloxazol-5(4H)-one under the same condition yielded 72% of dimethyl 2-methyl-5-phenyl-1H-pyrrole-3,4-dicarboxylate, 78% of dimethyl 2-methyl-5-phenyl-1H-pyrrole-3,4-dicarboxylate, 60% of dimethyl 2-(2-nitrophenyl)-5-phenyl-1H-pyrrole-3,4-dicarboxylate, and 98% of dimethyl 2-(4-methoxyphenyl)-5-phenyl-1H-pyrrole-3,4-dicarboxylate, respectively [262]. Similarly, the reaction of 4-methyl-2-phenyloxazol-5(4H)one with dimethyl but-2-ynedioate afforded 71% of dimethyl 2-methyl5-phenyl-1H-pyrrole-3,4-dicarboxylate upon decarboxylation, whereas the reaction from the in situ generated 2-methyl-4-phenyloxazol-5(4H)-one with dimethyl but-2-ynedioate afforded 78% of dimethyl 2-methyl-5-phenyl1H-pyrrole-3,4-dicarboxylate [263]. When 2-(N-methylbenzamido)-2-phenylacetic acid was heated with Ac2O at 55°C for a few minutes, crystalline mesoionic 3-methyl-2,4-diphenyloxazol-3-ium-5-olate (or its resonance structure 3-methyl-5-oxo-2,4-diphenyl4,5-dihydrooxazol-3-ium-4-ide) was obtained in 90% yield. This mesoionic compound undergoes a smooth 1,3-dipolar cycloaddition with a series of acetylene derivatives at 0–70°C to afford N-substituted pyrrole derivatives in good to excellent yields, upon removal of CO2. For example, the reaction with dimethyl but-2-ynedioate gave 92% of dimethyl 1-methyl-2,5-diphenyl1H-pyrrole-3,4-dicarboxylate [264], a reaction of higher yield and occurrence at a lower temperature than the corresponding non-mesoionic azlactone as mentioned above. In addition, the mesoionic compound is not necessarily isolated in this case. Such a reaction has been extensively explored after its initial report [265]. For comparison, the reaction of the mesoionic azlactone with electron-deficient alkenes gives 2,3-dihydropyrrole derivatives. For example, the reaction between 3-methyl-2,4-diphenyloxazol-3-ium-5-olate

Azlactones 137

and dimethyl maleate yielded dimethyl 1-methyl-2,5-diphenyl-2,3-dihydro1H-pyrrole-3,4-dicarboxylate. Many alkene substrates such as styrene, dimethyl fumarate, stilbene, methacrylonitrile, 1-hexene, acenaphthylene, among others have been tested in this study [266, 267]. In addition to the 1,3-cycloaddition of azlactones with C-C double bond and C-C triple bond, the azlactone has been found to be able to react with C-N triple bond in nitriles, N-O double bond in nitro or nitroso compounds, and N-N double bond in diazo compounds. For example, treatment of 5-hydroxy-3-methyl2,4-diphenyloxazolium hydroxide inner salt with ethyl carbonocyanidate (NCC(O)OEt) gave 71% of ethyl 1-methyl-2,5-diphenyl-1H-imidazole4-carboxylate via extrusion of CO2 from ethyl 7-methyl-3-oxo-1,4-diphenyl2-oxa-6,7-diazabicyclo[2.2.1]hept-5-ene-5-carboxylate (Scheme 1.95) [268]. Possibly due to the strong triple bond, the O-N double bond in the nitro group shows the favored reactivity over the C-N triple bond when the same mesoionic azlactone is allowed to react with 4-nitrobenzonitrile, containing both nitro and cyano group. Extrusion of CO2 from 2-(4-cyanophenyl)-7-methyl-6-oxo1,4-diphenyl-3,5-dioxa-2,7-diazabicyclo[2.2.1]heptane 2-oxide intermediate gives 2-(4-cyanophenyl)-4-methyl-2-oxido-3,5-diphenyl-2,3-dihydro-1,2,4oxadiazol-4-ium-3-ide, which is unstable and rearranges to (E)-N-(((4-cyanophenyl)imino)(phenyl)methyl)-N-methylbenzamide by losing oxygen. This structure is supported by its decomposed products of benzoic acid and (Z)-N’(4-cyanophenyl)-N-methylbenzimidamide upon treatment with hydroxide. The whole process is displayed also in Scheme 1.95 [268]. O

O

O N

O + N

N

Ph

O

CO2

O

Ph

N

Ph

Ph

N

N

EtO2C

EtO2C O O

O Ph

O N

+ O2N

CN

N

N

Ph O N O

CO2

Ph

O

Ph N O

CN

CN (O)

N CO2H

+ NC

Ph

N

Ph OH

N

HN

Ph O

NC

SCHEME 1.95  The mechanism for the 1,3-dipolar cycloaddition of 3-methyl-2,4diphenyloxazol-3-ium-5-olate with nitro- or cyano-containing compound.

138

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Similarly, reaction of the mesoionic azlactone with compound of both diazo and cyano groups also selectively occurs on the diazo functionality, as demonstrated in the reaction with (E)-2-(4-chlorophenyl)diazene1-carbonitrile, affording 3-(4-chlorophenyl)-7-methyl-6-oxo-1,4-diphenyl5-oxa-2,3,7-triazabicyclo[2.2.1]heptane-2-carbonitrile intermediate. Extrusion of CO2 generates a new mesoionic 2-(4-chlorophenyl)-1-cyano4-methyl-3,5-diphenyl-2,3-dihydro-1H-1,2,4-triazol-4-ium-3-ide, which rearranges to (E)-N’-(4-chlorophenyl)-N-((E)-(cyanoimino)(phenyl) methyl)-N-methylbenzimidamide. This structure has been supported by the formation of (Z)-N’-(4-chlorophenyl)-N-methylbenzimidamide upon treatment of hydroxide, as displayed in Scheme 1.96. 2 2

2

1 &1 1

 &O

1

3K

1

2

1 1 1&

3K

&2

&O 3K

1

3K

1 1 1&

3K 1&

&O

1 1

3K

1

2+

1

&O

3K

+1

&O

SCHEME 1.96  The mechanism for the 1,3-dipolar cycloaddition of 3-methyl-2,4diphenyloxazol-3-ium-5-olate with a diazo compound.

The reaction of the same mesoionic azlactone with diethyl (E)-diazene1,2-dicarboxylate is very interesting, which yields 4-methyl-3,5-diphenyl4H-1,2,4-triazole and tetraethyl hydrazine-1,1,2,2-tetracarboxylate as final products. This reaction is believed to involve the initial 1,3-dipolar cycloaddition, and generate the mesoionic 1,2-bis(ethoxycarbonyl)-4-methyl-3,5-diphenyl-2,3-dihydro-1H-1,2,4-triazol-4-ium-3-ide after extrusion of CO2. This mesoionic compound then adds to additional diethyl (E)-diazene-1,2-dicarboxylate to form 3-ethoxy-1,2,5-tris(ethoxycarbonyl)-7-methyl-6,7a-diphenyl2,3,5,7a-tetrahydro-1H-[1,2,4]triazolo[4,3-b][1,2,4]triazol-7-ium-3-olate. Decomposition of this intermediate gives 1-(ethoxycarbonyl)-4-methyl-3,5diphenyl-1H-1,2,4-triazol-4-ium and 1,2,2-tris(ethoxycarbonyl)hydrazin1-ide. Then acyl substitution between these two species leads to the final two products, as illustrated in Scheme 1.97 [268].

Azlactones 139

O

O

O + EtO

N

CO2 N

N

OEt

Ph 0°C

O

EtO2C

N

N

CO2Et

Ph

Ph

N

CO2Et

Ph CO2Et N Ph N CO2Et N N EtO2C O OEt

N

Ph CO2Et N N N EtO2C N CO2Et EtO O

CO2Et N CO2Et + EtO2C N N CO Et 2

Ph

N N EtO2C

N

Ph N

N

Ph

N N N

CO2Et Ph + EtO C N N CO2Et 2 CO2Et

SCHEME 1.97  The mechanism for the 1,3-dipolar cycloaddition between 3-methyl-2,4diphenyloxazol-3-ium-5-olate and diethyl (E)-diazene-1,2-dicarboxylate, affording 4-methyl3,5-diphenyl-4H-1,2,4-triazole and tetraethyl hydrazine-1,1,2,2-tetracarboxylate.

In addition to function as a münchnone in the 1,3-dipolar cycloaddition, azlactone can serve as the dipolarophile in the 1,3-dipolar cycloaddition as well. For example, in the presence of catalytic amount of a chiral bifunctional bisguanidinium hemisalt [e.g., 71, 72, 75 in Figure 1.13, or (S,E)-N-benzhydryl-1-(N,N’-dicyclohexylcarbamimidoyl)piperidine-2carboxamide (92, Figure 1.17), (3S,3’S)-N,N’-(1,2-phenylene)bis(2-((E)-N,N’dicyclohexylcarbamimidoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide) (93, Figure 1.17), or (3S,3’S)-N,N’-(1,3-phenylene)bis(2-((E)-N,N’dicyclohexylcarbamimidoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide) (94, Figure 1.17)], enantioselective 1,3-dipolar cycloaddition of azomethine imines with azlactones has been achieved [269]. Particularly, in the presence of bisguanidinium salt (93) of tetrakis(3,5-bis(trifluoromethyl)phenyl)-λ4-borate (HBArF4), the reaction between (Z)-2-arylidene-5-oxopyrazolidin-2-ium-1-ide and 4-benzyl-2-phenyloxazol-5(4H)-one in Et2O at 30°C generates optically active bicyclic pyrazolidinone derivatives in high yields (up to 99%) with good diastereoselectivity (up to 88:12) and excellent enantioselectivity (up to 99% ee). For example, the specific reaction between (Z)-2-(2-bromobenzylidene)5-oxopyrazolidin-2-ium-1-ide and 4-benzyl-2-phenyloxazol-5(4H)-one yields 96.5% of N-((1S,2S)-2-benzyl-1-(2-bromophenyl)-3,5-dioxotetrahydro-1H,5Hpyrazolo[1,2-a]pyrazol-2-yl)benzamide, with a diastereo selectivity of 82:18 and excellent enantioselectivity (94% ee), as shown in Scheme 1.98 [269]. Another example of this type reaction can be found in the reaction between an azlactone (e.g., 2,4-diphenyloxazol-5(4H)-one) and propyl

140

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

(E)-2-(naphthalen-2-yl)diazene-1-carboxylate in the presence of a chiral phosphoric acid in acetonitrile. For this particular 1,3-dipolar cycloaddition, (11bS)-4-hydroxy-2,6-di(phenanthren-9-yl)-8,9,10,11,12,13,14,15octahydrodinaphtho[2,1-d:1’,2’-f][1,3,2]dioxaphosphepine 4-oxide (95, Figure 1.17) is most effective among the seven screened acids, yielding propyl (S)-(1benzamido-2-oxo-1-phenyl-1,2-dihydro-3H-benzo[e]indol-3-yl)carbamate in good yield with excellent enantioselectivity (95% ee) [270]. This preliminary result has been extended to various azlactones with different combinations of substituents at C2 and C4, all affording the expected products in acceptable to excellent yields, and very good to excellent enantioselectivity. In addition, both 2,4-diphenyloxazol-5(4H)-one and ethyl 2-(4-methoxyphenyl)-5-oxo4,5-dihydrooxazole-4-carboxylate have been subject to react with propyl (or isopropyl, benzyl, cyclopentyl) (E)-2-(6-substituted-naphthalen-2-yl) diazene-1-carboxylate or related amides in the presence of 95 in acetonitrile at –30°C, generating the corresponding 1,3-dipolar cycloadducts in generally good to excellent yields (up to 99%) and excellent enantioselectivity (up to 98% ee). A representative reaction between methyl 2-(4-methoxyphenyl)-5-oxo4,5-dihydrooxazole-4-carboxylate and propyl (E)-2-(6-phenylnaphthalen-2-yl) diazene-1-carboxylate to give methyl (S)-1-(4-methoxybenzamido)-2-oxo-7phenyl-3-((propoxycarbonyl)amino)-2,3-dihydro-1H-benzo[e]indole-1-carboxylate is demonstrated in Scheme 1.99, in a 95% yield with 96% ee [270]. O

Br

O

O

N N O

93 HB(ArF)4 (10 mol%) Et2O, 30 °C

O

+ Ph

N

N N

Ph

NHCOPh Bn

Br

SCHEME 1.98  The reaction between (Z)-2-(2-bromobenzylidene)-5-oxopyrazolidin-2ium-1-ide and 4-benzyl-2-phenyloxazol-5(4H)-one. O

O

O

O N MeO

CO2Me +

N

N

O

10 mol% 95 ° CH3CN, -30 C

Ph

HN MeO2C

O O N NH

Ph

O

O

95% yield, 96% ee

SCHEME 1.99  The 1,3-dipolar cycloaddition between methyl 2-(4-methoxyphenyl)-5-oxo4,5-dihydrooxazole-4-carboxylate and a diazo compound in the presence of chiral phosphoric acid.

Azlactones 141

O N N Cy N

O

CHPh2 H Cy

Cy N

H 92

N N

N N Cy Cy H

H

O N

H H

N

N

O

O N

N

H

H

Cy

Cy

N

Cy N

N Cy

N

H

H

93

CF3 N

O

P HO O

H N

95

S N H

N H

Ph

S CF3 N

N H

96

N H

Ph NHTs

97 O

O

NH

N H

CF3

N

OMe N

N

N Cy

94

OMe O

N

N

Ph

S

N H 98

N H

CF3

Ph MeO NHTs

N 99

FIGURE 1.17  Chiral organic catalysts for the 1,3-dipolar cycloaddition of azlactones that function as dipolarophiles.

One more example of 1,3-dipolar cycloaddition involving azlactone as the dipolarophile is the reaction between azlactone and (3,4-dihydroisoquinolin-2-ium-2-yl)(phenylsulfonyl)amide in the presence of a chiral thiourea (e.g., 44, 45 in Figure 1.8, 65 in Figure 1.11), 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R)-(6-methoxyquinolin-4-yl) ((2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)thiourea (96, Figure 1.17), N-((1R,2R)-2-(3-((1R,2R)-2-(dimethylamino)cyclohexyl)thioureido)-1,2diphenylethyl)-4-methylbenzenesulfonamide (97, Figure 1.17), N-((1R,2R)2-(3-((1S)-(6-methoxyquinolin-4-yl)((2S,4S,5R)-5-vinylquinuclidin-2-yl) methyl)thioureido)-1,2-diphenylethyl)-4-methylbenzenesulfonamide (98, Figure 1.17) or a bifunctional squaramide, e.g., 3-((3,5-bis(trifluoromethyl) phenyl)amino)-4-(((1S)-(6-methoxyquinolin-4-yl)((2S,4S,5R)-5vinylquinuclidin-2-yl)methyl)amino)cyclobut-3-ene-1,2-dione (99, Figure 1.17). Among these chiral catalysts, chiral thioureas 44 and 96 are especially effective, leading to nearly quantitative yields of the respective products [271]. A typical reaction between 4-isobutyl-2-phenyloxazol-5(4H)-one and (1,2-dihydrobenzo[f]isoquinolin-3-ium-3-yl)(tosyl)amide is demonstrated in Scheme 1.100, which is catalyzed by chiral thiourea 96 to yield

142

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

N-((3R,3aS)-3-isobutyl-2-oxo-1-tosyl-1,2,3,3a,10,11-hexahydrobenzo[f] pyrazolo[5,1-a]isoquinolin-3-yl)benzamide, in 99% of yield with 98% ee and diastereoselectivity greater than 20:1 [271].

O O Ph

Ts N N

Ts +

N N

N

5 mol% 96 xylene, -20 °C

O

O

N H 99% yield, 98% ee, dr > 20:1

SCHEME 1.100  The 1,3-dipolar cycloaddition between 4-isobutyl-2-phenyloxazol5(4H)-one and (1,2-dihydrobenzo[f]isoquinolin-3-ium-3-yl)(tosyl)amide.

1.4.1.4.2 [4+2] Cycloaddition Similar to the dual features of azlactone in 1,3-dipolar cycloaddition to function as either dipolar component or dipolarophile, azlactone also behaves as diene or dienophile in the Diels-Alder cycloaddition (also known as [4+2] cycloaddition in general). In the case of unsaturated azlactones, once converted into their enolate forms, will provide a 4π-electron system to react with the highly electron-demanding dienophile, such as the carbonyl group. For example, in the presence of a cinchona alkaloid, (Z)-2-phenyl-4-(1-phenylethylidene)oxazol-5(4H)-one undergoes a [4+2] cycloaddition with the carbonyl group of isatin (i.e., indoline-2,3-dione) to afford (R)-N-(2,6’-dioxo4’-phenyl-3’,6’-dihydrospiro[indoline-3,2’-pyran]-5’-yl)benzamide. For this Diels-Alder cycloaddition, several cinchona alkaloids have been applied as the catalysts, including 44 in Figure 1.8, and (R)-(6-methoxyquinolin-4-yl) ((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methanol (100), (R)-((1S,2S,4S,5R)5-ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methanol (101), 4-((R)hydroxy((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)quinolin-6-ol (102), (S)-quinolin-4-yl((1S,2R,4S,5R)-5-vinylquinuclidin-2-yl)methanol (103), 4-((1S,3R,5R,8S)-3-ethyl-4-oxa-1-azatricyclo-[4.4.0.03,8]decan-5-yl) quinolin-6-ol (104), (1S,3R,5R,8S)-3-ethyl-5-(6-methoxyquinolin-4-yl)4-oxa-1-azatricyclo[4.4.0.03,8]decane (105), and (1S,3R,5R,8S)-3-ethyl-5(quinolin-4-yl)-4-oxa-1-azatricyclo[4.4.0.03,8]decane (106, Figure 1.18) [272]. Among these cinchona alkaloids, compounds 44 and 102 have been found ineffective in catalyzing this cycloaddition, whereas the more rigid

Azlactones 143

chiral tertiary amines (104, 105 and 106) are promising catalysts, and 104 is especially effective, leading to the best selectivity (84% ee) so that it has been used to elaborate this cycloaddition. It is found that N-substituted isatins are superior to the unsubstituted ones, particularly for the isatin with an ethyl group, i.e., N-ethyl-isatin, which surrenders 99% ee of the final product. On the other hand, among the screened solvents that include 1,2-dichloroethane, THF, CH2Cl2, acetonitrile, toluene, and acetone, 1,2-dichloro ethane works the best. Regarding the effect of substituents on azlactones, it is shown that electron-withdrawing groups lead to better enantioselectivities than electron-donating and bulky substituents. Comparing with the substituents at C5, C6, and C7 of isatins, % ee value has been obtained from isatins with a C7 substituent. An example of such cycloaddition is demonstrated in Scheme 1.101 for the reaction between (Z)-4-(1-(4-fluorophenyl) ethylidene)-2-phenyloxazol-5(4H)-one and 1-ethyl-5-methylindoline2,3-dione to yield (R)-N-(1-ethyl-4’-(4-fluorophenyl)-5-methyl-2,6’-dioxo3’,6’-dihydrospiro[indoline-3,2’-pyran]-5’-yl)benzamide in 82% yield with nearly quantitative enantioselectivity [272]. OMe

OMe

OH

N

N

N

OH

OH

OH

N

N

OH

N

100

N

101

OH

N

102

103

OMe H

O N N

H

O

N N

104

H

O

N N

105

106

FIGURE 1.18  Cinchona alkaloid catalysts for the [4+2] cycloaddition of azlactones.

In addition to isatins with a structural scaffold of cyclic α-keto amide, unsaturated azlactones also react with regular α-keto esters to afford α,β-unsaturated lactones. This reaction has been screened for a series of chiral organic catalysts, including 1,1’-((1S,2S)-cyclohexane-1,2-diyl) bis(3-(3,5-bis(trifluoromethyl)phenyl)thiourea), 1-(3,5-bis(trifluoromethyl)

144

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

phenyl)-3-((1R)-quinolin-4-yl((2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl) thiourea, 44 and 45 in Figure 1.8, 3-((3,5-bis(trifluoromethyl)phenyl)amino)4-(((1R,2R)-2-(dimethylamino)cyclohexyl)amino)cyclobut-3-ene-1,2-dione (enantiomer of 49 in Figure 1.9), 67 in Figure 1.12, 96 in Figure 1.17, and 102 and 103 in Figure 1.18. The model reaction of a series of (Z)-2-phenyl4-(1-aryl-ethylidene)oxazol-5(4H)-ones with ethyl 2-oxo-2-phenylacetate has been carried out in toluene in the presence of 4Å molecular sieves in the presence of the most effective catalyst (i.e., 1-(3,5-bis(trifluoromethyl) phenyl)-3-((1R)-quinolin-4-yl((2R,4S,5R)-5-vinylquinuclidin-2-yl) methyl)thiourea) [273]. Under this condition, the unsaturated azlactones even react with β,γ-unsaturated α-keto esters to form the Diels-Alder cycloadducts without complication of the competitive Michael addition products. For example, under the standard condition, the reaction between (Z)-2-phenyl-4-(1-phenylethylidene)oxazol-5(4H)-one and ethyl (E)-4-(4chlorophenyl)-2-oxobut-3-enoate affords 80% of ethyl (S,E)-6-benzamido3-(4-chlorostyryl)-5-oxo-2,3,4,5-tetrahydro-[1,1’-biphenyl]-3-carboxylate with 93% enantioselectivity (Scheme 1.102). Particularly, when this reaction is scaled up to 3 mmol for the azlactone and 9 mmol for the β,γ-unsaturated α-keto ester, 1.04 g of (S,E)-6-benzamido-3-(4-chlorostyryl)-5-oxo-2,3,4,5tetrahydro-[1,1’-biphenyl]-3-carboxylate is obtained, in 73% yield with 94% ee [273]. O O N

Ph

NHCOPh

O O +

F O

N

O

20 mol% 104 ClCH2CH2Cl, 30°C

O N

F

104 82% yield, > 99% ee 104

ing

o

pr

p ea

si

h ac

fac

N

* *

O R1 N R2 H H O Ph O O N O

[4+2]

Ph R2 N R 1 H N O O O

O H F

O N F

SCHEME 1.101  The mechanism for the [4+2] cycloaddition between (Z)-4-(1-(4fluorophenyl)ethylidene)-2-phenyloxazol-5(4H)-one and 1-ethyl-5-methylindoline-2,3-dione.

Azlactones 145

Compared to the role of dienes for the unsaturated azlactones (olefinic azlactones) in the Diels-Alder cycloaddition, the enol or enolate forms of regular azlactones more likely function as the dienophiles in DielsAlder cycloaddition. In this case, the enol or enolate form of azlactone would be considered as electron-enriched, so that it often reacts with an electron-deficient 4π-electron system such as α,β-unsaturated ketone, ester, etc. Such cycloaddition of inverse order of electron density requirement is known as inverse-electron-demand hetero-Diels–Alder reaction (IEDHDA). On the other hand, the Diels-Alder cycloaddition under this condition is often complicated with the Michael addition, as indicated in various examples outlined previously. A detailed mechanistic study on IEDHDA with the complication of Michael addition has been found in the reaction between 4-benzyl-2-phenyloxazol-5(4H)-one and ethyl (E)-2-oxo-4-phenylbut-3-enoate in the presence of a chiral guanidine (i.e., N-methyl-6,12-bis(3,3”,5,5”-tetra-tert-butyl-[1,1’:3’,1”-terphenyl]-5’-yl)7,8,10,11-tetrahydro-9H-dinaphtho[2,1-e:1’,2’-g][1,3]diazonin-9-imine) to afford 99% of ethyl (3R,4S)-3-benzamido-3-benzyl-2-oxo-4-phenyl-3,4dihydro-2H-pyran-6-carboxylate with 99:1 of diastereoselectivity and 91% ee (Scheme 1.103) [5]. H H N

F3C

H N

O

N O

S O

O O Ph

O

+ N

Ph

Cl

O

CF3

O

N

O

NHCOPh Ph

toluene, 4Å MS, 72 hrs.

Cl 80% yield, 93% ee

SCHEME 1.102  A chiral thiourea catalyzed [4+2] cycloaddition between (Z)-2-phenyl-4(1-phenylethylidene)oxazol-5(4H)-one and ethyl (E)-4-(4-chlorophenyl)-2-oxobut-3-enoate.

For this particular reaction, although the steric and electronic properties of the aryl group at C2 of azlactone do not have an apparent effect on the chemical yields, they do profoundly influence the enantioselectivity and diastereoselectivity of the expected products. For example, the introduction of electron-donating groups at the meta-positions of the C2-aryl group leads to a slight decrease in diastereoselectivity, and the introduction of an electrondonating methoxy group at the para-position of the C2-aryl group results in

146

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

the formation of racemic products. Further improvement of the enantioselectivity and diastereoselectivity can be achieved by carrying out the reaction in acyclic ether, particularly in diethyl ether at the low reaction temperature [5]. While this reaction may occur in two mechanisms as illustrated in Scheme 1.104, the three cascading reaction pathways, involving Michael addition, ring-opening, and cyclization, are more plausible as evidenced in the conversion of the trapped Michael addition intermediate to the final product with an achiral base (e.g., DBU) that has exactly the same enantioselectivity as the one-step reaction product. The reaction of azlactone with β,γ-unsaturated α-keto esters with either an electron-withdrawing or electron-donating substituent on the aromatic ring also afford the corresponding products with similarly high enantio- and diastereoselectivity [5]. O

O

O

OEt

+ N

Ph

O

Ph

O

2 mol% cat. Et2O, -60°C to r.t. Ph 99% yield

O

CO2Et

O

O +

N H Bn Ph 91% ee

O

O

CO2Et

N H Bn Ph

Ph

99 : 1

G H N cat. =

t-Bu

G = t-Bu

N N H G

t-Bu

t-Bu

SCHEME 1.103  Enantioselective [4+2] cycloaddition between 4-benzyl-2-phenyloxazol5(4H)-one and ethyl (E)-2-oxo-4-phenylbut-3-enoate. EtO

B O O

OEt

+ N

Ph

H

O B path a

O

O

O

B H O

O

O Ph

Ph

B O

Ph

O

O O Michael addition Ph

N

CO2Et

Bn Ph

H

path b B EtO

O

N B

N

Ph

O

[4+2] Ph

O

O

Ph

O

CO2Et

Ph

O N

O

O

CO2Et

N H Bn Ph

DBU Ph quenched at low temp.

O

O O

Ph

OEt O

N Ph

SCHEME 1.104  The mechanism for the enantioselective [4+2] cycloaddition of Scheme 1.103.

Azlactones 147

It is found that the potential Michael addition could be suppressed to improve the yield of IEDHDA product when substituted chalcones are applied to the reactions with azlactones, in the presence of a C2-symmetric chiral bisguanidine, such as (2S,2’S)-N,N’-((1S,2S)-1,2-diphenylethane-1,2-diyl) bis(1-((E)-N,N’-dicyclohexylcarbamimidoyl)piperidine-2-carboxamide) (75, Figure 1.13). A representative reaction is illustrated in Scheme 1.105 for the cycloaddition between 4-benzyl-2-phenyloxazol-5(4H)-one and (E)-chalcone in a mixed solvent in the presence of 75 that affords N-((3S,4R)3-benzyl-2-oxo-4,6-diphenyl-3,4-dihydro-2H-pyran-3-yl)benzamide in 73% yield with 96% ee [274]. While all the 25 reactions of 4-benzyl-2phenyloxazol-5(4H)-one with different α,β-unsaturated ketones give the expected lactones in reasonably good yields, excellent enantioselectivity has been achieved for the individual product. In contrast to the previous example, even though this reaction is complicated with the Michael addition, it failed to convert the Michael addition product (i.e., 4-benzyl-4-(3-oxo-1,3diphenylpropyl)-2-phenyloxazol-5(4H)-one) into the cycloaddition product. Under the optimal condition, the yield of Michael addition product is less than 20%, greatly suppressed in comparison to the case shown in Scheme 1.104. The chiral bisguanidine can be easily prepared by treatment of (2S,2’S)N,N’-((1S,2S)-1,2-diphenylethane-1,2-diyl)bis(piperidine-2-carboxamide) in THF with 4.2 equivalents of n-butyl lithium at –20°C, followed by the addition of DCC [274].

O Ph

+ N

Ph

O

O

Ph

10 mol% 75 THF/CHCl3 (1:1) -20°C

Ph HN

O Bn

Ph

O

O

73% yield, 96% ee SCHEME 1.105  The [4+2] cycloaddition between 4-benzyl-2-phenyloxazol-5(4H)-one and (E)-chalcone.

Similarly, the [4+2] cycloaddition involving azlactone can be applied to prepare 3,4-dihydropyridin-2(1H)-one with high enantioselectivity by means of an asymmetric three-component reaction of azlactone, cinnamaldehyde, and a primary amine, in the presence of a chiral Brønsted acid catalyst [275]. For comparison, the three-component reaction of 4-methyl-2-phenyloxazol-5(4H)-one with p-nitro-cinnamaldehyde and p-anisidine in the absence of any promoter proceeds smoothly to afford

148

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

38% of N-(1-(4-methoxyphenyl)-3-methyl-4-(4-nitrophenyl)-2-oxo1,2,3,4-tetrahydropyridin-3-yl)benzamide, along with 33% of amidation product of N-(1-((4-methoxyphenyl)amino)-1-oxopropan-2-yl)benzamide. For this reaction, the amidation product is formed from the nucleophilic attack of the primary amine to the azlactone, resulting in the ring-opened product. Whereas the 3,4-dihydropyridin-2(1H)-one derivative is formed from the normal [4+2] cycloaddition between azlactone and imine deriving from the condensation of primary amine and cinnamaldehyde [275]. The Brønsted acid is assumed to activate the azlactone through a hydrogen bond so that the presence of chiral phosphoric acid might affect the stereochemistry of the cycloadducts. However, the addition of (11bR)-2,6-bis(4-chlorophenyl)-4-hydroxydinaphtho[2,1-d:1’,2’-f][1,3,2] dioxaphosphepine 4-oxide promotes the amidation product, affording 79% of N-(1-((4-methoxyphenyl)amino)-1-oxopropan-2-yl)benzamide, whereas only 7% of the cycloadduct is obtained. What is more, the direct reaction between the azlactone and the preformed imine intermediate (i.e., (1E,2E)-N-(4-methoxyphenyl)-3-(4-nitrophenyl)prop-2-en-1-imine) still cannot eliminate the amidation product. After screening several chiral phosphoric acids, it is found that (11bR)-4-hydroxy-2,6-bis(triphenylsilyl) dinaphtho[2,1-d:1’,2’-f][1,3,2]dioxaphosphepine 4-oxide facilitates the [4+2] cycloaddition in chloroform. Under the optimized condition, all reactions of cinnamaldehydes bearing electronically deficient substituents afford 3-amino-3,4-dihydropyridin-2(1H)-ones in high yields and enantioselectivities. Also, azlactones with a sterically bulky group at C4 smoothly undergo the three-component reaction, yielding the cycloadducts of high enantioselectivity. However, this reaction only applies to 3-aryl α,β-unsaturated aldehydes, whereas the aliphatic α,β-unsaturated aldehydes fail in this reaction. Regarding the primary amines, the substituted aryl ethylamines are especially good reaction partners, as the newly generated 3,4-dihydropyridin-2(1H)-one moiety can further react with the aryl group to form fused pyridin-2(1H)-one derivative, as demonstrated in Scheme 1.106, for the three-component reaction of 4-methyl-2-phenyloxazol-5(4H)-one, (E)-4-nitrocinnamaldehyde and diethyl 2-amino-2-(3,4-dimethoxybenzyl)malonate to afford diethyl 2-((3S,4S)-3-benzamido-3-methyl-4-(4-nitrophenyl)-2-oxo3,4-dihydropyridin-1(2H)-yl)-2-(3,4-dimethoxybenzyl)malonate and its further conversion into diethyl (2S,3S,11bS)-3-benzamido-9,10dimethoxy-3-methyl-2-(4-nitrophenyl)-4-oxo-1,2,3,4,7,11b-hexahydro6H-pyrido[2,1-a]isoquinoline-6,6-dicarboxylate [275].

Azlactones 149

MeO O

O O Ph

+ N

H 2N H + OMe

O2N

20 mol% cat. CHCl3

O N

Ph

O

MeO

NH

O

+

N H

H N

Ph O

NO2

MeO O

O O Ph

N

CO2Et CO2Et

MeO H +

+

NH2

MeO

O2N

MeO

CO2Et CO2Et N O O

20 mol% cat. CHCl3, 0 °C

N H

NO2 MeO MeO

CO2Et CO2Et N O O

BF3 Et2O

N H

CH2Cl2, -15 °C

SiPh3

cat. =

O O P OH O SiPh3

NO2 66% yield, 91% ee

SCHEME 1.106  Preparation of 3,4-dihydropyridin-2(1H)-one from the [4+2] cycloaddition of 4-methyl-2-phenyloxazol-5(4H)-one and (E)-4-nitrocinnamaldehyde in the presence of a primary amine and chiral phosphoric acid.

It should be pointed out that the [4+2] cycloaddition involving azlactone may not be complicated with the Michael addition under several occasions. The first example can be found in a chiral scandium(III)-complex catalyzed IEDHDA between azlactone and (E)-6-(4-methoxybenzylidene)benzo[d][1,3] dioxol-5(6H)-one in THF, with imidazole as the additive, where the azlactone functions as the dienophile. Although other transition metal (e.g., Ni, and Yb) complexes also promote this reaction, the enantioselectivity of the corresponding product is low. Thus, chiral L-proline-derived N,N’-dioxide ligands have been developed to combine with Sc(OTf)3 for the purpose of improving chemical yields as well as enantioselectivity. These chiral N,N’-dioxide ligands are: (1R,1’R,2S,2’S)-1,1’-(propane-1,3-diyl)bis(2-((2,6-dimethylphenyl)carbamoyl)-pyrrolidine 1-oxide) (107, Figure 1.19), (1R,1’R,2S,2’S)-1,1’(propane-1,3-diyl)bis(2-((2,6-diisopropylphenyl)carbamoyl)-pyrrolidine 1-oxide) (108, Figure 1.19), (1R,1’R,2S,2’S)-1,1’-(propane-1,3-diyl) bis(2-((4-(tert-butyl)-2,6-dimethylphenyl)carbamoyl)pyrrolidine 1-oxide) (109, Figure 1.19), (1R,1’R,2S,2’S)-1,1’-(propane-1,3-diyl)bis(2-((4-(tertbutyl)-2,6-dimethylphenyl)carbamoyl)piperidine 1-oxide) (110, Figure 1.19), and (1S,1’S,2S,2’S,3aS,3a’S,6aS,6a’S)-1,1’-(propane-1,3-diyl)bis(2-((4-(tertbutyl)-2,6-dimethylphenyl)carbamoyl)octahydrocyclopenta[b]pyrrole 1-oxide)

150

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

(111, Figure 1.19) [276]. In addition to the chiral ligand, additive is also critical in terms of both chemical yield and enantioselectivity, for which Na2CO3 and DABCO enhance the yields but lower the enantioselectivity, whereas DMAP and particularly imidazole improve both yield and enantioselectivity. Mechanistically, this reaction occurs purely via [4+2] cycloaddition, as demonstrated in the reaction between 4-benzyl-2-phenyloxazol-5(4H)-one and (E)-6-(4-methoxybenzylidene)benzo[d][1,3]dioxol-5(6H)-one that yields N-((7R,8R)-7-benzyl-8-(4-methoxyphenyl)-6-oxo-7,8-dihydro-6H-[1,3] dioxolo[4,5-g]chromen-7-yl)benzamide (Scheme 1.107). Different from the one shown in Scheme 1.98, the Michael addition product (e.g., 4-benzyl-4-((6hydroxybenzo[d][1,3]dioxol-5-yl)(4-methoxyphenyl)methyl)-2-phenyloxazol5(4H)-one) is unable to be converted into the expected cycloaddition product under the same condition [276]. N N O

N

N

O N H

O

O

O H N

O N H

i-Pr

O

N O

i-Pr 107

O H N

N

i-Pr

O

t-Bu 109

N O

O

H N

t-Bu

O H N

t-Bu

N

O N H

O

i-Pr

108

O

N

O N H

N

O N H

O

t-Bu t-Bu 110

O H N

t-Bu 111

FIGURE 1.19  Chiral N,N’-dioxide ligands for the [4+2] cycloaddition of azlactones. O

O

O

O

O + Ph N OMe

Sc(OTf)3/111 (1:1.05, 10 mol%) imidazole (0.15 eq.) Bn THF, 35 °C

O

O

O

O Bn O N H

Ph

OMe 90% yield, 91% ee

SCHEME 1.107  Sc(OTf)3 catalyzed [4+2] cycloaddition between 4-benzyl-2-phenyloxazol5(4H)-one and (E)-6-(4-methoxybenzylidene)benzo[d][1,3]dioxol-5(6H)-one.

Azlactones 151

In addition to (E)-6-(4-methoxybenzylidene)benzo[d][1,3]dioxol5(6H)-one, other molecules that can be transformed in-situ into structures containing an (E)-6-arylidenecyclohexa-2,4-dien-1-one or even an (E)-6-alkylidenecyclohexa-2,4-dien-1-one moiety also proceed [4+2] cycloaddition with azlactones. One example is to apply a triple Brønsted acid activation strategy, in which 2-hydroxyl α-substituted benzyl alcohol once being protonated with a Brønsted acid is converted into 6-methylenecyclohexa-2,4-dien-1-one derivative (i.e., ortho-quinone methide); meanwhile, the azlactone is transformed into its enol form to undergoes [4+2] cycloaddition with the 6-methylenecyclohexa-2,4-dien1-one derivative to yield substituted chroman-2-one (2-oxo-chromane or 3,4-dihydrocoumarin), for which the stereochemistry is controlled by the Brønsted acid [277]. It is found that no reaction occurs in the absence of a Brønsted acid, whilst all five (R)-BINOL-derived chiral phosphoric acids efficiently promote the reaction to afford the corresponding products in 55–73% yields with variable stereoselectivities, particularly in the presence of (11bR)-2,6-di(anthracen-9-yl)-4-hydroxydinaphtho[2,1d:1’,2’-f][1,3,2]dioxaphosphepine 4-oxide. Also, the use of toluene as the solvent slightly increases the diastereo- and enantioselectivity. Compared to 2-methylazlactone, azlactones with a C2 aryl group containing different electron-donating or electron-withdrawing groups appear amenable to this reaction, whereas a C2 para-methoxyphenyl group in azlactone leads to a significant improvement of reaction efficiency and stereoselectivity [277]. On the other hand, 2-hydroxyl benzyl alcohols with alkenyl, allyl, or alkyl group at the α-position are all suitable for the reaction to give 3,4-dihydrocoumarins with excellent results. The mechanistic study did not demonstrate an obvious nonlinear effect, indicating that only a single molecule of chiral catalyst is involved in a concerted pathway (inverseelectron demand oxa-Diels–Alder reaction) for 6-methylenecyclohexa2,4-dien-1-one intermediate, so that the 2-hydroxyl group of the benzyl alcohol is critical for the generation of such intermediate. A representative reaction between ethyl 5-hydroxy-2-(4-methoxyphenyl)oxazole-4carboxylate and 2-(1-hydroxy-3-phenylprop-2-yn-1-yl)-5-methylphenol promoted with a catalytic amount of (11bR)-2,6-di(anthracen-9-yl)4-hydroxydinaphtho[2,1-d:1’,2’-f][1,3,2]dioxaphosphepine 4-oxide that yields ethyl (3R,4R)-3-(4-methoxybenzamido)-7-methyl-2-oxo-4(phenylethynyl)chromane-3-carboxylate is illustrated in Scheme 1.108 [277].

152

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Ph

Ph O

O

N

CO2Et

+ MeO OH

OMe O 93% yield, dr > 95:5, 91% ee

CPA cat.

O

CPA cat.

Ph

OH

O NH O

OH

OH2

O

5 mol% cat. toluene, 0 °C

Ph

Ph

EtO2C

N

HO

O

H 2O OH

CO2Et H N

OMe

OMe O

O OH

cat. = O P O HO

O

SCHEME 1.108  The mechanism for the chiral phosphoric acid catalyzed reaction between 2-(1-hydroxy-3-phenylprop-2-yn-1-yl)-5-methylphenol and ethyl 2-(4-methoxyphenyl)5-oxo-4,5-dihydrooxazole-4-carboxylate.

Similarly, 6-alkylidene-cyclohexa-2,4-dien-1-one intermediate can also be generated under a basic condition from 2-(1-tosylalkyl)-phenol, where the inorganic base (e.g., Na2CO3) should not promote the Michael addition between the enolate form of azlactone and the 6-alkylidenecyclohexa-2,4dien-1-one intermediate to guarantee the high chemical yield of cycloadduct as well as effective control of enantioselectivity by the bifunctional squaramidebased organo-catalyst. A typical reaction under this condition is the one between 4-benzyl-2-phenyloxazol-5(4H)-one and 2-(phenyl(tosyl)methyl) naphthalen-1-ol in the presence of Na2CO3 and 3-((3,5-bis(trifluoromethyl) phenyl)amino)-4-(((1S)-(6-methoxyquinolin-4-yl)-((2S,4S,5R)-5vinylquinuclidin-2-yl)methyl)amino)-cyclobut-3-ene-1,2-dione (94, Figure 1.17) to afford 89% of N-((3S,4S)-3-benzyl-2-oxo-4-phenyl-3,4-dihydro2H-benzo[h]chromen-3-yl)benzamide with 96% ee [278]. 2-Hydroxyl α-substituted styrenes can also be converted into 6-alkylidenecyclohexa-2,4-dien-1-one intermediates for the purpose to react with azlactones [279]. For this particular case, chiral phosphoric acid is necessary

Azlactones 153

for the conversion of 2-hydroxyl stryenes into the 6-alkylidenecyclohexa2,4-dien-1-one intermediates, whereas chiral guanidine is essential for the cycloaddition in order to control the enantioselectivity. The synergistic interaction of chiral phosphoric acid and chiral guanidine has offered a unique catalytic system for asymmetric cooperative catalysis, using 2-hydroxyl styrenes as oxa-diene precursors in catalytic asymmetric cycloadditions with azlactones. Based on the screening of chiral phosphoric acids and chiral organic bases, the combination of 20 mol% of (1r,5aS)-1,10di(anthracen-9-yl)-12-hydroxy-4,5,6,7-tetrahydrodiindeno[7,1-de:1’,7’fg][1,3,2]dioxaphosphocine 12-oxide and 10 mol% of (2S,6S)-2,6-di-tertbutyl-2,3,5,6-tetrahydro-1H-imidazo[1,2-a]imidazole in toluene in the presence of magnesium sulfate at 30°C surrenders an optimal condition for the reaction between 2-hydroxyl styrenes and azlactones, affording (S)-N-(3,4,4-trimethyl-2-oxochroman-3-yl)benzamide in 84% yield and 93% ee from 2-hydroxyl α-methylstyrene and 2,4-diphenyloxazol-5(4H)one as an example [279]. Computational study (DFT calculation) using the M06-2X functional with 6-31G(d) basis set indicates a stepwise [4+2] cycloaddition reaction involving three consecutive steps, which are C−C bond formation, C−O bond formation, and opening of the azlactone ring. The synergistic cooperation of CPA and chiral guanidine plays an important role in the simultaneous activation of both 2-hydroxy styrene and azlactone via hydrogen-bonding interactions. While in the mono-catalytic Diels-Alder reaction, both the R- and S-products have the predicted rate-determining steps of comparable magnitude, under the synergistic cooperation of CPA and chiral guanidine, the formation of the S-product is more facile in line with the experimental observations [280]. Also, under cooperative catalysis of iridium complex and a Brønsted acid, 1-tosyl-4-vinyl-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one reacts with ethyl 5-oxo-2-aryl-4,5-dihydrooxazole-4-carboxylates via [4+2] cycloaddition to afford ethyl (3R,4S)-3-benzamido-2-oxo-1-tosyl-4-vinyl1,2,3,4-tetrahydroquinoline-3-carboxylates (from ethyl 5-oxo-2-phenyl-4,5dihydrooxazole-4-carboxylate), in 91% yield with diastereoselectivity of 94:6, as shown in Scheme 1.109 [281]. In contrast, the same reaction only affords 84% of the product with 64:36 of diastereoselectivity if only [Ir(cod)Cl]2 is used. While the diastereoselectivity is enhanced with Pd(PPh3)4 (> 95:5), the reaction is retarded to give only a 20% yield. Under the optimized condition, the reactions of 1-tosyl-4-vinyl-1,4-dihydro-2H-benzo[d][1,3] oxazin-2-one with a series of azlactones containing different C2 aryl group all give the expected cycloaddition products in good to excellent yield

154

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

with excellent diastereoselectivity. However, azlactones with a C2 alkyl group (e.g., ethyl, benzyl) do not apply to this reaction. On the other hand, azlactones with a C4 aryl group undergoes a completely different reaction route rather than the [4+2] cycloaddition, as exemplified in the reaction between 1-tosyl-4-vinyl-1,4-dihydro-2H-benzo[d]-[1,3]oxazin-2-one and 2,4-diphenyloxazol-5(4H)-one that affords 92% of (R,E)-4-methyl-N-(2(3-(5-oxo-2,4-diphenyl-4,5-dihydrooxazol-4-yl)prop-1-en-1-yl)phenyl) benzenesulfonamide (Scheme 1.109) [281]. O O

O

O

N

CO2Et

+

N O Ts 1 mmol

O

O

N

Ph

+ O

O NH N O O Ts 91% yield, 94:6 dr

1.5 mmol

O N Ts

5 mol% [Ir(cod)Cl]2 20 mol% TsOH H2O acetone, 25 °C

5 mol% [Ir(cod)Cl]2 20 mol% TsOH H2O acetone, 25 °C

Ph O O N NH Ph Ts 92%, E/Z = 83:17

SCHEME 1.109  Different reaction pathway for 1-tosyl-4-vinyl-1,4-dihydro-2H-benzo[d] [1,3]oxazin-2-one with azlactones.

A true case of [4+2] cycloaddition involving four atoms of the azlactone ring has been demonstrated by the silylation of 2-oxazolin-5-ones using Me3SiCl and Et3N to give 5-trimethylsiloxyoxazoles (e.g., 4-benzyl2-methyl-5-trimethylsiloxyoxazole) in high yields. The latter was then allowed to undergo the Diels-Alder reaction with N-phenylmaleinimide or dimethyl maleate to afford the corresponding pyridine derivatives in high yields. This method has been extended to the synthesis of vitamin B6 derivatives starting from N-formylalanine [282]. To illustrate this concept, an example of making a pyridine derivative is given in Scheme 1.110, where N-acetyl-valine was treated with ethyl chloroformate to give 4-isopropyl2-methyloxazol-5(4H)-one, which was then treated with TMSCl in the presence of triethylamine in Et2O, yielding 92% of 4-isopropyl-2-methyl5-((trimethylsilyl)oxy)oxazole (b.p., 96–97°C at 21 mmHg). Subsequent Diels-Alder cycloaddition between 4-isopropyl-2-methyl-5-((trimethylsilyl) oxy)oxazole and 1-phenyl-1H-pyrrole-2,5-dione without any solvent at 0°C

Azlactones 155

to room temperature for 1 hour, generated an intermediate of 6-isopropyl4-methyl-2-phenyl-7-((trimethylsilyl)oxy)-3a,4,7,7a-tetrahydro-1H-4,7epoxypyrrolo[3,4-c]pyridine-1,3(2H)-dione, which decomposed to give 92% of 7-hydroxy-6-isopropyl-4-methyl-2-phenyl-1H-pyrrolo[3,4-c] pyridine-1,3(2H)-dione, m.p., 101–103.5°C [282]. O N H

OH

O

O

N

Et3N/TMSCl Et2O

N

ClCO2Et

O

O

OSiMe3

O O

N Ph O

Ph

O

N O

Me3SiO O N

Ph N O

HO N

SCHEME 1.110  The [4+2] cycloaddition between 4-isopropyl-2-methyloxazol-5(4H)-one and 1-phenyl-1H-pyrrole-2,5-dione in the presence of Et3N and trimethylsilyl chloride.

1.4.1.4.3 [8+2] Cycloaddition A Brønsted acid catalyzed reaction between tropone and azlactone is an example of [8+2] cycloaddition reaction that affords dihydro-2Hcyclohepta[b]furan derivative. For this reaction, several Brønsted acids, e.g., diphenylphosphoric acid, benzoic acid, camphorsulfonic acid, toluenesulfonic acid, trifluoroacetic acid, have been screened based on the model reaction between tropone and 4-methyl-2-phenyloxazol-5(4H)-one in CH2Cl2, that affords N-((3S,3aS)-3-methyl-2-oxo-3,3a-dihydro-2Hcyclohepta[b]furan-3-yl)benzamide and N-((3S,3aR)-3-methyl-2-oxo-3,3adihydro-2H-cyclohepta[b]furan-3-yl)benzamide, with the 3aS diastereomer as the major product (> 70% ratio) [283]. Among these Brønsted acids, TFA is more effective than others in terms of the conversion rate as well as diastereoselectivity. Thus, this reaction has been further tested in the presence of TFA in different solvents, e.g., CH2Cl2, THF, CHCl3, toluene, p-xylene, to locate p-xylene as the solvent of choice. Under this optimized condition, the reactions of tropone with azlactones deriving from alanine, norvaline, homophenylalanine, valine, etc., all give the cycloaddition products in good to excellent yields and good diastereoselectivity. The stereoselectivity may arise from a hydrogen bond initially formed between the OH group of the

156

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

enol and the oxygen atom of the protonated tropone. Incorporation of a substituent at the α-position (e.g., Cl) of tropone leads to a profound impact on the chemoselectivity because it would produce an additional destabilization of the transition state involving the close interaction between Cl and R whilst not affecting the alternative transition state that leads to the preferred 3aS cycloadduct, with corresponding diastereoselectivity greater than 98:2 [283]. However, under basic conditions, e.g., in the presence of 10 mol% Et3N, the 3aR diastereomer becomes the dominant product, with diastereoselectivity of 36:64. Subsequent treatment of the [8+2] cycloaddition products with a nucleophile leads to α,α-disubstituted amino acids bearing a seven-membered ring at the quaternary carbon atom. Particularly, the use of homochiral amino acids as nucleophiles provides separable mixtures of enantiomerically pure α-(2-tropyl), α-alkyl α-amino acid dipeptides. On the other hand, the nucleophilic treatment of the [8+2] cycloadduct from α-chloro-tropone with azlactone would generate a quaternary amino acid with tropone ring at C-α due to the elimination of chlorine. For comparison, the individual reaction of 4-methyl-2-phenyloxazol-5(4H)-one with tropone or α-chloro-tropone in the presence of TFA in p-xylene and subsequent treatment with methyl glycinate to form the corresponding dipeptide is demonstrated in Scheme 1.111 [283]. O O + Ph

O

O

N

5 mol% TFA p-xylene, r.t. 95% yield

O O

H

NH

O

O

O +

H

Ph (dr = 93:7)

O

NH

Ph

N H

Ph

O O HN CO2Me

NH2CH2CO2Me (4.5 eq.) 60% yield Cl Cl O

O + Ph N

O

O 5 mol% TFA p-xylene, r.t. 97% yield

O H

NH

O Ph dr > 98:2

NH2CH2CO2Me O (4.5 eq.) Ph N K2CO3 H 100% yield

O O HN CO2Me

SCHEME 1.111  Examples of [8+2] cycloaddition between 4-methyl-2-phenyloxazol5(4H)-one and tropones.

Azlactones 157

1.4.2 CHEMICAL REACTIVITIES OF UNSATURATED AZLACTONES 1.4.2.1 NUCLEOPHILIC VINYLOGOUS REACTIVITY OF OLEFINIC AZLACTONES It has been generally accepted that the C4 of azlactone is nucleophilic, and the hydrogen atom on C4 with a pKa around 9 [7, 142–144], can be easily deprotonated even in the presence of a weak base as evidenced in so many examples outlined above. As a result, the methyl group attaching to an olefinic azlactone would behave in a manner very similar to C4 in a saturated azlactone. Alternatively, the α-hydrogen on the C4-alkylidene azlactone should be acidic enough to be easily deprotonated. One of the early examples to explore such reactivity of C4-alkylidene azlactone is the extended Michael addition of (Z)-2-phenyl-4-(1-phenylethylidene)oxazol-5(4H)-one to cinnamaldehyde in the presence of a catalytic amount of Et3N (as a base to deprotonate the methyl group) and (S)-2-(((tert-butyldimethylsilyl)-oxy)diphenylmethyl)pyrrolidine, which proceeds with a very high level control of double-bond configuration and excellent enantioselectivity to yield 75% of (S,Z)-5-(5-oxo-2-phenyloxazol-4(5H)-ylidene)-3,5-diphenylpentanal with a Z/E ratio of 7:1 and enantioselectivity of 98% ee (Scheme 1.112) [284]. This extended Michael addition has been developed further for the unprecedented intermolecular enantioselective vinylogous 1,6-addition to linear 2,4-dienals (e.g., (2E,4E)undeca-2,4-dienal), for which the site selectivity of this process is extended from the β-position to the remote δ-position of the 2,4-dienal. The organic catalyst controls the newly generated stereocenter six bonds away from the stereocenter of the catalyst with a high level of enantioselectivity. The product is obtained also with full control of double-bond configurations, as exemplified in the reaction between (Z)-2-phenyl-4-(1-phenylethylidene) oxazol-5(4H)-one (with an initial 30% of E-configuration) and (2E,4E)undeca-2,4-dienal. In this reaction, DIPEA is used as base and the same chiral pyrrolidine catalyst is applied. However, (S,E)-5-((Z)-2-(5-oxo-2phenyloxazol-4(5H)-ylidene)-2-phenylethyl)undec-2-enal is obtained with the olefinic configuration greater than 20:1 for both the olefinic azlactone (Z:E) and the one conjugated to the aldehyde group (E:Z) (Scheme 1.112) [284]. (Note: this product should be in S-configuration for the chiral stereogenic center).

158

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Ph

Ph

N OTBS O Ph O H Ph (20 mol%) N Ph + N O Et N (20 mol% Ph Ph 3 brine (3.0 eq.) O O Ph O (3.0 eq.) CH2Cl2, r.t. (Z:E = 7:3) 75% yield, Z:E = 7:1, 98% ee (1.0 eq.) workup

Et3N

O

O

Ph

Ph

TBSO

Ph

O

O

Ph

Ph

N

N

Ph

N Ph

N

OTBS

Ph Ph Ph Ph N Ph O

O (Z:E = 7:3) (1.0 eq.)

+ C6H13 (3.0 eq.)

Ph

Ph

N OTBS Ph C6H13 H (20 mol%) N O O DIPEA (20 mol% Ph brine (3.0 eq.) O O CH2Cl2, r.t. 66% yield, Z:E > 20:1, 88% ee

SCHEME 1.112  A chiral pyrrolidine catalyzed extended conjugation addition between (Z)-2-phenyl-4-(1-phenylethylidene)oxazol-5(4H)-one and cinnamaldehyde (or (2E,4E)undeca-2,4-dienal).

Furthermore, the Michael addition of (Z)-2-phenyl-4-(1phenylethylidene)-oxazol-5(4H)-one has been extended to (E)-3-methyl-4nitro-5-styrylisoxazole in the presence of 2.0 equivalents of base and a catalytic amount of chiral urea or thiourea. These urea and thiourea include (S)-1benzyl-1-(2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-3-phenylpropyl) pyrrolidin-1-ium bromide (112, Figure 1.20), (S)-1-benzyl-1-(2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-2-phenylethyl)pyrolidin-1-ium bromide (113, Figure 1.20), (S)-1-benzyl-1-(2-(3-(3,5-bis(trifluoromethyl)phenyl) ureido)-3,3-dimethylbutyl)pyrrolidin-1-ium bromide (114, Figure 1.20), (S)1-benzyl-1-(2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-3,3dimethylbutyl)pyrrolidin-1-ium bromide (115, Figure 1.20) and (S)-1benzyl-1-(2-(3-(3,5-bis(trifluoromethyl)phenyl)ureido)-3,3-dimethylbutyl) piperidin-1-ium bromide (116, Figure 1.20) [285]. Evaluation on the chemical yield as well as enantioselectivity indicates that chiral urea 114 behaves better than others, thus it has been selected to optimize the reaction conditions (5.0 equivalents of KF, toluene, room temperature). Under the

Azlactones 159

optimized condition, the reaction between (Z)-2-phenyl-4-(1-phenylethylidene)oxazol-5(4H)-one and (E)-3-methyl-4-nitro-5-styrylisoxazole affords 91% of N-((1’R,6’R)-6’-(3-methyl-4-nitroisoxazol-5-yl)-5’-oxo1’,2’,5’,6’-tetrahydro-[1,1’: 3’,1”-terphenyl]-4’-yl)benzamide with 93% ee, and a trace amount of (S,Z)-4-(4-(3-methyl-4-nitroisoxazol-5-yl)-1,3diphenylbutylidene)-2-phenyloxazol-5(4H)-one as shown in Scheme 1.113 [285]. While the substituent on the styrene moiety of (E)-3-methyl-4nitro-5-styrylisoxazole slightly affects the yield, the olefinic group on the azlactones has profound impact on the reactivity, although all reactions with excellent enantioselectivity. For example, (Z)-2-phenyl-4-(1-arylethylidene) oxazol-5(4H)-ones containing an electron-withdrawing substituent (Cl, Br) on the para-position of aryl group lower the yields to 77%, the one with an electron-donating group (OMe) results in a 92% yield. In contrast, (Z)-4-(2-alkylidene)-2-phenyloxazol-5(4H)-ones such as (Z)-4-(octan2-ylidene)-2-phenyloxazol-5(4H)-one, (Z)-4-(hex-5-en-2-ylidene)-2phenyloxazol-5(4H)-one and (Z)-2-phenyl-4-(4-phenylbutan-2-ylidene) oxazol-5(4H)-one only afford the respective products of less than 51% yields. Particularly, the cyclic olefinic azlactones will give the respective products with three chiral centers, as shown in the reaction between (Z)-4(3,4-dihydronaphthalen-1(2H)-ylidene)-2-phenyloxazol-5(4H)-one and (E)-5-(3-bromostyryl)-3-methyl-4-nitroisoxazole under the optimized condition to yield 82% of N-((1R,2R,10aR)-1-(3-bromophenyl)-2-(3-methyl4-nitroisoxazol-5-yl)-3-oxo-1,2,3,9,10,10a-hexahydrophenanthren-4-yl) benzamide. Further treatment of this compound with 5.0 equivalents of SnCl2 affords 78% of N-((1S,10aR)-1-(3-bromophenyl)-3-oxo-1,2,3,9,10,10ahexahydrophenanthren-4-yl)benzamide (Scheme 1.113) [285]. CF3

CF3 O

F3C

N H

N H

CF3

Ph

O

N Br

Ph N H

N H

F3C Ph

112

O N

Br

Ph

113 CF3

N H

N Br

Ph

114 CF3

S F3C

N H

F3C

N H 115

O N H

N Br

F3C Ph

N H

N H

N Br

Ph

116

FIGURE 1.20  The chiral urea and thiourea used as catalysts for the extended Michael reaction of unsaturated azlactones.

160

3K

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

2

2

12 

1 3K

1

3K

2

PRO HT.) WROXHQHUW

3K

3K 3K

2

12

2

21 2

2 1

1



3K .) 3K

3K 3K

3K 1

%U 2 2

PRO HT.) WROXHQHUW

 2 1

12

3K

2

21 2

2 1

2 1 2

+1

12

2

2

%U

1 2

%]1 +)

3K 3K

1

3K +)

1 2

1 2

%]+1

HT6Q&O+&O 7+)+2 

3K 2

2

+1 %U

+

+

\LHOG !GUHH

\LHOG !GUHH

SCHEME 1.113  The mechanism for the reaction between (Z)-2-phenyl-4-(1phenylethylidene)oxazol-5(4H)-one and (E)-3-methyl-4-nitro-5-styrylisoxazole.

In addition to α,β-unsaturated aldehyde in the presence of chiral pyrrolidine catalyst, alkylidene azlactones also undergo allylic alkylation to substituted tert-butyl (1-phenylallyl) carbonates. A representative reaction has been performed between (Z)-2-phenyl-4-(1-phenylethylidene)oxazol5(4H)-one and methyl 2-(((tert-butoxycarbonyl)oxy)(phenyl)methyl) acrylate in the presence of 14 nucleophilic chiral catalysts, affording methyl (R,Z)-2-methylene-5-(5-oxo-2-phenyloxazol-4(5H)-ylidene)3,5-diphenylpentanoate [286]. It is found that (S)-((1S,2R,4S,5R)-5ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methanol (the diastereomer of 101 in Figure 1.18) is superior to other tested chiral catalysts in terms of the chemical yield and stereoselectivity of the allylation product (96% yield, 93% ee and 11:1 for Z:E for the olefinic configuration). Based on this preliminary screening result, (Z)-2-phenyl-4-(1-arylethylidene) oxazol-5(4H)-ones have been subject to the reactions with methyl 2-(((tertbutoxycarbonyl)oxy)(arylmethyl)acrylates in the presence of the ideal chiral catalyst in mesitylene at 10°C, all affording the allylation products in good to excellent yields, as well as excellent enantioselectivity and Z:E ratio for the olefinic azlactones. With respect to the acrylates, both electron-donating and electron-withdrawing substituents of the aryl ring are compatible with this catalytic system, where the acrylates with an aryl group containing an electron-withdrawing substituent lead to slightly lower reactivity but higher % ee values with respect to the acrylates of an aryl group containing an electron-donating substituent. Also, the acrylates with

Azlactones 161

its aryl group containing an ortho-substituent give a lower yield than the corresponding acrylates containing an aryl group with a meta- or parasubstituent, probably due to its steric hindrance [286]. In contrast, the reaction of (Z)-2-phenyl-4-(1-phenylethylidene)oxazol5(4H)-one with methyl 3-((tert-butoxycarbonyl)oxy)-2-methylenebutanoate does not proceed smoothly, leading to only 6% of product with very low Z:E selectivity. Furthermore, the two vinylogous methyl groups in 2-phenyl4-(propan-2-ylidene)oxazol-5(4H)-one can undergo the allylation with methyl 2-(((tert-butoxycarbonyl)oxy)(phenyl)methyl)acrylate, yielding 42% of (3S,7S)-2,8-dimethylene-5-(5-oxo-2-phenyloxazol-4(5H)-ylidene)3,7-diphenylnonanedioic acid dimethyl ester, with 98% ee and greater than 20:1 of diastereoselectivity (Scheme 1.114). Further treatment of methyl (R,Z)-2-methylene-5-(5-oxo-2-phenyloxazol-4(5H)-ylidene)-3,5diphenylpentanoate under basic conditions, gives 80% of dimethyl (R,Z)2-benzamido-6-methylene-3,5-diphenylhept-2-enedioate (with K2CO3 in methanol) and 85% of methyl (7R,8S)-4-oxo-2,8,10-triphenyl-3-oxa1-azaspiro[4.5]deca-1,9-diene-7-carboxylate (with DABCO and DMC), respectively, as shown in Scheme 1.114 [286]. 2 2

2

3K

3K

2 

1

2

2

2

PROFDW ƒ PHVLW\OHQH&

2

3K

2

&20H

1

3K

3K &20H

1 2+

+ 2

FDW

1 3K 3K

2

2 

1

3K

2 2

2

2 2

0H2+UW

2 3K

3K

1

3K

&20H 1 +

3K

2

3K .&2

&20H

2

PROFDW ƒ PHVLW\OHQH&

3K

'$%&2'0& WROXHQHUHIOX[

&20H 3K 0H2& 0H2&

.&2 3K 1+%]

HH

0H2+UW

2 2 3K

&20H 3K

1 3K

HH

SCHEME 1.114  Vinylogous nucleophilic addition of unsaturated azlactone to methyl 2-(((tert-butoxycarbonyl)oxy)(phenyl)methyl)acrylate.

162

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

1.4.2.2 VINYLOGOUS ARYLATION OF AZLACTONES In contrast to the nucleophilic nature of the methyl group attaching to an olefinic azlactone, the carbon atom on the exocyclic olefinic azlactone has an electrophilic nature, as demonstrated in the treatment of (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one in benzene with anhydrous aluminum chloride that yields 62% of 4-benzhydryl-2-phenyloxazol-5(4H)-one after recrystallization. Since azlactone is normally considered to be an anhydride, it has been argued that such treatment of (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one in benzene with AlCl3 would give Friedel-Crafts acylation products, such as (Z)-N-(3-oxo-1,3-diphenylprop-1-en-2-yl)benzamide and N-(1-oxo-1H-inden-2-yl)benzamide [287]. The unexpected product of 4-benzhydryl-2-phenyloxazol-5(4H)-one is assumed to form by 1,4-addition of benzene to the unsaturated azlactone. Interestingly, subsequent repeating of this experiment gives N-(2-oxo-2-phenylethyl)benzamide, and the same product is obtained from the treatment of (Z)-4-(4-chlorobenzylidene)-2phenyloxazol-5(4H)-one in benzene with AlCl3. However, different products are reached when (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one is treated with AlCl3 in toluene, m-xylene, or chlorobenzene [288], indicating that the azlactone is split. The inconsistent results from these two reports prompt a detailed mechanistic study on this reaction that reproduces the result to form 4-benzhydryl-2-phenyloxazol-5(4H)-one with anhydrous AlCl3, whereas N-(2-oxo-2-phenylethyl)benzamide is obtained when water-containing AlCl3 is used by means of exposing the finely ground anhydrous catalyst, in a thin layer, to the atmosphere for five minutes [289]. This reaction behavior has been illustrated in Scheme 1.115. 1.4.2.3 REACTIONS OF UNSATURATED AZLACTONES WITH CARBON NUCLEOPHILES Unsaturated azlactones may undergo unusual reactions with some carbonbased nucleophiles. For example, treatment of (E)-4-(ethoxymethylene)-2phenyloxazol-5(4H)-one with Grignard reagent (phenylethynyl)magnesium bromide in THF yields ethyl (Z)-2-benzamido-5-phenylpent-2-en-4-ynoate. Under this condition, the reaction between (E)-4-(ethoxymethylene)-2phenyloxazol-5(4H)-one and hex-1-yn-1-ylmagnesium bromide affords ethyl (Z)-2-benzamidonon-2-en-4-ynoate (Scheme 1.116). While no mechanism has been provided for this unexpected result, it is possible that the Grignard reagent initially adds to the exocyclic double bond to form

Azlactones 163

3K

2

2 1

2

3K

1

2

3K

1 3K

3K

2+

2

3K

3K

1

3K

2

2

ZRUNXS 3K

$O&O 2 +

1

3K

$O&O

2

2

3K

1

3K

+

3K

2 $O&O

2

3K

1

3K

3K

$O&O

2

2

$O&O 3K

2+ 

1

3K

2

2

3K

3K & +  

3K&+

+

3K

2

$O&O

1 +

1

2

&+

1 +

2

2

SCHEME 1.115  The mechanism for the generation of 4-benzhydryl-2-phenyloxazol5(4H)-one, triphenylmethane, and N-(2-oxo-2-phenylethyl)benzamide for the reaction of (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one in benzene in the presence of AlCl3.

4-(1-ethoxy-3-phenylprop-2-yn-1-yl)-5-oxo-2-phenyl-4,5-dihydrooxazol4-ide which eliminates the ethoxide to generate (Z)-2-phenyl-4-(3phenylprop-2-yn-1-ylidene)oxazol-5(4H)-one. Subsequently, the addition of ethoxide to the C5-carbonyl group leads to the ring-opening product [177]. O EtO

Ph

Ph

O

Ph + Br Mg

N

NHBz O

THF O

workup O

O

O

EtO

N

Ph

EtO

N

O Ph

Ph

Ph

+ Br

Mg

Ph O

N

O

n-C4H9

n-C4H9

O N

EtO

Ph

Ph O

O

NHBz O

THF O

SCHEME 1.116  The mechanism for the reaction of (E)-4-(ethoxymethylene)-2phenyloxazol-5(4H)-one with Grignard reagent.

164

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

On the other hand, the reaction of (E)-4-(ethoxymethylene)-2-phenyloxazol-5(4H)-one with diethyl 3-oxoglutarate gives different products depending on the base and solvent used. For example, the reaction in benzene in the presence of sodium hydride forms diethyl 5-benzamido2,4-dihydroxyisophthalate, whereas the reaction in CH2Cl2 in the presence of Et3N affords ethyl 3-benzamido-6-(2-ethoxy-2-oxoethyl)-2-oxo-2Hpyran-5-carboxylate. Since sodium hydride is a hard and strong base, which would deprotonate diethyl 3-oxoglutarate to form carbanion. This carbanion initially adds to the exocyclic double bond of the azlactone followed by the elimination of the ethoxy group. Subsequent transformations lead to the formation of diethyl 5-benzamido-2,4-dihydroxyisophthalate (several steps are omitted due to limited space). For comparison, when diethyl 3-oxoglutarate is treated with Et3N, a weak and soft base, enolate (Z)-1,5-diethoxy1,5-dioxopent-2-en-3-olate is formed, which then adds to the C5 carbonyl group of the azlactone leading to a ring-opening intermediate. The addition of carbanion to the double bond followed by the elimination of the ethoxy group from the lactone ring, and subsequent tautomerization lead to the final product of ethyl 3-benzamido-6-(2-ethoxy-2-oxoethyl)-2-oxo-2H-pyran5-carboxylate. The details of these transformations are outlined in Scheme 1.117 [177]. Furthermore, treatment of (E)-4-(ethoxymethylene)-2-phenyloxazol-5(4H)-one with 5-phenylisoxazole in the presence of sodium ethoxide affords N-(5-cyano-2-oxo-6-phenyl-2H-pyran-3-yl)benzamide (also known as 3-benzoylamino-5-cyano-6-phenyl-2H-pyran-2-one), as demonstrated in Scheme 1.118. In this reaction, treatment of 5-phenylisoxazole with sodium ethoxide gives 5-phenylisoxazol-4-ide, which adds to the exocyclic double bond of the azlactone to form 4-(ethoxy(5-phenylisoxazol-4-yl)methyl)5-oxo-2-phenyl-4,5-dihydrooxazol-4-ide. Elimination of ethoxy anion yields (Z)-2-phenyl-4-((5-phenylisoxazol-4-yl)methylene)oxazol-5(4H)-one, from which the further deprotonation with ethoxide leads to the opening of isoxazole ring to (1Z,3Z)-2-cyano-3-(5-oxo-2-phenyloxazol-4(5H)-ylidene)-1phenylprop-1-en-1-olate. Isomerization of the enolate allows the required geometry for the cyclization and opening of the azlactone ring that affords benzoyl(5-cyano-2-oxo-6-phenyl-2H-pyran-3-yl)amide. Final workup gives N-(5-cyano-2-oxo-6-phenyl-2H-pyran-3-yl)benzamide [177].

2

(W2

(W2

2

2

2

2

2

2

2

1

2

(W2

%]+1

2

2(W

2

2

2(W

3K

(W2 2

(W2

(W1 &+&O (W2

ZRUNXS

2(W

1 +

2

2

2

2

2

2

2

2

1

2

1

2

1

2

2

3K

2

(W2

(W2

(W2

2

2

2

2

2

2

+

2

(W2

2

1D+

2

2

2

2

2

2

2

2(W

2(W

2

2

1

2

2

2

3K

2

3K

2

(W2

(W2

3K

&2(W 2

2(W

3K

+1 (W2

1

2

2

1D+ EHQ]HQH

(W2

(W2

2(W (W1+

2(W

(W1

2

2(WRU1D+

2(W

3K

3K

3K 

2(W

1 +

(W2 2

(W2

2

2

1

2+ 2

2

2

2

+

1

2(W

&2(W

(W2

2(W

1+%] 2+

(W2

2

2 2

3K

SCHEME 1.117  The mechanism for the formation of ethyl 3-benzamido-6-(2-ethoxy-2-oxoethyl)-2-oxo-2H-pyran-5-carboxylate or diethyl 5-benzamido-2,4-dihydroxyisophthalate from the reaction of (E)-4-(ethoxymethylene)-2-phenyloxazol-5(4H)-one and diethyl 3-oxopentanedioate in the presence of Et3N or NaH.

%]+1

(W2

3K

(W2 (W2 + 2

Azlactones 165

166

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

2  1 2

2

(W2

3K

1

1D2(W

3K

2

2

2

1 +

1&

3K 3K

1D2(W (W2+

(W2

1 1 2

2 1

2 2

2 2(W 3K

2 3K

1

1 (W2

3K +

1

2

&1

3K

2

&1

3K

1 (W2+

3K

2

2

2

2

3K

2

1&

3K

2

1

3K 2

2

1&

1 2

3K

2

1

3K

2

2

3K

2

SCHEME 1.118  The mechanism for the formation of N-(5-cyano-2-oxo-6-phenyl-2Hpyran-3-yl)benzamide from the reaction between (E)-4-(ethoxymethylene)-2-phenyloxazol5(4H)-one and 5-phenylisoxazole.

1.4.2.4 NUCLEOPHILIC ADDITION OF BENZIMIDAMIDE TO UNSATURATED AZLACTONES Due to the electrophilic nature of the carbon atom on the exocyclic olefinic azlactone, nucleophilic addition to such an exocyclic double bond is feasible, as demonstrated in the CsF catalyzed reaction between N-(4-chlorophenyl)benzimidamide and (Z)-4-(4-nitrobenzylidene)-2-phenyloxazol-5(4H)-one under microwave irradiation at 70°C (Scheme 1.119) [290]. The initial reaction has been carried out in CH3CN under refluxing in the presence of a catalytic amount of base, such as Et3N, DIPEA, DABCO, NaOAc, Na2CO3, K2CO3, KF, and CsF, from which CsF has been identified as the ideal base for this reaction. Then, CH3CN has been determined to be the solvent of choice. This approach has been approved to be an efficient, practical, scalable, and expeditious strategy for the synthesis of a wide range of transN-(6-oxo-1,4,5,6-tetrahydropyrimidin-5-yl)benzamides under microwave irradiation, from which nearly sole trans-diastereomers have been obtained from various arylidene azlactones and amidines. These dihydropyrimidinones have exhibited antifungal and particularly antibacterial activities [290].

Azlactones 167

O2N Cl

O2N

NH

0.1 eq. CsF N O CH3CN, mw 70 °C Ph

+

N H

N

O

N

HN O

O

Cl

CsF

F

HF O

Ph

O

HF

N

Cl

O2N

NH

N

N

N

N NO2 O Ph

HF HN N

Ph

O N

O

Cl

Ph

O

Cl

O

N

O Cl

O F

HN

NO2 N

NO2 HF

N

O Cl

N N

NO2

SCHEME 1.119  The mechanism for the reaction between N-(4-chlorophenyl) benzimidamide and (Z)-4-(4-nitrobenzylidene)-2-phenyloxazol-5(4H)-one.

1.4.2.5 THE REACTION OF UNSATURATED AZLACTONES WITH WATER Azlactones as reactive and unstable species will also react with water to form N-acyl α-amino acids. This is essentially the reverse reaction for the preparation of azlactone from N-acyl-α-amino acids and dehydrating agents. Therefore, this reaction has not been applied for the purpose of synthesis, unless for the synthesis of α,α-disubstituted unnatural amino acids. However, hydrolysis of unsaturated azlactones would give acrylic acid derivatives. For example, when the unsaturated azlactones obtained from the reaction of N-acylglycine and aromatic aldehydes in the presence of acetic anhydride are hydrolyzed, the N-acyl α-amino acrylic acids are yielded which can be hydrogenated into N-acyl α-amino acids. In addition, it is possible to catalytically reduce the unsaturated azlactones in an alkaline medium to eliminate the conversion stage into α-acylamino acrylic acids. This process becomes a standard procedure to make α-amino acids. For example, the amino acids of phenylalanine (84%), tyrosine (78%), 3,4-dimethoxyphenylalanine (64%), 4-hydroxy-3methoxyphenylalanine (46.5%), valine (75%), isoleucine (62%), leucine (54%) and certain other amino acids have been successfully prepared by this method, with the percentage yields in the corresponding parentheses [226].

168

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

On the other hand, for the unsaturated azlactones or 4-arylidene or arylalkylidene azlactones, both C2 and C4 are electrophilic in reaction with water. Although the hydrolysis of unsaturated azlactone in pure water gives the same product (i.e., the hydrolyzed product of substituted 2-amino acrylic acid), no matter whether it occurs at the C2 or C4 position, a sophistically designed reaction with H218O does reveal that such hydrolysis occurs at C2 rather than C4, indicating that C2 is more electrophilic than the C4 position. For example, after the hydrolyzes of 2-methyl-4-methyleneoxazol-5(4H)-one, (Z)-4-ethylidene-2-(trifluoromethyl) oxazol-5(4H)-one, (Z)-4-benzylidene-2-methyloxazol-5(4H)-one, and (Z)-4benzylidene-2-phenyloxazol-5(4H)-one with 61% H218O, the resulting 2-acetamidoacrylic acid, (Z)-2-(2,2,2-trifluoroacetamido)but-2-enoic acid, (Z)-2-acetamido-3-phenylacrylic acid, and (Z)-2-benzamido-3-phenylacrylic acid were transformed back to the corresponding unsaturated azlactones by dehydration, which were then hydrolyzed with normal water. Analysis of the resulting acrylic acid derivatives indicated a nearly equal distribution of 18O in the amido group and carboxyl group. The reaction of azlactone with hydrogen sulfide or ammonia also occurs at C2 [291]. 1.4.2.6 THE REACTION OF UNSATURATED AZLACTONES WITH AMINES Amines are more nucleophilic than water, which can easily open the azlactone ring so that the reaction between azlactone and amine has been applied to the preparation of peptides (see the section in the saturated azlactone) and modification of azlactone-containing polymer (see Section 1.5). Similarly, unsaturated azlactones also react with amines. One of the many reactions involving azlactones and amino acids is the DMAP promoted reaction between tert-butyl (S,Z)-(1-(4-benzylidene5-oxo-4,5-dihydrooxazol-2-yl)-3-methylbutyl)carbamate and methyl glycinate in CH2Cl2 to yield methyl (S,Z)-(2-(2-((isopropoxycarbonyl) amino)-4-methylpentanamido)-3-phenylacryloyl)glycinate. The azlactone has been prepared from dehydration of (tert-butoxycarbonyl)-L-leucylL-phenylalanine with DCC in THF followed by the oxidation with DDQ in 1,2-dimethoxyethane. The resulting tripeptide has been further converted into (3S,6S)-12-((Z)-benzylidene)-3-isobutyl-1,6,7-trimethyl1,4,7,10-tetraazacyclododecane-2,5,8,11-tetraone (i.e., tentoxin) after subsequent methylation, coupling with N-Boc-N-methyl alanine and final cyclization as demonstrated in Scheme 1.120 [125].

Azlactones 169

O

O H N

O O

O N H

Gly-OMe DMAP CH2Cl2

OH

DCC THF

N

O

O

DDQ MeOCH2CH2OMe

O

N H

N

N H

O

O H N

O O

O N H

H N

N

O O

O O

O

O O

O

N H N H

N O

SCHEME 1.120  Preparation of L-phenylalanine based unsaturated azlactone and its coupling with methyl glycinate.

In addition to the nucleophilic opening of the azlactone ring to form an amide or peptide functional group, the reaction between azlactone and amine also leads to the formation of a cyclic compound, such as 3,5-dihydro-4Himidazol-4-one derivative, particularly from the unsaturated azlactone. For example, the reaction of (Z)-4-(4-hydroxybenzylidene)-2-methyloxazol5(4H)-one with methylamine yields (Z)-5-(4-hydroxybenzylidene)-2,3dimethyl-3,5-dihydro-4H-imidazol-4-one, where the azlactone is prepared from the condensation between 4-hydroxybenzaldehyde and N-acetyl-glycine in acetic anhydride in the presence of KOAc [21]. Similarly, the reaction between (Z)-4-(4-methylbenzylidene)-2-phenyloxazol-5(4H)-one and diethyl (2-(aminomethyl)-5-(piperidin-1-yl)oxazol-4-yl)phosphonate afford both the azlactone ring-opened product of diethyl (Z)-(2-((2-benzamido3-(p-tolyl)acrylamido)methyl)-5-(piperidin-1-yl)oxazol-4-yl)phosphonate and cyclized product of diethyl (Z)-(2-((4-(4-methylbenzylidene)-5oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl)methyl)-5-(piperidin-1-yl) oxazol-4-yl)phosphonate. It is found that the 4,5-dihydro-1H-imidazol-1-yl moiety is stable in aqueous acetic acid at 75°C whereas the oxazol-4-yl component within this compound decomposes, yielding diethyl (Z)-(1-(2(4-(4-methylbenzylidene)-5-oxo-2-phenyl-4,5-dihydro-1H-imidazol-1-yl) acetamido)-2-oxo-2-(piperidin-1-yl)ethyl)phosphonate as shown in Scheme 1.121 [292]. Likewise, the oxazol-4-yl component inside diethyl (Z)-(2-((2benzamido-3-(p-tolyl)acrylamido)methyl)-5-(piperidin-1-yl)oxazol-4-yl) phosphonate also decomposes in aqueous acetic acid, leading to the formation of diethyl (Z)-(1-(2-(2-benzamido-3-(p-tolyl)acrylamido)acetamido)-2-oxo2-(piperidin-1-yl)ethyl)phosphonate.

170

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

2(W 2 3 2(W 1+ 1 1

2  2 2

1

1

1 2

2(W 3 2(W 2

+1 +1

2 2

&+&2++2 ƒ &

2

2

1 2

1 1

&+&2++2 ƒ &

(W2 2(W 3 2

1



2 (W2 3 (W2 1 2

1+

+1

+1

1

2 2(W 3 2(W 1+

2 2 2

2 2

1 1

SCHEME 1.121  The reaction between (Z)-4-(4-methylbenzylidene)-2-phenyloxazol5(4H)-one and diethyl (2-(aminomethyl)-5-(piperidin-1-yl)oxazol-4-yl)phosphonate.

Different from the initial nucleophilic addition of substituted benzimidamide to unsaturated azlactone, the reaction between substituted benzene-1,2-diamines and unsaturated azlactones takes a different approach. A representative reaction between (Z)-4-(4-(dimethylamino)benzylidene)2-phenyloxazol-5(4H)-one and 4-methylbenzene-1,2-diamine refluxed in dioxane and acetic acid to afford (Z)-N-(2-(4-(dimethylamino)phenyl)1-(5-methyl-1H-benzo[d]imidazol-2-yl)vinyl)benzamide is shown in Scheme 1.122. In this case, the amino group in para-position to an electrondonating methyl group is more nucleophilic than the other amino group so that it adds to the carbonyl group of the azlactone moiety. Ring-opening leads to the formation of (Z)-N-(3-((2-amino-4-methylphenyl)amino)-1(4-(dimethylamino)-phenyl)-3-oxoprop-1-en-2-yl)benzamide. Further nucleophilic addition of the remaining amino group to the carbonyl group

Azlactones 171

gives (Z)-N-(2-(4-(dimethylamino)-phenyl)-1-(2-hydroxy-5-methyl-2,3dihydro-1H-benzo[d]imidazol-2-yl)vinyl)benzamide. Dehydration results in the formation of the final product, with potential intramolecular hydrogen bond between the carbonyl group and 1H-benzo[d]imidazole moiety. Unfortunately, not many reaction details (e.g., yields) and correct structures have been provided in the original literature [293]. Similarly, the reactions between unsaturated azlactones and aliphatic 1,2-diamines or 1,3-diamines all lead to the ring-opening products, instead of the conjugate addition products, as outlined in Scheme 1.78 [225]. Me2N

O N

Me2N

H2 N +

O

N

dioxane/AcOH N OH

HN H2N Ph

Ph

H2 O HO

Me2N N

O

H N H2N

Ph H

H 2N O

Me2N

N H NHBz

HO

Me2N

N

N H NHBz

SCHEME 1.122  The mechanism for the formation of (Z)-N-(2-(4-(dimethylamino)phenyl)1-(5-methyl-1H-benzo[d]imidazol-2-yl)vinyl)benzamide from (Z)-4-(4-(dimethylamino) benzylidene)-2-phenyloxazol-5(4H)-one and 4-methylbenzene-1,2-diamine.

Also, the reaction of the unsaturated azlactones with substituted anilines lead to the formation of 5-alkylidene-3,5-dihydro-4Himidazol-4-ones, as demonstrated in a series reaction of (Z)-4((4-oxo-4H-chromen-3-yl)methylene)-2-phenyloxazol-5(4H)-one with substituted anilines, e.g., 4-nitroaniline, which affords (Z)-3-(4-nitrophenyl)-5-((4-oxo-4H-chromen-3-yl)methylene)-2phenyl-3,5-dihydro-4H-imidazol-4-one. Similarly, the reactions of (Z)-4-((4oxo-4H-chromen-3-yl)methylene)-2-phenyloxazol-5(4H)-one with amino acids, such as serine and phenylalanine, yield (S,Z)-3-hydroxy-2-(5-oxo-4((4-oxo-4H-chromen-3-yl)methylene)-2-phenyl-4,5-dihydro-1H-imidazol1-yl)propanoic acid and (S,Z)-2-(5-oxo-4-((4-oxo-4H-chromen-3-yl)

172

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

methylene)-2-phenyl-4,5-dihydro-1H-imidazol-1-yl)-3-phenylpropanoic acid, respectively. The formation of all these products does not involve the conjugate addition of an amine to the exocyclic double bond [41]. In a different reaction condition, the aminolysis of unsaturated azlactones (e.g., (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one) with primary amines, such as aniline, benzylamine, butylamine, etc., in acetic acid for 5–10 minutes, (Z)-N-(3-oxo-1-phenyl-3-(phenylamino)prop-1-en-2-yl)benzamide or (Z)-N-(3-(benzylamino)-3-oxo-1-phenylprop-1-en-2-yl)benzamide is formed. When the reaction mixture was heated for additional 4 hours in the presence of a catalytic amount of sodium acetate, (Z)-5-benzylidene2,3-diphenyl-3,5-dihydro-4H-imidazol-4-one or its analogs were obtained [294]. The reaction of unsaturated azlactone with ammonia leads to the formation of imidazolone, as represented in the conversion of (E)-2-phenyl4-(quinolin-4-ylmethylene)oxazol-5(4H)-one in 95% EtOH in the presence of concentrated ammonium hydroxide and K2CO3 (additional NaOH added later on) into (E)-2-phenyl-5-(quinolin-4-ylmethylene)-3,5-dihydro-4Himidazol-4-one (m.p., 304–305°C, decomposed), in nearly 80% yield [295]. The application of such reactivity of unsaturated azlactones with amines, particularly the α-amino acids, provides a general method to make dehydropeptides, especially the solid-phase dehydropeptide synthesis [296]. The reductive aminolysis of Δ2-oxazolin-5-ones (e.g., 2-methyl-4-(propan2-ylidene)oxazol-5(4H)-one, (Z)-4-benzylidene-2-methyloxazol-5(4H)-one, (Z)-4-(4-methoxybenzylidene)-2-methyloxazol-5(4H)-one, (Z)-4-((2-methyl5-oxooxazol-4(5H)-ylidene)methyl)phenyl acetate, 2-phenyl-4-(propan-2ylidene)oxazol-5(4H)-one, (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one, among others) with S-(-)-α-phenylethylamine and H2 in the presence of PdCl2 yields α-phenylethylamides of N-acyl amino acids of the S,S-configuration. Subsequent hydrolysis of these amides gave optically pure amino acids and recycled chiral amine. However, it is found that the solvent used plays a role in this case. For example, in the reductive aminolysis in t-BuOH, the alkylideneor arylidene-double bond is hydrogenated to give saturated oxazolinones as reaction intermediates, which then undergo aminolysis with chiral amine. In contrast, when the reaction is performed in DME, double bond saturation and ring opening in Δ2-oxazolin-5-one occur within the catalytic complex sphere without the intermediate formation of saturated oxazolinones or unsaturated amides [297]. A similar hydrogenation approach under elevated H2 pressures in NH3-EtOH using Raney Ni as catalyst transforms the Δ2-oxazolin-5ones into N-benzoylamino acid amides, which can be hydrolyzed to the

Azlactones 173

corresponding N-benzoylamino acids or amino acids in sufficiently high yields under different conditions [298]. 1.4.2.7 AZIDOLYSIS OF UNSATURATED AZLACTONES While this reaction has not been explored extensively, limited experimental results indicated that 4-alkylidene-5(4H)-oxazolones react differently from the corresponding 4-arylidene-5(4H)-oxazolones. For example, treatment of 4-isopropylidene-5(4H)-oxazolones (e.g., 2-phenyl-4-(propan2-ylidene)oxazol-5(4H)-one, 2-(4-methoxyphenyl)-4-(propan-2-ylidene) oxazol-5(4H)-one, 2-(4-chlorophenyl)-4-(propan-2-ylidene)oxazol-5(4H)one) with sodium azide in acetic acid for 5 minutes or with hydrazoic acid (i.e., hydrogen azide) in benzene, the corresponding diazides (Me2C(N3) CH(CON3)NHBz) were resolved. Thermolysis of the diazide by refluxing in benzene gave 6-phenyl-4-(propan-2-ylidene)-3,4-dihydro-2H-1,3,5-oxadiazin-2-one, which upon hydrolysis, N-isobutyrylbenzamide was formed. For the case of 2-(4-chlorophenyl)-4-(propan-2-ylidene)oxazol-5(4H)-one) (or 2-(4-methoxyphenyl)-4-(propan-2-ylidene)oxazol-5(4H)-one), both 4-chloro-N-isobutyrylbenzamide and 5-(4-chlorophenyl)-1H-tetrazole (or N-isobutyryl-4-methoxybenzamide and 5-(4-methoxyphenyl)-1H-tetrazole) were obtained, respectively (Scheme 1.123) [299]. In comparison, the reaction of 4-arylidene-5(4H)-oxazolones (e.g., (Z)-4-(4-methoxybenzylidene)2-phenyloxazol-5(4H)-one) with hydrazoic acid under the same condition afforded only the α-(tetrazol-1-yl)acrylic acid derivatives. It is assumed that 1,3-dipolar cycloaddition occurs between 4-arylidene-5(4H)-oxazolones and hydrazoic acid, affording (Z)-6-(4-methoxybenzylidene)-3a-phenyl-1,3adihydrooxazolo[3,2-d]tetrazol-5(6H)-one, which undergoes intramolecular rearrangement to give (Z)-3-(4-methoxyphenyl)-2-(5-phenyl-1H-tetrazol1-yl)acrylic acid. While this hypothesized mechanism has not been proposed in the original publication, the structures of the final products might convince this rationalization.

174

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

2 1

2

2

+1

1

1

2

2

+1

1 +

2

%HQ]HQH

1 +

1

20H

20H

0H2

%HQ]HQH 2 +1

2

20H

1

2 2

0H2

1

2

0H2

2

+ 2

+ 1

20H

1+

1 1

1

2

2 +1 0H2

1 1 +

2+

2 1

1

0H2

1

1 1 1

SCHEME 1.123  The azidolysis of unsaturated azlactone.

1.4.2.8 REACTION OF HYDRAZINE WITH UNSATURATED AZLACTONES Hydrazines function very similar to amines in reaction with azlactones so that the unsaturated azlactones usually function as the acylating agents to acylate the hydrazines. This type of reaction is known as hydrazinolysis. For example, (Z)-N-(1-(2-methoxyphenyl)-3-oxo-3-(2-phenylhydrazineyl)prop-1-en-2-yl)benzamide was obtained from the reaction of phenylhydrazine and (Z)-4-(2-methoxybenzylidene)-2-phenyloxazol5(4H)-one. No further cyclization occurs for this case [300]. However, additional cyclization may take place in some cases to form N-substituted 1H-imidazol-4-one derivatives. For example, refluxing of (Z)-4-(4methoxybenzylidene)-2-phenyloxazol-5(4H)-one with two equivalents of (4-nitrophenyl)hydrazine in tenfold (w/w) of dry xylene gives 99% of the ring-opening product of (Z)-N-(1-(4-methoxyphenyl)-3-(2-(4-nitrophenyl)hydrazineyl)-3-oxoprop-1-en-2-yl)benzamide, whereas refluxing of (Z)-4-(4-methoxybenzylidene)-2-phenyloxazol-5(4H)-one with three equivalents of phenylhydrazine or 1.0 equivalent of (4-nitrophenyl) hydrazine in a twofold (w/w) of acetic acid leads to the formation of (Z)-5-(4-methoxybenzylidene)-2-phenyl-3-(phenylamino)-3,5-dihydro4H-imidazol-4-one or (Z)-5-(4-methoxybenzylidene)-3-((4-nitrophenyl) amino)-2-phenyl-3,5-dihydro-4H-imidazol-4-one, in 82.3% and 91.4% yield, respectively [301].

Azlactones 175

O

O

NH2NH2 H2O

O

OMe

4% NaOH

NH

N OMe

NH NH2

O

N

N

O

N

H3O+

N

OH

N

N

OMe

OMe 98.1%

SCHEME 1.124  Hydrazinolysis 5(4H)-one.

of

(E)-4-(2-methoxybenzylidene)-2-phenyloxazol-

While the hydrazinolysis of unsaturated azlactones with simple hydrazine hydrate often gives the ring-opening products; due to the existence of additional nitrogen atom in the hydrazine moiety, different reactivity may appear. For example, after the hydrazinolysis of (E)-4-(2-methoxybenzylidene)2-phenyloxazol-5(4H)-one, (E)-N-(3-hydrazineyl-1-(2-methoxyphenyl)3-oxoprop-1-en-2-yl)benzamide was obtained. Further treatment of this compound with 4% NaOH (1.0 M), 98.1% of 5-(2-methoxybenzyl)-3phenyl-1,2,4-triazin-6-ol was obtained after neutralization with acid, as of the cyclization (Scheme 1.124) [302]. O H N

R

O

NH2 OH +

NHAc or

O

O

O

O

NaOAc Ac2O

N NH

NH2NH2

R

O O NH

O

O N H O

HN

NH2

OH

H N N

N R

O

H3O+

H N N

NH

N R

NH2 O

R N

H N N

H N

N R

N

N

N

R

(R = CH3 or Ph)

SCHEME 1.125  Synthesis of 3-methyl-5,10-dihydro-[1,2,4]triazino[6,5-b]quinoline or 3-phenyl-5,10-dihydro-[1,2,4]triazino[6,5-b]quinoline from the reaction of 2-aminobenzaldehyde with acetylglycine or hippuric acid.

176

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

A special case of the hydrazinolysis of unsaturated azlactones leads to the formation of [1,2,4]triazino[6,5-b]quinoline derivatives. In this case, the reaction of acetylglycine (or hippuric acid) with either 2-aminobenzaldehyde or N-(2-formylphenyl)acetamide (i.e., N-acetyl-2-aminobenzaldehyde) in acetic anhydride in the presence of sodium acetate gives (Z)-N-(2-((2methyl-5-oxooxazol-4(5H)-ylidene)methyl)phenyl)acetamide (or (Z)-N-(2((5-oxo-2-phenyloxazol-4(5H)-ylidene)methyl)phenyl)acetamide). (Note: the configuration of these azlactones have been labeled in E-configuration in the original report, but they should be in the Z-configuration as discussed above). Treatment of these two azlactones with hydrazine hydrate (NH2NH2·H2O) similarly gave the ring-opening products of (Z)-N-(2-(2acetamido-3-hydrazineyl-3-oxoprop-1-en-1-yl)phenyl)acetamide and (Z)-N(1-(2-acetamidophenyl)-3-hydrazineyl-3-oxoprop-1-en-2-yl)benzamide, respectively. These amides quickly cyclize under alkaline condition to give N-(2-((3-methyl-6-oxo-1,6-dihydro-1,2,4-triazin-5-yl)methyl)phenyl)acetamide and N-(2-((6-oxo-3-phenyl-1,6-dihydro-1,2,4-triazin-5-yl)methyl) phenyl)acetamide. However, acidic deacetylation has failed to isolate the expected 5-(2-aminobenzyl)-3-methyl-1,2,4-triazin-6(1H)-one and 5-(2-aminobenzyl)-3-phenyl-1,2,4-triazin-6(1H)-one, as they further cyclize to form 3-methyl-1,5-dihydro-[1,2,4]triazino[6,5-b]quinoline and 3-phenyl1,5-dihydro-[1,2,4]triazino[6,5-b]quinoline. Subsequent 1,3-H shift occurs to give the final products of 3-methyl-5,10-dihydro-[1,2,4]triazino[6,5-b] quinoline and 3-phenyl-5,10-dihydro-[1,2,4]triazino[6,5-b]quinoline, respectively (Scheme 1.125) [303]. This unique case can be attributed to the use of 2-aminobenzaldehyde. 1.4.2.9 THE REACTION OF ALCOHOLS OR THIOLS WITH UNSATURATED AZLACTONES By means of alcoholysis of unsaturated azlactone in the presence of base, e.g., KOH/EtOH, substituted 2-benzoylaminoacrylic acid or 2-acetaminoacrylic acid can be obtained, along with a small amount of the corresponding ethyl ester. The methyl ester can be obtained when the alcoholysis is performed in MeOH [304]. The reactivity of thiol such as benzylthiol with unsaturated azlactones varies depending on the substituent on the exocyclic double bond as well as the reaction condition. In all of these cases, conjugate addition of benzylthiol to the exocyclic double bond is not the predominating reaction.

Azlactones 177

For example, treatment of (Z)-4-(ethoxymethylene)-2-phenyloxazol5(4H)-one with benzylthiol in the presence of triethylamine in benzene generates a mixture of (Z)-4-((benzylthio)methylene)-2-phenyloxazol5(4H)-one, S-benzyl (Z)-2-benzamido-3-(benzylthio)prop-2-enethioate and S-benzyl 2-benzamido-3,3-bis(benzylthio)propanethioate (Scheme 1.126), where (Z)-4-((benzylthio)methylene)-2-phenyloxazol-5(4H)-one is formed by the replacement of ethoxy group by benzylthio group, from which the nucleophilic addition of benzylthiol yields the ring-opening product of S-benzyl (Z)-2-benzamido-3-(benzylthio)prop-2-enethioate and further addition of benzylthiol to the double bond leads to the formation of S-benzyl 2-benzamido-3,3-bis(benzylthio)propanethioate [305]. In contrast, refluxing of (Z)-4-(ethoxymethylene)-2-phenyloxazol-5(4H)-one with aniline in ethanol gives (Z)-2-phenyl-4-((phenylamino)methylene) oxazol-5(4H)-one, which under further treatment of benzylthiol in ethanol in the presence of Et3N affords S-benzyl (Z)-2-benzamido-3-(phenylamino) prop-2-enethioate. Direct refluxing of (Z)-4-(ethoxymethylene)-2phenyloxazol-5(4H)-one in ethanol in the presence of benzylthiol and aniline also gives S-benzyl (Z)-2-benzamido-3-(phenylamino)prop-2-enethioate. However, treatment of (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one in refluxing ethanol in the presence of benzylthiol and Et3N gives a mixture of E- and Z-ethyl 2-benzamido-3-phenylacrylates. The isomerization between these cis- and trans-isomers also reaches an equilibrium under this reaction condition [305]. On the other hand, treatment of (Z)-2-((5-oxo-2-phenyloxazol-4(5H)ylidene)methyl)phenyl acetate with benzylthiol in refluxing ethanol gives (Z)-2-(2-benzamido-3-(benzylthio)-3-oxoprop-1-en-1-yl)phenyl acetate, which upon further treatment with Et3N in refluxing ethanol is converted into N-(2-oxo-2H-chromen-3-yl)benzamide. Hydrolysis of N-(2-oxo2H-chromen-3-yl)benzamide or (Z)-2-((5-oxo-2-phenyloxazol-4(5H)ylidene)methyl)phenyl acetate in the presence of KOH generates the same product of (Z)-2-benzamido-3-(2-hydroxyphenyl)acrylic acid. In comparison, refluxing of (Z)-2-((5-oxo-2-phenyloxazol-4(5H)-ylidene) methyl)phenyl acetate in ethanol with Et3N gives ethyl (Z)-3-(2acetoxyphenyl)-2-benzamidoacrylate, which upon further treatment with benzylthiol and Et3N in ethanol is transformed into N-(2-oxo-2Hchromen-3-yl)benzamide via the intermediate stage of N-(4-(benzylthio)2-oxochroman-3-yl)benzamide (Scheme 1.126) [305]. Basic hydrolysis of the unsaturated azlactone (Z)-2-((5-oxo-2-phenyloxazol-4(5H)-ylidene) methyl)phenyl acetate yields (Z)-2-benzamido-3-(2-hydroxyphenyl)

178

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

acrylic acid. This reactivity has been applied to the syntheses of natural products thalassotalic acid A, thalassotalic acid B and thalassotalic acid C, respectively [306]. In contrast, 2-mercaptoacetaldehyde undergoes a conjugate addition to (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one in the presence of a nitrogenous organo-catalyst, such as N4-((1S)-((1R,2S,5S)-5-ethylquinuclidin-2-yl) (6-methoxyquinolin-4-yl)methyl)-N6-((1S)-((1S,2R,5R)-5-ethylquinuclidin2-yl)(6-methoxyquinolin-4-yl)methyl)-2,5-diphenylpyrimidine-4,6-diamine, affording a spiro cyclic molecule, i.e., (5R,6R,8S)-6-hydroxy-2,8-diphenyl3-oxa-7-thia-1-azaspiro[4.4]non-1-en-4-one, which is subsequently esterified with acetic anhydride in the presence of DMAP and Et3N, yielding (5R,6R,8S)-4-oxo-2,8-diphenyl-3-oxa-7-thia-1-azaspiro[4.4]non-1-en-6-yl acetate with greater than 20:1 of diastereoselectivity and 80% ee (Scheme 1.127). In this reaction, 2-mercaptoacetaldehyde can be generated in situ from the decomposition of 1,4-dithiane-2,5-diol so that only half equivalent of such compound is needed. Several other chiral catalysts have been tested for the control of stereochemistry, but they are not as good as the one displayed in Scheme 1.126 [307]. 1.4.2.10 OXYGENATION OF UNSATURATED AZLACTONES It is found that oxygen reacts with unsaturated 2-arylazlactones under basic conditions, as demonstrated in the reaction between oxygen and (Z)-4-(2methylpropylidene)-2-phenyloxazol-5(4H)-one (or (Z)-2-phenyl-4-(1phenylpropan-2-ylidene)oxazol-5(4H)-one) in acetonitrile in the presence of a weak base Et3N, which rapidly absorbs oxygen at room temperature and decomposes to N-(3-methylbut-2-enoyl)benzamide (or (Z)-N-(3-methyl4-phenylbut-2-enoyl)benzamide) (Scheme 1.128) [308]. Analysis of the crude oxygenation mixture indicates a 3:1 ratio of N-(3-methylbut-2-enoyl) benzamide over (E)-2-benzamido-4-methylpenta-2,4-dienoic acid. The absorption of oxygen mostly occurs in the early nine hours, and nearly 1.0 equivalent of oxygen is absorbed. Although 4-alkylidene-2-alkylazlactones will be consumed under this condition, no imides have been obtained, as shown in the reaction of (Z)-2-methyl-4-(2-methylpropylidene)oxazol5(4H)-one with oxygen which fails to afford N-acetyl-3-methylbut-2enamide. This result indicates the necessary contribution for the stabilization of the intermediate from the 2-aryl group. While a mechanism has been proposed to rationalize the formation of imide in the original literature, the formation of (E)-2-benzamido-4-methylpenta-2,4-dienoic acid is not

3K

2

3K

2

%]+1

2

1 +

1

2

6

3K

2



%Q

2

2+

2 2(W 1D 6  (W2+

.2+ +&O

2+ $F 21D2$F 

%]

3K+1

%]+1

2+

%Q6+(W1 (W2+

%Q6+(W1 1+%] (W2+

2

%Q6+

1+%]

2

.2+ +&O

1

2

%Q6

%Q6+3K1+ (W2+

%Q6+(W1 EHQ]HQH

3K1+(W2+

1

2

2

2$F

%Q

6

2

1+

%Q6+(W1 (W2+

2(W %Q6+(W 1  (W2+

6

6%Q

2

6%Q

%] +1

%Q6+

(W1(W2+

%Q6+(W1 (W2+

2(W 

1+%]

2

2$F

2

3K

%] +1

%Q

2

%]+1

%Q6+(W1 (W2+

%Q

6

%]

%Q6+(W2+

(W1(W2+

2

2



2 3K

%Q

1

6

2 3K

2

1+

1

2$F

6

%]+1

%Q

%]

SCHEME 1.126  Reactions of unsaturated azlactones with benzylthiol under various conditions.

6%Q

2

2

3K+1

(W2

2

1+%]

2

2(W 3K

2

Azlactones 179

180

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

justified [308]. Based on the experimental results, it is possible that the treatment of (Z)-4-(2-methylpropylidene)-2-phenyloxazol-5(4H)-one with Et3N gives triethylammonium 4-(2-methylprop-1-en-1-yl)-2-phenyloxazol5-olate, which undergoes either [2+2] cycloaddition with O2 to afford 5-(2-methylprop-1-en-1-yl)-3-phenyl-2,6,7-trioxa-4-azabicyclo[3.2.0] hept-3-en-1-olate or [4+2] cycloaddition with O2 to give 3,3-dimethyl-6phenyl[1,2]dioxino[4,3-d]oxazol-7a(3H)-olate. The further transformation of the former cycloadduct leads to the formation of N-(3-methylbut-2enoyl)benzamide, whereas the subsequent transformations of the [4+2] cycloadduct result in the formation of (E)-2-benzamido-4-methylpenta2,4-dienoic acid (Scheme 1.128). In either case, a deprotonated benzoyl amide intermediate is involved. If this mechanism is plausible, then a deprotonated acetamide intermediate will be formed that is not stable enough to give N-acetyl-3-methylbut-2-enamide from the treatment of (Z)-2-methyl-4-(2-methylpropylidene)oxazol-5(4H)-one [308]. Ph

Ph

O O 20 mol% cat. toluene, 10 °C

O + HS

N

O N

O HO

Ph

S cat.

Ac2O O DMAP, Et3N AcO

O

N S

Ph

Ph > 95% conversion > 20:1 dr, 80% ee

cat. Ph

S

O

Ph

O cat.* H N

Ph

O

cat.* H

O

N

O O S

Ph

Ph

N cat. =

H

H

Ph

H N N

H N

N

N

N

N OMe

Ph

MeO

SCHEME 1.127  The mechanism for the reaction between (Z)-4-benzylidene-2phenyloxazol-5(4H)-one and 2-mercaptoacetaldehyde.

Azlactones 181

O O O O

H O

O O

O

O O

N

O O O

N

N Et3NH

Ph

[4+2] O2

Et3N O

O N

Et3N CH3CN

OH

N

Ph

O

O

Et3NH O

O O2

O

O +

N H

N

O

OH

N H

(3 : 1) [2+2]

O O

O O

Et3N O2

Et3NH O O

O O N

N

CO2

O

O N

SCHEME 1.128  The mechanism for the oxygenation of (Z)-4-(2-methylpropylidene) -2-phenyloxazol-5(4H)-one.

1.4.2.11 1,3-Dipolar Cycloaddition with Exocyclic Double Bond of Unsaturated Azlactones Examples collected here are the 1,3-dipolar cycloadditions in which the unsaturated azlactones behave as dipolarophiles through their exocyclic double bonds. In one of these practices, the model reaction between (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one and ethyl buta2,3-dienoate has been performed in toluene at room temperature in the presence of a chiral phosphorus catalyst, which gives ethyl (5S,9R)-4oxo-2,9-diphenyl-3-oxa-1-azaspiro[4.4]nona-1,6-diene-6-carboxylate and ethyl 4-oxo-2,6-diphenyl-3-oxa-1-azaspiro[4.4]nona-1,7-diene-7carboxylate by means of α- and γ-addition (Scheme 1.129). The screened catalysts include (R)-2’-(diphenylphosphaneyl)-[1,1’-binaphthalen]2-ol (117, Figure 1.21), (1E,1’E)-N,N’-((1R,2R)-cyclohexane-1,2diyl)bis(1-(2-(diphenylphosphaneyl)phenyl)methanimine) (118, Figure 1.21), 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1S,2S)-2(diphenylphosphaneyl)cyclohexyl)thiourea (119, Figure 1.21), 1,2-bis((2R,5R)-2,5-diisopropylphospholan-1-yl)ethane (120, Figure

182

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

1.21) and (S)-4-(tert-butyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1’,2’-e] phosphepine (121, Figure 1.21), (R)-2,2’-bis(diphenylphosphaneyl)1,1’-binaphthalene (122, Figure 1.21, the enantiomer of 24 in Figure 1.5) and (((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene)) bis(diphenylphosphane) (123, Figure 1.21). Among these catalysts, 121 affords the product of the highest regio- and enantioselectivity [309]. Additional screening of solvents and concentrations show that the best results can be obtained in toluene with an ideal concentration of azlactone at 0.1 M if its solubility allows. In addition, this reaction is insensitive to the presence of air. Further evaluation of different allene esters indicates that ethyl buta-2,3-dienoate in combination with an azlactone containing a C2 phenyl group gives the highest, yet disappointing conversion and selectivity. While proton donors such as water, alcohols, acids, as well as buffered systems have been applied as additives to promote proton shift, none of these additives apparently improve the conversion of the transformation. Regarding the reaction temperature, the initial reaction at room temperature followed by heating at 80°C leads to the best combined results with respect to yield, regioselectivity, and enantioselectivity. Further, direct treatment of the crude reaction mixture with MeOH/ TMSCl results in the opening of azlactone rings [309]. CF3 OH PPh2

PPh2 Ph2P 117

S

N

N

F3C

118

HN

N H

119

O

P PPh2 PPh2

P P

120

121

PPh2

122

O P

P

123

FIGURE 1.21  Catalysts for the 1,3-dipolar cycloaddition involving unsaturated azlactones as the dipolarophiles.

For a similar reaction between (Z)-4-benzylidene-2-phenyloxazol5(4H)-one and benzyl buta-2,3-dienoate, (S)-12-phenyl4,5,6,7,12,13hexahydro-11H-diindeno[7,1-cd:1’,7’-ef]phosphocine (124, Figure 1.22)

Azlactones 183

has been selected as the catalyst of choice after screening 10 chiral phosphorus catalysts. These 10 catalysts are: (R)-2’-(diphenylphosphaneyl)[1,1’-binaphthalen]-2-ol (117, Figure 1.21), (R)-N-(2’(diphenylphosphaneyl)-[1,1’-binaphthalen]-2-yl)acetamide (125, Figure 1.22), (3R,3’R,4S,4’S)-4,4’-di-tert-butyl-4,4’,5,5’-tetrahydro-3H,3’H3,3’-bidinaphtho[2,1-c:1’,2’-e]phosphepine (126, Figure 1.22), (S)-N-(1(diphenylphosphaneyl)-3-methylbutan-2-yl)benzamide (127, Figure 1.22), (S)-1-benzhydryl-3-(2-(diphenylphosphaneyl)-1-(naphthalen-2-yl)ethyl) thiourea (128, Figure 1.22), 1,1,1-trichloro-2-methylpropan-2-yl ((S)-1(((2R,3S)-3-((tert-butyldiphenylsilyl)oxy)-1-(diphenylphosphaneyl) butan-2-yl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (129, Figure 1.22), 1,2-bis((R)-(2-methoxyphenyl)(phenyl)phosphaneyl)ethane (130, Figure 1.22), (1R,1’R,2S,2’S)-2,2’-di-tert-butyl-2,2’,3,3’tetrahydro1H,1’H-1,1’-biisophosphindole (131, Figure 1.22), and (S)-1,13bis(diphenylphosphaneyl)-7,8-dihydro-6H-dibenzo[f,h][1,5]dioxonine (132, Figure 1.22) [310]. Under the optimized condition with 20 mol% of 124 in CH2Cl2 in the presence of 4Å molecular sieves at room temperature, the reactions between benzyl buta-2,3-dienoate and a variety of 4-arylideneazlactones all afford the respective spiro-azlactones in good to excellent yields, as well as excellent diastereoselectivity and enantioselectivity [310]. O

Ph

O

O +

N

C

10 mol% 121 toluene, r.t.

O

O N

O Ph

O Ph +

O O

94% ee

(12:1)

CO2Et PR’2R”

PR’2R” or

O Ph

N

Ph

Ph

121

O

PR’2R”

O

CO2Et N

Ph

Ph

O

N Ph

PR’2R”

PR’2R”

O

O

N Ph CO2Et

121

EtO2C O

O

O

Ph + O

O N O

O

Ph

SCHEME 1.129  The mechanism for the 1,3-dipolar cycloaddition between (Z)-4benzylidene-2-phenyloxazol-5(4H)-one and ethyl buta-2,3-dienoate.

184

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Different from the reactions between 4-arylidene azlactones and ethyl buta-2,3-dienoate [309] or benzyl buta-2,3-dienoate [310], the reactions of 4-arylidene azlactones with ethyl penta-3,4-dienoate or penta-3,4-dienenitrile of an additional electron-withdrawing group at position 3, such as 1-benzyl 4-ethyl 2-vinylidenesuccinate, diethyl 2-vinylidenesuccinate, and ethyl 2-(cyanomethyl)buta-2,3-dienoate, afford spiro-compounds with both azlactone and cyclohexene components. In order to control the stereochemistry, this reaction has been tested in the presence of a bulky phosphorus catalyst, such as (11bS)-4-(tert-butyl)-4,5-dihydro-3H-dinaphtho[2,1-c:1’,2’-e] phosphepine (121, Figure 1.21), (S)-12-phenyl-4,5,6,7,12,13-hexahydro11H-diindeno[7,1-cd:1’,7’-ef]phosphocine (124, Figure 1.22), (11bS)4-phenyl-4,5-dihydro-3H-dinaphtho[2,1-c:1’,2’-e]phosphepine (133, Figure 1.23), (11bS)-N,N-dimethyl-3,5-dihydro-4H-dinaphtho[2,1-c:1’,2’e]phosphepin-4-amine (134, Figure 1.23), (S)-N-(1-(diphenylphosphaneyl)3-methylbutan-2-yl)-3,5-bis(trifluoromethyl)benzamide (135, Figure 1.23) and a ferrocene catalyst (136, Figure 1.23) [311].

t-Bu P H H P t-Bu

NHAc

P Ph

PPh2

124

126

125

OTBDPS PPh2

Ph2P

N H

Ph

127

PPh2

N H

Ph

N H

t-Bu

NH O

128

H

H P

O

CCl3

129

P t-Bu

OMe MeO P

NH

Ph

S

O

O

PPh2

O O

PPh2

P t-Bu

Ph Ph 130

131

132

FIGURE 1.22  More chiral catalysts for the 1,3-dipolar cycloaddition of unsaturated azlactones.

Azlactones 185

However, no product has been obtained under these conditions. Instead, this reaction requires the use of a small sterically less-hindered tertiary phosphine (e.g., tributylphosphine) but does not proceed in the presence of tertiary amines or sterically hindered phosphines. Thus, enantioselectivity is a potential issue in this reaction. This cyclization predominantly proceeds through the γ-addition of the phosphine-activated allenoates, and β’-addition is clearly disfavored. An example of such reaction between (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one and 1-benzyl 4-ethyl 2-vinylidenesuccinate is provided in Scheme 1.130, which affords 65.0% of 7-benzyl 6-ethyl 4-oxo-2,10-diphenyl-3-oxa-1-azaspiro[4.5] deca-1,7-diene-6,7-dicarboxylate and 16.7% of 8-benzyl 7-ethyl 4-oxo-2,6diphenyl-3-oxa-1-azaspiro[4.5]deca-1,8-diene-7,8-dicarboxylate [311]. The mechanism for the generation of the favored product is also illustrated in Scheme 1.130. F3C

P Ph

P N

CF3

O

Et

NH PPh2

133

134

135

t-Bu P t-Bu P Fe Et

H

CH3

136

FIGURE 1.23  The chiral catalysts for the 1,3-dipolar cycloaddition between 4-arylidene azlactones and ethyl penta-3,4-dienoate or penta-3,4-dienenitrile.

Another example of 1,3-dipolar cycloaddition involving the unsaturated azlactone is the reaction of either 4-arylidene or 4-alkylidene azlactone with 2-vinylcyclopropane containing two electron-withdrawing groups at position 1, such as bis(2,2,2-trifluoroethyl) 2-vinylcyclopropane-1,1-dicarboxylate, which can easily be converted into 1,3-dipole in the presence of a palladium catalyst (e.g., Pd2(dba)3). In order to control the stereochemistry of the cycloadducts, four chiral phosphorus ligands have been screened, including N,N’-((1S,2S)-cyclohexane-1,2-diyl)bis(2-(diphenylphosphaneyl) benzamide) (137, Figure 1.24), N,N’-((1S,2S)-cyclohexane-1,2-diyl)bis(2(diphenylphosphaneyl)-1-naphthamide) (138, Figure 1.24), N,N’-((1R,2R)1,2-diphenylethane-1,2-diyl)bis(2-(diphenylphosphaneyl)benzamide) (139, Figure 1.24) and N,N’-((11S,12S)-9,10-dihydro-9,10-ethanoanthracene11,12-diyl)bis(2-(diphenylphosphaneyl)benzamide) (140, Figure 1.24, the enantiomer of 22 in Figure 1.5). Among these ligands, ligand 137 results in

186

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

better control of stereochemistry so it has been selected for this particular 1,3-dipolar cycloaddition. Also, the reaction has been performed in toluene, α,α,α-trifluorotoluene (i.e., (trifluoromethyl)benzene), THF, CH2Cl2 , and dioxane [312]. Although the yield is higher in CH2Cl2 and dioxane, superior diastereoselectivity and enantioselectivity have been retained in toluene. While the majority of tested (Z)-4-arylidene)-2-phenyloxazol-5(4H)-ones afford reasonably good yields of bis(2,2,2-trifluoroethyl) (5S,6R,9S)-6-aryl-4oxo-2-phenyl-9-vinyl-3-oxa-1-azaspiro[4.4]non-1-ene-7,7-dicarboxylates, the reaction with (Z)-4-(2-methoxybenzylidene)-2-phenyloxazol-5(4H)-one fails to yield any product. A representative reaction is provided in Scheme 1.131 for the reaction between (Z)-4-(4-nitrobenzylidene)-2-phenyloxazol5(4H)-one and bis(2,2,2-trifluoroethyl) 2-vinylcyclopropane-1,1-dicarboxylate in the presence of ligand 137 to afford 72% of bis(2,2,2-trifluoroethyl) (5S,6R,9S)-6-(4-nitrophenyl)-4-oxo-2-phenyl-9-vinyl-3-oxa-1-azaspiro[4.4] non-1-ene-7,7-dicarboxylate. Ph O

O

C

O Ph

OBn 20 mol% PBu3 OEt THF, 4Å MS 60 °C

+ N

Ph N

Ph

+ O OEt O O

PBu3

OEt OBn

EtO2C

O Ph O OEt OBn

Bu3P O

Ph

N

Ph

O

O Ph

Ph OEt OBn

Bu3P O H

O N

PBu3

O O

O

CO2Bn

O

Ph

Ph

16.7% yield

(3.9 : 1)

O

N

CO2Bn

O

dr = 3.8 : 1 65.0% yield

PBu3

O

CO2Et

O

O BnO

Bu3P O

Ph N

Ph

O

N

Ph

SCHEME 1.130  The mechanism for the PBu3 catalyzed 1,3-dipolar cycloaddition between (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one and 1-benzyl 4-ethyl 2-vinylidenesuccinate.

Azlactones 187

In comparison, the 4-alkylidene azlactones generally give lower yields than the corresponding 4-arylidene azlactones, the reaction of (Z)-4-(cyclohexylmethylene)-2-phenyloxazol-5(4H)-one under this condition does not yield any cycloadduct [312]. Careful examination of the substrate structures indicates that modification of the azlactone substituent might allow unreactive substrates to be reactive enough. Specifically, if the azlactone substituent is electron-withdrawing, the (reversible) conjugate addition step should be faster (to prevent polymerization) and the stereodetermining ring-closing step should be slower, and therefore potentially more selective [313].

O

O

O

O

NH HN

NH HN

PPh2 Ph2P

PPh2 Ph2P

137

138

Ph

Ph O

O

O NH HN

N H

N H

PPh2 Ph2P

Ph2P PPh2

139

140

O

FIGURE 1.24  Chiral phosphorus ligands for the palladium catalyzed 1,3-dipolar cycloaddition of 4-arylidene or 4-alkylidene azlactone with 2-vinylcyclopropane. O Ph

O

O N

+ F F NO2

O F

O O F

F F

2 mol% [Pd2dba3] CHCl3 6 mol% 137 toluene, r.t., 16 hrs.

O O

NO2

N CO2CH2CF3 CO2CH2CF3

72% yield, 8:1 dr, 85% ee

SCHEME 1.131  The 1,3-dipolar cycloaddition between (Z)-4-(4-nitrobenzylidene)-2phenyloxazol-5(4H)-one and bis(2,2,2-trifluoroethyl) 2-vinylcyclopropane-1,1-dicarboxylate.

Another example of 1,3-dipole is azomethine ylide generated from diethyl (E)-2-((2-hydroxybenzylidene)amino)malonate in the presence of a chiral thiourea, which then undergoes the [3+2]-cycloaddition with unsaturated azlactone, such as (Z)-4-(3-chlorobenzylidene)-2phenyloxazol-5(4H)-one in dichloromethane at room temperature to

188

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

afford 97% of diethyl (3R,3aS,9bR)-3a-benzamido-3-(3-chlorophenyl)-4oxo-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole-2,2(3H)-dicarboxylate with greater than 20:1 of diastereoselectivity and 99% ee as shown in Scheme 1.132 [314]. For this reaction, different chiral thioureas have been screened, such as 1-(3,5-bis(trifluoromethyl)phenyl)-3-((S)(6-methoxyquinolin-4-yl)-((1S,2S,4S,5R)-5-vinylquinuclidin-2-yl) methyl)thiourea (44, Figure 1.8), 1-(3,5-bis-(trifluoromethyl)phenyl)3-((1R,2R)-2-(dimethylamino)cyclohexyl)thiourea (45, Figure 1.8), 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((1S)-(6-methoxyquinolin4-yl)((2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl)amino)cyclobut-3ene-1,2-dione (50, Figure 1.9), 1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R)(6-methoxyquinolin-4-yl)((2R,4S,5R)-5-vinylquinuclidin-2-yl)methyl) thiourea (96, Figure 1.17), (S)-1-(3,5-bis(trifluoromethyl)phenyl)-3-(1(dimethylamino)-3-methylbutan-2-yl)thiourea and (S)-1-(3,5bis(trifluoromethyl)phenyl)-3-(3,3-dimethyl-1-(piperidin-1-yl)butan-2-yl) thiourea. Among these chiral thioureas, 44 works the best in terms of chemical yield and enantioselectivity. The optimized reaction condition has been applied to 23 combination of different azlactones and diethyl (E)-2((2-hydroxybenzylidene)amino)malonate with substituent on the phenyl moiety, all affording the respective products with excellent yields as well as diastereoselectivity (> 20:1) and enantioselectivity (> 99% ee) [314]. EtO O Cl

CO2Et O

+

N OH

Ph

OEt

HN

O

O

NH O O

1 mol% 44 CO2Et CH Cl , r.t. 2 2

N

O

Cl

97% yield dr > 20:1, > 99% ee

44 CO2Et N

CO2Et

Cl

Cl O

OH O

O O

N Ph

N

O OEt OEt

O N H

O

SCHEME 1.132  The mechanism for the 1,3-dipolar cycloaddition between (Z)-4-(3chlorobenzylidene)-2-phenyloxazol-5(4H)-one and diethyl (E)-2-((2-hydroxybenzylidene) amino)malonate.

Azlactones 189

Similarly, the model reaction between (Z)-4-benzylidene-2phenyloxazol-5(4H)-one and methyl (E)-2-(benzylideneamino)acetate has been performed at temperature from –10°C to room temperature in the presence of 10 mol% AgOAc and 10 mol% (S)-5,5’-bis(bis(3,5di-tert-butyl-4-methoxyphenyl)phosphaneyl)-4,4’-bibenzo[d][1,3] dioxole in toluene, with or without base Et3N. After further treatment of the cycloaddition mixture with 3 M HCl in methanol, three azlactone ring-opening products are obtained, which are dimethyl (2R,3S,4S,5R)4-benzamido-3,5-diphenylpyrrolidine-2,4-dicarboxylate, dimethyl (2R,3R,4R,5R)-4-benzamido-3,5-diphenylpyrrolidine-2,4-dicarboxylate and dimethyl (2S,3R,4R,5R)-4-benzamido-3,5-diphenylpyrrolidine-2,4dicarboxylate, where the (2R,3S,4S,5R)-isomer is always favored, whereas the percentages of the other two isomers vary depending on the solvent (higher in THF or CH2Cl2). Based on the optimized reaction condition, the (2R,3S,4S,5R)-products can be obtained as single products in good yields from the reaction of (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one with different methyl (E)-2-(arylideneamino)acetates, all with excellent diastereoselectivity and enantioselectivity. In contrast, the reaction with methyl (E)-2-((cyclohexylmethylene)amino)acetate fails to give the expected product. On the other hand, the reaction of methyl (E)-2-(benzylideneamino) acetate with twelve 4-arylidene azlactones all afford the expected products with excellent diastereoselectivity and enantioselectivity [315]. 1.4.2.12 [4+2] CYCLOADDITION WITH EXOCYCLIC DOUBLE BOND OF UNSATURATED AZLACTONES In addition to functioning as 1,3-dipolarophiles in [3+2] cycloadditions, unsaturated azlactones also behave as dienophiles in Diels-Alder cycloadditions, as represented in the reaction between (Z)-4-(naphthalen2-ylmethylene)-2-phenyloxazol-5(4H)-one and (2E,4E)-hexa-2,4-dienal in the presence of a catalytic amount of (R)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine in chloroform (Scheme 1.133). For this reaction, the presence of an aromatic ring-substituent on the azlactone is critical, and the formation of (R)-2-(diphenyl((trimethylsilyl)oxy)methyl)-1-((1E,3E)hexa-1,3,5-trien-1-yl)pyrrolidine can be significantly enhanced in polar aprotic media. In order to determine the enantioselectivity and improve the stability of the product, the aldehyde cycloadduct generated in situ has been homologated with a phosphonium ylide (e.g., Ph3P=CHCO2Et or Ph3P=CBr2) [316]. While the presence of o-fluorobenzoic acid might facilitate the

190

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

formation of trienamine, the addition of o-nitrobenzoic acid with higher acidity as an additive in fact completely diminishes the reactivity. In contrast, the employment of a weak acid, base, or no additive at all could improve the conversion of reactants. Particularly, doubling the substrate concentration without additional additives may lead to full conversion of substrates. Also, a reaction at 40°C is necessary in order to retain a reasonable reaction rate. Under the optimized reaction condition, a variety of aromatic azlactones with either electron-donating (OMe, Me) or electron-withdrawing substituents (F, Cl, Br, CO2Me, NO2) undergo the Diels-Alder cycloadditions to provide the desired products with excellent control of stereochemistry [316].

O O +

CHO

N Ph

Ph Ph N H OTMS (10 mol%) CHCl3, 40 °C Ph3P=X

Ph N

O

X = CHCO2Et, 70% yield dr = 5:1, 98% ee X = CBr2, 82% yield dr = 7:1, 98% ee O X

chiral catalyst Ph3P=X

Ph Ph

N

O

OTMS Ph O N

Ph Ph TMSO

Ph O

O

Ph

N

O O

N

O

Ph Ph

O Ph

O + N Ph

CHO

N

N H OTMS (20 mol%) 1) CHCl3, 60 °C 2) L-Phe-OMe HCl, 60 °C

Ph

H

N

CO2Me

O NHBz Ph Et 43% yield, 99% ee

SCHEME 1.133  The [4+2] cycloaddition between arylidene azlactones and (2E,4E)-hexa2,4-dienal or (2E,4E)-octa-2,4-dienal.

This reaction is also unbiased towards the substitution pattern (e.g., para, meta, and ortho) on the aryl group at 4-arylidene moiety. Moreover, heteroaromatic groups, such as pyridyl and thiophenyl as well as doubly

Azlactones 191

substituted aryl groups are also compatible with this reaction condition. However, azlactones carrying an aliphatic side chain are unstable under this reaction condition, which decompose readily in the reaction solution. Treatment of the azlactone with TMSCl in MeOH affords the corresponding benzamide methyl ester as a single diastereoisomer in 50–85% yields without epimerization of the stereogenic centers. Further extension of this reaction by treatment of the cycloadducts with amino acid hydrochloride generates peptides of high enantioselectivity, as illustrated in the reaction of (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one with (2E,4E)-octa-2,4-dienal in the presence of (R)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine and subsequent treatment with methyl L-phenylalaninate hydrochloride to yield 43% of methyl (S)-2-((4aR,7R,8R,8aR)-8a-benzamido-7-ethyl-1-oxo8-phenyl-4a,7,8,8a-tetrahydroisoquinolin-2(1H)-yl)-3-phenylpropanoate with 99% ee. This reaction demonstrates an approach for direct peptide ligation to give enantiopure non-proteinogenic dipeptides of up to five stereogenic centers in a one-pot fashion [316]. 1.4.2.13 CYCLOPROPANATION OF UNSATURATED AZLACTONES In addition to the normal [3+2] cycloaddition and [4+2] cycloaddition that generally afford azlactones with spiral five or six-membered structures, unsaturated azlactones also undergo the [1+2] cycloaddition with carbenes, yielding azlactones containing a spiral three-membered ring. One example is the reaction of 2-diazo-1,1,1-trifluoroethane (also known as 2,2,2-trifluorodiazoethane) with either 2-alkyl-4-arylidene azlactones or 2-phenyl4-alkylidene azlactones in the presence of saturated brine in acetonitrile under refluxing. It should be pointed out that 2-diazo-1,1,1-trifluoroethane is a gaseous compound under ambient conditions and easily decomposes under harsh conditions. In order to maximize the reactivity of such diazo-compound, four of the most widely used metal complexes for cyclopropanation of olefins have been screened at room temperature, that include Cu(OTf)2, [Fe(TPP)Cl] (TPP = 5,10,15,20-tetraphenylporphyrin), [Co(TPP)], and [Rh2(esp)2] [esp = 3,3′-(1,3-phenylene)bis(2,2-dimethylpropanoate)]. However, under this condition, 2-diazo-1,1,1-trifluoroethane decomposes completely, whereas the model azlactone (E)-4-benzylidene-2-methyloxazol-5(4H)-one has been fully recovered. Interestingly, direct heating of the mixture of 2-diazo1,1,1-trifluoroethane and (E)-4-benzylidene-2-methyloxazol-5(4H)-one in acetonitrile at 80°C in the absence of any transition metal complexes affords

192

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

27% of the cyclopropanation product with excellent diastereoselectivity. The addition of either water or NaCl to the reaction system leads to an increased yield, whereas the reaction in an alternative solvent such as THF, DMF, toluene, or benzene results in a significantly low yield ( 99:1 dr

N O

O

CF3 O Ph

+

F 3C

N

N

9 mL saturated NaCl ° 4 mL CH3CN, 80 C

O N Ph 95% yield, > 87:13 dr

SCHEME 1.134  Cyclopropanation of (E)-4-benzylidene-2-methyloxazol-5(4H)-one and (E)-4-(cyclohexylmethylene)-2-phenyloxazol-5(4H)-one with 2-diazo-1,1,1-trifluoroethane.

1.4.2.14 PHOTODIMERIZATION OF UNSATURATED AZLACTONES A unique reaction for the unsaturated azlactone is its dimerization to cyclobutane with two spiro-azlactone moieties. It should be pointed out that normal [2+2] cycloaddition is forbidden under thermal conditions according to the

Azlactones 193

Woodward-Hoffmann rule, but is allowed under photochemical conditions. In addition, there are two potential manners of cycloadditions, i.e., head-tohead (or tail-to-tail) and head-to-tail. For the case of unsaturated azlactones, the favored cycloaddition mold should be the head-to-tail due to steric hindrance. For example, glucagon-like peptide-1 (GLP-1) has proven to be an efficacious agent for the treatment of type 2 diabetes, but its two obvious drawbacks have restricted its wild application in such areas, including the high degradation rate with a half-life of 2−3 min in the circulation due to its cleavage by dipeptidyl peptidase-4. In a project to search for nonpeptidic small molecule GLP-1 receptor (GLP-1R) agonists, a diverse library of 48160 synthetic and natural compounds against HEK293 cells stably transfected with a rat GLP-1R expression vector and a multiple response element/cAMP response element (MRE/CRE)-driven luciferase reporter plasmid (HEK293-rGLP-1R cells) have been screened. S O

O

O MeO

O

NH O

h [2+2] DMSO

N

O CO2H NH

HN HO2C

O

O NH O

O

HN

MeO O

NH

O O

OMe O

O

O

S

N

S

142

144 S O O

O O

S

O MeO

NHBoc O N

O h [2+2]

141

DMSO MeO O

O

BocHN CO2H NH

HN HO2C

O

O

NHBoc O

S 143

OMe O

S 145

SCHEME 1.135  Photochemical dimerization of unsaturated azlactone.

194

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Within this large molecular pool, (Z)-4-((2-(4-acetamidophenyl)5-oxooxazol-4(5H)-ylidene)methyl)-2-ethoxyphenyl thiophene-2carboxylate (SH14800, 141 in Scheme 1.135) displayed activity to invoke luciferase activity, to elevate cAMP and to displace [125I] GLP-1(7−36) amide from the receptors. After slight structure modification, (Z)-4((2-(4-(cyclopentanecarboxamido)phenyl)-5-oxooxazol-4(5H)-ylidene) methyl)-2-methoxyphenyl thiophene-2-carboxylate (NC133908, 142) and (Z)-4-((2-(4-((tert-butoxycarbonyl)amino)phenyl)-5-oxooxazol-4(5H)ylidene)methyl)-2-methoxyphenyl thiophene-2-carboxylate (NC133909, 143) have been confirmed to undergo [2+2] cycloaddition in a headto-tail fashion under natural light in DMSO solution, which yields (1S,2S,3S,4S)-1,3-bis(4-(cyclopentanecarboxamido)-benzamido)-2,4bis(3-methoxy-4-((thiophene-2-carbonyl)oxy)phenyl)cyclobutane1,3-dicarboxylic acid (144) and (1S,2S,3S,4S)-1,3-bis(4-((tertbutoxycarbonyl)amino)benzamido)-2,4-bis(3-methoxy-4-((thiophene2-carbonyl)oxy)phenyl)cyclobutane-1,3-dicarboxylic acid (145), respectively (Scheme 1.135). These two cycloadducts have displayed even greater luciferase activity [318]. Based on this preliminary result, a series of cyclobutane derivatives have been prepared from tert-butyl (Z)-(4-(4-(3-methoxybenzylidene)-5-oxo-4,5-dihydrooxazol-2-yl) phenyl)carbamate and its analogs after further modifications of the functional groups on their east ends and west ends [319]. It should be pointed out that four possible products can be formed in a headto-tail fashion from the [2+2]-photo-dimerization of unsaturated azlactone, which are generally known as the alpha-isomer, epi-isomer, epsilon-isomer, and gamma-isomer, as illustrated in Scheme 1.136 for the reaction of (Z)-4benzylidene-2-phenyloxazol-5(4H)-one [320]. A good photo-dimerization condition with blue light (465 nm) provided by light-emitting diode (LED) lamps of low power (around 1 W) in CH2Cl2 can generate these cyclobutane derivatives in very good to excellent yields (75−100%), for which the epsilon-isomers are always the major products, regardless of the electrondonating or electron-withdrawing group on the arylidene moiety; whereas the amounts of other isomers vary depending on the actual substituents on either aryl groups. DFT calculation indicates that the photo-dimerization involves a stepwise formation of two new C−C bonds through a transient diradical singlet intermediate. In addition, the mechanistic study shows that the variation of distribution on the four possible products is not because of reaching equilibrium among these isomers, but primarily due to the kinetic preference of C−C bond formation at the rate-limiting step [320].

Azlactones 195

Based on the illustration in Scheme 1.136, there supposes to have two more isomers originating from the [2+2] cycloaddition of the (E)-arylidene azlactones from either syn- or anti-combination. However, it has been reported that the (E)-4-arylidene azlactone and (Z)-4-arylidene azlactone can easily establish an equilibrium under photo-irradiation. From all the unsaturated azlactones evaluated by UV-vis spectroscopy, the (Z)-4arylidene azlactones are always the predominant isomers, weighing more than 75% of the isomers, except for (Z)-4-(2-methoxybenzylidene)-2methyloxazol-5(4H)-one that accounts for 64% of the Z/E mixtures. Using trans-azobenzene as the actinometer, the photochemical quantum yield for the Z→E isomerization has been quantified as 0.25 ± 0.01, whereas the E→Z isomerization corresponds to a quantum yield of 0.11 ± 0.02 for 4-benzylidene-2-methyloxazol-5(4H)-one. On the other hand, the relative kinetic rate constant of kE→Z is 4.5 times faster than that of the Z→E isomerization (i.e., kZ→E), resulting in the preference of the Z-isomers. Thus, the other two potential cyclobutane derivatives will be minor products if existing. Due to the comparable isomerization quantum yield for both processes (E→Z and Z→E), the 4-arylidene azlactones have been explored as photoswitches [321]. While the E-isomers outweigh the Z-isomers for some 4-benzylidene-2-methyloxazol-5(4H)-ones carrying an electrondonating group on the arylidene moiety at the photo-stationary state [322], other reports indicate that almost all 4-arylidene azlactones prefer the Z-configuration at the photo-stationary states [323]. Further exploration of this photo-dimerization has established a stereoselective synthesis of epsilon-isomers of the corresponding 4-arylidene azlactones that involves three steps in the presence of a palladium complex (e.g., Pd(OAc)2) in CF3CO2H. The reaction occurs with the regioselective activation of the ortho-C-H bond of the 4-arylidene ring to give binuclear complexes with bridging carboxylates, which is followed by a [2+2]-photocycloaddition of the exocyclic C=C bonds of the azlactone skeleton to afford the corresponding binuclear ortho-palladated cyclobutanes irradiated with LED light sources of different wavelengths (465, 525, or 625 nm) in flow microreactors. Final hydrogenation of the cycloadduct in methanol results in depalladation that affords the epsilon-isomers as the sole products, without other three possible cycloadducts [324]. Similarly, the photochemical dimerization of (Z)-4-(4-chlorobenzylidene)2-phenyloxazol-5(4H)-one irradiated with 60W LEDs in CH2Cl2 in the presence of 2 mol.% of Ru(bpy)3(PF6)2 (146, Figure 1.25) affords 38% of 11,12-bis(4chlorophenyl)-2,8-diphenyl-3,9-dioxa-1,7-diazadispiro[4.0.4 6 .2 5 ]

196

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

dodeca-1,7-diene-4,10-dione, even accompanied with the competing cycloreversion to the starting material as the highly strained tricyclic system is unstable. Likewise, irradiation of (Z)-4-benzylidene-2-phenyloxazol-5(4H)one in methanol in the presence of 146 gives 37% of dimethyl (1R,2S,3R,4R)1,2-bis(benzamido)-3,4-diphenylcyclobutane-1,2-dicarboxylate and 8% of methyl (1R,2R,3R,4S)-1-benzamido-8-oxo-2,3,6-triphenyl-7-oxa-5azaspiro[3.4]oct-5-ene-1-carboxylate [325]. For this reaction, the addition of LiBF4 and (±)-camphorsulfonic acid improves the yield of the former product to 52% but almost diminishes the latter product. In contrast, the photochemical dimerization in the presence of other two visible light catalysts (e.g., a complex of bis(2-(pyridin-2-yl)phenyl)iridium and 4,4’-di-tert-butyl2,2’-bipyridine with PF6– counterion, 147 and 2’,4’,5’,7’-tetrabromo-3’,6’dihydroxy-3H-spiro[isobenzofuran-1,9’-xanthen]-3-one (eosin Y, 148, Figure 1.25) results in a yield of cycloadduct lower than that from 146. However, such photochemical dimerization in the presence of 5 mol% of 148 leads to an asymmetric cycloadduct as the major product. Detailed examinations of the reaction conditions indicate that both photocatalyst and the light source are necessary for the dimerization, as the treatment of (Z)-4-benzylidene-2-phenyloxazol-5(4H)-one by photocatalyst without the light source only yields the ring-opening product (i.e., methyl (Z)-2-benzamido-3-phenylacrylate); likewise, no cycloadducts form under LED light irradiation in the absence of photocatalyst. Moreover, the addition of the photocatalyst to the solution of methyl (Z)-2-benzamido-3-phenylacrylate does not lead to cycloadducts, suggesting that these derivatives are inactive in the formation of [2 + 2] cycloaddition products [325]. 2+

N Ru N

t-Bu

N N

N

2 PF6

PF6

Ir

N

O

Br

N N

N

O

N

t-Bu

O

HO Br

146

147

Br OH Br

148

FIGURE 1.25  Catalysts used in the photo-dimerization of unsaturated azlactones.

Therefore, photochemical dimerization in the presence of different photocatalyst under visible light irradiation provides a tool to form alternative [2+2] cycloadducts. For this reaction, azlactones with either electron-donating or

1

2

=

1

2

2

3K

3K 1

2

2

HSVLORQLVRPHU

1

+ +

3K

2

1 =

1

2 2

3K

2 3K

+ 2

3K 1 +

DOSKDLVRPHU

1

2 2

3K

KHDGWRWDLO DQWLRIWZR=D]ODFWRQHV

2

=

2 1

2 =

(

2

1

1

2

2

2

3K 2

3K

2 3K 1

+ +

HSLLVRPHU

2

1

2 3K

KHDGWRWDLO V\QRI(DQG=D]ODFWRQHV

K

2

1 =

1

2

2

3K

2

3K

+ 2

3K 1 + 2 JDPPDLVRPHU

2

1

3K

KHDGWRWDLO DQWLRI(DQG=D]ODFWRQHV

2

(

SCHEME 1.136  Four possible dimerization products from (E)- and (Z)-4-benzylidene-2-phenyloxazol-5(4H)-ones under photoirradiation.

3K

2

2

KHDGWRWDLO V\QRIWZR=D]ODFWRQHV

2

=

2

2

1

Azlactones 197

198

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

electron-withdrawing substituent on the arylidene moiety, as well as heteroarylidene azlactones are suitable for the dimerization, providing the desired products in yields between 22 and 56% with >19:1 dr. A representative example is given by the photochemical dimerization of (Z)-4-benzylidene2-phenyloxazol-5(4H)-one in the presence of 146 followed by the treatment with CSA to give 54% of dimethyl (1R,2S,3R,4R)-1,2-bis(benzamido)3,4-diphenylcyclobutane-1,2-dicarboxylate, or alternatively in the presence of 148 to afford 44% of methyl (1R,2R,3R,4S)-1-benzamido-5-oxo-2,3,7-triphenyl-6-oxaspiro[3.4]oct-7-ene-1-carboxylate as illustrated in Scheme 1.137. Taking advantage of the photochemical dimerization in the presence of 148 by the addition of 1.1 equivalent of a nucleophile (e.g., octan-1-amine) in the presence of CSA prior to the final workup, methyl (1R,2S,3R,4R)1,2-bis(benzamido)-2-(octylcarbamoyl)-3,4-diphenylcyclobutane-1-carboxylate is obtained in 44% yield [325]. It is believed that the ring-opening of azlactone occurs after the cycloaddition reaction. Computational study of the geometries of starting materials and photocatalyst 148 using density functional theory (DFT) with the hybrid M06-2X functional and the 6-31G(d,p) basis set and the geometries of transition states with the Hartree-Fock method in combination with 6-31G(d,p) basis set indicate that only the triplet state of 148 is compatible with the blue light LED energy with both calculated and recorded energy barrier of 1.89 eV. After activation of 148, the excited 148 then can follow two possible pathways: electron transfer between the activated 148 and azlactone affords either radical anion or radical cation. The combination of 148+•/azlactone−• is favored over 148−•/azlactone+• but is unselective for azlactone isomers. Due to steric hindrance, in order to form the diastereomer of head-to-head dimer prior to the ring-opening of azlactone, a reaction between the E- and Z-4-arylidene azlactones is required whilst only the Z-starting material is initially present, thus a photochemical isomerization from the Z-isomer to E-isomer must take place. While the isomerization barrier of neutral 4-arylidene azlactone does not allow such an event to proceed at room temperature, the formation of the Z-azlactone radical anion by the electron transfer from the excited triplet catalyst 148 facilitates the isomerization to afford the E-arylidene azlactone radical anion, with a calculated ΔG⧧ of 14.65 Kcal/mol and a reaction ΔG of only 2.91 Kcal/mol. Based on the evaluation of the formation of all possible head-to-head dimeric intermediates, i.e., 1,2-Z,E-anti, 1,2-E,E-anti, 1,2-Z,Z-anti, 1,2-Z,E-syn, 1,2-E,E-syn, and 1,2-Z,Z-syn, it is found that the dimeric radical anion is thermodynamically favored only for

Azlactones 199

the coupling of E−E- and Z−E-azlactones, and the anti-coupling is favored over the syn-addition (anti = −5.12 to −7.8 Kcal/mol; syn = −2.9 to −3.6 Kcal/mol). Particularly, the formation of 1,2-Z,E-anti intermediate is the most probable to occur. Subsequently, an electron transfer from this intermediate to the 148+• regenerates the neutral catalyst 148, along with the ring closure to form the cyclobutane moiety. This step is greatly favored in thermodynamics, with a ΔG between −34.5 and −45.9 Kcal/mol [325].

MeO2C

CO2Me

BzHN

NHBz

Ph

Ph

54% yield > 19:1 dr

1) 2 mol% 146 2.0 eq. LiBF4, MeOH 60 W Blue LEDs r.t., N2 atm. 2) 10 mol% CSA

O

N

5 mol% 148 Ph MeOH O 60 W Blue LEDs r.t., N2 atm. Ph

O

O CO2Me NHBz

Ph Ph 44% yield > 19:1 dr 1.1 eq. octan-1-amine 10 mol% CSA

O CO2Me

HN BzHN Ph

NHBz Ph

44% yield

SCHEME 1.137  The photochemical dimerization of (Z)-4-benzylidene-2-phenyloxazol5(4H)-one under different conditions.

When the two types of 4-cycloalkylideneoxazol-5(4H)-ones are irradiated in solid, they undergo a different dimerization approach. These 4-cycloalkylidene-oxazol-5(4H)-ones are: 4-cyclohexylidene-2-(m-tolyl) oxazol-5(4H)-one (149), 4-cyclohexylidene-2-(2-methoxyphenyl)oxazol5(4H)-one (150), 4-cyclohexylidene-2-(3-methoxyphenyl)oxazol-5(4H)-one (151), (Z)-4-(3-methylcyclohexylidene)-2-phenyloxazol-5(4H)-one (152), 4-(4-(tert-butyl)cyclohexylidene)-2-phenyloxazol-5(4H)-one (153), and 4-cycloheptylidene-2-phenyloxazol-5(4H)-one (154, Figure 1.26). It is found that the photo-dimerization in the solid state underwent an uncommon C=N cycloaddition whilst still in a head-to-tail fashion, instead of the expected exocyclic C=C cycloaddition, giving centrosymmetric 1,3-diazetidines in very good to nearly 100% yields. A representative reaction is illustrated in Scheme 1.138 for the dimerization of 4-cyclohexylidene-2-(m-tolyl)oxazol5(4H)-one to yield 95% of (4aR,8aS)-3,7-dicyclohexylidene-4a,8a-di-mtolyl-4aH,8aH-[1,3]diazeto[2,1-b:4,3-b’]bis(oxazole)-2,6(3H,7H)-dione.

200

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Due to the high steric hindrance of the 1,3-diazetidine core, the dimers are stable only in the solid state, but may rapidly cyclo-revert to the original azlactones even in neutral solution [326]. O

O

O

O

O

N

O

N

N

OMe

OMe 149

150

151

t-Bu

O

O

O

O

O

N

O

N

152

N

154

153

FIGURE 1.26  Unsaturated azlactones that undergo photo C=N cycloaddition in solid states.

O O N

O h crystal

O

N N O

95%

O

SCHEME 1.138  Photodimerization of solid 4-cyclohexylidene-2-(m-tolyl)oxazol-5(4H)one.

Azlactones 201

1.4.2.15 MISCELLANEOUS REACTION OF UNSATURATED AZLACTONES In addition to so many types of reactions involving the unsaturated azlactones, there are some reactions that are difficult to be classified in any of the above categories. For example, treatment of the mixture of (Z)-4-benzylidene-2phenyloxazol-5(4H)-one and diethyl 3-oxopentanedioate in freshly purified tetrahydrofuran of analytical grade with potassium tert-butoxide led to the formation of diethyl 6-benzamido-5-hydroxy-3-oxo-1,2,3,6-tetrahydro[1,1’-biphenyl]-2,4-dicarboxylate. Upon further treatment with 5% Ba(OH)2 aqueous solution, N-(3-hydroxy-5-oxo-1,2,5,6-tetrahydro-[1,1’-biphenyl]2-yl)benzamide was obtained, as shown in Scheme 1.139 [327]. In contrast, a similar reaction between dimethyl 3-oxopentanedioate and methyl (E)-2-(5oxo-2-phenyloxazol-4(5H)-ylidene)-2-phenylacetate in THF in the presence of NaH surprisingly afforded 44% of dimethyl 4-benzamido-2-hydroxy-4-(2methoxy-2-oxo-1-phenylethyl)-5-oxocyclopent-1-ene-1,3-dicarboxylate as single crystalline product, instead of the analogous trimethyl 6-benzamido5-hydroxy-3-oxo-3,6-dihydro-[1,1’-biphenyl]-1,2,4(2H)-tricarboxylate (Scheme 1.139) [328]. One more reaction that deserves comment is the highly regioselective divergent intramolecular ene-yne reaction to form phosphine-containing indane or indene derivatives in good yields, as illustrated in the reaction between (Z)-2-phenyl-4-(2-(phenylethynyl)benzylidene)oxazol-5(4H)-one and diphenylphosphine oxide. The outcome of this reaction is sensitive to the base used as well as the additive. For example, when the mixture of the above two compounds was heated at 100°C in DMF, (Z)-1-benzylidene3-(diphenylphosphoryl)-2’-phenyl-1,3-dihydro-5’H-spiro[indene-2,4’oxazol]-5’-one (155) was obtained in 76% or 61% yield when Et3N or NaOAc was applied as the base, respectively, whereas only trace amount of the product arising from the ring-opening of azlactone were obtained. In contrast, when Na2CO3 or K2CO3 was applied as the base, the above azlactone was obtained in 15% or 11%, respectively, whereas a mixture of N-(1-benzyl3-(diphenylphosphoryl)-1H-inden-2-yl)benzamide (156) and N-(3-benzyl1-(diphenylphosphoryl)-1H-inden-2-yl)benzamide (157) were obtained in 53% or 59% yield correspondingly, and the ratio of these two isomers was 60:40 or 36:64, respectively (Scheme 1.140) [329]. Interestingly enough, when 2.0 equivalent of 1,4-benzoquinone (BQ) was added as an additive, a mixture in 77:23 ratio of the above indene derivatives was obtained, in a total of 35% yield. For comparison, when N-methylmorpholine-N-oxide (NMO) was used as the additive, 39% of the above two indene products were

202

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

obtained, but in a ratio of 15:85. In both cases, no azlactone product was obtained. However, when 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added as the additive, none of the above products were obtained. O O

O

O

O

+

N

EtO

KOBut OEt THF

HN

EtO2C

Ba(OH)2

O OH

HN

CO2Et O

MeO

O

O

O O

O

+

N

MeO

O

O

O OH

NaH OMe THF

CO2Me OH MeO2C HN O O

CO2Me

SCHEME 1.139  The reaction of unsaturated azlactones with dimethyl or diethyl 3-oxopentanedioate under basic conditions. (Refer to Scheme 1.117 for similarity).

O O N Ph Ph

O + H P Ph Ph

Cs2CO3 (0.5 eq.) additive (2.0 eq.) DMF, 100 °C 1 hr.

O Ph Ph P O O N Ph 155

+

O Ph P O Ph Ph + NH

O Ph P O Ph Ph NH

Ph Ph 156

Ph 157

SCHEME 1.140  The reaction between (Z)-2-phenyl-4-(2-(phenylethynyl)benzylidene) oxazol-5(4H)-one and diphenylphosphine oxide.

1.5 APPLICATIONS Due to their anhydride character and tremendous reactivities as outlined above, azlactones have been widely adopted in material sciences, to make functional materials for bioconjugation, drug delivery, and surface modification through further reactions of azlactones with various nucleophiles, especially amines. For example, 4,4-dimethyl-oxazol-5(4H)-one moiety can be easily incorporated into the polymer as a side chain (or pendant) or terminal group by means of DMV. In this case, DMV can copolymerize with another monomer to form polymers containing many units of azlactone pendants, arranged either throughout the polymer chains (via copolymerization) or in a particular region of block-copolymers, in addition to the homopolymer of DMV. In order to make functional polymers, polymers of controlled topology are often prepared

Azlactones 203

by living radical polymerization, such as atom transfer radical polymerization (ATRP [330], also known as transition metal-mediated living radical polymerization) [331], reversible addition-fragmentation chain transfer polymerization (RAFT) [332], nitroxide-mediated “living” free radical polymerization (NMP) [333], and copper-mediated living radical polymerization [334]. In addition, azlactone can also be introduced to the terminal of polymer, either through the reaction of DMV with polymer involving Michael addition or DMV containing a chain transfer agent (CTA) initiated polymerization of vinyl monomers. Scheme 1.141 illustrates the preparation of DMV from 2-amino2-methylpropanoic acid and acryloyl chloride and the concepts of incorporation of DMV into polymer chains [335]. O

H N

Cl OH + O

NH2

O

N EtOC(O)Cl OH Et3N

O E

I

N +

O

O

O

ATRP or RAFT

n

N

O

O O I = initiator E = ending group CTA

N O O

Linker

N +

n

RAFT polymerization

E

O O

SCHEME 1.141  Preparation of 4,4-dimethyl-2-vinyloxazol-5(4H)-one copolymerization with other vinyl monomers under ATRP or RAFT condition.

and

In a real practice of making azlactone-containing polymers, poly(DMV)s prepared in benzene at 65°C using either 2-(2-cyanopropyl) dithiobenzoate or 2-dodecylsulfanylthiocarbonylsulfanyl-2-methylpropionic acid as RAFT CTA have been covalently attached to epoxy-modified silicon wafers via esterification to produce polymeric scaffolds that can be subsequently functionalized for various bio-inspired applications [10]. Several “Rasta” resins with well-defined macromolecular architectures have been prepared by means of transition metal-mediated living radical polymerization using a supported initiator prepared from Wang resin [331]. These “Rasta” resins include homopolymers of poly(4,4-dimethyl-2-vinyloxazol-5(4H)-one)s, polystyrenes, statistical poly(styrene-stat-DMV), block

204

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

poly(styrene-b-DMV), and poly[styrene-b-(styrene-stat-DMV)] copolymers. “Rasta” resins are resin beads consisting of a polystyrene core with long, linear polymer chains prepared by solvent-free suspension polymerization. The new outward polymer chains containing the desired reagent (often electrophilic groups), catalyst, or scavenger, are produced by a unique living free-radical polymerization process [336]. As a result, “Rasta” resins usually have loading capacity higher than typical polymer-bound reagents so less polymer material is required to achieve the same synthetic results [337]. From the Wang resin, isolated poly(DMV)s reach a molar mass of 18.0 kg/ mol and a polydispersity index (PDI) of 1.22 after 6 hours of polymerization with 86.7% conversion of DMV. Also, block copolymers are prepared in two steps, involving the synthesis of polystyrene of low conversions (< 15%) to maintain the bromide end-chain functionality and subsequent formation of poly(DMV)s or poly(styrene-stat-DMV) block with a loading capacity of azlactone around 6.0 mmol/g [331]. In a specific example for the preparation of block copolymer of styrene and DMV, polystyrene is prepared with a RAFT agent of S-1-dodecyl-S’(α,α’-dimethyl-α”-acetic acid)trithiocarbonate, and the resulting polystyrene is used as macroinitiator in combination with 48 mol% of AIBN to trigger the radical polymerization of DMV (DMV/PS = 425) to achieve a poly(styrene-block-DMV) copolymer with a final molecular weight of the poly(DMV)s region at 9.85 kg/mol. Thermal annealing of this asymmetric copolymer drives microphase separation in thin films, resulting in reactions between the azlactone groups and the underlying substrate [338]. As a result, the copolymer contains high defect densities and poor long-range order. In contrast, solvent annealing of poly(styrene-block-DMV) thin films with toluene drives high fidelity microphase separation of the thin films, enabling control over domain orientation and ultimately yielding defectfree morphologies over large areas. Further treatment of this copolymer thin film with primary amine demonstrates that the reactions between azlactone groups and incoming amines are confined primarily to the uppermost ∼4 nm of the thin film as characterized by depth-profiling with X-ray photoelectron spectroscopy. On the other hand, a metal precursor (e.g., trimethylaluminum) has been incorporated into copolymer thin films of either parallel or perpendicular orientation by using vapor phase infiltration technology, and incorporated trimethylaluminum is then converted into hard masks of Al2O3 nanowires and nanodots with dimensions of 16 and 12 nm. This approach may have potential applications in advanced lithography [339].

Azlactones 205

It should be pointed out that azlactone-containing polymers are particularly well-suited materials for covalently attaching performance-specific functionality as the electrophilic azlactone ring undergoes facile addition reaction with alcohol, thiol, and especially amine nucleophiles, providing a four-atom spacer between the polymer backbone and bound ligand [340, 341]. For example, cross-linked, hydrophilic, porous supports containing azlactone moiety at the surface exhibit excellent capacities for the covalent immobilization of protein ligands [342]. Also, the grafted homopolymers [poly(DMV)s] and block copolymers [poly(styrene-stat-DMV)] have demonstrated good efficiency in removing benzylamine [331]. Particularly, 4,4-dimethyl-2-(4-vinylphenyl)oxazol-5(4H)-one has been polymerized with the RAFT process in bulk, followed by copolymerization with styrene to yield a copolymer of low PDI (PDI = 1.10–1.20). The resulting copolymer has been engineered into a variety of functional materials for potential applications in different domains, including electrochemical probes (by reaction with aminomethylferrocene), host-guest supramolecular chemistry (by grafting amino-cyclodextrin and 2-(2-((5-(2-(2-methoxyethoxy)ethoxy)naphthalen-1-yl)oxy)ethoxy)ethan-1-amine), biohybrid (by grafting glutathione), catalysis (by grafting cyclodextrin) and coating (by grafting 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctan-1-amine). During the preparation of these materials, it is found that the azlactone moiety readily reacts with primary amine without any catalyst, where a total change of the surface properties has been observed only by changing the nature of the primary amine. In contrast, the reaction between azlactone and secondary amine or alcohol occurs only in the presence of a base (e.g., DBU) in mild conditions, and azlactone is not much reactive with thiol or acid either [332]. In order to quantify the effect of polarity of a polymer backbone on the reactivity of DMV pendant, a highly cross-linked copolymer of high surface area has been prepared by dispersion polymerization of DMV, 2-hydroxyethyl methacrylate (HEMA), and trimethylolpropane trimethacrylate (TMPTMA, i.e., 2-ethyl-2-((methacryloyloxy)methyl)propane-1,3diyl bis(2-methylacrylate)). The polarity of the resulting polymer network is adjusted by varying the amount of HEMA in the polymer formulations and is quantified by a lipophilicity index derived from solvent partition data collected on the constituent monomers. Additional lipophilicity is introduced by esterification of the polymer network with acetic anhydride/pyridine. The reactivity of azlactone with butylamine is measured by infrared spectroscopy, which increases linearly along with the increment of the polarity of the network, regardless of the cross-link density of the network [341].

206

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Also, the characterization of poly(DMV)s thin films modified with a series of primary amines by neutron reflectometry indicates that the brush thickness of poly(DMV)s increases due to the functionalization of azlactone rings with primary amines. Both neutron reflectometry and ellipsometry show that the degree of functionalization with small amine molecules depends on the size of the amines, the grafting density of brush chains, and their molecular weights. In other words, the functionalization with amines is incomplete and the extent of functionalization is strongly dependent on the size of n-alkylamine. Moreover, the functionalization with the primary amine is not uniform, even in modestly dense brushes. There appear a loss of poly(DMV)s chains during functionalization, because of chain scission resulting from additional stretching during functionalization. Furthermore, end-tethered poly(DMV)s brush chains do not achieve their bulk mass density due to the increased steric demand caused by the addition of amines to azlactone rings [343]. Once the azlactone-containing polymers are formed, additional functional groups or segments with important biological features can be mounted onto the polymers. For example, azlactone-functionalized polymers (i.e., poly(DMV)s) have been converted into materials of gene delivery, where poly(DMV)s are individually treated with 1,2-, 1,3- or 1,4-diamines with both primary and tertiary amino groups to form tertiary amine functionalized poly(DMV)s, from which the tertiary amino groups can be protonated to form cations to bind DNA. The resulting poly(DMV)s library is used to construct DNA/polymer complex or polyplexes at 10 different DNA/polymer ratios (w/w) ranging from 1: 1 to 1: 10. In this practice, plasmid DNA (pCMV-Luc) encoding firefly luciferase is applied to form the DNA/polymer polyplexes as this plasmid DNA allows quantitative characterization of transgene expression using a bioluminescence-based assay. The screening results from COS-7 cells indicate that poly(DMV)s modified with N1,N1-diisopropylethane-1,2-diamine, 2-(pyrrolidin-1-yl)ethan-1-amine, and 2-(piperidin-1-yl)ethan-1-amine have gene transfection capability comparable to that mediated by branched polyethyleneimine (BPEI) and linear polyethyleneimine (LPEI), whereas other nine poly(DMV)s engineered with alternative diamines are inferior to BPEI/ LPEI. These three poly(DMV)s have a common structural feature containing sterically hindered tertiary amino groups which are two carbons away from the amide/amide linker to the poly(DMV)s backbones. The screening result also indicates that the degree of polymerization for poly(DMV)s will affect the ability of the corresponding polymers to transfect cells [344]. Also, post modification of the multi-layer mixture of poly(DMV)s and branched PEI

Azlactones 207

with n-decylamine allows the generation of slippery liquid-infused porous surfaces with unique and robust anti-fouling behavior [345]. Due to the high reactivity of azlactone moiety with the primary amine, poly(DMV)s have been applied to form thin films via layer-by-layer assembly of poly(DMV)s with nondegradable aliphatic diamine linkers. The resulting films are stable upon incubation in physiologically relevant media. By contrast, films fabricated using poly(DMV)s and varying amounts of disulfidecontaining diamine linker (e.g., cystamine) are stable in normal physiological media, but will erode rapidly upon exposure to chemical reducing agents [346]. One application of poly(DMV)s films is to immobilize proteins. For example, poly(DMV)s brushes have been grown on the surface of [chloro(dimethyl) silyl]propyl 2-bromo-2-methylpropanoate functionalized wafer via ATRP using N,N,N′,N″,N″‐pentamethyldiethylenetriamine as catalyst and surfaceanchored dimethylsilylpropyl 2-bromo-2-methylpropanoate as the initiator in toluene at 80°C. Then model protein of RNase A is immobilized up to 7.5 μg/cm2 on a 50 nm thick poly(DMV)s brushes. Evaluation of the activity of immobilized RNase A indicates that the binding kinetics is controlled by the rate of protein adsorption with a rate constant of 2.8 × 10–8 μg–1·s–1·cm3. The maximum relative activity close to that of free RNase A is reached at 1.2 μg/ cm2 (∼3.0 monolayers) of immobilized RNase A, which also demonstrates a temperature and pH dependence similar to free RNase A. When other biotechnologically relevant enzymes, such as deoxyribonuclease I, glucose oxidase, glucoamylase, and trypsin, are immobilized on poly(DMV)s, their relative activities are either higher than or comparable to those enzymes immobilized by other means [347]. Poly(DMV)s coated magnetic nanoparticles have been applied to immobilize proteins as well. The magnetic nanoparticle is prepared from FeCl3/FeCl2 (2:1) in water with adjustment of pH to 12 by 25% NH3, and the resulting Fe3O4 nanoparticle is then added into a mixture of 100 mL ethanol and 25 mL water, followed by dropwise addition of 25% NH3 solution and tetraethoxysilane to improve the stability and biocompatibility of Fe3O4 nanoparticle. Further treatment of SiO2-Fe3O4 nanoparticles with 3-aminopropyltriethoxysilane allows the introduction of the primary amino group to the surface of the nanoparticle. Poly(DMV)s have been prepared by reversible addition-fragmentation chain transfer polymerization of DMV, which are then mounted to the surface of SiO2-Fe3O4 nanoparticles. The model protein of L-asparaginase reaches a loading capacity of 318.0 μg/mg magnetic nanoparticle in reaction with the remaining azlactone moiety of poly(DMV). Evaluation of protein activity indicates that its enzymatic  

208

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

efficiency increases slightly with the lengthened polymer chain, owing to the increased amount of immobilized enzyme. On the other hand, the immobilized enzyme could retain more than 95.7% of its activity after 10 repeated uses and maintain more than 72.6% of activity after 10 weeks of storage [348]. Magnetic nanoparticles are also prepared by grafting a copolymer prepared from a surface-initiated ATRP of DMV and (poly(ethylene glycol) methacrylate with the other end of PEG capped with a methyl group (PEGMA), where the molar ratio of DMV over PEGMA varies from 30% to 100%. In addition, the thermal decomposition method is applied to control the size of nanoparticles. After that, folic acid is grafted to the surface of the magnetic nanoparticles to develop drug delivery vehicles for cancer treatment [330]. In order to attach gold nanoparticles to the pore surface of the monolith, the pore surface is modified with the photo-grafting method by flushing the pore volume of a methacrylate monolith with DMV and irradiating with UV light in the presence of benzophenone (free radical initiator), where DMV is covalently bonded to the surface by a process of hydrogen abstraction from the pore surface. This approach brings much more azlactone groups to the pore surface with respect to the copolymerization methods. The surface is then modified with cysteamine or ethylenediamine for binding gold nanoparticles [349]. It should be pointed out that block copolymers of poly(ethylene glycol)​-​ b-​poly(2-​vinyl-​4,​4-​dimethylazlactone) (PEG-b-PVDMA) can be turned into well-​defined nanoparticles in aqueous solutions by means of microphase segregation. Hydrolysis of the azlactone moieties induces gradual dissociation of the block copolymer nanoparticles, whereas treatment of the nanoparticles with functional amines allows the creation of azobenzene- or pyridine-containing nanoparticles. The said nanoparticles can incorporate molecular cargoes and release them upon external stimuli, such as pH, making the azlactone-containing block copolymers attractive platforms for the development of controlled delivery vehicles [350]. Another application of poly(DMV)s is to fabricate chemically reactive and topographically patterned hydrogels by treatment of poly(DMV)s with hydrophilic diamine Jeffamine®. The gels are initially assembled in DMSO and subsequently transferred into aqueous media to form hydrogels. Residual azlactones not consumed during the crosslinking are further treated with hydrophobic, hydrophilic, or macromolecular amines to influence the physicochemical properties of gel materials in aqueous solvents [351]. Post-polymerization modification of poly(DMV)s with (4-((5,6-dihydropyrimidin-1(4H)-yl)methyl)phenyl)methanol at room temperature yields

Azlactones 209

polyacrylamide with a 4-((5,6-dihydropyrimidin-1(4H)-yl)methyl)benzyl ester functionality, which is capable of selective and reversible capturing CO2 at room temperature from a nearly pure (99%) CO2 source to a mixed source containing only 20% of CO2. Experimental details indicate that the presence of two CO2 binding sites in this polymer leads to a two-step CO2 release at room temperature, and the incomplete release of CO2 at 25 and 55°C is caused by the formation of amidinium bicarbonate triggered by small amounts of moisture. The modification reagent is prepared from (4-(chloromethyl)phenyl)methanol and propane-1,3-diamine and subsequent treatment of (4-(((3-aminopropyl)amino)methyl)phenyl)methanol with 1,1-dimethoxyN,N-dimethylmethanamine, as demonstrated in Scheme 1.142 [352]. Likewise, the poly(DMV)s-Jeffamine gel with encapsulation of photolabile 2-(2-nitrophenyl)propyl (2-(dimethylamino)ethyl)carbamate has been developed. Upon photo-irradiation, the newly released N1,N1-dimethylethane-1,2-diamine will attack the 4,4-dimethylazlactone ring, and the resulting gel is then hydrolyzed to decompose the remaining azlactone moieties. Such photo-mediated postfabrication modification of reactive, azlactone-containing gels can be used to generate a gradient in chemical functionality, exhibiting rapid and reversible shape deformations in response to changes in pH [353]. 2+ +1 2+

1

0H2

1+

&+&OUWKUV

EHQ]HQH& PLQ

ƒ

&O

2+

20H

1 +

1+

1

1

Q

2

1

2

1

2

2 2 1+

Q

&+&OUW RYHUQLJKW

1

SCHEME 1.142  Example for the functionalization of DMV-containing polymer side chain.

It should be pointed out that the simple azlactone can be applied to form polyamide with a certain initiator. For example, treatment of the solution of oxazol-5(4H)-one or 4-methyloxazol-5(4H)-one (prepared from glycine or DL-alanine respectively) with a cationic initiator such as methyl trifluoromethanesulfonate (MeOTf) at room temperature resulted in a smooth

210

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

polymerization to give white powdery polymeric materials. All these polymeric materials are hygroscopic and soluble in highly polar organic solvents such as Me2SO, DMF, pyridine, and triethyl phosphate but are insoluble in water, ethanol, benzene, and diethyl ether. It is found that methyl iodide can also initiate the polymerization of 4-methyloxazol-5(4H)-one, and the polymer obtained using the MeI initiator was determined to be poly(Nformyl-a-alanine) of materials of relatively lower molecular weights. Other cationic initiators such as TiCl4 and BF3·OEt2 seem less effective for this case [354]. Another type of application involving azlactone is to make polypeptides of hindered amino acids origin, which allows the preparation of polymers containing alternating D- and L-amino-acid residues, and in principle, other defined repeating sequences, as well as stereochemically homogeneous polypeptides. While some examples of preparation dipeptides from amino acid azlactones have been provided previously, under certain conditions, the use of azlactones for the stepwise lengthening of benzyloxycarbonyl peptides is limited to the preparation of tri- and higher peptides, since benzyloxycarbonyl-amino acids themselves do not form stable azlactones. The easy conversion of N-trifluoroacetyl-a-ethylalanine into the corresponding azlactone in the presence of DCC, allows the quick formation of a dipeptide by addition of appropriate amino acid ester to the filtered solution without prior separation of azlactone. Specifically, the application a-methylalanine t-butyl ester in reaction with azlactone allowed the quick lengthening of the peptide chain, although with increasing chain length the lowering of azlactone reactivity was evident. By a repetitive process of cleaving t-butyl esters with trifluoroacetic acid and forming azlactone by brief warming with acetic anhydride, a hexapeptide in better than 50% overall yield was obtained. The very high efficiency of this process and the absence of side reactions indicated the possibility of making a-methylalanine polymer. Likewise, when optically active dipeptide azlactone of a-ethylalanine was applied as the starting materials, 61% of the isotactic polymer was obtained with a mean molecular weight of 8070 Daltons/mol, whereas 38% of the syndiotactic polymer was obtained with a mean molecular weight at 3890 Daltons/mol [355]. Similarly, the Z-protected dipeptide azlactone prepared from 1-aminocyclohexane-1-carboxylic acid, i.e., benzyl (1-(4-oxo-3oxa-1-azaspiro[4.5]dec-1-en-2-yl)cyclohexyl)carbamate was subject to polymerization, by hydrogenolysis of the benzyloxycarbonyl group to yield the oily 2-(1-aminocyclohexyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one. This compound was first heated in toluene solution and then in the solid-state

Azlactones 211

to yield involatile residue with an approximate degree of polymerization containing 55 residues (mean molecular weight ca. 6900 Daltons/mol) as estimated by viscosity measurement in dichloroacetic acid solution [356]. Furthermore, oxazol-5(4H)-one and 4-methyloxazol-5(4H)-one can serve as nucleophilic monomers toward electrophilic monomers like acrylamide and 2-hydroxyethyl acrylate. Copolymerization between these two types of monomers took place without added initiator at either room temperature or 110°C to give solid alternating copolymers of low molecular weight ( 108 ~ 109 > 110, while no apparent antibacterial activity in dark (with the same agar well diffusion as 6% EtOH). This result indicates that the expanded ring system on E-ring rather than oxazolidin-5-one attenuates the antimicrobial properties normally associated with the Jadomycins [24]. Similarly, when Jadomycin 23 (Figure 2.5) has been functionalized with (2-naphthoxy)acetic acid N-hydroxysuccinimide ester, nonanoic acid N-hydroxysuccinimide ester or phenoxyacetic acid N-hydroxysuccinimide ester, the corresponding three amides have been subject to similar agar well diffusion assay with 6% EtOH as the control, almost no apparent activity has been identified against the tested bacteria [27]. The antibacterial activity of Jadomycin DNL (38) and Jadomycin DNV (39 in Figure 2.6) have been screened using CLSI methods to measure the minimum inhibitory concentration, against five strains of Gram-positive bacteria (Staphylococcus aureus C622, Staphylococcus aureus MRSA C623, Staphylococcus epidermis C960, Bacillus subtilis C971, and Enterococcus faecalis C625) and three strains of Gram-negative bacteria (Salmonella enterica typhimurium C587, Escherichia coli C498, and Pseudomonas aeruginosa H187). While neither 38 nor 39 have demonstrated activity against the three Gram-negative strains, they are active against Staphylococcus epidermidis C960 (MIC50 4 μg/mL) and a clinical MRSA strain (MIC50 32 μg/mL). Apparently, the difference in length of the amino acid side chain between (R)-2-aminohexanoic acid and (R)-2-aminopentanoic acid to form Jadomycins DNL and DNV does not affect the antibacterial activity of these two Jadomycins [23]. It has been well documented that the alkynyl moiety easily undergoes the “Click Chemistry” with azide to form a triazole heterocycle. Then, a group of Jadomycin derivatives containing a triazole moiety associated with the E-ring have been prepared by the 1,3-dipolar cycloaddition between Jadomycin 22 and an azide. Jadomycin 22 has been generated from the cell culturing media in the presence of (S)-2-ammonio-3-(prop-2-yn-1-yloxy) propanoate which is prepared from t-Boc-L-serine and propargyl bromide.

284

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

The azides used in this study include 1-azidooctane, (azidomethyl)benzene, O-2,3,4,6-tetraacetyl-β-D-glucosyl azide, β-D-glucosyl azide, 6-deoxy-2,3,4O-triacetyl-α-L-mannosyl azide, 6-deoxy-2,3,4-O-triacetyl-β-L-mannosyl azide, 2,3,4,6-O-tetraacetyl-β-D-mannosyl azide and 2,3,4,6-O-tetraacetylα-D-mannosyl azide. The corresponding 1,3-dipolar cycloadducts are: (1S)-12-(((2S,4R,5R,6S)-4,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl) oxy)-7-hydroxy-5-methyl-1-(((1-octyl-1H-1,2,3-triazol-4-yl)methoxy) methyl)-8H-benzo[b]oxazolo[3,2-f]phenanthridine-2,8,13(1H,3aH)trione (111), (1S)-1-(((1-benzyl-1H-1,2,3-triazol-4-yl)methoxy)methyl)12-(((2S,4R,5R,6S)-4,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl) oxy)-7-hydroxy-5-methyl-8H-benzo[b]oxazolo[3,2-f]phenanthridine2,8,13(1H,3aH)-trione(112),(2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-((((1S)12-(((2S,4R,5R,6S)-4,5-dihydroxy-6-methyl-tetrahydro-2H-pyran-2-yl) oxy)-7-hydroxy-5-methyl-2,8,13-trioxo-1,2,3a,13-tetrahydro-8H-benzo[b] oxazolo[3,2-f]phenanthridin-1-yl)methoxy)methyl)-1H-1,2,3-triazol-1-yl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (113), (1S)-12-(((2S,4R,5R,6S)-4,5dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-7-hydroxy-5methyl-1-(((1-((2R, 3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)-8Hbenzo[b]oxazolo[3,2-f]-phenanthridine-2,8, 13(1H,3aH)-trione (114), (2R,3R,4R,5S,6S)-2-(4-((((1S)-12-(((2S,4R,5R,6S)-4,5-dihydroxy-6methyltetrahydro-2H-pyran-2-yl)oxy)-7-hydroxy-5-methyl-2,8,13-trioxo1,2,3a,13-tetrahydro-8H-benzo[b]oxazolo[3,2-f]phenanthridin-1-yl)-methoxy) methyl)-1H-1,2,3-triazol-1-yl)-6-methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (115), (2S,3R,4R,5S,6S)-2-(4-((((1S)-12-(((2S,4R,5R,6S)-4,5dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-7-hydroxy-5methyl-2,8,13-trioxo-1,2,3a,13-tetrahydro-8H-benzo[b]oxazolo[3,2-f] phenanthridin-1-yl)methoxy)methyl)-1H-1,2,3-triazol-1-yl)-6methyltetrahydro-2H-pyran-3,4,5-triyl triacetate (116), (2R,3R,4S,5S,6R)2-(acetoxymethyl)-6-(4-((((1S)-12-(((2S,4R,5R,6S)-4,5-dihydroxy-6methyltetrahydro-2H-pyran-2-yl)oxy)-7-hydroxy-5-methyl-2,8,13-trioxo-1,2,3a, 13-tetrahydro-8H-benzo[b]oxazolo[3,2-f]phenanthridin-1-yl)methoxy) methyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (117) and (2R,3R, 4S,5S,6S)-2-(acetoxymethyl)-6-(4-((((1S)-12-(((2S,4R,5R,6S)4,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-7-hydroxy-5methyl-2,8,13-trioxo-1,2,3a,13-tetrahydro-8H-benzo[b]oxazolo[3,2-f] phenanthridin-1-yl)methoxy)methyl)-1H-1,2,3-triazol-1-yl)tetrahydro-2Hpyran-3,4,5-triyl triacetate (118) as shown in Scheme 2.3. Screening of antibacterial activity of these triazole-containing Jadomycin derivatives as

Oxazolidin-5-ones 285

well as 22 against five Gram-positive bacteria strains (Staphylococcus aureus C622, Staphylococcus aureus MRSA C623, Staphylococcus epidermidis C960, Bacillus subtilis C971, and Enterococcus faecalis C625) and three Gramnegative bacteria strains (Salmonella enterica typhimurium C587, Escherichia coli C498, and Pseudomonas aeruginosa H187) using CLSI methods (vancomycin as the control) indicates that only 22 is active against Gramnegative strain (E. coli C498), although all are effective against Staphylococcus epidermidis C960 [26]. HO O HO O N N HO

OH O

O

O O

O

HO

OH O

O

O O

O

NH

NH

O O

O O

108

107

HO O HO O

N

N HO

OH O

O

O

HO

O

OH O

O

O

O O NH

O

O

NH O 109

110

FIGURE 2.15  The Jadomycin JDOct based amide derivatives.

Recently, it is reported that in the presence of L-ornithine, in addition to the formation of Jadomycin Oct (27, Figure 2.5), a novel lactam has been characterized which is assumed to derive from the spontaneous rearrangement of the expected Jadomycin derivative containing an oxazolidinone ring, i.e., (1S)-1-(3-aminopropyl)-12-(((2S,4R,5R,6S)-4,5-dihydroxy-6-

286

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

methyltetrahydro-2H-pyran-2-yl)oxy)-7-hydroxy-5-methyl-8H-benzo[b]oxazolo[3,2-f]phenanthridine-2,8,13(1H,3aH)-trione (119), affording 8-(((2S,4R,5R,6S)-4,5-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)1,5-dihydroxy-3-methyl-6-((S)-2-oxopiperidin-3-yl)-5,6-dihydrobenzo[b]phenanthridine-7,12-dione (120). Upon treatment with methanol, the corresponding 8-(((2S,4R,5R,6S)-4,5-dihydroxy-6-methyltetrahydro-2Hpyran-2-yl)oxy)-1-hydroxy-5-methoxy-3-methyl-6-((S)-2-oxopiperidin-3yl)-5,6-dihydrobenzo[b]phenanthridine-7,12-dione (121) has been isolated, as demonstrated in Scheme 2.4 [74]. Compound 121 has been subject to antibacterial test against Gram-positive MRSA and Staphylococcus warneri (vancomycin as control); VRE (rifampicin as control); and Gram-negative Pseudomonas aeruginosa (gentamicin as control) and Proteus vulgaris (ciprofloxacin as control); as well as fungal species Candida albicans (nystatin as control). The results indicate that compound 120 is nearly as effective as the control against MRSA and S. warneri, but is much less effective against other species with respect to the corresponding reference [74]. 2+

2 2

1 +

2

 1D+%U&+& &+ ƒ '0)1&KUV &O 2+  0+&O(W2$FPLQ + 1 

6YHQH]XHODH,63 96 KUV

2 2 2

+2 2

+2 2

1 2+ 2

+2

2

2 2

2

+

1

&X62+2$VFRUELF$FLG ƒ (W2++2 &PLQ 51

2

+2

2+ 2

2

2 2 1 1 1 5



$F2 $F2 

5 $F2

$F2 

2$F

$F2

2 $F2 

2$F 

 2

2$F 2

2$F



2+ 

2$F 2

$F2 $F2 $F2

2+ 2

+2 +2

$F2 $F2 $F2 

SCHEME 2.3  The Jadomycin triazoles prepared from the Click Chemistry.

2$F 2

+

2 2

Oxazolidin-5-ones 287

2.3.2 ANTICANCER ACTIVITY AND CLEAVAGE OF DNA In addition to their antibacterial and antimicrobial activities, Jadomycins have demonstrated anticancer activity. Anticancer activity is a general term to demonstrate the ability of a chemical substance or a reagent to inhibit the growth of cancer cells or to cause necrosis or apoptosis of cancer cells. For example, the anticancer activity of Jadomycin DNL (38) and Jadomycin DNV (39 in Figure 2.6) have been evaluated by the percent growth and mean optical density of cancer cell lines according to the protocol suggested by National Cancer Institute (NCI). A total of 59 cancer cell lines, including six leukemia, nine non-small-cell lung carcinoma, six colons, six central nervous systems (CNS), nine melanoma, seven ovarian, eight renal, two prostate, and six breast cancer cell lines have been assayed at five doses spanning a 5 log10 concentration range. Specifically, the optical densities are plotted versus Jadomycin concentration to obtain half growth inhibition concentration (GI50, the concentration at which growth inhibition is half its maximal value), total growth inhibition concentration (TGI, the concentration of test drug that causes total growth inhibition), and cytotoxicity (LC50, the concentration at which half the cells are killed, i.e., lethal concentration). The anticancer screening indicates that Jadomycin DNL and Jadomycin DNV are effective to inhibit the growth of the majority of cancer cells, with the median GI50 and TGI in the low micromolar range; as well as lethal to 41 or 44 out of the 59 cancer cell lines [23]. HO O

Streptomyces venezuelae ISP5230 +

H2N

O

H 2N

CO2H

OH NH2

OH O

HO

O

HO O

O OH NH2

O

N

O

HO

OH O

O CO2H

O

NH2

HO O

HO O

N HO N

HO

OH O

O

O

OH O

O

HO O

O

O O NH2

O O

N

119 HO

NH2 HO O

Jadomycin Oct (27)

O O

HO O

OH O

O

O R

O O NH2

(R = CO2H)

MeOH N HO

OH O

O

O

NH 120

N

OH O HO

OH O

O

O

OMe O NH

121

SCHEME 2.4  Formation of Jadomycin Oct and the mechanism to form a δ-lactamcontaining Jadomycin.

288

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

The anticancer activity (e.g., cytotoxicity) of Jadomycin L (11, Figure 2.4) and Jadomycin T (15, Figure 2.4), as well as D-olivosyl-Jd-Leu (53, Figure 2.8) and D-olivosyl-Jd-Thr (57, Figure 2.8) have been screened against five human cancer cell lines, i.e., MCF-7 (human breast cancer cell line), KB (human epidermoid carcinoma cell line), A549 (human lung cancer cell line), HepG2 (human hepatocellular carcinoma cell line) and HCT116 (human colon cancer cell line) by the MTT assay. The MTT assay is a highly reliable, colorimetric assay for assessing cell metabolic activity as well as in vitro cell proliferation to reflect the number of viable cells present, by means of colorimetry during the reduction of tetrazolium dye MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] to its insoluble formazan in purple color, and has become a major technique for testing of tumor cell resistance to anticancer agents [75]. A very closely related method of MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay is often used in cytotoxicity assay as well [21]. While all these four Jadomycin derivatives have demonstrated anticancer activity against the five cancer cell lines with IC50 ranging from 0.1942 to 13.13 μM, compound 53 performs better than Jadomycin L against MCF-7, whereas compound 57 is less effective than its parent congener (Jadomycin T), partly due to the instability of 57 under bioassay condition [18]. While compounds 107–110 in Figure 2.15 have demonstrated antimicrobial activity, they have limited cytotoxicity against their 60 DTP human tumor cell line, despite their ability to invoke Cu(II)-mediated DNA damage [24]. The MTT assay of seven Jadomycin derivatives [Jadomycin B (4, Figure 2.2), F (7), L (11), S (14), T (15, Figure 2.4), DNV (39) and SPhG (26, Figure 2.5)] against MCF-7 indicates that six Jadomycin analogs except for DNV are effective agents in the eradication of MCF-7 breast cancer cells. In addition, the cytotoxicity of these compounds is minimally affected by ABCB1, ABCC1, and ABCG2 efflux transporters according to lactate dehydrogenase cytotoxicity assays, because the inhibition of ABCB1, ABCC1, or ABCG2 with verapamil, MK-571, or Ko-143, respectively, has not increased the cytotoxicity of these Jadomycins in drug-resistant MCF-7 cells [76]. The lactate dehydrogenase assay couples a bioluminescent NADH detection system with the oxidation of lactate to pyruvate and production of NADH. In the presence of NADH, a pro-luciferin substrate is converted by reductase to luciferin, which is then used in a luciferase reaction to produce light. The luminescent signal increases proportionally to the amount of lactate in

Oxazolidin-5-ones 289

the sample and a stable luminescent signal is achieved when all lactate is consumed [77]. In another experiment, Jadomycin B (4), as well as Jadomycins Ala (19, Figure 2.4), F (7), S (14), T (15) and V (16) have been screened with MTT/ MTS assays against four cancer cell lines (HepG2, IM-9, IM-9/Bcl-2 and H460), showing that Jadomycin S is most potent against HepG2, IM-9 and IM-9/Bcl-2 while Jadomycin F is most potent against H460. These results demonstrate that the side chains of the E-ring derived from the incorporated amino acids have a significant impact on biological activity [21]. More structure-activity relationships have been revealed when a group of 18 Jadomycin derivatives [B (4), DV (34), DT (35), DM (36), R-Phe (37), S-Phe (26), S (14), F (7), G (8), H (9), M (12), N (13), V (16), T (15), W (17), Y (18), βala (42), ILEVS1080 (61)] as well as Dalomycin T (73) are subject to cytotoxicity screening against two cancer cell lines (T-47D and MDA-MB-435 cells), showing a 30-fold change in potency. More active derivatives are those with small polar side chains, such as Jadomycins DT, S, T, and Dalomycin T, indicating the importance of polar functionality on the E-ring, as Jadomycin G with hydrogen as the side chain is less active than the ones with polar groups. On the other hand, the least active analogs are Jadomycins with aromatic amino acid functionalities in the side chain, including Jadomycins Y, H, and W. Jadomycins with nonpolar aliphatic side chain on E-ring demonstrate cytotoxicity between the above two groups. While Jadomycin R-Phe is more active against both cell lines than Jadomycin S-Phe, the cytotoxicity between Jadomycin V and DV looks similar [20]. Jadomycins are also effective in dealing with multidrug-resistant (MDR) breast cancer cell lines. For example, Jadomycins B, F, and S demonstrate equal potency against drug-sensitive control MDA-MB-231 cells (231-CON) and a paclitaxel-resistant, triple-negative breast cancer cell line [paclitaxelresistant MDA-MB-231 breast cancer cells (231-TXL)]. These Jadomycins also increase reactive oxygen species (ROS) activity in both cell lines by up to 7.3-fold using ROS-detection assay. In addition, they cause DNA double-strand to break as measured by gH2AX Western blotting and induce apoptosis of these two cell lines as measured by annexin V affinity assays. It is suggested that the anticancer activity is at least partially dependent on the ROS based on bacterial plasmid DNA cleavage studies [29], whilst still acts through ROS-independent mechanism because when the ROS is inhibited, Jadomycins still retain 100% cytotoxic efficacy albeit with lower potency. The overall assay in combination with polymerase chain reaction, Western blotting, and direct topoisomerase inhibition assays indicates that

290

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

these Jadomycins inhibit type II topoisomerases and that Jadomycins B and F selectively poison topoisomerase IIβ [78]. Similarly, WaterLOGSY NMR spectroscopy has been applied to study the binding between Jadomycin DS and validated anticancer target human topoisomerase IIβ both qualitatively and quantitatively [79]. Jadomycins, B (4), F (7), S (14), and SPhG (26), representing three structural classes of Jadomycins (with polar, non-polar, and aromatic side chains on the E-ring) have been tested with MTT cell viability measuring assays in BT474, SKBR3, MDA-MB-231, and drug-sensitive control (CON) and Taxol (TXL)-resistant MCF-7 breast cancer cells. With the general intracellular ROS-detecting probe CMDCFH2-DA, the ROS activity has been found to be dose-dependent in MCF7-CON breast cancer cells, where Jadomycins induce breast cancer cell death in vitro by increasing cytosolic superoxide and H2O2 in a Cu(II)-dependent reaction, and that these ROS are reduced in the cytosol by SOD1 and the Prx/Trx and GST/GPx antioxidant pathways [29]. It should be pointed out that Jadomycins might also be cytotoxic towards normal cells (e.g., human microvascular epithelial cells) in the same concentration range for the cancer cell lines, indicating that they are not selective between tumor and normal cells. This has been demonstrated when a group of 11 Jadomycin derivatives [B (4), K (10), L (11), S (14), T (15), V (16), Abu (29), Daba (31), Hse (32), Nle (30), and Orn (28)] is subject to evaluation with sulforhodamine B assay against two human cancer cell lines (MCF-7 breast cancer cells and HCT116 colon cancer cells) and human microvascular epithelial cells, where Jadomycins with alkyl side chains (Jadomycin B, V, L, Abu, and Nle) or small polar side chains (Jadomycin S, T, Orn) show higher activities, whereas Jadomycin Hse displays much lower activity with respect to S and T, indicating the importance for the local orientation of the side chain [31]. In addition to the ROS-dependent mechanism, the anticancer activity of Jadomycins might also be related to their ability to cleave DNA (single-strand or double-strand). For example, Jadomycin derivatives with a triazole moiety as represented by compounds 111 to 118 in Scheme 2.3 all lead to singlestrand cleavage (form II), but not the double-stranded DNA (supercoiled, form I) [23] cleavage, in a concentration-dependent manner in the presence of equimolar Cu(OAc)2, with a decreasing activity order of 112 > 111 ≈ 113 > 118 > 116 > 117 [26]. Assessment of the cleavage of DNA backbone in the presence of metal ions (especially the copper ion) and natural products is a robust and proven strategy for documenting the DNA-damaging properties of the natural products. Copper ion has been a known oxidant of prodigiosin

Oxazolidin-5-ones 291

(i.e., (Z)-4-methoxy-5-((5-methyl-4-pentyl-2H-pyrrol-2-ylidene)methyl)1H,1’H-2,2’-bipyrrole) involved in DNA cleavage. For example, at a 10 μM concentration of Jadomycin B, no DNA damage has been detected, whereas the addition of copper ions (Cu(OAc)2) promotes a single-strand cleavage of duplex DNA (nicked, form II) in a concentration-dependent manner. Optimal cleavage occurred for the concentration ratio of Jadomycin B/Cu(OAc)2 in a range from 0.5 to 1, whereas lowering the concentration of either Jadomycin B or Cu(OAc)2 reduces the extent of cleavage, indicating a non-catalytic behavior of the DNA cleavage. Other three Jadomycins [G (8), L (11), and SPhe (26)] have been tested with respect to Jadomycin B, indicating the possibility for effectively “turning on” the DNA damaging properties of Jadomycins, as Jadomycin G has completely inhibited the DNA damage, whereas a double-strand DNA could be cleaved by Jadomycin L [30]. It is suggested that the damage to DNA is primarily caused by ROS generated by copper (I), as illustrated in Scheme 2.5. The oxygen dependence in copper-mediated DNA cleavage is evidenced by the inhibitory effect of catalase, an enzyme that disproportionates H2O2 to yield water and oxygen. It is possible that Jadomycin B may exert a synergistic damaging effect with copper through a similar oxygen-dependent pathway due to the requirement for the coexistence of Cu(OAc)2 and Jadomycin B. The requirement for copper was further confirmed by the inhibitory effect of EDTA, a known chelator of copper ions, leading to no damage to DNA. Similarly, catalase completely inhibits the DNA cleavage, implicating a role for H2O2 in DNA damage in the presence of Jadomycin B. Different from the DNA cleavage with prodigiosin, the presence of superoxide dismutase (SOD), a metalloenzyme that converts superoxide O2− to H2O2 and H2O, completely protects DNA, suggesting that superoxide is an intermediate involved in the DNA damage with Jadomycin B. Sodium azide, a singlet oxygen scavenger, and DMSO or t-butyl alcohol, a hydroxyl radical scavenger also inhibit DNA damage in the presence of Jadomycin B, albeit DMSO (or t-BuOH) inhibits to a slightly lesser extent. Thus, the copper and Jadomycin B initiated DNA cleavage may involve multiple oxygen-dependent pathways, including freely diffusible hydroxyl radicals, superoxide, singlet oxygen, and H2O2, with the initial reduction of Cu(II) to Cu+. In this case, Jadomycin B donates electrons to Cu(II), so that the cleavage of DNA could be accelerated under conditions where the formation of the angucyclinone-based π-radical cation is favored [80]. Another possibility to render Jadomycin of anticancer activity might be its inhibitory activity against Aurora kinases, which are well-conserved in all

292

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

eukaryotes and play a critical role in mitosis. In a virtual screening attempt, 22 compounds have been identified from nearly 15,000 microbial natural products as potential small molecular inhibitors of human Aurora-B kinase. Particularly, Jadomycin B inhibits the growth of IPL1-321 temperaturesensitive mutant (encoded on ILP1 gene) more dramatically than wild-type yeast cells. In addition, in vitro biochemical assay using purified recombinant human Aurora-B kinase shows that Jadomycin B competes with ATP for the kinase domain and inhibits Aurora-B activity in a dose-dependent manner, and blocks the phosphorylation of histone H3 on Ser10 in vivo. Evidence also shows that Jadomycin B induces apoptosis in tumor cells without obvious effects on the cell cycle [81]. Cu(I) + O2

Cu(II) + O2

2O2 + 2H+

H2O2 + O2

Cu(I) + H2O2

copper-oxo species

copper-oxo species + DNA

DNA cleavage

SCHEME 2.5  The mechanism of DNA damage caused by reactive oxygen species involving Cu(I).

2.3.3 SIGNAL MOLECULES In addition to antimicrobial activity (antibacterial activity included) and anticancer activity, Jadomycins can function as signal molecules. Streptomyces coelicolor is a Gram-positive soil bacterium with high G-C content, which undergoes a complex life cycle of mycelial growth and spore formation, and produces a variety of antibiotics and other drugs during the differentiation process. It is found that Jadomycin B at subinhibitory concentrations can induce Streptomyces coelicolor to undergo premature differentiation (formation of sporulating aerial mycelium) and early production of the redpigmented antibiotic Red. In a bioassay experiment based on the pigment production by S. coelicolor, Jadomycin B has been identified in addition to γ-butyrolactone (GBL), growth cycle-related signaling molecules produced by Streptomycetes. When a lawn of S. coelicolor mycelium grown on supplemented minimal medium (SMM) agar has been spotted with Jadomycin B, a pink zone surrounding the spot of Jadomycin B has been noticed. Among the tested antibiotics that include Jadomycin B, Ampicillin, Erythromycin, and Kanamycin, only Jadomycin B leads to pigment production, whereas

Oxazolidin-5-ones 293

the other three antibiotics have not induced obvious phenotypes. Jadomycin B also induces pink pigment production in liquid cultures at subinhibitory concentrations (1–5 μM). Further study indicates that the pigment production induced by Jadomycin B involves the binding of JdB by a “pseudo” γ-​butyrolactone receptor, ScbR2, which binds two target promoters (redDp and adpAp)​, and directly regulates undecylprodigiosin (Red) production and morphological differentiation, respectively [32]. 2.4 PREPARATIVE METHODS As displayed in structure 1 in Figure 2.1, oxazolidin-5-one can be considered as an N,O-acetal of aldehyde or an N,O-ketal of ketone, in combination with an α-amino acid. Currently, the term “acetal” has been used more often than ketal, so ketal is also called acetal in many cases. Generally, acetal is formed when aldehyde is treated with alcohol in the presence of acid (can be a catalytic amount), and ketal is formed similarly with a ketone in the presence of alcohol and acid catalyst, as illustrated in Scheme 2.6. The corresponding intermediate is known as hemiacetal or hemiketal. The whole process from aldehyde to hemiacetal and then to acetal (similar to ketal) is thermodynamically reversible so that the preparation of acetal derivative can be favored when the byproduct of water is removed (e.g., by the Dean-Stark apparatus). Since water will be the leaving group during the formation of hemiacetal and acetal, the process will not proceed under the basic condition as hydroxide is a bad leaving group. Due to the reversible nature of this reaction, acetal is unstable under acidic conditions, but will be very stable under basic conditions, due to its partial characteristic of ether. As a result, the acetal (or ketal) has often been applied as the protecting group for aldehyde (or ketone) functionality as well as alcohol during organic synthesis. Alternatively, acetal can also be prepared from aldehyde (or ketone) and another simple acetal such as 2,2-dimethyl-1,3-dioxolane or 2-phenyl-1,3-dioxolane (Scheme 2.7). The cyclic acetals formed from 1,2-diol or 1,3-diol are especially stable with respect to those formed from mono-alcohols [82–84]. Hetero-acetals contain other atoms rather than oxygen connecting to the carbon atom originating from the carbonyl group of aldehyde or ketone, such as N,O-acetal [85], N,S-acetal [86] (or S,N-acetal) [87], etc. Oxazolidin-5-one is a type of N,O-acetal, thus it can be generally prepared from the reaction of α-amino acid with an aldehyde or a ketone. On the other hand, since aldehyde or ketone also reacts with

294

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

the amine to yield imine or enamine from the primary amine and secondary amine, respectively, all the amino groups on amino acids should be protected prior to the reaction with aldehyde or ketone, in order to form the expected oxazolidin-5-ones accordingly. O + R” R

HO

H+

OH

OR” R”

R

R’

OH, H+

R’

R

’OR”

R

OR”

hemiacetal (hemiketal) O R

R’

H+

OH

+ HO

HO

O

R

R’

+ H2 O

acetal (ketal) H+

OH

R = alkyl, aryl R’ = H, alkyl, aryl R” = alkyl

O + H O 2 R R’ cyclic acetal O

SCHEME 2.6  A general mechanism for the formation of acetal (or ketal) and cyclic acetal. O R

+ O R’

O

O + R

O

R’

O

O

R

R’

+

O

O O

O +

R

R’

O

SCHEME 2.7  Preparation of cyclic acetals from 1,3-dioxolanes.

According to the aldehyde or ketone used in the preparation of oxazolidin5-ones, the individual reaction conditions might be different so they are classified into the following groups. 2.4.1 PREPARATION OF OXAZOLIDIN-5-ONES FROM α-AMINO ACID DERIVATIVES AND FORMALDEHYDE The simplest aldehyde is formaldehyde, with a boiling point of –19°C. It is very soluble in water so formaldehyde is often sold as a 37% aqueous solution of formaldehyde, generally known as formalin, which is used as an antiseptic to preserve the biological specimen, disinfectant, and a fixative for histology [88]. However, this solution is not feasible in the preparation of acetal with alcohol according to Scheme 2.6, due to an excess amount of

Oxazolidin-5-ones 295

water. Another source of formaldehyde is paraformaldehyde, the smallest polyoxymethylene generally abbreviated as (CH2O)n, where n = 8 ~ 100 and mainly n = 12, which depolymerizes to formaldehyde upon dry heating [89]. Sometimes, 1,3,5-trioxane has been applied as a source of formaldehyde as well [90]. The general method to make N-protected oxazolidin-5-ones is the treatment of N-protected amino acids with paraformaldehyde in the presence of a catalytic amount of para-toluenesulfonic acid (PTSA) [91]. In addition, some other methods have also been developed, such as the reaction between N-protected amino acid and paraformaldehyde in CH2Cl2 in the presence of MgSO4 [92], in CH2Cl2 in the presence of both PTSA and silica gel [93], in the presence of BF3·Et2O [93] and the reaction of N-protected amino acid with 37% CH2O by addition of PTSA dissolved in THF [94]. Some preparations of oxazolidin-5-ones from paraformaldehyde are detailed below. The first example for the preparation of oxazolidin-5-one derivatives from α-amino acid derivatives and paraformaldehyde in benzene is illustrated in Scheme 2.8. This reaction has been carried out using camphorsulfonic acid (CSA) as a catalyst, and the α-amino acids tested include N-benzyloxycarbonyl-L-serine (N-Cbz-L-serine), N-Cbz-L-threonine, N-Cbz-L-tyrosine, N-Cbz-L-methionine, N2,N5-bis-Cbz-L-glutamine, N-Cbz-DL-glutamic acid, 4-benzyl-N-Cbz-aspartic acid, N-Cbz-L-cysteine, N-Cbz-L-tryptophan, N-Cbz-L-asparagine, N-Cbz-L-glutamine, N2,N6-bis-Cbz-L-lysine, and N-Cbz-S-phenylglycine, etc., where the α-amino group has been protected with the benzyloxycarbonyl group (Cbz). This protocol works well for the majority of amino acids except for the ones with basic side chains. However, these amino acids can be subject to this transformation as long as the basic group on the side chain is protected, such as the amino group in L-lysine and L-histidine as well as the amido group in L-glutamine that have been protected with a Cbz group. The resulting oxazolidin-5-ones have been converted into the corresponding N-methyl amino acids via reductive cleavage of the oxazolindin-5-one scaffold (with H2/Pd-C or triethylsilane/trifluoroacetic acid) followed by the deprotection of Cbz group [95]. It should be pointed out that several oxazolidin-5-one derivatives with reactive side chains would not afford the N-Cbz-N-methyl amino acids under the condition of hydrogenolysis, yielding the simple amino acid instead. Readers should consult this particular literature to find out the specific conditions to give N-methyl amino acid (e.g., with Et3SiH/TFA to open the oxazolidin-5-one ring followed by removal of the Cbz protecting group via hydrogenolysis) [96]. Similarly, hydrogenolysis of benzyl 5-oxooxazolidine-3-carboxylate and benzyl

296

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

(S)-4-benzyl-5-oxooxazolidine-3-carboxylate in the presence of Et3SiH/TFA yields N-Cbz-N-methylglycine and N-Cbz-N-methylphenylalanine [97].

O

O

R

O Bn

N H

OH O

(CH2O)n cat. CSA benzene, reflux

R = CH2OH R = CH(OH)CH3 R = CH2C6H4-OH R = CH2CH2CONHCbz R = CH2CH2CO2H (DL) R = CH2CO2Bn R = C6H5

O

R

R H2/Pd-C, MeOH

N

O

Et3SiH/CF3CO2H

O

Cbz

OH

N O

R = CH2SH R = CH2CH2SCH3 R = CH2CH2CH2CH2NPhth R = CH2CH2CH2CH2NHCbz R = R’CH2 (R’ = indol-3-yl) R = R”CH2 (R” = N-Cbz imidazol-4-yl) R = CH2CONH2 R = CH2CH2CONH2

SCHEME 2.8  Preparation of oxazolidin-5-ones and N-Cbz-N-methyl-amino acids from N-Cbz-α-amino acids and paraformaldehyde in benzene.

A very easy procedure involves the reaction between N-tosyl amino acid and paraformaldehyde under microwave irradiation for 2 minutes to give high yields of the corresponding oxazolidin-5-ones. To do so, the 1:5 ratio of N-tosyl amino acid and paraformaldehyde in CH2Cl2 was mixed with K10 clay. After removal of the solvent, the remaining clay powder was left in the microwave for 2 minutes and the products were extracted by EtOAc. In addition to N-tosyl amino acids, N-acetyl or N-benzoyl amino acids also work under this condition, however, N-Boc or N-Cbz protected amino acids are not suitable for this procedure [98]. Still under microwave irradiation, the slurry of N-Fmoc, N-Boc, and N-Cbz protected amino acids and paraformaldehyde in toluene was irradiated in the domestic microwave for 3–6 minutes to afford the corresponding oxazolidin-5-ones of 80–96% yields [99]. Treatment of benzyl (S)-4-benzyl-5-oxooxazolidin-3-carboxylate with four equivalents of trimethyl(trifluoromethyl)silane (Me3SiCF3) in solkane®365mfc in the presence of 0.5 equivalent of CsF at room temperature affords a mixture of benzyl (4S,5R)-4-benzyl-5-hydroxy-5-(trifluoromethyl) oxazolidine-3-carboxylate and benzyl (4S,5S)-4-benzyl-5-(trifluoromethyl)5-((trimethylsilyl)oxy)oxazolidine-3-carboxylate, in a ratio of 51:49, respectively [100]. When the dipeptide of (S)-Nα-phthaloyl-O-benzyltyrosinylglycine (i.e., (S)-(3-(4-(benzyloxy)phenyl)-2-(1,3-dioxoisoindolin-2-yl)propanoyl) glycine) was treated with 13.8 equivalents of paraformaldehyde in the presence of a catalytic amount of p-toluenesulfonic acid through azeotropic

Oxazolidin-5-ones 297

removal of water in benzene, 3-[2(S)-(1,3-dihydro-1,3-dioxo-2H-isoindol2-yl)-3-(4-benzyloxyphenyl)propanoyl]-1,3-oxazolidin-5-one was obtained in 95% yield as a pale-yellow solid [10]. Interestingly, the nearby aromatic ring activated with a benzyloxy group might undergo a Friedel-Crafts alkylation with the iminium cation that is generated from the acid-promoted decomposition of the 1,3-oxazolidin-5-one moiety, resulting in the formation of (S)-2-(4-(1,3-dioxoisoindolin-2-yl)-3,9-dioxo-2-azaspiro[5.5]undeca7,10-dien-2-yl)acetic acid (122), (S)-2-(8-(benzyloxy)-4-(1,3-dioxoisoindolin-2-yl)-3-oxo-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)acetic acid (123), and (S)-2-(4-(1,3-dioxoisoindolin-2-yl)-8-hydroxy-3-oxo-1,3,4,5tetrahydro-2H-benzo[c]azepin-2-yl)acetic acid (124), in the presence of trifluoromethylsulfonic acid, as shown in Scheme 2.9 [10]. Compound 124 is generated from 123 as the result of acid-catalyzed or promoted hydrolysis of benzyl ether. In contrast, in the presence of Lewis acid (SnCl4), only compound 124 and (S)-2-(7-benzyl-4-(1,3-dioxoisoindolin-2-yl)-8hydroxy-3-oxo-1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl)acetic acid (125) are formed [10]. Similarly, when (S)-(2-(1,3-dioxoisoindolin-2-yl)-3-phenylpropanoyl) glycine was refluxed with paraformaldehyde in toluene, 89% of (S)-2-(1oxo-1-(5-oxooxazolidin-3-yl)-3-phenylpropan-2-yl)isoindoline-1,3-dione was obtained. Upon the treatment with an acid, such as polyphosphoric acid (PPA), methylsulfonic acid, trifluoromethylsulfonic acid, or trimethylsilyl trifluoromethylsulfonate, 2-(4-(1,3-dioxoisoindolin-2-yl)-3-oxo-1,3,4,5tetrahydro-2H-benzo[c]azepin-2-yl)acetic acid was obtained as a mixture of two enantiomers, due to the cyclization at the two ortho positions of phenyl group, with a yield ranging from 80 to 94% (Scheme 2.10) [101]. Some other preparations of oxazolidin-5-ones from paraformaldehyde can be found in the preparation of 4-(3-Cbz-5-oxooxazolidin-4-yl) butanoic acid by refluxing N-Cbz-aminoadipic acid and paraformaldehyde in 1,1,2-trichloroethane in the presence of TsOH, which is an important intermediate in the synthesis of Penicillin N [102]. Similarly, refluxing of Nα-(tert-butyloxycarbonyl)-L-α-aminoadipic acid (also known as (S)-2-((tert-butoxycarbonyl)amino)hexanedioic acid) with nearly two equivalents of paraformaldehyde in 1,1,2-trichloroethane in the presence of TsOH affords 86% of (S)-4-(3-(tert-butoxycarbonyl)-5-oxooxazolidin4-yl)butanoic acid [103]. Treatments of N-Cbz protected alanine, valine, isoleucine, and phenylalanine with paraformaldehyde in toluene containing TsOH at 110°C afford 87–97% of the corresponding oxazolidin-5ones [104]. Likewise, the reaction of methyl N-Cbz-tyrosinate with paraformaldehyde in toluene with TsOH at 80°C yields 56% of benzyl

298

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

(S)-4-(4-hydroxybenzyl)-5-oxooxazolidine-3-carboxylate [105]. N-Cbz-Lisoleucine and O-acetyl-N-Cbz-L-threonine have been converted into benzyl (S)-4-((S)-sec-butyl)-5-oxooxazolidine-3-carboxylate and benzyl (S)-4-((R)1-acetoxyethyl)-5-oxooxazolidine-3-carboxylate respectively, when they are refluxed with paraformaldehyde in benzene in the presence of CSA [106]. Interestingly, treatment of unprotected L-cysteine in dry CH2Cl2 with a total of four equivalents of paraformaldehyde in the presence of anhydrous MgSO4 generates (R)-dihydro-1H,3H,5H-thiazolo[3,4-c]oxazol-1-one in nearly quantitative yield as shown in Scheme 2.11 [92]. Repeat of this transformation at the same reaction scale gives the product in 90% yield [107]. BnO

BnO OBn (CH2O)n

O N NH

O

O N N

O

N O

O

O

95 %

CF3SO3 O

OBn

O

Ph

N

O

H

+

N

O O

N N

O

O

O

OH

O3SCF3

O

O

O

O

OH

N

TsOH benzene, reflux

O

O

O

CF3SO3H

OH OH Bn O

OBn

O O

N

N N

N

O O

O

OH

O

N N

O O

O

OH

O

N

O O

O

N O

O

O

OH

OH

OH

123

122

OH 125

124

SCHEME 2.9  The mechanism for the benzyltyrosinylglycine and paraformaldehyde.

reaction

between

(S)-Nα-phthaloyl-O-

O O

(CH2O)n

N NH O

TsOH O toluene, reflux

O

N N O

OH

N

O

O 89 %

SCHEME 2.10  The paraformaldehyde.

reaction

between

(HPO3)n, CH3SO3H O CF3SO3H or TMSOSO2CF3

O O

O

N O OH

80-94 %

(S)-Nα-phthaloylphenylalanylglycine

and

Oxazolidin-5-ones 299

O (CH2O)n HS

OH NH2

dry MgSO4 S CH2Cl2, r.t.

H

O O

N 100 %

SCHEME 2.11  Conversion of L-cysteine into (R)-dihydro-1H,3H,5H-thiazolo[3,4-c] oxazol-1-one.

The preparation of the oxazolidin-5-one of L-aspartic acid and L-glutamic acid is especially worth of comments as it allows further functionalization of the side chain carboxyl group. However, the reported yields of the corresponding oxazolidin-5-ones vary a lot. For example, while the conversion of N-Cbz-glutamic acid into (S)-3-(3-((benzyloxy)carbonyl)-5oxooxazolidin-4-yl)propanoic acid in benzene in the presence of p-TsOH gives a 63% yield [108], another preparation of this particular oxazolidin5-one corresponds to a 82% yield under the same condition [109]. For comparison, when N-Cbz-glutamic acid is refluxed with paraformaldehyde in toluene in the presence of p-TsOH, the yield has been improved to 91%. Such transformation has been routinely carried out at a 15 gram scale [110]. However, a low 51% yield has also been reported for such preparation [111]. When N-Cbz-γ-fluoroglutamic acid is refluxed in benzene with paraformaldehyde and a catalytic amount of TsOH, 65% of 3-((S)-3-Cbz-5oxooxazolidin-4-yl)-2-fluoropropanoic acid is obtained [112]. Refluxing of N-Cbz-L-aspartic acid in benzene with paraformaldehyde in the presence of TsOH affords 96% of (S)-2-(3-((benzyloxy)carbonyl)-5-oxooxazolidin-4-yl)acetic acid [113]. It should be specifically pointed out that while the oxazolidin-5-one ring in (S)-3-(3-Cbz-5-oxooxazolidin-4-yl)propanoic acid is stable under the condition for side-chain functionalization, such as the conversion of carboxyl group into iodide, affording benzyl (S)-4-(2-iodoethyl)-5oxooxazolidine-3-carboxylate, and further treatment of this intermediate with zinc to yield (S)-(2-(3-((benzyloxy)carbonyl)-5-oxooxazolidin-4-yl) ethyl)zinc(II) iodide [114]; some drawbacks have been identified during the regioselective functionalization of β- or γ-carboxyl group of aspartic acid or glutamic acid with aromatic amines, benzyl alcohol or phenols [115]. To avoid these drawbacks, L-aspartic acid and L-glutamic acid are treated with 2,2,2-trichloroethylchloroformate in aqueous solution of sodium bicarbonate, and the resulting ((2,2,2-trichloroethoxy)carbonyl)-L-aspartic acid and ((2,2,2-trichloroethoxy)carbonyl)-L-glutamic acid are then treated with polyoxymethylene in toluene in the presence of TsOH, generating the

300

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

corresponding (S)-2-(5-oxo-3-((2,2,2-trichloroethoxy)carbonyl)oxazolidin4-yl)acetic acid and (S)-3-(5-oxo-3-((2,2,2-trichloroethoxy)carbonyl) oxazolidin-4-yl)propanoic acid. After functionalization of the side chain carboxyl group with phenol, benzyl alcohol, 1H-1,2,4-triazole, etc., the N-(2,2,2-trichloroethoxycarbonyl)oxazolidinone moiety can be converted into the original α-amino acid, affording the side-chain functionalized aspartic acid and glutamic acid, as illustrated in Scheme 2.12 [115]. O HO

O CCl3 OH Cl NaHCO3, H2O

n

Cl3C

O

NH2

O

O (n = 1, 2)

CCl3 (CH2O)n, TsOH O toluene, reflux OH

O HN HO

n

O O O

O HO

n

O

Cl3C

O O O

SOCl2

Cl3C O

Cl

n

R

X

NH2

O Zn R X O AcOH/H2O (1:2)

N

OH n

O

n

O

O

PhNH2 HN-O2S Ac N R XH: NH N

O

O O O

R XH

N

N

PhOH NH2

OH Cl

N N N

OH Cl

N N Cl

N

SCHEME 2.12  Derivatization of the carboxyl side chains of aspartic acid and glutamic acid.

In addition to protect the α-amino group with benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (t-Boc) or phthaloyl groups, other amino protecting groups have also been applied during the syntheses of oxazolidin-5-ones. For example, in the preparation of oxazolidin-5-one from L-valine, the amino group has been protected with 1-naphthoyl, ortho-phenylbenzoyl, and ortho-tert-butylbenzoyl group respectively, and the corresponding (S)-3-(1-naphthoyl)-4-isopropyloxazolidin-5-one, (S)-3-([1,1’-biphenyl]-2carbonyl)-4-isopropyloxazolidin-5-one, and (S)-3-(2-(tert-butyl)benzoyl)4-isopropyloxazolidin-5-one are formed from (1-naphthoyl)-L-valine, ([1,1’-biphenyl]-2-carbonyl)-L-valine, and (2-(tert-butyl)benzoyl)-L-valine, in yields of 61%, 39% and 29%, respectively [116]. Also, the formation of oxazolidin-5-one occurs in the presence of Fmoc protecting group, as demonstrated in the transformation of (2S,3S)-2-((((9H-fluoren-9-yl)-

Oxazolidin-5-ones 301

methoxy)carbonyl)amino)-3-methylpent-4-enoic acid into (9H-fluoren9-yl)methyl (S)-4-((S)-but-3-en-2-yl)-5-oxooxazolidine-3-carboxylate with paraformaldehyde in toluene in the presence of TsOH [117]. Likewise, phenylsulfonyl (PhSO2) protecting group has recently been applied to the generation of oxazolidin-5-one for L-valine, L-phenylalanine, L-leucine, and L-isoleucine with paraformaldehyde in refluxing toluene using TsOH as catalyst [118, 119]. In addition, tert-butylsulfonyl group has been used in the preparation of (S)-3-(tert-butylsulfonyl)-4-methyloxazolidin-5-one and (S)-3-(tert-butylsulfonyl)-4-isobutyloxazolidin-5-one by refluxing N-tertbutylsulfonyl alanine and leucine in chloroform with paraformaldehyde and TsOH [120]. p-Toluenesulfonyl group has also been used in the preparation of oxazolidin-5-ones from alanine, valine, leucine, isoleucine, methionine, (S)-2-amino-3,3-dimethylbutanoic acid, (S)-2-amino-2-phenylacetic acid and S-methyl-L-cysteine [121]. Even small methoxycarbonyl group has been used in the conversion of (S)-2-((methoxycarbonyl)amino)-4-phenylbutanoic acid into methyl (S)-5-oxo-4-phenethyloxazolidine-3-carboxylate (i.e., (4S)-N-(methoxycarbonyl)-4-(2-phenylethyl)-5-oxazolidinone) in benzene with two equivalents of paraformaldehyde (with small amount of TsOH) [122]. Regarding the formation of oxazolidin-5-one with formaldehyde, one of such preparations has been carried out in THF with a catalytic amount of p-TsOH and formaldehyde at room temperature, where formaldehyde is a 26% wt% aqueous solution, and the amino group of the α-amino acid is protected with a 9-phenylfluoren-9-yl group. The amino acids tested under this condition include alanine, leucine, phenylalanine, cyclohexylalanine, (S)-2-amino-2-phenylacetic acid, (S)-2-amino-3-cyclohexylpropanoic acid and O-benzyl-L-serine [123]. In addition, 1,3,5-trioxane has been applied for the generation of oxazolidin-5-one moiety in the presence of TsOH from (S)-4-((9H-fluoren-9-yl)methoxy)-2-((tert-butoxycarbonyl)amino)4-oxobutanoic acid and (S)-5-((9H-fluoren-9-yl)methoxy)-2-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid [4]. As of the diversity of the functional groups presenting on the side chains of amino acids, in a few cases, the side chain can complicate the formation of oxazolidin-5-one moiety, as shown in the case of L-cysteine (Scheme 2.11). Threonine presumably will react with formaldehyde in a manner similar to cysteine, therefore the β-hydroxyl group is also necessarily protected (e.g., by THP). However, THP is an acid sensitive protecting group, which does not sustain under the reaction condition. In order to form oxazolidin-5-one of L-threonine with its β-hydroxyl group also protected with THP, a unique but

302

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

convenient condition has been developed, in which the N-t-Boc protected amino acid is treated with methylene iodide or methylene bromide in refluxing acetonitrile in the presence of K2CO3, as illustrated in Scheme 2.13. This protocol has been applied to prepare the corresponding oxazolidin-5-ones of alanine, glycine, methionine, valine, leucine, O-(tert-butyldimethylsilyl)-Lserine, (S)-2-amino-2-phenylacetic acid and O-(tetrahydro-2H-pyran-2-yl)L-threonine, with all amino groups protected by t-Boc groups [1]. O

O t-Bu O OH

HN R O

CH2I2 or CH2Br2 K2CO3, CH3CN reflux

t-Bu

O

N R

O O

R = H, Me, Ph, MeSCH2CH2, (CH3)2CH, (CH3)2CHCH2 TBSOCH2, (S)-CH3CH(OTHP)

SCHEME 2.13  Preparation of oxazolidin-5-ones from N-t-Boc amino acids and methylene iodide (or bromide).

There are still many examples for the preparations of oxazolidin-5-ones from paraformaldehyde, which are not presented here. Some of them might be mentioned in the section of reaction where oxazolidin-5-ones prepared in such way are used as the starting materials for making other derivatives. 2.4.2 PREPARATION OF OXAZOLIDIN-5-ONES FROM α-AMINO ACID DERIVATIVES AND ACETALDEHYDE Acetaldehyde is generally less reactive than formaldehyde due to the electron-donating nature of the methyl group. While acetaldehyde has not been commonly applied in the construction of oxazolidin-5-one derivatives, α-substituted acetaldehydes have been used for such purpose. For example, in order to make α-alkyl proline, proline has been treated with 2,2,2-trichloroacetaldehyde (i.e., chloral) in acetonitrile to afford (3R,7aS)3-(trichloromethyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one of very high stereoselectivity (> 95:5). Upon treatment of this oxazolidin-5-one with LDA, the oxazolidin-5-one is alkylated with methyl, allyl, benzyl, and methyl acetate as illustrated in Scheme 2.14. The resulting oxazolidin-5-ones can be decomposed under either basic or acidic condition to give different proline derivatives. For example, upon treatment with sodium methoxide in methanol, methyl (S)-1-formyl-2-alkyl substituted pyrrolidine-2-carboxylate

Oxazolidin-5-ones 303

is formed; in contrast, for the case of α-allyl substituted oxazolidin-5-one, (R)-2-allylpyrrolidine-2-carboxylic acid or methyl (R)-2-allylpyrrolidine2-carboxylate hydrochloride can be obtained when the oxazolidin-5-one is hydrolyzed in 6 N HCl solution or in anhydrous methanol with a catalytic amount of HCl (Note: a catalytic amount of HCl can be generated by mixing a small amount of acetyl chloride with anhydrous methanol). For comparison, the reaction between proline and seven equivalents of pivalaldehyde in pentane under refluxing in the presence of a catalytic amount of trifluoroacetic acid also gives the corresponding oxazolidin-5-one, which is unstable under acidic condition [2].

O OMe HCl

NH

cat. HCl/dry MeOH when R = allyl O

NH

Cl3CCHO OH CH CN, r.t. 12 hrs. 3

H

O

N

O

LDA RX

R

O

N

O

CCl3

R NaOMe MeOH

N

CCl3

O OMe O CCl3

6 N HCl when R = allyl R

O NH

CCl3

N

OH

O OMe CHO

R = allyl, Me, Bn, CH2CO2Me

SCHEME 2.14  The preparation of (3R,7aS)-3-(trichloromethyl)tetrahydro-1H,3Hpyrrolo[1,2-c]oxazol-1-one from proline and subsequent α-alkylation. O O

O HO O

NH2

Ac2O/HCO2H OH Br CCHO/AcOH HO2C 3 OHC

O O

NH2

N CBr3

O HO

N H O HN CHO

O O

SCHEME 2.15  Preparation of dipeptide methyl N-formyl-aspartylalaninate involving an oxazolidin-5-one intermediate.

304

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

In addition to chloral, bromal (i.e., 2,2,2-tribromoacetaldehyde) has been applied to form the oxazolidin-5-one derivative of aspartic acid containing a N-formyl group, and the resulting oxazolidin-5-one is further treated with α-amino acid ester to form aspartic acid-containing dipeptides, as shown in Scheme 2.15 [124]. To do this, aspartic acid is added to a mixture of acetic anhydride, formic acid and acetic acid, followed by bromal, and the resulting solution is heated at 70°C. After removal of solvent under reduced pressure at 50°C, the residue is dissolved in CH2Cl2 and cooled to –10°C to form 74% of 2-((4S)-3-formyl-5-oxo-2-(tribromomethyl)oxazolidin-4-yl)acetic acid as a crystal. This oxazolidin-5-one is then allowed to react with six different amino acid esters to generate the corresponding dipeptides, such as (S)-3formamido-4-(((S)-1-methoxy-1-oxopropan-2-yl)amino)-4-oxobutanoic acid from the reaction with methyl alaninate [124]. The same procedure has been repeated to treat L-alanine to yield (4S)-4methyl-5-oxo-2-(tribromomethyl)oxazolidine-3-carbaldehyde, which is then coupled with methyl prolinate, methyl phenylalaninate, methyl methioninate, methyl alaninate and methyl (R)-2-amino-2-methyl-3-phenylpropanoate to yield the expected dipeptides [125]. 2.4.3 PREPARATION OF OXAZOLIDIN-5-ONES FROM α-AMINO ACID DERIVATIVES AND BENZALDEHYDE Benzaldehyde has a slightly higher electrophilicity than acetaldehyde, as phenyl group is a weaker electron-donating group comparing to methyl group. In fact, phenyl group normally is not considered either an electron-donating or electron-withdrawing group. In one of the practices to form oxazolidin5-one involving benzaldehyde, equal amount of benzaldehyde and sodium D-alaninate in dry CH2Cl2 is refluxed using a Dean-Stark apparatus for 21 hours, then cooled to 0°C. After that, benzyl chloroformate is added to form benzyl (2S,4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate and benzyl (2R,4R)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate, in a 2.5: 1 ratio. Although these two cis- and trans-isomers cannot be separated by TLC, they can be separated by crystallization from isopropyl ether at –18°C, to afford 30.5% of the (2S,4R) isomer. Upon treatment of this oxazolidin-5-one with LDA or LHMDS, the resulting lithium enolate is allowed to undergo SN2 reaction with alkyl halide (e.g., t-butyl bromoacetate or N,N-bis[(tert-butyloxy)carbonyl]-4-iodobutanamine) or Michael addition with t-butyl acrylate, as demonstrated in Scheme 2.16. Decomposition of the

Oxazolidin-5-ones 305

resulting benzyl (2S,4R)-4-(2-(tert-butoxy)-2-oxoethyl)-4-methyl-5-oxo-2phenyloxazolidine-3-carboxylate, (2S,4R)-3-Cbz-4-[4-[bis[(tert-butyloxy) carbonyl]amino]butyl]-4-methyl-2-phenyl-1,3-oxazolidin-5-one and benzyl (2S,4R)-4-(3-(tert-butoxy)-3-oxopropyl)-4-methyl-5-oxo-2-phenyloxazolidine-3-carboxylate, gives the corresponding α-alkyl substituted D-alanines [126]. O 1) LDA or LHMDS 2) BrCH2CO2-t-Bu

O 1) CH2Cl2, reflux ONa + PhCHO 2) BnOC(O)Cl NH2

Ph BnO

H O

O O

1) LDA or LHMDS

N

CO2-t-Bu

N BnO

O

O

O

Ph

2) ICH2(CH2)2CH2N(Boc)2

O

Ph N BnO O

Ph 1) LDA N 2) CH2CHCO2-t-Bu BnO O

Boc N Boc

O O CO2-t-Bu

SCHEME 2.16  Preparation of oxazolidin-5-one derivative from D-alanine and benzaldehyde and further alkylation at the α-position.

For the reaction of L-proline and ortho-chlorobenzaldehyde, it has been calculated that the formations of (3R,7aS)-3-(2-chlorophenyl)tetrahydro1H,3H-pyrrolo[1,2-c]oxazol-1-one and (3S,7aS)-3-(2-chlorophenyl) tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one are favored by –1.76 Kcal/ mol and –1.64 Kcal/mol in free energy change, respectively [127], meaning that the ratio of these two diastereomers is about 55% versus 45% at 25°C. This might be different from experimental results as the reaction of proline with benzaldehyde has shown higher diastereoselectivity depending on the reaction condition. In order to synthesize (R)-7-hydroxy-2,3-dimethyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and (R)-7-methoxy-2,3-dimethyl-1,2,3,4tetrahydroisoquinoline-3-carboxylic acid, the important intermediates in the preparation of JDTic analogs, the first highly potent and selective κ-opioid receptor antagonist, sodium D-alaninate was condensed with benzaldehyde and the resulting imine was cyclized with benzoyl chloride to form (2S,4R)3-benzoyl-4-methyl-2-phenyloxazolidin-5-one. This oxazolidin-5-one was then deprotonated with LiHMDS to form enolate which then reacted with 1-(bromomethyl)-4-methoxybenzene to yield (2S,4R)-3-benzoyl-4(4-methoxybenzyl)-4-methyl-2-phenyloxazolidin-5-one. Hydrolysis of

306

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

this benzylated oxazolidin-5-one in concentrated HCl solution leads to the formation of (R)-2-amino-3-(4-methoxyphenyl)-2-methylpropanoic acid, from which the two important intermediates can be prepared [128]. Nearly the same procedure has been repeated for L-alanine, and the resulting (2R,4S)-3-benzoyl-4-methyl-2-phenyloxazolidin-5-one is then treated with LiHMDS and alkylated with 2-(bromomethyl)isoindolin-1,3-dione to afford 74% of 2-(((2R,4S)-3-benzoyl-4-methyl-5-oxo-2-phenyloxazolidin-4-yl)methyl)isoindolin-1,3-dione. Similarly, (S)-2-amino-2-phenylacetic acid has been converted into 70% of (2R,4S)-3-benzoyl-2,4-diphenyloxazolidin5-one, but in low diastereoselectivity (3:2) [129]. Similar to the case of alanine, when S-methyl-L-cysteine is applied to form oxazolidin-5-one, it is first treated with NaOH in water to form sodium S-methyl-L-cysteinate. The dry sodium S-methyl-L-cysteinate is then refluxed with benzaldehyde in petroleum spirit to form (2R,4R)-4((methylthio)methyl)-2-phenyloxazolidin-5-one, which is protected with a propionyl group to give (2R,4R)-4-((methylthio)methyl)-2-phenyl-3-propionyloxazolidin-5-one. Upon oxidation with Oxone® followed by elimination with base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), (R)-4-methylene2-phenyl-3-propionyloxazolidin-5-one is obtained. This intermediate is then coupled with 2,6-dichlorobenzonitrile oxide, generated in situ from (Z)-2,6-dichloro-N-hydroxybenzimidoyl chloride by treatment with Et3N, via 1,3-dipolar cycloaddition to form a single diastereomer of (5S,7R)-3-(2,6dichlorophenyl)-7-phenyl-6-propionyl-1,8-dioxa-2,6-diazaspiro[4.4]non2-en-9-one, as displayed in Scheme 2.17 [130]. SMe O

O S

OH NH2

NaOH H2O

PhCHO ONa petro. spirit H HN NH2 reflux H

S

SO2Me O N O H Cl

Cl N Cl

N

O

C Cl

N

1) (EtCO)2O 2) Oxone

Ph

O

Cl C

Cl

O

O H

Ph

Cl OH Et3N

O

O DBU

H

O

N

Ph

N

O

Cl

N O H

O

O O Ph

Cl

SCHEME 2.17  Transformation of S-methyl-L-cysteine into (R)-4-methylene-2-phenyl-3propionyloxazolidin-5-one and its 1,3-dipolar cycloaddition with nitrile oxide.

Oxazolidin-5-ones 307

Following a similar protocol, several cyclic α-amino acids have been prepared starting with sodium S-methyl-L-cysteinate, which is reacted with benzaldehyde or pivalaldehyde to afford (2R,4R)-4-((methylthio)-methyl)2-phenyloxazolidin-5-one or (2S,4R)-2-(tert-butyl)-4-((methylthio)methyl)oxazolidin-5-one. The former is then protected with either benzoyl or acetyl group, whereas the latter is protected with the benzoyl group. After oxidation with Oxone® and elimination with DBU, the resulting (R)-3-benzoyl-4-methylene-2-phenyloxazolidin-5-one, (R)-3-acetyl-4methylene-2-phenyloxazolidin-5-one, or (S)-3-benzoyl-2-(tert-butyl)-4methyleneoxazolidin-5-one is then cycloadded with cyclopentadiene or cyclohexa-1,3-diene. After hydrogenation of the remaining C=C double bond and acidic hydrolysis, the cyclic amino acids are obtained, as illustrated in Scheme 2.18 [131, 132]. In these practices, it is found that the reaction of sodium S-methyl-L-cysteinate with benzaldehyde or pivalaldehyde affords the oxazolidin-5-one with different stereochemistry. Similarly, for the 1,3-dipolar cycloaddition between cyclopentadiene and (S)-3-benzoyl-2-(tert-butyl)4-methyleneoxazolidin-5-one, (1R,2R,2’S,4R)-3’-benzoyl-2’-(tert-butyl) spiro[bicyclo-[2.2.1]heptane-2,4’-oxazolidin]-5-en-5’-one is obtained as the major product, whereas in the presence of LiClO4, (1S,2R,2’S,4S)-3’benzoyl-2’-(tert-butyl)spiro[bicyclo[2.2.1]heptane-2,4’-oxazolidin]-5en-5’-one is the major product. In contrast, for the cycloaddition between (R)-3-benzoyl-4-methylene-2-phenyloxazolidin-5-one and cyclopentadiene, (1S,2S,2’R,4S)-3’-benzoyl-2’-phenylspiro[bicyclo[2.2.1]heptane-2,4’oxazolidin]-5-en-5’-one is obtained as the single product. Hydrogenation of these cycloadducts followed by acidic hydrolysis afford cyclic amino acids, such as (1S,2R,4S)-2-aminobicyclo-[2.2.2]octane-2-carboxylic acid and (1R,2S,4S)-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid [131, 132]. Interestingly, the reaction of (S)-3-benzoyl-2-(tert-butyl)-4-methyleneoxazolidin-5-one at room temperature with isopropylidenetriphenylphosphorane generated by the treatment of isopropyltriphenylphosphonium iodide in benzene with a hexane solution of n-BuLi, affords a 1:1 ratio of (3R,5S)-4benzoyl-5-(tert-butyl)-1,1-dimethyl-6-oxa-4-azaspiro[2.4]heptan-7-one and (3S,5S)-4-benzoyl-5-(tert-butyl)-1,1-dimethyl-6-oxa-4-azaspiro[2.4]heptan7-one diastereomers, which can be separated by recrystallization (hexane/ ether = 2/1) and further flash chromatography. The low diastereoselectivity is assumed to be caused by the high-temperature reaction. Refluxing of the isolated diastereomers in 2 N HCl generates (R)- or (S)-1-amino-2,2-dimethylcyclopropane-1-carboxylic acid, which is obtained after treatment with propylene oxide in ethanol under reflux. In comparison, acidic hydrolysis

308

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

of the diastereomer in 6 N HCl also gives 3-amino-5,5-dimethyldihydrofuran-2(3H)-one hydrochloride [133]. O

O Ph

N

O

t-Bu t-Bu O O H Ph 70% yield (97:3) 67% yield (35:65 with LiClO4)

O O

O H

O

N O

t-Bu

1) H2/Pd-C 2) 6 M HCl

OH NH2

Ph O

O N

N

O

O H t-Bu

Ph

+

N

O N

Ph

H

O H t-Bu

Ph

O O

O O

O H Ph

N Ph

1) H2/Pd-C 2) 6 M HCl

O H

Ph

NH2

O O

O H Ph

OH

O

O N

O

O

N H

Ph

SCHEME 2.18  The Diels-Alder cycloaddition between (S)-3-benzoyl-2-(tert-butyl)-4methyleneoxazolidin-5-one (or (R)-3-acyl-4-methylene-2-phenyloxazolidin-5-one) and dienes.

During the reaction between benzaldehyde and sodium methioninate, it is assumed that a Schiff base is initially formed between the α-amino group and benzaldehyde, after that, the carboxylate anion adds to the imine group to close the ring, as illustrated in Scheme 2.19 [134]. The resulting (2S,4S)-4-(2-(methylthio)ethyl)-5-oxo-2-phenyloxazolidin-3-ide is then protected with Cbz group to yield benzyl (2S,4S)-4-(2-(methylthio)ethyl)5-oxo-2-phenyloxazolidine-3-carboxylate. After further treatment of this oxazolidin-5-one with a strong base (e.g., KN(TMS)2), the newly generated enolate undergoes an SN2 reaction with allyl iodide to afford benzyl (2S,4S)4-allyl-4-(2-(methylthio)ethyl)-5-oxo-2-phenyloxazolidine-3-carboxylate. Hydrolysis of the resulting oxazolidin-5-one under a basic condition leads to (S)-2-(((benzyloxy)carbonyl)amino)-2-(2-(methylthio)ethyl)pent-4-enoic acid [134].

Oxazolidin-5-ones 309

O O

S

ONa

S

ONa Ph

NH2 HN H

O

O

N

ONa Ph H2O

H

O

O S

S

OH

O O

O

S

Na+

N

Cbz-Cl CH2Cl2

O

Na+ N

S O N Cbz

Ph

Ph

O KN(SiMe3)2, allyl iodide THF

O

S O N Cbz

Ph

NaOH THF/H2O

S OH NH

Ph

Cbz

SCHEME 2.19  The mechanism for the transformation of L-methionine into (S)-α-allyl-NCbz-methionine (i.e., (S)-2-(((benzyloxy)carbonyl)amino)-2-(2-(methylthio)ethyl)pent-4enoic acid).

A similar treatment has been applied to convert L-phenylalanine into sodium L-phenylalaninate followed by the reaction with benzaldehyde and subsequently Cbz-Cl to yield benzyl (2S,4R)-4-benzyl-5-oxo-2-phenyloxazolidine-3-carboxylate [135]. It should be pointed out that due to the auto-oxidation/reduction of benzaldehyde, known as the Cannizzaro reaction [136, 137], benzaldehyde has also been applied in a form of benzaldehyde dimethyl acetal (i.e., (dimethoxymethyl)benzene) under an acidic condition so that the acetal can be transformed back to benzaldehyde. In addition, either one of the diastereomers could be obtained in pure form. For example, after the addition of benzaldehyde dimethyl acetal to the anhydrous CH2Cl2 solution of (S)-2(((benzyloxy)carbonyl)amino)-2-phenylacetic acid followed by three equivalents of boron trifluoride etherate, the reaction at ice-bath temperature for 2 hours allows the formation of both benzyl (2S,4S)-5-oxo-2,4-diphenyloxazolidine-3-carboxylate and benzyl (2R,4S)-5-oxo-2,4-diphenyloxazolidine3-carboxylate, in a ratio of 3:1. After quenching the reaction with aqueous NaHCO3 solution, the organic phase is dried to afford a solid, which is then mixed with ether under stirring for 1.5 hours, the insoluble (2R,4S) isomer can be separated by filtration. After evaporation of the filtrate and washing

310

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

with hexane, the (2S,4S)-diastereomer is obtained, with a yield of 66%. For comparison, when this reaction between (S)-2-(((benzyloxy)carbonyl) amino)-2-phenylacetic acid and benzaldehyde dimethyl acetal is carried out in ether in the presence of 4 equivalents of boron trifluoride etherate at room temperature for 24 hours, the resulting (2R,4S)-diastereomer is isolated by filtration, and the filtrate is allowed to further react at room temperature for another day. This process is repeated one more time to increase the yield of the (2R,4S)-diastereomer to 89%. In contrast, the method starting with the formation of Schiff base between sodium (S)-2-amino-2-phenylacetate and benzaldehyde followed by the protection with Cbz group (refer to Scheme 2.16), yields 63% of the (2R,4S)-diastereomer, as demonstrated in Scheme 2.20 [138]. The resulting oxazolidin-5-one derivatives can be further treated with a mild base (e.g., K2CO3) in the presence of a phase transfer reagent (e.g., Bu4NI) to give α-alkylated oxazolidin-5-ones. It should be pointed out that even though paraformaldehyde has been commonly applied to generate oxazolidin-5-one derivatives, an obvious advantage exists in the formation of oxazolidin-5-one from benzaldehyde or other substituted aldehydes, that is to form an additional chiral center at position 4 of the oxazolidin-5-one moiety. The existence of this chiral center certainly will influence the overall chirality of α-alkylated amino acids should this oxazolidin-5-one be deprotonated to enolate and treated with an alkyl halide. This procedure initially developed by Seebach et al. is generally known as Self-Reproduction of Chirality (SROC) [139]. As indicated in Scheme 2.17, treatment of sodium S-methyl-L-cysteinate with benzaldehyde or pivalaldehyde affords oxazolidin-5-one of different stereochemistry [131], such difference of stereoselectivity has been shown also in the case to convert sodium (S,E)-2-((2,2-dimethylpropylidene)amino)propanoate and sodium (S,E)-2-(benzylideneamino)propanoate into 92% of (2S,4S)-3-benzoyl-2-(tert-butyl)-4-methyloxazolidin-5-one [11] and 94% of (2R,4S)-3-benzoyl-4-methyl-2-phenyloxazolidin-5-one [140] in methylene chloride in the presence of benzoyl chloride, with a diastereomeric ratio of 5:1 and 1:7.5, respectively. Other examples of different stereoselectivity can be found in alternative literature [141, 142]. As pointed out early, the oxazolidin-5-one formed from pivalaldehyde is unstable under acidic conditions [2], such trend has also been demonstrated in the case for (2S,4S)3-benzoyl-2-(tert-butyl)-4-methyloxazolidin-5-one when it is treated with ZnCl2 in CH2Cl2 to reach an equilibrium with its (2R,4S)-diastereomer via C2-epimerization, indicating the formation of oxazolidin-5-ones that give 5:1 or 1:7.5 of cis/trans ratio is under kinetic control [143]. In comparison,

Oxazolidin-5-ones 311

treatment of N-Cbz-L-alanine with benzaldehyde dimethyl acetal in the presence of Lewis acid favors the formation of benzyl (2S,4S)-4-methyl-5-oxo2-phenyloxazolidine-3-carboxylate over its diastereomer, particularly with a cis/trans ratio of 15:1 to 20:1 when ZnCl2/SOCl2 is used [7]. The formation of such oxazolidin-5-one under this condition is assumed to go through a different mechanism as outlined in Scheme 2.21. Alternatively, (tertbutoxycarbonyl)-L-alanine can be converted into tert-butyl (S)-(1-chloro1-oxopropan-2-yl)carbamate in CH2Cl2 in the presence of oxalyl chloride and a catalytic amount of DMF, and the carbamate is then transformed into (tert-butyl carbonic) (2S,4S)-4-methyl-5-oxo-2-phenyloxazolidine3-carboxylic anhydride in reaction with benzaldehyde in the presence of a catalytic amount of Lewis acid. Particularly, such oxazolidin-5-one can be isolated in a kilogram scale under the optimized condition in the presence of SnCl4 [143]. 1) PhCH(OMe)2, BF3 Et2O Bn CH2Cl2, 0 C, 2 hrs. O 2) ether workup

O H

O H

Ph Bn

°

O OH NHCbz

N

O

+

Ph H O 66 % (95% de, 97% ee)

O OH NHCbz

1) PhCH(OMe)2, BF3 Et2O Et2O, r.t., 24 hrs. 2) filtration 3) filtrate further reacts 1 day 4) repeated 2) and 3)

N

O

Ph O

Ph

H O 89 % (>98% de, 95% ee)

1) 1M NaOH, EtOH, r.t. 2) PhCHO, pentane, reflux 26 hrs. OH 3) Cbz-Cl, CH2Cl2, 0 C to r.t., 46 hrs. NHCbz O

O

Ph H O 21 % (>98% de, 95% ee) O H

Bn

N

O

Ph

O H Bn

°

N

O

Ph O

Ph

H O 63 % (>98% de, 97% ee)

SCHEME 2.20  Conditions to form the preferred oxazolidin-5-one diastereomer from N-Cbz-2-phenylglycine.

The concept of Self-Reproduction of Chirality has been applied to generate α-alkylated alanines with a C3-C6 alkyl group of a terminal double bond from N-Cbz-D-alanine, so that when these novel amino acids are incorporated into peptides, the side alkyl chain can be connected by metathesis

312

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

with Grubbs II catalyst, for the purpose to develop inhibitors for HIV-1 integrase [144]. O OMe

OMe ZnCl2/SOCl2 Cl

OMe

OH NHCbz ZnCl2/THF

O O NHCbz

Ph OMe

O

O H

ZnCl2

O NH Cbz

BnO Ph

N

O

O Ph H

SCHEME 2.21  Stereoselective conversion of N-Cbz-L-alanine into N-Cbz-(2S,4S)-4methyl-2-phenyloxazolidin-5-one.

In addition to benzaldehyde and benzaldehyde dimethyl acetal, substituted benzaldehydes such as salicylic aldehyde (i.e., salicylaldehyde or 2-hydroxybenzaldehyde) have also been applied in the generation of oxazolidin-5-one derivatives with amino acids. For example, the mixture of L-alanine, salicylaldehyde, and phosgene in chloroform leads to the formation of (3S,10bR)-3-methyl-3-hydro-5H,10bH-benzo[e]oxazolo[3,2-c][1,3]oxazine-2,5-dione, in the presence of mild base K2CO3. This tricyclic compound can be decomposed in the presence of amine such as n-hexylamine to afford (S)-N-((1-hexanamido-1-oxopropan-2-yl)carbamoyl)hexanamide. Similar to other oxazolidin-5-ones, this tricyclic compound can be converted into an enolate with a strong base which then reacts with allyl iodide (allyl bromide or methyl iodide) to form a substituted compound. Basic hydrolysis followed by acidification yields the α-substituted amino acid derivatives. In addition to L-alanine, this reaction has been applied to L-phenylalanine and L-leucine as well (Scheme 2.22) [145]. For the specific case of L-alanine, the tricyclic intermediate has been deprotonated with LiHMDS in the presence of DMPU in THF and alkylated with tert-butyl 3-(bromomethyl)1H-indole-1-carboxylate to yield 73% of tert-butyl 3-(((3R,10bR)-3-methyl2,5-dioxo-2,3-dihydro-5H,10bH-benzo[e]oxazolo[3,2-c][1,3]oxazin-3-yl)methyl)-1H-indole-1-carboxylate. Basic hydrolysis (with KOH) of this compound in aqueous dioxane affords 61% of (R)-2-amino-3-(1H-indol-3yl)-2-methylpropanoic acid (i.e., (R)-α-methyltryptophan) [146]. In contrast, treatment of L-alanine with salicylaldehyde, followed by NaBH4/MeOH and subsequently with trifluoroacetic anhydride lead to the formation of

Oxazolidin-5-ones 313

(3S,10aS)-3-methyl-10a-(trifluoromethyl)-5H,10aH-benzo[e]oxazolo[2,3-b][1,3]oxazin-2(3H)-one, as demonstrated in Scheme 2.23 [147]. H

O

N

LiHMDS, THF O H R’X, DMPU -78 C

R R

OH +

O OH +

NH2

Cl

O

K2CO3 CHCl3

Cl

R O

R’

O

N

O H

°

O

O

O

O

(R = H, Ph, i-Pr) 1) LiOH aqueous dioxane 2) HCl, pH=1

n-hexylamine H

R O HN

O

R’

O

NH HN C6H13

R

C6H13

OH Cl R’ = allyl, Me H 3N

SCHEME 2.22  Generation of a tricyclic compound from the reaction of salicylaldehyde, phosgene, and alanine (or phenylalanine, leucine) and further transformations. O O

OH

OH OH +

O

NH2

HO

a) NaBH4/MeOH b) (CF3CO)2O

O

O

N

N

O O

CF3

O

CF3 O N

O

CF3 OH

SCHEME 2.23  Synthesis of (3S,10aS)-3-methyl-10a-(trifluoromethyl)-5H,10aH-benzo[e] oxazolo[2,3-b][1,3]oxazin-2(3H)-one from L-alanine and salicyaldehyde.

In addition to preparing α-substituted amino acids, oxazolidin-5-one derivatives have been applied to the preparation of peptides [148], nonpeptidic trifluoromethyl ketones [149], and N-acyl aziridines [150].

314

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

2.4.4 PREPARATION OF OXAZOLIDIN-5-ONES FROM α-AMINO ACID DERIVATIVES AND PIVALALDEHYDE (t-BuCHO) Compared to the usage of benzaldehyde, the application of pivalaldehyde allows the formation of oxazolidin-5-ones containing a bulk tert-butyl group at position 2 that may enhance the stereoselectivity during the alkylation at position 4 of the oxazolidin-5-ones. Likewise, the formation of oxazolidin-5-one starts from the sodium salt of amino acid. For example, treatment of (S)-2-amino-5-methylhex-4-enoic acid in ethanol with NaOH allows the generation of sodium (S)-2-amino-5-methylhex-4-enoate, which is dried and refluxed in pentane with pivalaldehyde followed by addition of allyloxycarbonyl chloride to give 43% of allyl (2S,4S)-2-(tert-butyl)-4(3-methylbut-2-en-1-yl)-5-oxooxazolidine-3-carboxylate and 21% of allyl (2R,4S)-2-(tert-butyl)-4-(3-methylbut-2-en-1-yl)-5-oxooxazolidine-3-carboxylate. Deprotonation of the (2S,4S)-diastereomer with KHMDS in THF at –78°C followed by the addition of 1-(benzyloxy)-4-(bromomethyl)benzene lead to an isolation of 88% of allyl (2S,4R)-4-(4-(benzyloxy)benzyl)-2-(tertbutyl)-4-(3-methylbut-2-en-1-yl)-5-oxooxazolidine-3-carboxylate. Similarly, addition of ((chloromethoxy)methyl)benzene or alternative addition of 1,4-diiodobutane and subsequently sodium azide in DMSO to the potassium enolate solution of (2S,4S)-diastereomer in THF afford 70% of allyl (2S,4R)-4-((benzyloxy)methyl)-2-(tert-butyl)-4-(3-methylbut-2-en-1-yl)5-oxooxazolidine-3-carboxylate or 72% of allyl (2S,4S)-4-(4-azidobutyl)2-(tert-butyl)-4-(3-methylbut-2-en-1-yl)-5-oxooxazolidine-3-carboxylate, respectively [151]. While this reaction does not render good diastereoselectivity, conversion of L-alanine to sodium L-alaninate with NaOH, followed by the condensation with pivalaldehyde and further treatment with benzoyl chloride give 71% of 2,4-cis and 29% of 2,4-trans-diastereomers, corresponding to (2S,4S)-3-benzoyl-2-(tert-butyl)-4-methyloxazolidin-5-one and (2R,4S)-3-benzoyl-2-(tert-butyl)-4-methyloxazolidin-5-one, respectively. Radical bromination of the methyl group of the (2S,4S)-diastereomer (i.e., 2,4-cis diastereomer) followed by elimination afford (S)-3-benzoyl-2-(tertbutyl)-4-methyleneoxazolidin-5-one (Scheme 2.24) [152]. From this dehydroalanine derivative, γ-amido, γ-amino, γ-chloro, γ-hydroxy, γ-oxo, and γ-acyloxy amino acids can be prepared, as illustrated in the formation of L-leucine derivatives by the treatment of the dehydroalanine with 2-nitropropane. Likewise, an imine formed from sodium methioninate and pivalaldehyde is treated with benzoyl chloride to give (2S,4S)-3-benzoyl-2-(tert-butyl)

Oxazolidin-5-ones 315

-4-(2-(methylthio)ethyl)oxazolidin-5-one, which is purified by crystallization. Further conversion of this oxazolidin-5-one into lithium enolate followed by methylation with methyl iodide afford 10 g of (2S,4S)-3-benzoyl-2-(tertbutyl)-4-methyl-4-(2-(methylthio)-ethyl)oxazolidin-5-one [153]. A unique approach to preparing α-allylated amino acids has been developed by acylation of the resulting oxazolidin-5-ones formed from the condensation of the sodium salt of amino acids and pivalaldehyde with 2-iodobenzoyl chloride. The iodo group on the benzoyl moiety can be removed under radical conditions, and the newly formed phenyl radical can intramolecularly abstract a hydrogen atom from position 2. Subsequently, the radical center at position 2 can then react with allyltributyltin to introduce the allyl group to position 2. Hydrolysis of the oxazolidin-5-one derivatives leads to α-allylated amino acids. This novel approach is illustrated in Scheme 2.25 [3]. However, the diastereoselectivity of oxazolidin-5-one from L-alanine is only 1.2:1, much lower than that shown in Scheme 2.23, although the diastereoselectivity from L-valine or L-phenylalanine is fairly high. O

O

O

1) NaOH/H2O 2) t-BuPhO OH 3) PhCOCl

N

O N

+

O

NH2

O Ph

Ph

29 %

71 %

O

O 1) 2.0 eq. NBS/AIBN 2) KI/acetone

O

N O Ph NO2 ,F

O N

O

O N

+ O

O Ph

Ph

16 %

84 %

O

O 1) Bu3SnH/AIBN 2) HPLC

O

N O

NO2

Ph

SCHEME 2.24  Transformation of L-alanine into leucine oxazolidin-5-one derivatives.

Specifically, only one diastereomer is formed from sodium L-valinate upon refluxing with pivalaldehyde in pentane followed by treatment with 2-iodobenzoyl chloride. While thermal decomposition of AIBN is a general method to create radical, photochemical radical-generating condition at room temperature (using a standard medium pressure mercury vapor lamp) gives the best results for the C-4 allylation of the glycine-derived oxazolidin5-one (R = H) with an equimolar quantity of allyltributyltin, at a relatively high substrate concentration of 130 mM in benzene. An equivalent of AIBN

316

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

is still required under photochemical conditions. Other substituted allyltributyltins, such as 2-methylallyltributyltin, also work under this condition [3]. Interestingly, azeotropic removal of water from the reaction between L-proline and an excess amount of pivalaldehyde in pentane in the presence of a catalytic amount of acid (e.g., trifluoroacetic acid) leads to a single product of (3R,7aS)-3-(tert-butyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol1-one in 92% yield (Scheme 2.26) [154]. Treatment of this oxazolidin-5-one with LDA in THF at –78°C yields lithium (R)-3-(tert-butyl)-6,7-dihydro3H,5H-pyrrolo[1,2-c]oxazol-1-olate. Deuterolysis of the enolate in deuterated alcohol and methylation with methyl iodide prove the retention of the chirality. Similarly, all other types of electrophiles approach the nucleophilic center of the enolate from the Re face, making both the tert-butyl group and the newly introduced substituent cis to each other on the exo side of the 1-aza-3-oxabicyclo[3.3.0]octane, as demonstrated in alternative alkylation, addition to aldehyde and ketone as well as Michael addition products [155]. Similar to L-proline, other cyclic amino acids with a secondary amino group, e.g., azetidine-2-carboxylic acid and thiazolidine-4-carboxylic acid, also react stereospecifically with pivalaldehyde to give a single oxazolidin-5-one derivative [156]. O

O R

1) NaOH, H2O, EtOH 2) t-BuCHO, pentane, reflux 3) 2-iodobenzoyl chloride CHCl3, reflux

OH + O NH2

H

O

I

R O major diastereomer

O

O AIBN, benzene h , r.t.

N

SnBu3

N

O

N

O

R

O

R

O

O

O N

O

R

O

LiOH (3.0 eq.) H2O, MeOH

NH OMe R

major

SCHEME 2.25  A general method to make α-allylated amino acids.

O

Oxazolidin-5-ones 317

D-amino acids work in the same way as L-amino acids. For example, a mixture of D-tryptophan, pivalaldehyde (1.5 eq.), KOH, and a certain amount of 4 Å molecular sieves in anhydrous MeOH containing NaOH was stirred at 20°C for 6 hours, and the 4 Å molecular sieves was then removed from filtration and the filtrate was dried to afford lithium (R,E)-2-((2,2dimethylpropylidene)amino)-3-(1H-indol-3-yl)propanoate as a solid. The resulting imine derivative in anhydrous CH2Cl2 is then treated with ethyl chloroformate at 0°C for 6 hours and then at room temperature for overnight to generate (2R,4R)-2-(tert-butyl)-3-(ethoxycarbonyl)-4-(indol-3-ylmethyl)1,3-oxazolidin-5-one. A solution of this compound in anhydrous THF was then treated with LDA followed by the addition of methyl iodide. After quenching the reaction mixture with acetic acid, the reaction mixture was dried and purified by chromatography to form ethyl (2R,4R)-4-((1H-indol3-yl)methyl)-2-(tert-butyl)-4-methyl-5-oxooxazolidine-3-carboxylate [157]. R

O

N

O

H R-X O OH + O NH

cat. CF3CO2H pentane, reflux

H

O

N

O

OLi LDA/THF

N

R

O

R’OH O

R’ N

H

H

R

O

O

H

O

(R’ = H, CH3)

O HO O

O + N H

O

N

O

H

SCHEME 2.26  Preparation of (3R,7aS)-3-(tert-butyl)tetrahydro-1H,3H-pyrrolo[1,2-c] oxazol-1-one and further transformations.

More examples of making substituted amino acids by means of oxazolidin-5-one derivatives involving pivalaldehyde can be found in alternative references [158–160].

318

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

2.4.5 PREPARATION OF OXAZOLIDIN-5-ONES FROM α-AMINO ACID DERIVATIVES AND OTHER ALDEHYDES As demonstrated above for the preparation of oxazolidin-5-ones from benzaldehyde or pivalaldehyde, the diastereoselectivity is very important for the subsequent alkylation at position 2 of the oxazolidin-5-one moiety. In order to enhance the diastereoselectivity, even bulky aldehydes have been applied. For example, ferrocene carboxaldehyde has been condensed with sodium L-alaninate in absolute ethanol to afford imine in quantitative yield, which is then cyclized with pivaloyl chloride in CH2Cl2 to form cis1,3-oxazolidin-5-one. Treatment of this oxazolidin-5-one in THF with LDA at –78°C, followed by the addition of benzyl bromide gives the α-benzylated oxazolidin-5-one. Hydrolysis of this compound allows the recovery of the ferrocene carboxaldehyde and (R)-2-amino-2-methyl-3-phenylpropanoic acid in 98% ee, as shown in Scheme 2.27. This approach while not popularly applied in the preparation of α-substituted amino acids, has two features compared to the application of other aldehydes mentioned above, including the formation of oxazolidin-5-one of high diastereoselectivity due to the directing effect of the ferrocene moiety and easy decomposition of the oxazolidin-5-one ring [141, 161]. However, an additional group such as the trimethylsilyl group introduced to the ortho position of ferrocene carboxaldehyde exerts conformational restraints on the upcoming 3-pivaloyl group such that enolization and C-4 alkylation have been inhibited, as demonstrated in the failure of further functionalization of the oxazolidin-5-one prepared from (2R)-ortho-trimethylsilyl ferrocene carboxaldehyde, sodium (R)-Dalaninate and pivaloyl chloride (with 29:1 diastereoselectivity in favor of the cis-diastereomer) [162]. O

Fe

ONa NH2 EtOH

O

H N

Fe

t-BuCOCl/CH2Cl2 °

CHO

CO2Na 4Å MS, -18 C to r.t.

Fe

H O

Fe

H

°

O

N But

O

O BnBr -78 C °

O LDA/THF -78 C

Fe

H O

N Bn But

O

O

N H But O

hydrolysis

OH NH2

SCHEME 2.27  Preparation of α-methyl D-phenylalanine from L-alanine involving ferrocene carboxaldehyde in the control of stereoselectivity.

Oxazolidin-5-ones 319

On the other hand, the racemic mixtures of oxazolidin-5-one formed from the condensation between an aldehyde, glycine, and trifluoroacetic anhydride can be purified via an enzyme-catalyzed enantioselective ring cleavage. For example, when hydrolase-type enzymes such as pig liver esterase (PLE) and human leukocyte elastase (HLE) are applied to hydrolyze the oxazolidin-5-ones arising from glycine and benzaldehyde, isobutyraldehyde, pivalaldehyde, or 2,2-diphenylacetaldehyde, up to 46% of oxazolidin-5-one has been recovered, with enantiomeric excess up to 91%. In general, PLE works much better than HLE, the latter has no effect on the hydrolysis of oxazolidin-5-one prepared from isobutyraldehyde or pivalaldehyde [163]. 2.4.6 PREPARATION OF OXAZOLIDIN-5-ONES FROM α-AMINO ACID DERIVATIVES AND ACETONE As shown in Scheme 2.6 that in addition to aldehydes, ketones can also be protected in acetal forms. During the reaction between amino acid and ketone, N,O-ketal is formed. One advantage of using acetone to form the N,O-ketal of amino acid is that no additional chiral center will be formed, and often enantiomerically pure N,O-ketal is formed. For example, when the suspension of sodium L-valinate and 4Å molecular sieves dried in an oven in extra dry acetone is added with a catalytic amount of boron trifluoride etherate, the mixture is stirred for 5 minutes at 0°C and then 15 hours at room temperature under argon. After that, a stoichiometric amount of 1-naphthoyl chloride is added to trigger the cyclization to afford 73% of (S)-3-(1-naphthoyl)-4-isopropyl-2,2-dimethyloxazolidin5-one, as illustrated in Scheme 2.28. Even though this compound is an enantiomerically pure compound, it exists in four conformers, due to the rotation around the amide bond and the rotation around the bond between the carbonyl and naphthyl group, denoted as P cis conformer (P cis), M cis conformer (M cis), P trans conformer (P trans) and M trans conformer (M trans) (Figure 2.16) [164]. This compound in solid-state adopts a (P, cis) conformation, but forms an equilibrium in solution between (P, cis) and (M, cis) conformers at a ratio of 100:12 according to 1H NMR at low temperature and theoretical studies. This is because the trans conformers are destabilized by a decrease of conjugation in amide bond and (M, cis) conformer is destabilized by naphthyl distortion.

320

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O

ONa +

O

BF3 Et2O 4 Å MS r.t., 15 hrs.

O O

Cl O

ONa

N

N

NH2

O O

(P, cis) 73 %, > 99% ee

SCHEME 2.28  Preparation of (S)-3-(1-naphthoyl)-4-isopropyl-2,2-dimethyloxazolidin5-one.

Upon the deprotonation with KHMDS in toluene at –78°C in the presence of ether additive (1,2-dimethoxyethane, DME), followed by the addition of alkylating agent (e.g., MeI, MeOTf, EtOTf, allyl iodide, benzyl iodide, (4-methoxy)benzyl iodide, ethyl iodoacetate, and 2-methylpropan-2-ol-d), good to an excellent yield of alkylation product can be obtained with very good enantioselectivity (78–96% ee), and the ee% of the corresponding product can be further enhanced to > 94% after recrystallization. It is suggested that the stereochemical induction during the alkylation is caused by a dynamic resolution process, where the naphthyl-CO rotation is faster than metalation with KHMDS, leading to the preferential deprotonation of the (P, cis) conformer in which the active hydrogen at position 2 is more accessible. Subsequent alkylation occurs opposite to the second aromatic ring while the racemization of the enolate caused by the naphthyl-CO rotation is relatively slow, leading to global retention of configuration. In contrast, similar alkylation of benzyl (S)-4-isopropyl-2,2-dimethyl-5-oxooxazolidine3-carboxylate with allyl iodide affords a racemic alkylation product [165].

O

O N

O

N

O

N

O

O (P, cis)

O

(M, cis)

O

O

N

O (P, trans)

O O

(M, trans)

FIGURE 2.16  Four conformers of (S)-3-(1-naphthoyl)-4-isopropyl-2,2-dimethyloxazolidin5-one arising from the partial double-bond character of the amide bond.

Oxazolidin-5-ones 321

For comparison, when (S)-3-(1-naphthoyl)-4-isopropyloxazolidin5-one, (S)-3-([1,1’-biphenyl]-2-carbonyl)-4-isopropyloxazolidin-5-one, or (S)-3-(2-(tert-butyl)benzoyl)-4-isopropyloxazolidin-5-one, formed from the condensation of the corresponding N-acyl valine and an excess amount of paraformaldehyde in toluene at 95°C, is treated with 3 equivalents of LDA or LiHMDS and methyl iodide (3 eq.), the methylated oxazolidin-5-ones demonstrate much lower enantioselectivity. In the case of (S)-3-(1-naphthoyl)-4-isopropyloxazolidin-5-one, the (P, trans) and (M, trans) conformations predominate, whereas the (P, cis) and (M, cis) are the minor conformers [116]. In comparison, the corresponding N,O-ketals of L-alanine, L-leucine, L-phenylalanine, and L-methionine with acetone and 1-naphthoyl chloride have been prepared under conditions similar to the one for sodium L-valinate, which all display a preference in (P, cis) conformation over (M, cis) conformation, according to 1H NMR at 195 K. When these oxazolidin-5-ones are subject to alkylation with different alkylating agents, the respective alkylation products also demonstrate very good enantioselectivity [116]. 2.4.7 PREPARATION OF OXAZOLIDIN-5-ONES FROM α-AMINO ACID DERIVATIVES AND HEXAFLUOROACETONE Compared with acetone, hexafluoroacetone has been extensively used in the preparation of oxazolidin-5-one derivatives, partly due to an enhanced electrophilicity of the carbonyl group within hexafluoroacetone because the fluorine atom has the highest electronegativity. In this case, the N,O-ketal of hexafluoroacetone can be easily prepared by stirring a mixture of amino acid and hexafluoroacetone in DMSO at room temperature without prior treatment of amino acid with a base [166, 167]. The resulting 2,2-bis(trifluoromethyl)1,3-oxazolidin-5-one can be stored for several months at 0°C under moisture-free condition. In addition, due to the highest electronegativity of fluorine atoms, the nitrogen atom within the oxazolidin-5-one moiety is not as nucleophilic as the nitrogen in the case when acetone or aldehyde is used, and does not require an additional protecting group (e.g., acyl group). The approach is especially effective for concomitant protection of both α-amino group and terminal carboxyl group, offering an opportunity for further functionalization of the side chain group, such as in the case of glutamic acid, aspartic acid, serine, threonine, tyrosine, etc. Meanwhile, the carboxyl group in the oxazolidin-5-one moiety is also activated. Since hexafluoroacetone is

322

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

often used in excess, the hydroxy group in serine, threonine, 4-hydroxyproline and tyrosine can be partially protected as hemiketals, for which the additional hexafluoroacetone associated with hemiketal can be removed by stirring the respective molecules in CH2Cl2 in the presence of silica gel at room temperature [168]. When serine, threonine, 4-hydroxyproline and tyrosine are treated with hexafluoroacetone in DMSO at room temperature, the corresponding (S)-4-(hydroxymethyl)-2,2-bis(trifluoromethyl)oxazolidin-5-one, (S)-4-((R)-1-hydroxyethyl)-2,2-bis(trifluoromethyl)oxazolidin-5-one, (6R,7aS)-6-hydroxy-3,3-bis(trifluoromethyl)tetrahydro1H,3H-pyrrolo[1,2-c]oxazol-1-one, and (S)-4-(4-hydroxybenzyl)-2,2-bis(trifluoromethyl)oxazolidin-5-one are obtained in 61%, 83%, 65% and 84%, respectively. After that, the free hydroxy groups within these oxazolidin-5-ones are connected to 2,3,4,6-tetra-O-acetyl-β-Dglucopyranose in CH2Cl2 in the presence of a Lewis acid (BF3·Et2O), yielding 61%, 70%, 40% and 84% of (4S)-4-(2,3,4,6-tetra-O-acetyl-β-Dglucopyranosyloxymethyl)-2,2-bis(trifluoromethyl)-1,3-oxazolidin-5-one, (4S)-4-[(1R)-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)ethyl]-2,2bis(trifluoro-methyl)-1,3-oxazolidin-5-one,(5S,7R)-7-[2,3,4,6-tetra-O-acetyl-βD-glucopyranosyloxy]-2,2-bis(trifluoromethyl)-1-aza-3-oxabicyclo[3.3.0] octan-4-one, and (4S)-4-[4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy) benzyl]-2,2-bis(trifluoromethyl)-1,3-oxazolidin-5-one, as illustrated in Scheme 2.29, respectively [168]. In addition to cyclizing with α-amino acid, hexafluoroacetone also effectively cyclizes with α-hydroxy acid and α-mercapto acid, as demonstrated in the reaction of hexafluoroacetone with L-aspartic acid, (S)-2-hydroxysuccinic acid and (S)-2-mercaptosuccinic acid in DMSO, respectively (Scheme 2.30) [169]. The unreacted terminal carboxyl group in the resulting (S)-2-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)acetic acid, (S)-2-(5-oxo-2,2-bis(trifluoromethyl)-1,3-dioxolan-4-yl)acetic acid of (S)-2-(5-oxo-2,2-bis(trifluoromethyl)-1,3-oxathiolan-4-yl)acetic acid can be converted into acyl chloride by means of thionyl chloride (SOCl2) and further functionalized with alcohol, particularly the multi-hydroxy alcohol such as 1,1,1-tris(hydroxymethyl)ethane and pentaerythritol in boiling toluene to create star-like molecules with the 2,2-bis(trifluoromethyl)oxazolidin-5-one, 2,2-bis(trifluoromethyl)-1,3-dioxolan-4-one or 2,2-bis(trifluoromethyl)1,3-oxathiolan-5-one moieties as the end functional groups. Also, these five-membered rings can be easily cleaved by alcohol, affording terminal esters when these five-membered rings containing molecules are refluxed in methanol, releasing hexafluoroacetone. However, it should be pointed out

Oxazolidin-5-ones 323

2+

2

2+ 2 ) 2+  )

5 1+

)

)

) )

'062 UW

2$F 2

2$F 2$F %)(W2&+&O

$F2 $F2

5

2

+1

&) &) 5 + 5 0H 5

2$F 2

2 2$F

$F2 $F2

2

2 +1

5 + 5 0H 2 2+ 

+2

1+

2 )&

&)

'062 UW

+2

2 &) &)

+

2

1

2 &)

)& 

2$F 2

2$F 2$F %)(W2&+&O

$F2 $F2

$F2 $F2

2$F 2

2 2$F

+

2

1

2

)&

&)

 2 2+  1+

+2

2

2 )&

&)

'062 UW

+1

+2

 2$F 2

2$F 2$F %)(W2&+&O

$F2 $F2

2 &) &)

2

$F2 $F2

2$F 2

2 2$F

+1

2 &) &)

 SCHEME 2.29  Preparations of 2,2-bis(trifluoromethyl)oxazolidin-5-ones from hydroxylcontaining amino acids and further glycosylation on the hydroxyl group.

324

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

that this strategy of activating the side chain carboxyl group in L-aspartic acid is not applicable to hexafluoroacetone-protected L-glutamic acid and (S)-2-aminohexanedioic acid because the ω-acid chloride once formed spontaneously reacts intramolecularly to yield five- and six-membered lactams, respectively [169, 170]. O F3C CF3 OH DMSO, r.t.

HO O

NH2

O

O

O

HO

SOCl2

O O

HN

Cl O O

CF3

CF3 O O F3C CF3 OH DMSO, r.t.

HO O

O O O

O

O F3C CF3 OH DMSO, r.t.

HO O

SH

CF3 CF3

HO

OH

O

HN

CF3 CF3 O

HO O O

S

CF3 CF3

SCHEME 2.30  Formation of N,O-ketal, O,O-ketal, and S,O-ketal with hexafluoroacetone.

Particularly, starting with (S)-2-(5-oxo-2,2-bis(trifluoromethyl) oxazolidin-4-yl)acetyl chloride (in Scheme 2.30), a variety of tin compounds such as RSnMe3, RSn(n-Bu)3, where R = aryl, alkenyl, alkynyl, and alkyl can be coupled with the carbonyl group on the side chain in the presence of a palladium catalyst (e.g., Pd2(DBA)3·CHCl3, Pd(PPh3)4, etc.), affording (S)-4-(substituted acetonyl)-2,2-bis(trifloromethyl)oxazolidin-5-ones, as illustrated in Scheme 2.31. The palladium catalysts promoted coupling reactions are well-known, and many references can be easily found [171]. Hydrolysis of the resulting γ-keto-2,2-bis(trifloromethyl)oxazolidin5-ones yields (S)-2-amino-4-oxopentanoic acid derivatives [172]. For example, coupling of (S)-2-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin4-yl)acetyl chloride with trimethyl(phenyl)stannane in the presence of tris(dibenzylideneacetone)dipalladium(0) [Pd2(dba)3] yields 85% of (S)-4(2-oxo-2-phenylethyl)-2,2-bis(trifluoromethyl)oxazolidin-5-one, which upon hydrolysis in aqueous isopropanol leads to the formation of (S)-2amino-4-oxo-4-phenylbutanoic acid. Similarly, coupling with tributyl(vinyl) stannane in the presence of BnPd(PPh3)2Cl generates 75% of (S)-4-(2oxobut-3-en-1-yl)-2,2-bis(trifluoromethyl)oxazolidin-5-one, from which

Oxazolidin-5-ones 325

(S)-2-amino-4-oxohex-5-enoic acid is obtained from hydrolysis. Likewise, (S)-2-amino-4-oxo-6-phenylhex-5-ynoic acid can be obtained by coupling of (S)-2-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)acetyl chloride with tributyl(phenylethynyl)stannane followed by hydrolysis [172]. In addition, treatment of (S)-2-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)acetyl chloride with diazomethane allows the formation of (S)-4-(3-diazo-2oxopropyl)-2,2-bis(trifluoromethyl)oxazolidin-5-one, which upon treatment with formic acid and subsequent hydrolysis, leads to the formation of (S)-2amino-5-hydroxy-4-oxopentanoic acid (i.e., 5-hydroxy-4-oxo-L-norvaline). Other amino acid derivatives, including (S)-5-acetamido-2-amino-4oxopentanoic acid, (S)-4-oxopiperidine-2-carboxylic acid, and (2S,4R)-4hydroxypiperidine-2-carboxylic acid can be prepared from L-aspartic acid upon a similar synthetic route [172]. The chemistry of N-carboxymethyl glycine (i.e., 2,2’-azanediyldiacetic acid) has been explored with hexafluoroacetone, for which one of the carboxyl groups is protected in the form of oxazolidin-5-one, whereas the other carboxyl group is converted into methyl ester with diazomethane, tert-butyl ester with isobutene, and acid chloride with thionyl chloride. From acid chloride, additional functional groups such as ester, thioester, and amide can be introduced. On the other hand, the hexafluoroacetone involved oxazolidin-5-one can be easily converted into amide and ester in reaction with amine and alcohol as well. In addition, 2-(5-oxo-2,2bis(trifluoromethyl)oxazolidin-3-yl)acetyl chloride can be converted into 3-(3-diazo-2-oxopropyl)-2,2-bis(trifluoromethyl)oxazolidin-5-one, from which heterocycle can be introduced via 1,3-dipolar cycloaddition. All these possible transformations have been summarized in Scheme 2.32 [173]. It should be pointed out that the strategy and transformations outlined in Scheme 2.31 can be applied to both L-glutamic acid and L-aspartic acid, however, due to the potential formation of five-membered lactam from L-glutamic acid [169, 174], the application of hexafluoroacetone in formation of oxazolidin-5-one has been focused on L-aspartic acid, for nearly identical transformation as outlined in Scheme 2.32 [175]. Moreover, the side chain carboxyl group in L-aspartic acid once being converted into acid chloride, can be conjugated to 2,3,4,6-tetra-Oacetyl-β-D-glucopyranosylamine and 2-deoxy-2-N-acetylamino-3,4,5tri-O-acetyl-β-D-glucopyranosylamine in the presence of N-ethyl morpholine (NEM) to afford 78% and 81% of (2R,3R,4S,5R,6R)-2(acetoxymethyl)-6-(2-((S)-5-oxo-2,2-bis-(trifluoromethyl)oxazolidin4-yl)acetamido)tetrahydro-2H-pyran-3,4,5-triyl triacetate and

326

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O Ph O

HN 85 %

O

H2O/i-PrOH

O

OH

CF3

O

CF3

NH2

PhSnMe3 Pd2(DBA)3 CHCl3 toluene, 20 C °

O

O

Cl

Sn(n-Bu)3

O CF3

CF3

BnPd(PPh3)2Cl MeOCH2CH2OMe 60 C

O

HN

°

HN

O

O H2O/i-PrOH

O CF3

CF3

OH O

NH2

75 %

Ph Sn(n-Bu)3 Pd2(DBA)3 CHCl3 N-methylyrrolidone P(2-furyl)3 Ph

O

Ph

O

HN

O

H2O/i-PrOH

O CF3

CF3

OH O

NH2

40 %

SCHEME 2.31  Preparation of L-alanine derivatives with an extending conjugated carbonyl system at the β-position.

(2R,3S,4R,5R,6R)-5-acetamido-2-(acetoxymethyl)-6-(2-((S)-5-oxo-2,2bis(trifluoromethyl)oxazolidin-4-yl)acetamido)tetrahydro-2H-pyran-3,4diyl diacetate, respectively. However, in order to form similar N-glycosides of L-glutamic acid and (S)-2-aminohexanedioic acid (i.e., (S)-2-amino adipic acid), peptide condensation agent such as 2-(1H-benzotriazole-1yl)-1,1,3,3-tetramethyl-aminium tetrafluoroborate (TBTU) is used, to avoid the potential formation of lactam. Under this condition, (S)-3-(5-oxo-2,2bis(trifluoromethyl)oxazolidin-4-yl)propanoic acid is transformed into (2R,3R, 4S,5R,6R)-2-(acetoxymethyl)-6-(3-((S)-5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)propanamido)tetrahydro-2H-pyran-3,4,5-triyl triacetate in reaction with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylamine. Likewise, (S)-4-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)butanoic acid is conjugated with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylamine to yield 79% of (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(4-((S)-5-oxo2,2-bis(trifluoromethyl)oxazolidin-4-yl)butanamido)tetrahydro-2Hpyran-3,4,5-triyl triacetate, as demonstrated in Scheme 2.33 [174]. On the other hand, although the oxazolidin-5-one in these intermediates is stable in the presence of basic N-ethyl morpholine, it decomposes in

Oxazolidin-5-ones 327

the presence of 4-N,N-dimethylaminopyridine (DMAP). For example, in the presence of DMAP, (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6(2-((S)-5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)-acetamido) tetrahydro-2H-pyran-3,4,5-triyltriacetatedecomposestoafford(2R,3R,4S,5R,6R)2-(acetoxymethyl)-6-((Z)-3-((1,1,1,3,3,3-hexafluoropropan-2-yl)amino) acrylamido)tetrahydro-2H-pyran-3,4,5-triyl triacetate, and (2R,3R,4S,5R,6R)2-(acetoxymethyl)-6-(3-((S)-5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl) propanamido)tetrahydro-2H-pyran-3,4,5-triyl triacetate is converted into (2R,3R,4S,5R,6R)-2-(acetoxymethyl)-6-(7,7,7-trifluoro-6-(trifluoromethyl)hept4-enamido)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Scheme 2.33) [174]. Furthermore, (S)-2-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl) acetyl chloride arising from L-aspartic acid is first treated with sodium 2-sulfidopyridine 1-oxide in THF at –15°C, followed by BrCCl3 under UV light irradiation to afford (R)-4-(bromomethyl)-2,2-bis(trifluoromethyl) oxazolidin-5-one. This oxazolidin-5-one, identical to the bromination product of oxazolidin-5-one arising from L-serine, is then coupled with (3aR,6S,6aR)-4-(difluoromethylene)-6-((R)-2,2-dimethyl-1,3-dioxolan-4yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole, a derivative prepared from D-gulose under refluxing in benzene in the presence of radical initiator AIBN and proton transfer agent Bu3SnH, to afford (S)-4-(2-((3aR,4S,6S,6aR)6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,4-d] [1,3]dioxol-4-yl)-2,2-difluoroethyl)-2,2-bis(trifluoromethyl)oxazolidin5-one [176]. Conjugation with tert-butyl L-phenylalaninate in Et2O affords tert-butyl ((S)-2-amino-4-((3aR,4S,6S, 6aR)-6-((R)-2,2-dimethyl-1,3dioxolan-4-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-4,4difluorobutanoyl)-L-phenylalaninate, a serine-O-glycopeptide analog, as illustrated in Scheme 2.34 [176]. Additionally, treatment of (S)-2-(5-oxo-2,2-bis(trifluoromethyl) oxazolidin-4-yl)acetyl chloride with diazomethane in ether affords 91% of (S)-4-(3-diazo-2-oxopropyl)-2,2-bis(trifluoromethyl)oxazolidin-5-one, which upon the further treatment with formic acid, leads to the formation of 57% (S)-2-oxo-3-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)propyl formate. Hydrolysis of this compound in aqueous isopropanol affords 92% of (S)-2-amino-5-hydroxy-4-oxopentanoic acid, i.e., 5-hydroxy4-oxo-L-norvaline [177]. Another manipulation of L-aspartic acid with hexafluoroacetone is the treatment of (S)-2-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)acetic acid with chlorosulfonylisocyanate in toluene from room temperature to 110°C to afford (S)-3,3-bis(trifluoromethyl)dihydro3H-oxazolo[3,4-c]pyrimidine-1,5,7(6H)-trione. From this intermediate,

(i.e., HO

O

O

H N

O

HO

CH2N2

O

O

F3C CF3 DMSO, r.t.

ROH

acid

3-carboxymethyl-2,2O OH

O H N

R1R2NH

O O

Br

F3C CF3

N

OR HO

O

H+ O O

O

Cl

O

RO

O O

O

RCHN2 R N2

O O

R

O

O

O N

CF3

O O

R

S

R 2 R 1N

R1R2NH

RS

CO2Et

N

O

O

N

O

O

O

O

F3C CF3

N

O

N

O

OEt O

F3C CF3

N N S

O

O

F3C CF3

N

F3C CF3

N NH

CO2Me O

CO2Me

O

O

F3C CF3

N

MeO2C

MeO2C R=H

Laweson Reagent R=

RSH

F3C ROH

N

S NH2

F3C CF3

F3C CF3

NR1R2

N

HBr R = H

SOCl2

O

N

2-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-3-yl)acetic

O H N

O N

CF3 O

N

F3C CF3

of

HO

MeO

F3C

O

F3C CF3

SCHEME 2.32 Potential reactivities bis(trifluoromethyl)oxazolidin-5-one).

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O

O

O

O

HN

O

HN

Cl

O

HN

HN

OAc O

O CF3

CF3 CF3

O

O

CF3

O

O

NH2 AcO OAc AcO TBTU, NEM, DMF

AcO AcO

OAc O

N

H N OAc

OAc O O 79%

73%

N OAc H

O

, CH2Cl2

NH2 OAc

OAc O

, CH2Cl2

HN

HN

H N

CF3

O

O

CF3

DMAP

HN

HN

AcO AcO

AcO AcO

O 78%

OAc

OAc O

O

81%

H N NHAc

OAc O

CF3 CF3

O

O

AcO AcO

NH2 AcO NHAc AcO

OAc O

OAc O

N

AcO AcO

O

AcO AcO

NH2 AcO OAc AcO TBTU, NEM, DMF

AcO AcO

CF3

CF3

O

O

CF3 CF3

O

O

CF3 CF3

O

O

SOCl2

CF3

CF3

HN

HN

SOCl2

Cl

O

OAc

OAc O

H N

H N OAc

OAc O

CF3 CF3

O

O

CF3 CF3

O

O

O HN

O

CF3

CF3

H

CF3

CF3

DMAP

SCHEME 2.33  Transformation of the carboxy side chain and further decomposition of the heterocyclic ring of 2,2-bis(trifluoromethyl) oxazolidin-5-ones.

HO

HO

HO

HO

O

Oxazolidin-5-ones 329

330

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O Cl CF3 CF3

O

O

N

H

O

F

AIBN, Bu3SnH, C6H6

CF3 CF3

O

H

O HN

CF3 CF3

F

O O

Br

HN

O

O

O

H O

BrCCl3, light

O

°

HN

O S

SNa THF, -15 C

O O

O

N

O

O

H O

O

F

F HN

O CF3 CF3

O O-t-Bu

O

NH2 Et2O, r.t.

O

H O

H O

O

F

Ph

O F NH 2

N H

O-t-Bu O

SCHEME 2.34  An aspartic acid-based synthesis of glycopeptide.

(S)-2,6-dioxohexahydropyrimidine-4-carboxylic acid or (S)-1-methyl2,6-dioxohexahydropyrimidine-4-carboxylic acid can be generated by acidic hydrolysis or hydrolysis at room temperature after further reaction with diazomethane in THF. Likewise, a series of esters and amides of (S)-2,6-dioxohexahydropyrimidine-4-carboxylic acid and (S)-1-methyl2,6-dioxohexahydropyrimidine-4-carboxylic acid have been prepared by treatment of these two acids with different alcohols and amines, respectively, as displayed in Scheme 2.35 [178]. As illustrated in Schemes 2.34 and 2.35, one feature of using hexafluoroacetone is the potential reactivity of the corresponding oxazolidin5-one with alcohols and amines. Particularly, peptides can be formed when the oxazolidin-5-one is treated with another amino acid. For example, treatment of (S)-2-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)acetic acid with methyl L-phenylalaninate in Et2O at room temperature leads to the formation of (S)-3-amino-4-(((S)-1-methoxy-1-oxo-3phenylpropan-2-yl)amino)-4-oxobutanoic acid, i.e., aspartame. Similarly, when (S)-3-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)-propanoic acid and (S)-4-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)-

Oxazolidin-5-ones 331

O

O HN

NH

O

O

OR

HN

O O HO O HN

°

O

O O S C N O toluene, r.t. to 110 C Cl

CF3

CF3

O

O N

OH

NH O

N

OR

NH

O ROH

O HO

H3O+ O

O

O

N O O CF3 HN N HN CF3 HCl, SO CF3 3 Cl S O F3C O O O H3

CH2N2 THF

O+ O

O

O

O

OH

NH

ROH

N

N O F3C

O

O CF3

R1R2NH O

O HN

NH

NR1R2

O

O

O

R1R2NH N

NH

NR1R2

O

SCHEME 2.35  Transformation of aspartic acid based 2,2-bis(trifluoromethyl)oxazolidin5-one into dihydropyrimidine-2,4(1H,3H)-dione derivatives.

butanoic acid arising from L-glutamic acid and (S)-2-aminoadipic acid react with methyl L-phenylalaninate in Et2O, dipeptides of (S)-4-amino5-(((S)-1-methoxy-1-oxo-3-phenylpropan-2-yl)amino)-5-oxopentanoic acid and (S)-5-amino-6-(((S)-1-methoxy-1-oxo-3-phenylpropan-2-yl) amino)-6-oxohexanoic acid are formed, respectively. Refluxing of these two peptides in aqueous acetone leads to the formation of 3-((2S,5S)-5benzyl-3,6-dioxopiperazin-2-yl)propanoic acid and 4-((2S,5S)-5-benzyl3,6-dioxopiperazin-2-yl)butanoic acid, respectively (Scheme 2.36) [179]. Hexafluoroacetone has also been applied to make a series of phosphorus containing sarcosine (i.e., N-methylglycine) derivatives. For example, upon reaction of sarcosine and hexafluoroacetone, 3-methyl-2,2bis(trifluoromethyl)-oxazolidin-5-one is formed. The methylene group within the ring can be activated by bromination, and the resulting brominated oxazolidin-5-one is then treated with a variety of phosphorus-containing molecules. It is found out that different bromination products can be generated during the bromination, according to the actual reaction conditions. For example, treatment of 3-methyl-2,2-bis(trifluoromethyl)oxazolidin-5-one

332

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O O O

O

O

HO

CF3 F 3C OH DMSO

n

HO

O

O

HN

Et2O, r.t.

CF3

CF3 Ph

O n

NH2

°

HO

O

n

NH2

OMe NH2

N H

OMe O

40 C acetone/H2O

O

H N

O n

OH

N O H (n = 1, 2)

SCHEME 2.36  Application of 2,2-bis(trifluoromethyl)oxazolidin-5-one in the preparation of dipeptide and 2,5-diketopiperazine derivatives.

with NBS yields both 4-bromo-3-methyl-2,2-bis(trifluoromethyl)oxazolidin5-one and 4,4-dibromo-3-methyl-2,2-bis(trifluoromethyl)oxazolidin-5-one; whereas bromination of the same molecule with Br2 under photochemical condition also generate these two brominated products, as well as 4-bromo3-(bromomethyl)-2,2-bis(trifluoromethyl)oxazolidin-5-one. In contrast, bromination of 3-methyl-2,2-bis(trifluoromethyl)oxazolidin-5-one with half equivalent of Br2 using black light lamp leads to the formation of only 4-bromo-3-methyl-2,2-bis(trifluoromethyl)oxazolidin-5-one [180]. With this intermediate, a series of phosphorus-containing 1,3-oxazolidin5-ones can be prepared, as demonstrated in Scheme 2.37 in reaction with trimethyl phosphite [P(OMe)3], 2-phenoxy-1,3,2-dioxaphospholane, 2-phenoxy-1,3,2-dioxaphosphinane, diethyl phenylphosphonite and methoxydiphenylphosphane, that yields dimethyl (3-methyl-5-oxo-2,2bis(trifluoromethyl)oxazolidin-4-yl)phosphonate, 2-bromoethyl phenyl (3-methyl-5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)phosphonate, 3-bromopropyl phenyl (3-methyl-5-oxo-2,2-bis(trifluoromethyl)oxazolidin4-yl)phosphonate, ethyl (3-methyl-5-oxo-2,2-bis(trifluoromethyl) oxazolidin-4-yl)(phenyl)phosphinate and 4-(diphenylphosphoryl)-3-methyl2,2-bis(trifluoromethyl)oxazolidin-5-one, respectively (Scheme 2.37) [180]. Hydrolysis of dimethyl (3-methyl-5-oxo-2,2-bis(trifluoromethyl) oxazolidin-4-yl)phosphonate in concentrated HCl under heating decomposes both the oxazolidin-5-one ring and phosphonate, yielding 2-(methylamino)2-phosphonoacetic acid. Treatment of these important intermediates with benzylamine would afford the corresponding benzylamides, accordingly. Interesting, reaction of 2-mercaptoacetic acid with hexafluoroacetone generates

Oxazolidin-5-ones 333

2,2-bis(trifluoromethyl)-1,3-oxathiolan-5-one, which upon bromination with Br2 under photochemical condition yields 4-bromo-2,2-bis(trifluoromethyl)1,3-oxathiolan-5-one. Treatment of this compound with trimethyl phosphite leads to the formation of 2,2-bis(trifluoromethyl)-1,3-oxathiol-5-yl dimethyl phosphate, rather than the expected dimethyl (5-oxo-2,2-bis(trifluoromethyl)1,3-oxathiolan-4-yl)phosphonate [180]. Upon the protection with hexafluoroacetone, L-glutamic acid has been converted into (S)-5,5-difluoropiperidine-2-carboxylic acid and (2S,5S)-5fluoropiperidine-2-carboxylic acid respectively, as illustrated in Scheme 2.38 [170]. In this synthesis of fluorine-containing amino acids, hexafluoroacetone protected L-glutamic acid, i.e., (S)-3-(5-oxo-2,2-bis(trifluoromethyl) oxazolidin-4-yl)propanoic acid is treated with isobutyl chloroformate in the presence of N-methyl morpholine (NMM) followed by diazomethane to form (S)-4-(4-diazo-3-oxobutyl)-2,2-bis(trifluoromethyl)oxazolidin5-one, which is then treated with rhodium(II) acetate dimer to give (S)-3,3bis(trifluoromethyl)dihydro-3H-oxazolo[3,4-a]pyridine-1,6(5H,7H)-dione. From this key intermediate, treatment with diethylaminosulfur trifluoride (DAST) converts the carbonyl group to geminal difluoro group, i.e., leading to the formation of (S)-6,6-difluoro-3,3-bis(trifluoromethyl)tetrahydro-3Hoxazolo[3,4-a]pyridin-1(5H)-one. Hydrolysis of this molecule in dioxane in the presence of HCl and further treatment with propene oxide generates (S)-5,5-difluoropiperidine-2-carboxylic acid. In order to form (2S,5R)-5fluoropiperidine-2-carboxylic acid, the same key intermediate is reduced with BH3⋅THF to afford (6S,8aS)-6-hydroxy-3,3-bis(trifluoromethyl)tetrahydro-3H-oxazolo[3,4-a]pyridin-1(5H)-one, which is then esterified with trifluoromethanesulfonic anhydride to afford (6S,8aS)-1-oxo3,3-bis(trifluoro-methyl)hexahydro-3H-oxazolo[3,4-a]pyridin-6-yl trifluoromethanesulfonate. Substitution of trifluoromethanesulfonyl group with fluoride gives (6R,8aS)-6-fluoro-3,3-bis(trifluoromethyl)tetrahydro3H-oxazolo[3,4-a]pyridin-1(5H)-one. Finally, hydrolysis of this molecule completes the synthesis of (2S,5R)-5-fluoropiperidine-2-carboxylic acid [170]. Other syntheses of amino acid derivatives using hexafluoroacetone as a protecting group can be found in the literature [167, 181].

334

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

2 2 0H2 3 2+ FRQF+&O 0H2 2 1 3 2+ 2 &) 2+ )& 2

+ 1

1 )&

2 &)

HT%U EODFNOLJKWODPS

)& + 1

2 2+

2

1

&)

2 &)

2 3K2 3 2

2 1 )&

2 3 23K 2

3K320H 2 3K 3 3K

%U

&)

)&

2

1 )&

2 3 23K 2

2

%U

2

3K32(W 

320H  2

2 3K 3 (W2

2 1 )&

%U

2 &)

2 3K2 3 2

2 &)

2 1 )&

2 &)

SCHEME 2.37  Preparation of 4-bromo-3-methyl-2,2-bis(trifluoromethyl)oxazolidin-5-one and its potential reactivities.

2.4.8 PREPARATION OF OXAZOLIDIN-5-ONES FROM α-AMINO ACID DERIVATIVES AND OTHER KETONES In addition to simple ketones like acetone, hexafluoroacetone, some other ketones have also been applied to react with amino acids to form oxazolidin-5-one derivatives. One of such oxazolidin-5-ones is formed from the condensation between (1R,1ar,1a1S,3s,3aR,4s,5ar,6S)1,1a,1a1,2,2,3,3a,4,5a,6-decachlorooctahydro-5H-1,3,4-(epimethanetriyl) cyclobuta[cd]pentalen-5-one and an amino acid in refluxing m-xylene. In this practice, the ketone (C10Cl10O) is prepared from self-reaction of hexachlorocyclopentadiene in the presence of fuming sulfuric acid or sulfur trioxide and subsequent hydrolysis. α-Amino acids tested include glycine, alanine, DL-valine, leucine, isoleucine, methionine, and phenylalanine. The yields of oxazolidin-5-ones range from 32% to 87%. The particular oxazolidin5-one of this kind formed from L-alanine is (1’R,1a’R,1a1’S,3’S,3a’R,4S,4’ S,5a’R,6’S)-1’,1a’,1a1’,2’,2’,3’,3a’,4’,5a’,6’-decachloro-4-methyloctahydro

Oxazolidin-5-ones 335

2

2

2

+2

2+

)&

2

2

&) +2 +1

1+ 2

2

1

+1

2 &) &)

D &O&2 2L%X100 E &+1

2 5K2$F 

2

&+&O

&)  &)

2

1

2

&)

)&

2 1

7I2

)&

2

'$67 &+&O

) )

2

1 )&

2 7I2

+

&2+ ) )

2

1

+2

&)

&)

D +&OLQGLR[DQH E SURSHQHR[LGH

%+7+)

+

2

&)

)&

1+

+)(W1 2 ) +

2

1 )&

&)

&2+

D +&OLQGLR[DQH E SURSHQHR[LGH

) +

1+

SCHEME 2.38  The preparations of (S)-5,5-difluoropiperidine-2-carboxylic acid and (2S,5R)-5-fluoropiperidine-2-carboxylic acid from L-glutamic acid.

spiro[oxazolidin-2,5’-[1,3,4](epimethanetriyl)cyclobuta[cd]pentalen]-5-one (Scheme 2.39) [182]. Cl Cl Cl Cl 2

Cl 1) H2SO4 SO3 2) hydrolysis

Cl Cl

Cl

Cl

Cl Cl Cl

Cl L-alanine Cl m-xylene Cl

Cl

Cl Cl Cl Cl Cl Cl Cl Cl Cl Cl O HN

O O

SCHEME 2.39  Preparation of oxazolidine-5-one from L-alanine and a decachlorocyclic ketone.

336

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

2.4.9 PREPARATION OF OXAZOLIDIN-5-ONES FROM α-AMINO ACID AND ALTERNATIVE COMPOUNDS In addition to the use of acyl halide to cyclize the imine generated from the condensation of the sodium salt of amino acid and acetone to form the N,O-ketal of acetone with amino acid, isocyanate functions in a manner similar to acyl halide. For example, refluxing of L-tryptophan and n-ethyl isocyanate in acetone leads to the formation of 9% of (S)-4-((1H-indol3-yl)methyl)-N-ethyl-2,2-dimethyl-5-oxooxazolidine-3-carboxamide, in addition to the expected hydantoin and urea [183]. Similarly, the reaction between L-tryptophan and propyl isocyanate, ethyl isocyanate and isopropyl isocyanate in refluxing acetone has afforded (S)-4-((1H-indol-3-yl)methyl)2,2-dimethyl-5-oxo-N-propyloxazolidine-3-carboxamide, (S)-4-((1H-indol3-yl)methyl)-N-ethyl-2,2-dimethyl-5-oxooxazolidine-3-carboxamide and (S)-4-((1H-indol-3-yl)methyl)-N-isopropyl-2,2-dimethyl-5-oxooxazolidine3-carboxamide, respectively (Scheme 2.40). The reactions of 5-hydroxyL-tryptophan with ethyl isocyanate or isopropyl isocyanate would yield the expected oxazolidin-5-ones accordingly [184]. On the other hand, the [2+2]-cycloaddition product between the imino group formed from the condensation of the amino group and acetone and the isocyanato group, i.e., (S)-2-(3-ethyl-2,2-dimethyl-4-oxo-1,3-diazetidin-1-yl)-3-(1H-indol-3-yl) propanoic acid for the case of L-tryptophan and ethyl isocyanate, has not been isolated. R1

O

R1 O OH HN

OH

O

H2N

R1 = H, OH R = Et, n-Pr, i-Pr

R-N=C=O acetone

N

HN O

NH R

O

R1

N O N H not isolated

N R

SCHEME 2.40  Preparation of L-tryptophan-based 2,2-dimethyloxazolidin-5-ones with isocyanates in acetone.

Likewise, the direct refluxing of the mixture of (Z)-3-(4-oxo-3,4dihydroquinazolin-2-yl)acryloyl isothiocyanate, pyridine, and glycine in acetone for one hour, leads to the formation of (Z)-N-(2-mercapto-5oxooxazolidin-2-yl)-3-(4-oxo-3,4-dihydroquinazolin-2-yl)acrylamide,

Oxazolidin-5-ones 337

which has antimicrobial activity against Aspergillus niger, Bacillus cereus, Bacillus subtilis, Pseudomonas aeruginosa, Candida albicans, and Penicillium notatum [185]. Following this trend, the introduction of a carbonyl group to isothiocyanate would allow the formation of a fused oxazolidin-5-one, such as in the reaction between 4-isothiocyanato4-methylpentan-2-one and glycine that generates 7,7,8a-trimethyl-5thioxotetrahydro-5H-oxazolo[3,2-c]pyrimidin-2(3H)-one. However, the reaction between glycine and 4-isothiocyanatobutan-2-one affords 3-(3-oxobutyl)-2-thioxoimidazolidin-4-one, as shown in Scheme 2.41. This is because the presence of gem-dimethyl groups on the intermediate thiourea, i.e., (2-methyl-4-oxopentan-2-yl)carbamothioyl)glycine, formed in the former reaction, prevents the cyclization between the adjacent NH and terminal carboxyl group, instead they promote the condensation between alternative NH and the carbonyl group to form a six-member ring. In contrast, during the reaction between glycine and 4-isothiocyanatobutan-2-one, the resulting thiourea intermediate, i.e., ((3-oxobutyl)carbamothioyl)glycine, can quickly cyclizes intramolecularly to give 3-(3-oxobutyl)-2-thioxoimidazolidin-4-one [186].

S

O C

O + H N 2

N

H N

S

O

OH OH OH

HN

HN

OH

HN

N

S

OH

HN

O

S H N

S

O + H 2N

N

N

H 2O

O C

O

OH

S

O

S

O O

N

O OH

HN

OH

O

N

N HN

O

O

O

OH HO S

H 2O

HN

S

SCHEME 2.41  The mechanisms for the reaction of glycine with 4-isothiocyanato-4methylpentan-2-one and 4-isothiocyanatobutan-2-one.

338

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Different from the reaction between glycine and 4-isothiocyanatobutan2-one as outlined in Scheme 2.41, the reaction between tridecanoyl isothiocyanate and glycine yields N-(2-mercapto-5-oxooxazolidin-2-yl)tridecanamide. Similarly, the reaction between glycine and palmitoyl isothiocyanate or stearoyl isothiocyanate affords N-(2-mercapto-5oxooxazolidin-2-yl)palmitamide or N-(2-mercapto-5-oxooxazolidin-2-yl)stearamide, accordingly. The resulting oxazolidin-5-ones with a long hydrocarbon chain have demonstrated antimicrobial activities (e.g., against Bacillus circulans, Aspergillus niger, and Penicillium), as well as potential to be used as surfactants. However, no thiourea forms from these reactions [187]. Finally, a transition metal catalyzed multi-component reaction involving carbon monoxide, hydrogen (H2), β-vinyl ester and α-amino acids has recently been reported to form oxazolidin-5-one fused heterocyclic molecules. For example, the four-component reaction of L-valine with CO, H2 and 3-butenoic acid O-succinimidyl ester (i.e., 2,5-dioxopyrrolidin1-yl but-3-enoate) in the presence of 1% of Rh(CO)2acac and 2% of BiPhePhos ligand under autoclave heating at 70°C and 7 bar of H2/CO (1:1), and 10 mol% p-toluenesulfonic acid affords 70% of (3S,8aR)-3isopropyltetrahydro-5H-oxazolo[3,2-a]pyridin-2,5(3H)-dione [188]. The reaction using L-methionine under similar condition with 5% pyridinium p-toluenesulfonate (PPTS), affords 71% of (3S,8aR)-3-(2-(methylthio) ethyl)tetrahydro-5H-oxazolo[3,2-a]pyridin-2,5(3H)-dione. The later reaction under microwave irradiation in the presence of 10 mol% p-TsOH also afford 70% of product. In contrast, the reaction of L-phenylalanine and 2,5-dioxopyrrolidin-1-yl (S)-2-(((benzyloxy)carbonyl)amino)pent-4-enoate in the presence of 10 mol% p-TsOH, also with 7 bar of H2/CO (1:1) and the catalyst, leads to the formation of 65% of benzyl ((3S,6S,9aR)-3-benzyl-2,5-dioxooctahydrooxazolo[3,2-a]azepin-6-yl)carbamate. For comparison, the four-component reaction using D-amino acid (e.g., D-phenylalanine) or (R)-2-amino-2-phenylacetic acid generates (3R,8aS)-3-benzyltetrahydro-5H-oxazolo[3,2-a]pyridin-2,5(3H)-dione or (3R,8aS)-3-phenyltetrahydro-5H-oxazolo[3,2-a]pyridin-2,5(3H)-dione, respectively (Scheme 2.42). All these reactions afford single diastereomers of trans relationship for the two chiral centers as supported by the X-ray structures. Interestingly, the reaction of methyl L-tryptophanate with 2,5-dioxopyrrolidin-1-yl but-3-enoate at 5 bar of H2/CO (1:1) in the presence of 10 mol% p-TsOH and Rh(CO)2acac yields 66% of tetracyclic molecules, i.e., methyl (6S,12bR)-4-oxo-1,2,3,4,6,7,12,12boctahydroindolo[2,3-a]quinolizine-6-carboxylate, with the trans-

Oxazolidin-5-ones 339

diastereomer being the major product (trans: cis = 81%:19%). In this case, no oxazolidin-5-one moiety is formed [188]. 2.5 REACTIONS OF OXAZOLIDIN-5-ONES In most oxazolidin-5-ones, there is a protecting group at position 3 (on the nitrogen atom), so the reactivities of oxazolidin-5-ones are primarily focused on position 4 and position 5. Position 5 is a carbonyl group and essentially is electrophilic so that a nucleophilic attack at C-5 would give the ring-opening product. For instance, nucleophilic attack of C5 by an amino acid would result in the ring-opening product, affording a peptide. In contrast, position 4 would participate in the reaction of a nucleophilic character. For example, the hydrogen atom at position 4 can be easily deprotonated and the resulting

O

O

Rh(CO)2acac biphephos O 7 bar H2/CO (1:1) 10 mol% pTSA THF, 70 C

O OH +

N

O

NH2

O

O

O S

O OH +

Rh(CO)2acac biphephos N 7 bar H2/CO (1:1) O 5 mol% PPTS O THF, 70 C

O NHCbz

O

O

O

O OH +

O

NH2

N O

O

O

O OH +

Ph

N

O

N O

O

N

Rh(CO)2acac biphephos 7 bar H2/CO (1:1) 5 mol% PPTS THF, 70 C Rh(CO)2acac biphephos 7 bar H2/CO (1:1) 10 mol% PPTS THF, 70 C

N

O

O 69 %

Ph

O

N

O Ph

O 65 % O

°

OH + NH2

O 71 %

S

CbzHN Rh(CO)2acac biphephos 7 bar H2/CO (1:1) O 10 mol% pTSA Ph THF, 70 C

°

O

°

O

O

N

O

°

NH2

H 2N

O 70 %

°

O

N

O 54 % O

SCHEME 2.42  Four-component reaction to form bicyclic oxazolidin-5-ones.

340

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

enolate can undergo alkylation, Aldol reaction, etc. Moreover, extrusion of carbon dioxide from oxazolidin-5-ones generally leads to mesoionic intermediates, which then undergo 1,3-dipolar cycloaddition with dipolarophiles. The details of the reactivities of oxazolidin-5-ones are outlined in subsections. 2.5.1 OXAZOLIDIN-5-ONES IN ALKYLATION AT C-4 Adjacent to an electron-withdrawing carbonyl group, C-4 in oxazolidin-5-one is relatively acidic, although C-4 is also connected to an electron-donating amino group. As a result, C-4 is usually deprotonated with a strong base. The resulting carbanion or enolate is often treated with an alkylating agent to create a quaternary α-carbon. Hydrolysis of the resulting oxazolidin-5-ones would give α,α-disubstituted amino acid derivatives. This principle has been demonstrated in a clever total synthesis of (-)-cephalotaxine, the major alkaloid of Cephalotaxus harrigntonia var. drupacae of potential antileukemic activity. Proline was first converted into (3S,7aR)-3-(tert-butyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one according to the procedure outlined above section 2.4.4 [154, 155]. Deprotonation at C4 with strong base LDA, the resulting carbanion was allowed to react with (E)-(3-bromoprop-1-en-1-yl)trimethylsilane to give (3S,7aS)-3-(tert-butyl)-7a-((E)-3-(trimethylsilyl)allyl)tetrahydro-1H,3Hpyrrolo[1,2-c]oxazol-1-one, which was then transformed into (3S,7aS)3-(tert-butyl)-7a-((E)-3-iodoallyl)tetrahydro-1H,3H-pyrrolo[1,2-c] oxazol-1-one with ICl in the presence of trifluoroacetic acid. After that, acidic hydrolysis with 10% H2SO4 opened the oxazolidin-5-one ring, the secondary amino group was protected with Boc2O, and the carboxyl group was converted into methyl ester with diazomethane to afford 1-(tert-butyl)- 2-methyl (S,E)2-(3-iodoallyl)pyrrolidine-1,2-dicarboxylate. Deprotection of the Boc group with trifluoroacetic acid, the amino group underwent nucleophilic substitution with 3,4-dimethoxyphenethyl 4-nitrobenzenesulfonate to give methyl (S,E)-1-(3,4-dimethoxyphenethyl)-2-(3-iodoallyl)pyrrolidine2-carboxylate. After conversion of the methyl ester group to aldehyde (i.e., (S,E)-1-(3,4-dimethoxyphenethyl)-2-(3-iodoallyl)pyrrolidine-2carbaldehyde), TMSSnBu3 initiated radical cyclization led to the formation of (5S)-1-(3,4-dimethoxyphenethyl)-1-azaspiro[4.4]non-7-en-6-ol. PPA treatment generated carbocation which underwent electrophilic aromatic substitution, resulting in the intramolecular cyclized product of (10bS,13aS)-8,9-dimethoxy-2,3,5,6,10b,13-hexahydro-1H-benzo[d]

Oxazolidin-5-ones 341

cyclopenta[b]pyrrolo[1,2-a]azepine, which has the main framework of (-)-cephalotaxine. After several subsequent transformations, the final (-)-cephalotaxine (i.e., (11bS,12R,14aS)-2,3,5,6,11b,12-hexahydro1H-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]cyclopenta[b]pyrrolo[1,2-a] azepin-12-ol) was obtained, as shown in Scheme 2.43 [189]. 706

+ 2

2

1

2+

2

1+ ,

1

2

 /'$  %U

2

 +62  %RF21D2+

2

 &+1

706

 ,&O&)&2+

2

1

 .)+2'062

,  &)&2+

2

1

 L3U1(W&+&1 20H 0H2 2 %RF 2 6 0H2 2

12 1

1

2

+

20H 0H2

20H

2

,

0H2

20H

0H6L6Q%X&V)

,

20H 20H 33$ +2

1

0H2 0H2

1

1 +

2 2

+ +2

SCHEME 2.43  L-Proline based total synthesis of (-)-cephalotaxine.

Similarly, (3R,7aS)-3-(tert-butyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one prepared in a similar way was deprotonated with strong base LDA, the resulting carbanion was allowed to react with ortho-iodobenzyl bromide to form (3R,7aR)-7a-benzyl-3-(tert-butyl)tetrahydro-1H,3Hpyrrolo[1,2-c]oxazol-1-one, from which the ortho-iodo group was replaced

342

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

by lithium to give (2-(((3R,7aR)-3-(tert-butyl)-1-oxodihydro-1H,3Hpyrrolo[1,2-c]oxazol-7a(5H)-yl)methyl)phenyl)lithium before worked up. Subsequent intramolecular attack at the carbonyl group yielded (R)-spiro[indene-2,2’-pyrrolidin]-1(3H)-one after work-up (Scheme 2.44). This compound was further converted into spiro diamine to catalyze Henry reaction [190]. Similarly, when 4-((6-bromobenzo[d][1,3]dioxol-5-yl)methyl)-3-(9-phenyl-9H-fluoren-9-yl)oxazolidin-5-one was treated with BuLi, the bromo lithium exchange resulted in aryl anion, which underwent intramolecularly nucleophilic attack at the C5 of the oxazolidin-5-one ring to give 82% of 6-(9-phenyl-9H-fluoren-9-yl)-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxol-5-one [94]. In contrast, when (3R,7aS)-3-(tert-butyl)tetrahydro-1H,3H-pyrrolo[1,2c]oxazol-1-one was treated with a strong base to create its enolate in THF, under the condition that half equivalent of ethane-1,2-diyl bis(trifluoromethanesulfonate) was added, both ends of the triflates were substituted by the enolate via C-alkylation (not O-alkylation) to afford (3R,3’R,7aR,7a’R)-7a,7a’-(ethane-1,2-diyl)bis(3-(tert-butyl)tetrahydro1H,3H-pyrrolo[1,2-c]oxazol-1-one). Upon refluxing in 6 N HCl, the oxazolidin-5-one ring was decomposed, and (2’R)-2,2’-(ethane-1,2-diyl)di-D-proline was resolved. Treatment of this compound with thionyl chloride followed by methanol, (2R,2’R)-2,2’-(ethane-1,2-diyl)bis(2(methoxycarbonyl)pyrrolidin-1-ium) dichloride was obtained. Interestingly, when this compound was treated with N-methylmorpholine (NMM), (5aR,10aR)-tetrahydro-1H,5H,6H,10H-5a,10a-ethanodipyrrolo[1,2-a:1’,2’d]pyrazin-5,10-dione (a type of DKP) was obtained, whereas when it was under heating, methyl (6R,8aR)-5-oxotetrahydro-5H-spiro[indolizin6,2’-pyrrolidine]-8a(1H)-carboxylate was formed, which can also be converted into the same DKP upon treatment with NMM, and the DKP can be transformed back to this molecule with HCl/MeOH, as illustrated in Scheme 2.45 [191]. Li O O N

O 1) LDA, THF, -78°C, 0.5 hr. 2) o-iodobenzyl bromide -78°C -30°C, 3 hrs.

work-up N

O

N O

N H

O

SCHEME 2.44  Synthesis of (R)-spiro[indene-2,2’-pyrrolidin]-1(3H)-one from L-proline based oxazolidin-5-one.

Oxazolidin-5-ones 343

2 1

2

2

1

2

7I2

27I ƒ 7+)&

2



+1 1+&O

&O +1 0H2

2 2

+2

2 2

1+

2

1 2

1 2

62&O 0H2+

1+

20H 20H

2+

2

2

+1 100

1

2

&O

+&O0H2+

1 1 2

100 SCHEME 2.45  Synthesis of (5aR,10aR)-tetrahydro-1H,5H,6H,10H-5a,10a-ethanodipyrrolo [1,2-a:1’,2’-d]pyrazin-5,10-dione from L-proline based oxazolidin-5-one.

It should be pointed out that the C-4 alkylation can be performed as one step reaction by mixing both oxazolidin-5-one and alkylating agent together, followed by the addition of strong base (e.g., LiHMDS); instead of the treatment of oxazolidin-5-one with the strong base prior to the addition of the alkylating agent [143]. When D-proline was refluxed with pivalaldehyde in pentane in the presence of a catalytic amount of TFA for 3–5 days, (3S,7aR)-3-(tert-butyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one was isolated as the single product. It was then treated with LDA in THF at –78°C, and the resulting carbanion was allowed to react with 3-bromo-2-methylprop-1-ene to give (3S,7aS)3-(tert-butyl)-7a-(2-methylallyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol1-one, of which the olefinic bond was hydrogenated in the presence of Pt-C in isopropanol to give (3S,7aS)-3-(tert-butyl)-7a-isobutyltetrahydro-1H,3Hpyrrolo[1,2-c]oxazol-1-one. When this compound was added to a mixture of N-(4-bromo-2-chlorophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine and n-BuLi in THF at –78°C, (S)-(4-amino-3-chlorophenyl)(2-isobutylpyrrolidin-2-yl)methanone was obtained after further treatment with 1 N HCl, as shown in Scheme 2.46 [192].

344

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O H

H

O

OH NH

t-Bu H cat. TFA pentane

N

O

1) LDA/THF -78°C 2) Br

O O

H2/Pt-C N

O

i-PrOH

Br O n-BuLi,

Cl O

Cl THF, -78 C

NH2

°

N

O

N(TMS)2

NH

SCHEME 2.46  D-Proline based synthesis of (S)-(4-amino-3-chlorophenyl)(2-isobutylpyrrolidin-2-yl)methanone.

Following the same strategy, (3R,7aS)-3-(tert-butyl)tetrahydro-1H,3Hpyrrolo[1,2-c]oxazol-1-one has been applied to the synthesis of lepadiformine/ cylindricine tricyclic framework as detailed in Scheme 2.47. In this approach, (3R,7aS)-3-(tert-butyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one was treated with unusual lithium diethylamide in THF in the presence of hexamethylphosphoramide (HMPA), and the carbanion was then treated with 5-bromopent-1-ene to give (3R,7aS)-3-(tert-butyl)-7a-(pent-4-en-1-yl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one. The oxazolidin-5-one ring was then decomposed in aqueous MeOH in the presence of SiO2 to form (S)-2(pent-4-en-1-yl)pyrrolidine-2-carboxylic acid. Subsequent protection of the amino group with Boc and conversion of the carboxyl group to methyl ester with CH3I/DBU in benzene afford 1-(tert-butyl) 2-methyl (S)-2-(pent-4-en1-yl)pyrrolidine-1,2-dicarboxylate. The methyl ester group was converted into an aldehyde group by reducing the ester to alcohol with uncommon LiBH4 then oxidation of the alcohol with SO3/pyridine in DMSO/CH2Cl2. tert-Butyl (S)-2formyl-2-(pent-4-en-1-yl)pyrrolidine-1-carboxylate was then transformed into tert-butyl (S)-2-ethynyl-2-(pent-4-en-1-yl)pyrrolidine-1-carboxylate. Removal of the Boc protecting group with TMSOTf in CH2Cl2 and subsequent reaction with acryloyl chloride in CH2Cl2 in the presence of Et3N afforded (S)-1-(2ethynyl-2-(pent-4-en-1-yl)pyrrolidin-1-yl)prop-2-en-1-one, which is the final target for metathesis ring-closing reaction to give the tricyclic (R)-2,3,10,11tetrahydro-1H-pyrrolo[2,1-j]quinolin-5(9H)-one [193]. Very similarly, the same starting material used in Scheme 2.47 (i.e., (3S,7aR)-3-(tert-butyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one) has been treated with n-BuLi

Oxazolidin-5-ones 345

in the presence of i-Pr2NH in THF at –78°C, and the resulting carbanion was allowed to react with allyl bromide to give 58% of (3R,7aR)-7a-allyl-3-(tertbutyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one. This compound was then subject to the synthesis of new monoamine reuptake inhibitors [194]. Almost in the same strategy, (S)-1-(tert-butoxycarbonyl)-2-(3-methylbut-2-en-1-yl)pyrrolidine-2-carboxylic acid was synthesized, which is the important intermediate for the syntheses of Notoamides F, I, and R and Sclerotiamide [195]. O N

O

O

LiNEt2, HMPA THF 5-bromo-1-pentene

N

O

SiO2 aq. MeOH

Boc N

OH NH O

1) LiBH4/Et2O 2) SO3/pyridine DMSO, CH2Cl2

OHC

1) TMSOTf, CH2Cl2 2) CH2=CHCOCl Et3N, CH2Cl2

OMe O

CH3COCN2PO(OMe)2 N Boc

N

K2CO3, MeOH

O

N Boc

Ru catalyst N O

SCHEME 2.47  Synthesis of (R)-2,3,10,11-tetrahydro-1H-pyrrolo[2,1-j]quinolin-5(9H)-one from L-proline based oxazolidin-5-one.

Another example of the C4-alkylation can be found in the preparation of (3R,7aS)-3-(tert-butyl)-7a-(methyl-13C)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one, which was further converted into (S)-2-(methyl-13C) pyrrolidine-2-carboxylic acid and (S)-1-(tert-butoxycarbonyl)-2(methyl-13C)pyrrolidine-2-carboxylic acid for the purpose of measuring the cis-trans peptide-bond isomerization in α-methylproline derivatives. After replacing a proline residue in the hexapeptide H-Ala-Tyr-Pro-Tyr-AspVal-OH with α-methylproline, the peptide displayed an anomalously high population (57%) of the cis configuration, whereas only 8% of proline is in cis figuration in peptide, and other amino acids all form peptide bonds of trans configurations [196].

346

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Bz

O

N

LiHMDS THF, -78° C

O O

Bz N

O

HN Bz

O Bz

N

O O

LiHMDS THF, -78° C

Bz

OLi

N

BF3 OEt2

O Bz N

O

O Bz

N

O

HN Bz H2O work-up

O C Ph N O

O O N

OLi Bz H Base

O C Ph N

O OLi O

O N Bz

SCHEME 2.48  The mechanism for the transformation of (2R,4R)-3-benzoyl-2-isopropyl4-methyloxazolidin-5-one into N-((R)-1-((2S,4R)-3-benzoyl-2-isopropyl-4-methyl-5-oxooxazolidin-4-yl)-2-methylpropyl)benzamide.

A unique reaction that occurs between the oxazolidin-5-one and its enolate should be pointed out, where the enolate attacks the acetal position rather than the C5 carbonyl group. For example, treatment of (2R,4R)3-benzoyl-2-isopropyl-4-methyloxazolidin-5-one in THF at –78°C yielded N-((R)-1-((2S,4R)-3-benzoyl-2-isopropyl-4-methyl-5-oxooxazolidin-4yl)-2-methylpropyl)benzamide. For comparison, treatment of (2R,4S)3-benzoyl-2-isopropyl-4-methyloxazolidin-5-one under the same condition, N-((S)-1-((2R,4S)-3-benzoyl-2-isopropyl-4-methyl-5-oxooxazolidin-4-yl)2-methylpropyl)benzamide was obtained. Also, when the enolate was treated with BF3·OEt2, the same product was obtained. A mechanism has been proposed to rationalize this transformation by eliminating lithium acrylate, as shown in Scheme 2.48 [197]. One more example for the C-4 alkylation can be found for the synthesis of (tert-butoxycarbonyl)-L-alanine from glycine by means of tert-butyl (R)-5-oxo-2-phenyloxazolidine-3-carboxylate [198].

Oxazolidin-5-ones 347

2.5.2 FORMATION OF N-METHYL AMINO ACIDS When oxazolidin-5-ones are reduced rather than hydrolyzed, N-methyl amino acid derivatives can be obtained. The preparation of N-methyl amino acids is of practical value as N-methyl amino acid containing peptides are gradually recognized as potential therapeutics, and N-methylation of amino acids also enhances pharmacological parameters such as membrane permeability, conformational rigidity, and proteolytic stability [199–203]. For example, the N-methyl asparagine, arginine, histidine, and tryptophan have been synthesized by reduction of the corresponding oxazolidin-5-one derivatives with triethylsilane, respectively. However, due to the existence of different side-chain groups of these amino acids, these N-methyl amino acids cannot be prepared in exactly the same procedure. As an example, the preparation of N-methyl asparagine is outlined in Scheme 2.49, and the syntheses of the other three amino acids can be found in the original report [204]. For this particular preparation, the L-asparagine side amido group was first tritylated with triphenylmethanol under an acidic condition, and the resulting N4-trityl-L-asparagine was then allowed to react with N-(benzyloxycarbonyloxy)succinimide (i.e., benzyl (2,5-dioxopyrrolidin1-yl) carbonate) to give N2-((benzyloxy)carbonyl)-N4-trityl-L-asparagine. Then the mixture of this asparagine derivative and paraformaldehyde was refluxed in benzene with a small amount of DMF added to improve the solubility of the amino acid derivative. Benzyl (S)-5-oxo-4-(2-oxo-2(tritylamino)ethyl)oxazolidine-3-carboxylate was obtained in 83% yield. Treatment of this intermediate in trifluoroacetic acid with triethylsilane concurrently reduces the oxazolidin-5-one ring and removes the trityl group, affording N2-((benzyloxy)carbonyl)-N2-methyl-L-asparagine in 75% yield. It should be pointed out that the reduction of oxazolidin-5-one ring with triethylsilane has been reported as early as 1992 for the preparation of N-methylglycine (sarcosine) and N-methylphenylalanine [97]. Therefore, this method should not be claimed as a novel preparation. The advantage of using Et3SiH over Pd/C hydrogenation is that N-Cbz group will not be cleaved under this condition.

348

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O Ph3COH, H2SO4

H 2N

OH O

NH2

AcOH, Ac2O

Ph Ph

(CH2O)n, CSA

O

DMF, C6H6,

N Cbz

O

H N Ph

BnOCO2-Succ OH O

NH2

Et3N/DMF

Ph Ph

O

H N Ph

O

OH NHCbz

O

O Ph

O N H

Ph Ph

Et3SiH CF3CO2H

H2N

OH O

N

Cbz

SCHEME 2.49  Conversion of L-asparagine into N2-((benzyloxy)carbonyl)-N2-methylL-asparagine.

Similarly, the N-Cbz protected oxazolidin-5-one derivatives of alanine, valine, phenylalanine, methionine, leucine, isoleucine, (S)-2-amino-3-(4(benzyloxy)phenyl)propanoic acid (i.e., O-benzyl tyrosine); the N-Boc protected oxazolidin-5-one derivatives of valine, leucine, isoleucine, phenylalanine, methionine, and O-benzyl tyrosine; and N-Tosyl protected oxazolidin-5-one derivatives of valine, leucine, isoleucine, phenylalanine, methionine, O-benzyl tyrosine have all been converted into the corresponding N-methyl amino acids by means of reduction with NaBH3CN in CH3CN at room temperature in the presence of Me3SiCl, with all yields above 90% [205]. Likewise, the N-Cbz protected alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, and O-TBDPS-serine have been transformed into the corresponding N-Cbz-protected oxazolidin-5-ones, which were hydrogenated in MeOH with 10% Pd/C and hydrogen to afford high yields of N-methyl amino acids. When the corresponding N-Boc protected oxazolidin-5-ones were hydrogenated under this condition, the N-Boc-Nmethyl amino acids were yielded instead. However, in either case, no actual yields have been provided unfortunately [206]. 2.5.3 OXAZOLIDIN-5-ONES IN NUCLEOPHILIC ADDITION Once the oxazolidin-5-one is deprotonated with a strong base, the resulting carbanion or enolate is electron-enriched and will undergo nucleophilic addition with electron-deficient species, in addition to the nucleophilic substitution as outlined in Section 2.5.1. In one example, benzyl (R)-2-(tert-butyl)-5-oxooxazolidine-3carboxylate was treated with LiHMDS (generated in situ in THF from HMDS and BuLi) at –78°C, the resulting enolate was allowed to react with 3,4-bis(benzyloxy)benzaldehyde to give 84% of benzyl (2R,4S)-4((R)-(3,4-bis(benzyloxy)phenyl)(hydroxy)methyl)-2-(tert-butyl)-

Oxazolidin-5-ones 349

5-oxooxazolidine-3-carboxylate. Hydrogenation of this intermediate in methanol with 5% Pd/C and 5% HCl afforded 88% of (2S,3R)-2-amino-3(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid, as shown in Scheme 2.50 [207]. 2 2

%X/L+0'6

1

2%Q

2

1

2 1 2

2%Q

+

+ 3G&

2%Q

2+ 2 +2 +2

2+ 2%Q

2

%Q2

2%Q

2

2

2

%Q2

2

2+ 1+

SCHEME 2.50  Preparation of (2S,3R)-2-amino-3-(3,4-dihydroxyphenyl)-3-hydroxypropanoic acid (i.e., (R)-β-hydroxyl L-dopa).

Likewise, addition of the carbanion generated from tert-butyl (R)-5-oxo2-phenyloxazolidine-3-carboxylate with LiHMDS to anisaldehyde in THF yielded tert-butyl (2R,4S)-4-((R)-hydroxy(4-methoxyphenyl)methyl)5-oxo-2-phenyloxazolidine-3-carboxylate and its enantiomer. Subsequent hydrogenation over Pd/C led to the formation of (2S,3R)-2-(benzyl(tertbutoxycarbonyl)amino)-3-hydroxy-3-(4-methoxyphenyl)propanoic acid and its enantiomer [198].

O N

O

KHMDS THF/DMF -78° C

O DDQ THF

O N

O

N

O

O

N

O

HO

O NO2

O

O N O

N

1) 48% HBr, , 20 hrs. 2) propylene oxide, EtOH

HN

O NO2

SCHEME 2.51  Preparation of (S)-2-(4-nitrophenyl)pyrrolidin-2-carboxylic acid from L-proline based oxazolidin-5-one.

350

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

An interesting nucleophilic addition of the enolate occurs at the paraposition of nitrobenzene, as displayed in Scheme 2.51 [208]. In this approach, (3R,7aS)-3-(tert-butyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one was treated with strong base KHMDS to generate the enolate, which then added to the para-position of the nitro group in nitrobenzene to form (4-((3S,7aS)3-(tert-butyl)-1-oxodihydro-1H,3H-pyrrolo[1,2-c]oxazol-7a(5H)-yl)cyclohexa-2,5-dien-1-ylidene)azinate. Upon oxidation of this intermediate with DDQ to regain the aromaticity, (3S,7aS)-3-(tert-butyl)-7a-(4-nitrophenyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one was produced. Acidolysis with 48% HBr for 20 hours, and subsequent treatment with propylene oxide in ethanol, yielded the final product of (S)-2-(4-nitrophenyl)pyrrolidine2-carboxylic acid. This compound would be difficult to make from other alternative methods, for the direct arylation at the α-position of amino acid. 2.5.4 DECARBOXYLATION TO MESOIONIC SPECIES FOR 1,3-DIPOLAR CYCLOADDITION As oxazolidin-5-ones belong to lactones, they should be stable enough for being used as starting materials in common transformations outlined above. Under certain conditions, they may extrude CO2 and generate azomethine ylides for 1,3-dipolar cycloaddition. Therefore, several fused cyclic compounds can be easily prepared in this way. For example, when a mixture of 0.3 g of proline (2.61 mmol), 0.2 g of paraformaldehyde (6.7 mmol) and 0.25 g of N-(p-tolyl)maleimide (1.32 mmol) was heated under reflux in toluene for 15 minutes, 0.36 g of a mixture of two stereoisomers (i.e., (3aR,8aR,8bS)-2-(p-tolyl)hexahydropyrrolo[3,4-a]pyrrolizin-1,3(2H,4H)-dione and (3aR,8aS,8bS)-2(p-tolyl)hexahydropyrrolo[3,4-a]pyrrolizin-1,3(2H,4H)-dione) was obtained (nearly 100% yield) as displayed in Scheme 2.52 [209]. For this particular reaction, it is possible that the reaction of proline and paraformaldehyde yields (S)-tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one, which extrudes CO2 to form the azomethine ylide of (3,4-dihydro-2H-pyrrol-1-ium-1-yl)methanide. This ylide then undergoes 1,3-dipolar cycloaddition with N-(ptolyl)maleimide to give the two stereoisomers. On the other hand, in the presence of acid (the carboxyl group of proline), the secondary amine reacts with paraformaldehyde to give N-(hydroxymethyl)-L-proline. Dehydration of this intermediate yields (S)-2-carboxy-1-methylenepyrrolidin-1-ium, which easily undergoes β-decarboxylation to give the azomethine ylide under heating, a process similar to the β-decarboxylation of β-keto acids. The first mechanism sounds more plausible as the reaction between oxazolidin-5-one

Oxazolidin-5-ones 351

and alkene also gives the 1,3-dipolar cycloaddition products. For example, when the mixture of N-phenylglycine and paraformaldehyde was heated for 30 minutes and then 2,3-dimethylbut-2-ene was added, the isolated product was 3,3,4,4-tetramethyl-1-phenylpyrrolidine. Several different reaction conditions have been studied in this report [209]. On the other hand, a report for the application of 1,3-dipolar cycloaddition to functionalize the carbon nanofiber may back up the second mechanism [210]. O

O

N

OH + (CH2O)n + NH

H+ N

N

O

O OH

N H

O

CO2

O

OH

H2O

N

Tol N

N

O N

HH O

O

N

O

CO2 O H

+

O

H2O

H

N

O

HH

toluene, O

O

H

N

N

H H+

Tol N

O

N

SCHEME 2.52  Generation of 1,3-dipole from L-proline and its cycloaddition with N-(ptolyl)maleimide.

The direct evidence for the decomposition of oxazolidin-5-ones to give azomethine ylides might be the base induced fragmentation of oxazolidin-5-ones to azo-compounds. For example, a series of 2,2-bis(trifluoromethyl)oxazolidin5-ones, including 4-methyl-2,2-bis(trifluoromethyl)oxazolidin-5-one, ethyl 2-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)acetate, 4-isopropyl-2,2bis(trifluoromethyl)oxazolidin-5-one, 4-isobutyl-2,2-bis(trifluoromethyl)oxazolidin-5-one, 4-phenyl-2,2-bis(trifluoromethyl)oxazolidin-5-one, 4-benzyl-2,2-bis(trifluoromethyl)oxazolidin-5-one, and 4,4-dimethyl-2,2bis(trifluoromethyl)oxazolidin-5-one, have been successfully transformed into the imines, such as (E)-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)ethanimine, ethyl (E)-3-((1,1,1,3,3,3-hexafluoropropan-2-yl)imino)propanoate, (E)-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-2-methylpropan-1imine, (E)-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-3-methylbutan-1-imine, (E)-N-(1,1,1,3,3,3-hexafluoropropan-2-yl)-1-phenylmethanimine, (E)-N(1,1,1,3,3,3-hexafluoropropan-2-yl)-2-phenylethan-1-imine and N-(1,1,1,3, 3,3-hexafluoropropan-2-yl)propan-2-imine [211].

352

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

Using FT-IR technology to track the wavenumber of reaction intermediates from the reaction between phenylalanine and glycolaldehyde (i.e., 2-hydroxyacetaldehyde), the decomposed species from the corresponding oxazolidin-5-one (i.e., 4-benzyl-2-(hydroxymethyl)oxazolidin-5-one) have been nicely detected [212]. The azomethine ylide strategy has been applied for the synthesis of β-lactam [213]. 2.5.5 PROLINE CATALYZED REACTIONS Regarding the catalyzed chemical reactions, most of the catalysts are inorganic compounds and organometallic compounds [214, 215]. While many organic molecules have been applied as the ligands for organometallic compounds for chemical catalysis, a few organic molecules have demonstrated catalytic capacity [216–218], proline is one of these molecules [219–222]. The application of proline as a simple organic catalyst has been awarded the 2021 Nobel Prize in Chemistry. Proline has been found to catalyze Aldol reaction/Aldol condensation [223, 224], Mannich reaction [225, 226], Michael addition [227, 228], Diels-Alder cycloaddition [229], oxidation [230], fluorination [231], α-aminoxylation [127], etc. Representative reactions are outlined in Scheme 2.53 accordingly. In the examples of catalyzed reactions with proline, there are two roles that proline has taken on, i.e., simply functioning as a catalyst to accelerate the chemical reaction (or to improve the yield) and a catalyst to induce/enhance stereoselectivity. In most cases, proline’s catalytic capacity has shown in the induction/enhancement of enantioselectivity or diastereoselectivity due to its own chirality. However, one may ask how proline induce stereochemistry. Taking the Aldol reaction of propionaldehyde as an example, it is possible that in the presence of L-proline, propionaldehyde reacts with the pyrrolidine moiety of proline to form the iminium species, and further transforms into the corresponding oxazolidin-5-one (i.e., (7aS)-3-ethyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one), which forms a parasitic equilibrium with enamine (E)-prop-1-en1-yl-L-proline (Scheme 2.54) [232, 233]. It is this enamine that undergoes addition to another propionaldehyde to give (2S,E)-1-(3-hydroxy-2-methylpentylidene)pyrrolidin-1-ium-2-carboxylate, which undergoes the parasitic equilibrium with (3R,7aS)-3-((2S)-3-hydroxypentan-2-yl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one. Hydrolysis of this oxazolidin-5-one releases L-proline and the Aldol reaction product of 3-hydroxy-2-methylpentanal. For this particular reaction with 1.0 equivalent of L-proline, among the NMR tracked intermediates,

Oxazolidin-5-ones 353

(3R,7aS)-3-ethyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one accounts for 72%, (3S,7aS)-3-ethyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one accounts for 19%, and its parasitic equilibrium isomer, i.e., (E)-prop-1-en-1-yl-L-proline is 9% [232]. The evidence for the parasitic equilibrium can be demonstrated between the reaction of L-proline with acetone, in which an equilibrium constant of 0.12 has been reported in favor of (S)-3,3-dimethyltetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one over prop-1-en-2-yl-L-proline. For the case of cyclic ketone, the percentage of oxazolidin-5-one is reduced in the equilibrium. For example, when cyclopentanone reacts with L-proline, an equilibrium constant of 0.50 is reported between (S)-tetrahydro-1’H-spiro[cyclopentane-1,3’-pyrrolo[1,2-c]oxazol]-1’-one and cyclopent-1-en-1-yl-L-proline, whereas the equilibrium constant increases to 0.68 between (S)-tetrahydro-1’H-spiro[cyclohexane1,3’-pyrrolo[1,2-c]oxazol]-1’-one and cyclohex-1-en-1-yl-L-proline for the case of cyclohexanone [220, 234, 235]. A similar phenomenon has been notified in Jadomycin B, which is a mixture of 3a-S (67%) and 3a-R (33%) stereoisomers in dynamic equilibrium as shown in Scheme 2.2 [16]. Further in situ NMR study with isotope labeling reveals that the proline catalyzed Aldol reaction in DMSO competes with Aldol condensation that yields (E)-2-methylpent-2-enal, where the rate-determining step of the condensation is the C-C bond formation. Also, the diastereoselectivity of the Aldol reaction is evidenced to be time-dependent due to the retro-aldolization and the competing irreversible Aldol condensation. For the self-Aldol reaction of propionaldehyde, (2S,3S)-3-hydroxy-2-methylpentanal is favored for short reaction time and low loading of proline catalyst, whereas (2S,3R)-3-hydroxy-2-methylpentanal is predominant when high loading of proline catalyst is used for a longer reaction time [236]. It is reported that the addition of thiourea such as 1,3-bis(3,5-bis(trifluoromethyl)phenyl)thiourea to the reaction solution can further enhance the enantioselectivity for the proline catalyzed Aldol reaction [237]. To provide further evidence for the potential involvement of oxazolidin5-one in the Aldol reaction, three aldol reactions, i.e., the one between 1-hydroxypropan-2-one and cyclohexanecarbaldehyde, the one between acetone and benzaldehyde and lastly, the one between cyclohexanone and 4-nitrobenzaldehyde have been performed in the presence of L-proline or purely the corresponding oxazolidin-5-one (3R,7aS)-3-(tert-butyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one in DMSO at room temperature. The results indicate that (3R,7aS)-3-(tert-butyl)tetrahydro-1H,3Hpyrrolo[1,2-c]oxazol-1-one is much more effective in catalyzing the above three Aldol reactions in terms of chemical yields, whereas no apparent difference has been observed for the ee% of products obtained from either

354

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

condition. Specifically, the yield of the product after 48 hours in the presence of L-proline initially is not as good as the one in the presence of (3R,7aS)-3(tert-butyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-1-one after 4 hours [238]. 2

1%RF



 3K

2



2

2 2

2+&

2



2

PRO/3UROLQH &+&O(W1HT UWKUV

12

3K

1+%RF &+2

ƒ

2

3K

2+ 2

&+&+2'3UROLQH &+&1&KUV

+

2

5

/3UROLQH

5&+2

3K

2

2 2

2 2

+

2

2

2

 2 20H

+

PRO/SUROLQH PRO&X&O

2

2

2

20H

PDMRU

 HH

PRO/3UROLQH 0H2+UWKUV

20H

0H2

2

3K 12

2 2

 HH

20H

 !GH

20H

PLQRU 2

FRQYHUVLRQ VHOHFWLYLW\ PRO&70$% HT7%+3+2 &KUV &70$% FHW\OWULPHWK\ODPPRQLXPEURPLGH 7%+3 WHUWEXW\OK\GURSHUR[LGH 2 +



22 3K /3UROLQH 6 6 1 &+&1UW 2 2 ) KUV

3K

SCHEME 2.53  Examples of L-proline catalyzed reactions.

2 )

+

 HH

Oxazolidin-5-ones 355

CHO

O

O OH

HO H2O

CHO H2O

NH

O

O

N

O N

* OH parasitic equilibrium O

O O parasitic equilibrium

N

N

H

O

* * OH

OH

N

O

CHO

O

SCHEME 2.54  The mechanism for L-proline catalyzed self-Aldol reaction of propanal involving parasitic equilibrium.

In addition to Aldol reaction, the Michael addition of ketone to electrondeficient species also shows a similar role of proline as outlined in Scheme 2.54. For example, the reaction between cyclohexanone and 2,6-di-tert-butyl4-(4-methylbenzylidene)cyclohexa-2,5-dien-1-one in the presence of proline and DBU afforded 2-((3,5-di-tert-butyl-4-hydroxyphenyl)(p-tolyl)methyl)cyclohexan-1-one in 65%, with a 81% diastereoselectivity and 53% of ee for the minor diastereomer (Scheme 2.55) [239]. t-Bu O

O N

O

O

O

DBU N

DBU-H+

t-Bu

O t-Bu HO t-Bu 65% yield 81% de 53% ee for minor diastereomer

SCHEME 2.55  The example of Michael addition involving L-proline oxazolidin-5-one and cyclohexanone.

356

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

2.5.6 TEMPORARY PROTECTION OF α-AMINO AND CARBOXYL GROUPS As the formation of oxazolidin-5-one ring from α-amino acid involves both α-amino and carboxyl groups, oxazolidin-5-one naturally becomes a good protecting group for these two groups and opens a door for further functionalization of the amino acid side chains. For example, in order to synthesize a series of Nα-Boc ureidoalanine derivatives, L-aspartic acid was converted into (tert-butoxycarbonyl)-L-aspartic acid, which was then treated with paraformaldehyde in refluxing benzene in the presence of p-TsOH to yield 72% of (S)-2-(3-(tert-butoxycarbonyl)5-oxooxazolidin-4-yl)acetic acid. After that, the side-chain carboxyl group was treated with ethyl carbonochloridate and sodium azide in N-methyl morpholine to afford tert-butyl (S)-4-(isocyanatomethyl)-5-oxooxazolidine3-carboxylate. This compound was then allowed to react with a variety of amines to create the ureas. For example, when it was treated with aniline in CH2Cl2, tert-butyl (S)-5-oxo-4-((3-phenylureido)methyl)oxazolidine3-carboxylate was obtained at a 57% yield. Deprotection of the oxazolidin5-one with 1 N NaOH in MeOH gives the final ureidoalanine derivative of (S)-2-((tert-butoxycarbonyl)amino)-3-(3-phenylureido)propanoic acid, as shown in Scheme 2.56 [240]. Following nearly the same experimental procedure, the Fmoc protected aspartic acid and glutamic acid were transformed into (9H-fluoren-9-yl)methyl (S)-4-(isocyanatomethyl)-5-oxooxazolidine3-carboxylate and (9H-fluoren-9-yl)methyl (S)-4-(2-isocyanatoethyl)5-oxooxazolidine-3-carboxylate, respectively; which were then reacted with allyl alcohol to form (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-(((allyloxy)carbonyl)amino)butanoic acid, (S)-2-((((9H-fluoren9-yl)methoxy)carbonyl)amino)-3-(((allyloxy)carbonyl)amino)propanoic acid, etc., after deprotection. The corresponding butyl and benzyl urethane derivatives were also prepared when butyl alcohol and benzyl alcohol were used instead of allyl alcohol [241]. It is reported that 68% of tert-butyl (S)-4((((benzyloxy)carbonyl)amino)methyl)-5-oxooxazolidine-3-carboxylate can be prepared from (S)-2-(3-(tert-butoxycarbonyl)-5-oxooxazolidin-4-yl)acetic acid in three steps, whereas when tert-butyl (S)-4-(isocyanatomethyl)5-oxooxazolidine-3-carboxylate was treated with two equivalents of water, 56% of di-tert-butyl 4,4’-((carbonylbis(azanediyl))bis(methylene))(4S,4’S)-bis(5-oxooxazolidine-3-carboxylate) was obtained in total yield of 56% if counted from (S)-2-(3-(tert-butoxycarbonyl)-5-oxooxazolidin-4-yl)acetic acid [242]. Likewise, oxazolidin-5-one was applied as the temporary

Oxazolidin-5-ones 357

protection group for Nα-Fmoc and carboxyl groups of aspartic acid and glutamic acid, and the corresponding side carboxyl chain was glycosylated with different aminosugars (e.g., 2,3,4,6-O-tetraacetyl-1-glucosamine, 2,3,4,6-O-tetraacetyl-1-galactosamine, 2,3,4,6-O-tetrabenzoyl-1-glucosamine, etc.). Decomposition of the oxazolidin-5-one ring and further reaction with amino acid allowed the preparation of N-glycopeptides [243]. O

O

N H

O

N O O

O

O

(CH2O)n, p-TsOH OH

benzene, , 72%

O

O N

O

1) EtOC(O)Cl NMM, NaN3 2) toluene, 75 °C

O Ph NH

O C O

N

OH

OH O

O

PhNH2 CH2Cl2, r.t. 30 min. 57%

NH O O

O

N O

1 N NaOH MeOH

H N

O O

O

O N H OH

N H

Ph

> 90%

SCHEME 2.56  Example of protecting amino acid in oxazolidin-5-one form and functionalization of the amino acid side-chain.

Another example of using oxazolidin-5-one as a temporary protecting group is illustrated in the synthesis of (2S,3R,6S)-2,6-diamino-3-hydroxyheptanedioic acid, (2R,3S,6S)-2,6-diamino-3-hydroxyheptanedioic acid and (2R,6S)-2,6-diamino-4-fluoroheptanedioic acid from glutamic acid, respectively. For example, (R)-1-benzoyl-2-(tert-butyl)-3-methylimidazolidin4-one was deprotonated with BuLi, and the resulting enolate was allowed to react with benzyl (S)-5-oxo-4-(3-oxopropyl)oxazolidine-3-carboxylate that can be prepared from L-glutamic acid in a few steps. The resulting benzyl (S)-4-((S)-3-((2R,4R)-3-benzoyl-2-(tert-butyl)-1-methyl-5-oxoimidazolidin-4-yl)-3-hydroxypropyl)-5-oxooxazolidine-3-carboxylate was hydrolyzed under acidic condition to give (2R,3S,6S)-2,6-diamino3-hydroxyheptanedioic acid. When the aldehyde was treated with (S)-1-benzoyl-2-(tert-butyl)-3-methylimidazolidin-4-one, (2S,3R,6S)2,6-diamino-3-hydroxyheptanedioic acid can be obtained similarly. Further treatment of (2R,3S,6S)-2,6-diamino-3-hydroxyheptanedioic acid with SF4/ HF yielded (2R,6S)-2,6-diamino-4-fluoroheptanedioic acid, as shown in Scheme 2.57, which involves protonation of a hydroxy group, dehydration, and proton shift and attachment of fluorine (not shown here) [244].

358

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O N O

O

O

HO

O

H

OH

O N

NH2

Bz t-Bu BuLi

Cbz OH

HCl H2O

OH

O

N

N

O N

NH2

CO2H NH2 F

NH2

N Bz Cbz

t-Bu

HO2C CO2H SF4/HF

HO2C

O

NH2

SCHEME 2.57  Preparation of (2R,6S)-2,6-diamino-4-fluoroheptanedioic acid from L-glutamic acid.

One more example of the temporary protection illustrates the strategy to synthesize β-amino acids as shown in Scheme 2.58. In this exercise, after the protection of α-amino and carboxyl group in oxazolidin-5-one ring, the side-chain carboxyl group of (R)-3-(3-((benzyloxy)carbonyl)5-oxooxazolidin-4-yl)propanoic acid was treated with thionyl chloride and then dibenzylamine to yield 52% of benzyl (R)-4-(3-(dibenzylamino)3-oxopropyl)-5-oxooxazolidine-3-carboxylate. After the side chain was protected, the oxazolidin-5-one ring was decomposed with TFA and Et3SiH to afford 90% of N5,N5-dibenzyl-N2-((benzyloxy)carbonyl)-N2-methylD-glutamine. Then the α-carboxyl group was allowed to react with ethyl carbonochloridate and then diazomethane to generate benzyl (R)-(1-diazo6-(dibenzylamino)-2,6-dioxohexan-3-yl)(methyl)carbamate, which is ready for the Arndt-Eistert synthesis. Subsequent treatment of the diazo-compound with silver trifluoroacetate yielded 85% of (R)-3-(((benzyloxy)carbonyl) (methyl)amino)-6-(dibenzylamino)-6-oxohexanoic acid (Scheme 2.58) [245]. O HO O

Cbz 1) SOCl2 N 2) 2.0 eq. Bn2NH O CH2Cl2

1) ClCO2Et, NMM 2) CH2N2

N

O

Bn2N O 52%

O Cbz CF3CO2H Et3SiH N Bn2N CH2Cl2 O 90%

N

Cbz N O

OH

O

O

N Cbz

O

CF3CO2Ag NBn2 H2O, sonicate 85%

NBn2

HO2C Cbz

N

65%

SCHEME 2.58  Preparation of (R)-3-(((benzyloxy)carbonyl)(methyl)amino)-6-(dibenzylamino) -6-oxohexanoic acid from D-glutamic acid based oxazolidin-5-one.

Oxazolidin-5-ones 359

More examples of temporary protection of both amino and carboxyl groups with oxazolidin-5-one can be found in the synthesis of L-homoserine lactone from L-aspartic acid [246, 247], practical synthesis of glutathione tripeptide [248], and preparation of N-protected α-amino hydroxamic acids [249]. 2.5.7 PREPARATION OF PEPTIDES As oxazolidin-5-one is essentially a lactone, it can be easily opened in the presence of a nucleophilic amine. When an amino acid is used to react with oxazolidin-5-one, a peptide is formed. For example, reactions of a series of N-Cbz protected oxazolidin-5-ones that were prepared from the corresponding N-Cbz protected glycine, alanine, valine, phenylalanine, leucine, isoleucine, and (S)-2-amino-2-phenylacetic acid, with α-amino esters afforded dipeptides of good to excellent yields in most cases, after further treatment with trifluoroacetic acid and triethylsilane. Aniline also reacts with the oxazolidin-5-ones [250]. As the ester group is more reactive than the amido and carboxyl group, the formation of oxazolidin-5-one ring for the case of aspartic acid and glutamic acid can be considered a way of activation of the α-carboxyl group so that regioselective amidation of aspartic acid and glutamic acid is possible [251]. The use of oxazolidin-5-one to join amino acids to form peptides is known as peptide ligation with oxazolidinone [252]. For example, the reaction of tert-butyl (S)-4-isopropyl-5-oxooxazolidine3-carboxylate (prepared from valine) and ethyl L-serinate in CH2Cl2 at room temperature gave 63% of ethyl (tert-butoxycarbonyl)-L-valyl-L-serinate. Similarly, the reaction of the same oxazolidin-5-one with alaninol (i.e., (S)-2-aminopropan-1-ol) under the same condition afforded 82% of tert-butyl ((S)-1-(((S)-1-hydroxypropan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate, as shown in Scheme 2.59 [252]. This initial approach has been extended to the reaction of alaninol with (S)-3-acetyl-4-isopropyloxazolidin5-one, (S)-3-acetyl-4-isobutyloxazolidin-5-one, (S)-3-acetyl-4-benzyloxazolidin-5-one, and (S)-3-acetyl-4-(2-(methylthio)ethyl)oxazolidin-5-one that were prepared from the corresponding valine, leucine, phenylalanine, and methionine, respectively. This approach developed a serine peptide assembly that complemented the classic native chemical ligation [253].

360

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O

O

O + HO N

OEt NH2

Boc

CH2Cl2 r.t., 48 hrs.

Boc

O O + N Boc

OH

O N H

NH

CO2Et

63%

O HO NH2

CH2Cl2 r.t., 60 hrs.

Boc

NH

N H

OH

82%

SCHEME 2.59  Application of amino acid oxazolidin-5-one in the preparation of peptides.

One advantage of peptide ligation through oxazolidin-5-one might be the absence of racemization. It is found that N-acetoacetyl amino acids lead to optically pure peptide derivatives when they are treated with dicyclohexylcarbodiimide (DCC), and the isolated reactive acylating agents were considered as 2-acetonylidenoxazolidin-5-ones [254]. It is found that the N-α-hydroxymethyl group of a peptide bond can protect not only the related peptide bond but also an adjacent peptide bond in facing proteolytic cleavage. For this reason, various dipeptides and tripeptides with this group have been prepared to test their stability in an aqueous solution as a function of pH [255]. This explains the above synthesis of peptide derivatives with alaninol (with an adjacent hydroxyl methyl group). In addition, nucleophilic attack of the oxazolidin-5-one with amine naturally creates a hydroxymethyl group on peptide bond, such as the treatment of (S)-3-acetyl-4-benzyloxazolidin-5-one with ammonia and benzylamine to afford (S)-2-(N-(hydroxymethyl)acetamido)-3-phenylpropanamide and (S)-N-benzyl-2-(N-(hydroxymethyl)acetamido)-3-phenylpropanamide, respectively. The stability of these two compounds were tested against α-chymotrypsin in an aqueous 0.1 m phosphate buffer at pH 7.4 [256]. The N-Cbz protected oxazolidin-5-ones prepared from glycine, alanine, valine and phenylalanine with paraformaldehyde, acetaldehyde, and benzaldehyde, respectively, have been subject to similar stability studies [257]. People should be aware of the potential issue using oxazolidin-5-one in peptide synthesis, as more than one equivalent amino acid might be needed to react with the oxazolidin-5-one to form the peptide. This potential issue has been illustrated in the reaction between benzyl 5-oxooxazolidine-3-carboxylate and benzylamine, where benzyl (2-(benzylamino)-2-oxoethyl)(hydroxymethyl)carbamate was obtained when only 1.0 equivalent of benzylamine was used, and the expected benzyl (2-(benzylamino)-2-oxoethyl)carbamate was obtained in the presence of an excess amount of benzylamine.

Oxazolidin-5-ones 361

The former can also be converted into benzyl (2-(benzylamino)-2-oxoethyl) carbamate with an additional reaction with benzylamine [91]. 2.5.8 REACTIONS OCCURRING AT C5 OF OXAZOLIDIN-5-ONES In addition to the formation of peptides through oxazolidin-5-ones, a few special reactions that occur at the C5 (i.e., the carbonyl) of oxazolidin-5-ones should be commented here. One example is the conversion of N-protected amino acids into trifluoromethyl ketone derivatives, as illustrated in Scheme 2.60, starting from tert-butyl (S)-4-methyl-5-oxooxazolidine-3-carboxylate [258]. When this molecule was treated with trimethyl(trifluoromethyl)silane in THF under sonication, 85% of tert-butyl (4S)-4-methyl-5-(trifluoromethyl)5-((trimethylsilyl)oxy)oxazolidine-3-carboxylate was obtained. Further removal of the TMS group by fluoride afforded tert-butyl (4S)-5hydroxy-4-methyl-5-(trifluoromethyl)oxazolidine-3-carboxylate in nearly quantitative yield. Hydrolysis of this intermediate generated tert-butyl (S)-(4,4,4-trifluoro-3-oxobutan-2-yl)carbamate. The N-Boc-oxazolidin5-one derivatives of other amino acids including phenylalanine, alanine, glycine, valine, leucine, and methionine as well as the corresponding N-Cbz-oxazolidin-5-ones also undergo similar reactions successfully [258]. Likewise, benzyl (2R,4S)-4-isopropyl-2-(4-methoxyphenyl)-5-oxooxazolidine-3-carboxylate was transformed into benzyl (S)-(1,1,1trifluoro-4-methyl-2-oxopentan-3-yl)carbamate. Upon the treatment of the oxazolidin-5-one with trimethyl(trifluoromethyl)silane in the presence of a catalytical amount of cesium fluoride under sonication, benzyl (2R,4S)-4isopropyl-2-(4-methoxyphenyl)-5-(trifluoromethyl)-5-((trimethylsilyl)oxy)oxazolidine-3-carboxylate was obtained. Removal of trimethylsilyl group with TBAF and hydrolysis with a strong acidic ion exchange resin lead to the formation of benzyl (S)-(1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl)carbamate, as shown in Scheme 2.61 [149]. F3C OTMS F3C OH Amberlite CsF (1.0 eq.) TMS-CF3 IR-120 O cat. CsF, THF O O THF CH3CN N N sonication Boc sonication Boc quant. 85%

O

Boc

N

O CF3 NHBoc

SCHEME 2.60  A general conversion of amino acid oxazolidin-5-ones into trifluoromethyl ketones.

362

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O BnO

O TMS-CF3 O cat. CsF and sonication or TMS-CF3 cat. TBAF, THF

N O

MeO

BnO

CF3

N

O OSiMe3

1 eq. TBAF

MeO O BnO

CF3

N

O

Amberlite R IR-120 O OH CH3CN

CF3 NHCbz

MeO

SCHEME 2.61  Preparation of benzyl (S)-(1,1,1-trifluoro-4-methyl-2-oxopentan-3-yl)carbamate.

While the mechanism for the first step of the reaction in Scheme 2.60 is not quite certain, the nucleophilic addition of alkyl lithium to C5 of oxazolidin5-one to convert the oxazolidin-5-one into α-amino ketone is quite understandable. For example, (9-phenyl-9H-fluoren-9-yl)-L-alanine was converted into 94% of (S)-4-methyl-3-(9-phenyl-9H-fluoren-9-yl)oxazolidin-5-one from the reaction with formaldehyde. The oxazolidin-5-one was then treated with 1.5 equivalents of phenyl lithium, and (S)-1-phenyl-2-((9-phenyl-9Hfluoren-9-yl)amino)propan-1-one was obtained after hydrolysis (Scheme 2.62) [259]. Treatment of the oxazolidin-5-one with methyl lithium, n-butyl lithium, and even t-butyl lithium, afforded the corresponding methyl ketone, and butyl ketones, respectively. It was observed that the reaction at 0°C gave a bit lower yield than the one at –78°C. H N Ph

O

O OH

H2CO/H+ 94%

O N Ph

OLi Ph

N Ph

H+

O

H N Ph

1.5 eq. PhLi -78 °C

O Ph

SCHEME 2.62  A preparation of (S)-1-phenyl-2-((9-phenyl-9H-fluoren-9-yl)amino)propan1-one involving the oxazolidin-5-one intermediate.

Oxazolidin-5-ones 363

Reduction of the oxazolidin-5-one ring with NaBH4 is sensitive to the equivalent of NaBH4 used. For example, the reduction of benzyl (S)-4-isobutyl-5-oxooxazolidine-3-carboxylate with 1.0 equivalent of NaBH4 in MeOH at a temperature from 0°C to room temperature afforded 96% of benzyl (4S)-5-hydroxy-4-isobutyloxazolidine-3-carboxylate. Further treatment of this compound with Grignard reagent (allyl magnesium bromide) in THF under nitrogen atmosphere opened the oxazolidin-5-one ring and gave a mixture of benzyl ((4S,5S)-5-hydroxy-2-methyloct-7-en-4-yl)carbamate and benzyl ((4S,5R)-5-hydroxy-2-methyloct-7-en-4-yl)carbamate. In contrast, when benzyl (S)-4-isobutyl-5-oxooxazolidine-3-carboxylate was treated with 2.4 equivalents of NaBH4, 92% of benzyl (S)-(1-hydroxy4-methylpentan-2-yl)carbamate was obtained directly (Scheme 2.63). The oxazolidin-5-ones of other amino acids have been treated in a similar way with excellent yields of the amino alcohols. Either condition leads to the adjacent amino alcohol [260]. This strategy has been applied to an enantioselective synthesis of (1S,2S)-pseudoephedrine [261]. 2+

&E]

1

2

2+ HT1D%+ 0H2+&UW ƒ

&E]

ƒ

+1

2 HT1D%+ 0H2+&UW

&E]

1

2

ƒ

$OO0J%U 7+)1  &UW 2+

2+ 

+1

&E]

+1

&E]

SCHEME 2.63  Conversion of L-leucine oxazolidin-5-one into amino alcohols.

The easy decomposition of oxazolidin-5-one in aqueous MeOH (1:1) in the presence of 0.01 m NaHCO3 to carboxylate provides a method to remove the methyl ester during peptide synthesis without potential racemization. Methyl ester has been commonly applied to protect the carboxyl group during peptide synthesis, however, removal of the methyl group for further connection of amino acid in peptide synthesis is a potential issue because the methyl group is relatively difficult to remove and there exists a potential racemization at the adjacent chiral center. Conversion of the amino

364

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

acid methyl ester into oxazolidin-5-one and subsequent mild decomposition would be an answer [262]. Also, the C5 position of oxazolidin-5-one can function simply as a carbonyl group that is used to form C=C double bond. When N-acetyl-Lphenylalanine was converted into (S)-3-acetyl-4-benzyloxazolidin-5-one with paraformaldehyde in the presence of a catalytic amount of p-TsOH in benzene, the oxazolidin-5-one was refluxed with PPh3 and CCl4 in THF to give 96% of (S)-1-(4-benzyl-5-(dichloromethylene)oxazolidin-3-yl)ethan1-one. Further treatment of this intermediate with sodium in refluxing THF reduces chloro to hydrogen and decomposes the oxazolidin-5-one ring to afford 72% of (S)-N-(1-phenylbut-3-en-2-yl)acetamide (Scheme 2.64). The oxazolidin-5-one derivative of alanine, valine, leucine, and isoleucine have been converted successfully into the corresponding chiral allyl amine derivatives in very good yields as well [263]. O OH NHAc

O (CH2O)n, cat. p-TsOH benzene, reflux

Cl

Cl O

AcN 96%

AcN

PPh3/CCl4 O THF, reflux

Na THF, reflux

NHAc 72%

SCHEME 2.64  Transformation of N-acetyl L-phenylalanine into (S)-N-(1-phenylbut-3-en2-yl)acetamide.

Under certain conditions, the electrophilic nature of C5 might be changed into nucleophilic. For example, when tert-butyl (S)-4-methyl-5oxooxazolidine-3-carboxylate was treated with (tributylstannyl)lithium in THF, both di-tert-butyl (4S,4’S,5R,5’R)-5,5’-dihydroxy-4,4’-dimethyl[5,5’-bioxazolidine]-3,3’-dicarboxylate (63% yield) and tert-butyl (4S)-5hydroxy-4-methyloxazolidine-3-carboxylate were obtained. It is believed that it is the addition of tributyltin anion to C5 to initially form lithium (4S)-3-(tert-butoxycarbonyl)-4-methyl-5-(tributylstannyl)oxazolidin5-olate, from which tributyltin migrated to the alkoxide anion to give carbanion intermediate, i.e., ((4S)-3-(tert-butoxycarbonyl)-4-methyl-5((tributylstannyl)oxy)oxazolidin-5-yl)lithium. Compared with the starting

Oxazolidin-5-ones 365

material, the electronic nature of C5 has been changed from electrophilic to nucleophilic, so that the carbanion would add to the C5 of regular oxazolidin-5-one to form di-tert-butyl (4S,4’S,5R,5’R)-5,5’-dihydroxy-4,4’dimethyl-[5,5’-bioxazolidine]-3,3’-dicarboxylate upon workup. The workup of the carbanion prior to its addition to oxazolidin-5-one leads to tert-butyl (4S)-5-hydroxy-4-methyloxazolidine-3-carboxylate. The oxazolidin-5-one derivatives of valine, phenylalanine, and methionine undergo similar reactions to the one shown in Scheme 2.65 [264]. For comparison, when methyl benzoate was treated under the same condition, 55% of benzil was formed. In fact, hydrolysis of the oxazolidin-5-one ring in di-tert-butyl (4S,4’S,5R,5’R)-5,5’-dihydroxy-4,4’-dimethyl-[5,5’-bioxazolidine]-3,3’dicarboxylate also gives 1,2-diketone derivative. LiO SnBu 3

O Bu3SnLi Boc

N

O

THF Boc

Bu3SnO Li

O

N

Boc

O

N

O N Boc work-up

O

OH

OH OH Boc N

O

O

O

N Boc

+ Boc

N

O

O O

Bu3SnLi

55%

THF O

SCHEME 2.65  Umpolung of the carbonyl group in oxazolidin-5-one ring

2.5.9 MISCELLANEOUS REACTION OF OXAZOLIDIN-5-ONES In addition to the types of reactions involving oxaozlidin-5-ones outlined above, there are still some reactions relating to oxazolidin-5-ones that are difficult to be categorized. These reactions are organized in this subsection. Flash vacuum pyrolysis (FVP) of (2R,4S)-3-benzoyl-4-substituted2-phenyloxazolidin-5-ones at 450°C gives ((2R,3S)-2-substituted-3-phenylaziridin-1-yl)(phenyl)methanones, which further rearrange at 550°C to (4R,5S)-4-substituted-2,5-diphenyl-4,5-dihydrooxazoles. For comparison, FVP of (2R,4S)-3-benzoyl-2,4-diphenyloxazolidin-5-one generates ((2S,3R)2,3-diphenylaziridin-1-yl)(phenyl)methanone which then rearranges to

366

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

(4S,5S)-2,4,5-triphenyl-4,5-dihydrooxazole (reader should pay attention to the difference of stereochemistry of this compound). The corresponding thiocarbonyl oxazolidin-5-one, such as (2R,4S)-4-isopropyl-2-phenyl-3(phenylcarbonothioyl)oxazolidin-5-one undergoes rearrangement directly to yield (4R,5S)-4-isopropyl-2,5-diphenyl-4,5-dihydrothiazole, however, ((2R,3S)-2-isopropyl-3-phenylaziridin-1-yl)(phenyl)methanethione is too unstable to be isolated. These reactions are summarized in Scheme 2.66 [150]. O

Ph

O Ph

N

O N

O O

-CO2 450 C

Ph

Ph

N

Ph

O

550 C

Ph

Ph

S O O

N

Ph

-CO2

N

Ph

Ph

O

S Ph

Ph

Ph Ph

Ph

O

550 C

°

Ph

Ph

°

O O

N

°

N

-CO2 450 C

°

Ph

FVP

Ph

N

Ph not isolable

N S Ph

SCHEME 2.66  Flash vacuum pyrolysis of amino acid oxazolidin-5-ones.

In addition to making N-methyl amino acid derivatives as mentioned above, the reaction of oxazolidin-5-one with allylsilane in the presence of Lewis acid provides a method to prepare amino acid with a longer hydrocarbon chain attaching to the nitrogen atom. This might open a door for further modification of the amino acids. For example, the reaction of (S)-3-benzyloxycarbonyl-4-methyl-1,3-oxazolidin-5-one (i.e., benzyl (S)-4methyl-5-oxooxazolidine-3-carboxylate) with 3.0 equivalents of (E)-but2-en-1-yltriphenylsilane in the presence of 2.0 equivalents of BF3·OEt2 in CH2Cl2 for 18 hours, with TLC monitoring, yielded 40% of N-((benzyloxy)carbonyl)-N-(2-methylbut-3-en-1-yl)-L-alanine (Scheme 2.67) [265]. It is believed that this reaction involves a Lewis acid promoted decomposition of the oxazolidin-5-one ring to form an iminium intermediate which then reacts with the alkene component.

Oxazolidin-5-ones 367

2.0 eq. BF3 OEt2 O

Cbz

SiPh3 (3.0 eq.)

O

N

CO2H N Cbz

CH2Cl2

work-up

BF3 O

Cbz

N

40%

BF3

O

O Cbz

BF3 Cbz

N

BF3

N O

O Ph3Si

O

SiPh3

SiPh3

SCHEME 2.67  The mechanism for the transformation of benzyl (S)-4-methyl-5oxooxazolidine-3-carboxylate into N-Cbz-N-(2-methylbut-3-en-1-yl)-L-alanine.

In another example, using hexafluoroacetone as the protecting group, L-glutamic acid is converted into (S)-3-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)propanoic acid, of which the side chain carboxyl group is transformed into acid chloride to yield (S)-3-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)propanoyl chloride. Intramolecular cyclization yields (S)-3,3bis(trifluoromethyl)dihydro-1H,3H-pyrrolo[1,2-c]oxazole-1,5(6H)-dione. Deprotection of hexafluoroacetone under aminolysis condition with NH3 in isopropanol affords (S)-5-oxopyrrolidine-2-carboxamide (Scheme 2.68) [266]. Similarly, L-aspartic acid is protected with hexafluoroacetone to afford (S)-2-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)acetic acid, which is also treated with thionyl chloride in CH2Cl2 to yield (S)-2-(5-oxo-2,2bis(trifluoromethyl)-oxazolidin-4-yl)acetyl chloride. From this intermediate, trimethyl(vinyl)stannane is then coupled with the side chain acid chloride to form (S)-4-(2-oxobut-3-en-1-yl)-2,2-bis(trifluoromethyl)oxazolidin-5-one, from which the amino group undergoes intramolecular Michael addition in the presence of Lewis acid BF3·Et2O to generate (S)-3,3-bis(trifluoromethyl)tetrahydro-3H-oxazolo[3,4-a]pyridin-1,7-dione. This compound can be further reduced with NaBH4 to afford (7R,8aS)-7-hydroxy-3,3-bis(trifluoromethyl)tetrahydro-3H-oxazolo[3,4-a]pyridin-1(5H)-one. Further hydrolysis yields (2S,4R)4-hydroxypiperidine-2-carboxylic acid, a molecule similar to 4-hydroxyproline (Scheme 2.69) [267]. When (S)-2-(5-oxo-2,2-bis(trifluoromethyl)oxazolidin4-yl)acetyl chloride is treated with sodium azide, (S)-3,3-bis(trifluoromethyl)dihydro-1H,3H-imidazo[1,5-c]oxazole-1,5(6H)-dione is formed. Hydrolytic deprotection of hexafluoroacetone leads to the formation of (S)-2-oxoimidazolidine-4-carboxylic acid, as shown in Scheme 2.70 [175].

368

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O F3C

H N

F3C

O

OH

1) SOCl2, CH2Cl2 2) NH3, i-PrOH

H N

O

H

O SOCl2/CH2Cl2

O NH2

NH3/i-PrOH

O O

Cl H N F3C F3C

O

F3C

N

F3C

O

O

O

SCHEME 2.68  Preparation of (S)-5-oxopyrrolidine-2-carboxamide from (S)-3-(5-oxo-2,2bis(trifluoromethyl)oxazolidin-4-yl)propanoic acid.

Likewise, with hexafluoroacetone as the protecting group, L-phenylalanine has been converted into (S)-4-benzyl-2,2-bis(trifluoromethyl)oxazolidin5-one, which then reacts with formaldehyde in the presence of thionyl chloride to give (S)-4-benzyl-3-(chloromethyl)-2,2-bis(trifluoromethyl)oxazolidin5-one. This compound undergoes intramolecular cyclization in the presence of BF3·Et2O at room temperature to afford (S)-3,3-bis(trifluoromethyl)10,10a-dihydro-3H-oxa-zolo[3,4-b]isoquinolin-1(5H)-one. Hydrolytic deprotection of the hexafluoroacetone group yields (S)-1,2,3,4tetrahydroisoquinoline-3-carboxylic acid, as displayed in Scheme 2.71 [268]. Alternatively, in the presence of trifluoroacetic acid in CHCl3, (S)-4-benzyl2,2-bis(trifluoromethyl)oxazolidin-5-one reacts with formaldehyde to give (S)-3,3-bis(trifluoromethyl)-10,10a-dihydro-3H-oxazolo[3,4-b]isoquinolin1(5H)-one by means of (S)-4-benzyl-3-(hydroxymethyl)-2,2-bis(trifluoromethyl)oxazolidin-5-one intermediate, which dehydrates in the presence of CF3CO2H to form (S)-4-benzyl-3-methylene-5-oxo-2,2-bis(trifluoromethyl)oxazolidin-3-ium. Intramolecular cyclization with phenyl ring followed by deprotonation also gives (S)-3,3-bis(trifluoromethyl)-10,10a-dihydro-3Hoxazolo[3,4-b]isoquinolin-1(5H)-one. In addition to the above reactions of 2,2-bis-(trifluoromethyl)-1,3oxazolidin-5-ones, some unexpected reactions should be pointed out as well. It is found that 2,2-bis(trifluoromethyl)oxazolidin-5-one itself formed from the condensation between glycine and hexafluoroacetone undergoes Aldol reaction with hexafluoroacetone in DMSO to yield 4-(1,1,1,3,3,3-hexafluoro2-hydroxypropan-2-yl)-2,2-bis(trifluoromethyl)oxazolidin-5-one. Ring opening of this intermediate at temperature ranging from 40 to 80°C in DMSO affords 4,4,4-trifluoro-3-hydroxy-2-((perfluoropropan-2-ylidene)

Oxazolidin-5-ones 369

+ 1

)& )&

2+

2

2

 62&O&+&O

6Q0H



2

%)(W2

)&

+ 1

)&

2

6Q0H

2

2

1D%+ &)2+

2

&O

2

&)

)&

+ 1

)&

2

1

 %)(W2EHQ]HQH

62&O&+&O )&

+ 2

2

+ 2

+2 2 + 2

+2

2

1

1+

)&

+ 2

&)

2+

SCHEME 2.69  Synthesis of (2S,4R)-4-hydroxypiperidine-2-carboxylic acid from (S)-2-(5oxo-2,2-bis(trifluoromethyl)oxazolidin-4-yl)acetic acid.

F3C F3C

O

H N O

OH O O

1) SOCl2 2) NaN3

NH

F3C

N

F3C

O

H 2O

O

NH OH

HN

H

H

O

O

SCHEME 2.70  Preparation of (S)-2-oxoimidazolidine-4-carboxylic acid from (S)-2-(5-oxo2,2-bis(trifluoromethyl)oxazolidin-4-yl)acetic acid. + 2 1+

2+

+2

)&

+ 1

)&

2

 &+2

62&O

&) &O

)&

2

2

%)(W2 UW

1

&)

)& 2

1

2 +

2 + &+&O 2+

)&

1

)&

2

2

&)

)&

&)&2+ )&

1

)&

2

2 2

+

1

2 +

SCHEME 2.71  The mechanism for the formation of (S)-1,2,3,4-tetrahydroisoquinoline-3carboxylic acid from (S)-4-benzyl-2,2-bis(trifluoromethyl)oxazolidin-5-one.

370

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

amino)-3-(trifluoromethyl)butanoic acid, which undergoes 5-endo trig cyclization process to form 2,2,5,5-tetrakis(trifluoromethyl)oxazolidine-4carboxylic acid. In comparison, 4-methyl-2,2-bis(trifluoromethyl)oxazolidin5-one generated from alanine and hexafluoroacetone also undergoes ring opening rearrangement to give 2-((perfluoropropan-2-ylidene)amino)propanoic acid. However, this molecule undergoes either retro-ene reaction to yield (E)-N(1,1,1,3,3,3-hexafluoropropan-2-yl)ethanimine or intramolecular 1,3-H shift to form (Z)-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)imino)propanoic acid, as illustrated in Scheme 2.72 [269]. These two molecules formed from either path then react with hexafluoroacetone to generate (E)-1,1,1trifluoro-4-((1,1,1,3,3,3-hexafluoropropan-2-yl)imino)-2-(trifluoromethyl)butan-2-ol and (Z)-5,5,5-trifluoro-2-((1,1,1,3,3,3-hexafluoropropan-2-yl)imino)-4-hydroxy-4-(trifluoromethyl)pentanoic acid, respectively. The former compound forms equilibrium with (E)-1,1,1-trifluoro-4-((1,1,1,3,3,3hexafluoropropan-2-yl)amino)-2-(trifluoromethyl)but-3-en-2-ol by means of 1,3-H shift, whereas the latter undergoes intramolecular lactonization to give (Z)-3-((1,1,1,3,3,3-hexafluoropropan-2-yl)-imino)-5,5-bis(trifluoromethyl) dihydrofuran-2(3H)-one, which then undergoes 1,3-H shift to form 3-((1,1,1,3,3,3-hexafluoropropan-2-yl)amino)-5,5-bis(trifluoromethyl) furan-2(5H)-one. Finally, a bicyclic oxazolidin-5-one, i.e., (1R,4R)-5-chloro-3-oxo-4-phenyl1-(trifluoromethyl)-2-oxa-7-azabicyclo[2.2.1]heptane-5-carbonitrile that is formed from the 1,3-dipolar cycloaddition between 4-phenyl-2-(trifluoromethyl)oxazol-5(2H)-one and 2-chloroacrylonitrile, has been converted into 2-phenyl5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile upon treatment with NaOH. This transformation is assumed to involve an elimination of hydrogen chloride to form (1R,4S)-3-oxo-4-phenyl-1-(trifluoromethyl)-2-oxa-7-azabicyclo[2.2.1]hept-5-ene-5-carbonitrile intermediate, which undergoes retro-Diels-Alder reaction to extrude CO2 to give 2-phenyl-5-(trifluoromethyl)-1H-pyrrole-3carbonitrile, as illustrated in Scheme 2.73 [270].

CF3

F3C

N

N

CF3

CF3

CO2H

CF3

CF3

F3C

CF3

retro ene

O

HN F 3C

CO2

F3C CF3 DMSO

CO2H

HO

OH N

F3C

O

HO F3C

F3C

CF3

CF3

CF3

CO2H

F 3C

40-80 C DMSO

CF3 CF3

H

CF3

O

O

F3C

N

CF3

H2 O

F3C

F 3C

N

F3C

CF3

CF3

O

CF3 O

CF3

H

5-endo trig

OH N

F3C

CF3

N

CF3 CO2H

F3C

HN

F3C

CF3

O

CF3 O

OH H

F3C

CF3

H N

CO2H NH

CF3

F3C

F3C

O

F3C

CF3

CF3

SCHEME 2.72  Transformation of 2,2-bis(trifluoromethyl)oxazolidin-5-one into 2,2,5,5-tetrakis(trifluoromethyl)oxazolidine-4-carboxylic acid, and the mechanism for the conversion of 4-methyl-2,2-bis(trifluoromethyl)oxazolidin-5-one into (E)-1,1,1-trifluoro-4-((1,1,1,3,3,3hexafluoropropan-2-yl)amino)-2-(trifluoromethyl)but-3-en-2-ol and 3-((1,1,1,3,3,3-hexafluoropropan-2-yl)amino)-5,5-bis(trifluoromethyl) furan-2(5H)-one.

O

CF3

F3C

F3C

O

°

HN

O

O

HN

O

Oxazolidin-5-ones 371

372

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

O

F3C H N

O N

CF3

Cl

CN NC

O O Cl Ph HCl

NaOH/H2O

F3C

H N

CN NaOH CO2

F3C H N O NC

Ph O

SCHEME 2.73  The mechanism for the transformation of 4-phenyl-2-(trifluoromethyl) oxazol-5(2H)-one into 2-phenyl-5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile.

2.6 APPLICATIONS Although not many simple 1,3-oxazolidin-5-one derivatives have been identified with important biological activities, such as antibacterial and antimicrobial activities [185, 187], the easiness of preparation and diversity of functional groups associated with 1,3-oxazolidin-5-ones may render their wide applications in medicinal chemistry, should these type of molecules have been greatly explored, particularly after the actual applications of Jadomycins. One reason for not many practical applications associated with oxazolidin-5-one derivatives (such as directly used in medicine) might be the relative stability of this type of molecule. However, 1,3-oxazolidin-5ones have a variety of applications in the total synthesis and development of synthetic methodologies, including the preparation of α-substituted amino acids, N-substituted amino acids, unnatural amino acids and peptides. Currently, the major synthetic applications of 1,3-oxazolidin-5-ones have been devoted to the syntheses of α-substituted amino acids, particularly the chiral amino acids with a quaternary α-carbon atom, by means of the strategy of self-reproduction of chirality [139, 143]. This potential has been greatly explored when benzaldehyde or pivalaldehyde is applied to react with amino acids, in the formation of 1,3-oxazolidin-5-ones of different diastereoselectivity. Due to the presence of a chiral center at position 2, the enolate generated from the deprotonation at position C4 of the oxazolidin-5-one ring would demonstrate a face preference in approaching an alkylating agent, resulting in 4-alkylated 1,3-oxazolidin-5-ones of predetermined chirality. Upon hydrolysis of the alkylated oxazolidin-5-ones, the α-substituted amino acids are obtained, as displayed in Schemes 2.16, 2.19, 2.22, 2.25, 2.27, and 2.43–2.47. In addition, the enolates generated can also undergo nucleophilic

Oxazolidin-5-ones 373

addition to aldehydes or ketones to create α-substituted amino acids, as illustrated in Schemes 2.26 and 2.50. In addition to this general approach of self-reproduction of chirality, some other α-substituted amino acids have also been prepared from a specific amino acid (i.e., L-cysteine [131, 132], L-alanine [152]), via cycloaddition as demonstrated in Scheme 2.18. The preparation of N-substituted amino acids has been focused on the generation of N-methyl amino acids by means of reduction of the 1,3-oxazolidin-5-ones from the reaction between amino acids and paraformaldehyde, as demonstrated in Schemes 2.8 and 2.49. In theory, the 1,3-oxazolidin-5-ones prepared from amino acids and other aldehydes (e.g., acetaldehyde, pivalaldehyde) can also be converted into N-substituted amino acids, but actual examples have not been found in the cited references yet. The synthesis of unnatural amino acids starting from 1,3-oxazolidin-5ones have been demonstrated in Scheme 2.24, for the preparation of D-leucine from L-alanine as well as a series of γ-amido, γ-amino, γ-chloro, γ-hydroxy, γ-oxo, and γ-acyloxy amino acids [152]. Another example of synthesis of unnatural amino acid is illustrated in Scheme 2.38 for the construction of (2S,5R)-5-fluoropiperidine-2-carboxylic acid and (S)-5,5-difluoropiperidine2-carboxylic acid from L-glutamic acid [170]. Alternatively, 1,3-oxazolidin-5-one can be applied as the concomitant protecting group for both α-amino and carboxyl groups so that the side chain functional group of the relevant amino acids can be further transformed, as demonstrated in Schemes 2.29, 2.31, 2.32, 2.35, and 2.56–2.58. In addition, 1,3-oxazolidin-5-one can be considered as an activation of the carboxyl group, particularly when hexafluoroacetone is used to form the 1,3-oxazolidin-5-one, for the synthesis of peptides in reaction with additional amino acid, as illustrated in Schemes 2.15, 2.34, 2.36, and 2.59. Overall, there have been many examples of the transformations of amino acids into other derivatives in the literature, which are too much to be collected in this chapter. More opportunities for using oxazolidin-5-ones as starting materials or reaction intermediates in organic total synthesis can be explored in the future.

374

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

KEYWORDS • • • • • • • • • •

1,3-Dipolar cycloaddition Aldol condensation hexafluoroacetone methicillin-resistant staphylococcus aureus minimum inhibitory concentrations multidrug resistant Michael reaction N-methyl amino acid parasitic equilibrium polyketide synthase

REFERENCES 1. 2. 3. 4. 5. 6.

7.

8.

Karmakar, S., & Mohapatra, D. K., (2001). A novel synthesis of oxazolidin-5-one under basic condition. Synlett, (8), 1326–1328. doi: 10.1055/s-2001-16035. Wang, H., & Germanas, J. P., (1999). 4-Alkyl-2-(trichloromethyl)oxazolidin-5-ones. Valuable precursors to enantiomerically pure C- and N-protected α-Alkylprolines. Synlett, (1), 33–36. doi: 10.1055/s-1999–2548. Chowdhry, M. I., Horton, P. N., Hursthouse, M. B., & Wood, M. E., (2009). α-Allylation of α-amino acids via 1,5-hydrogen atom transfer. Tetrahedron Letters, 50(26), 3400– 3403. doi: 10.1016/j.tetlet.2009.02.110. Sureshbabu, V. V., & Narendra, N., (2011). Protection reactions. In: Hughes, A. B., (ed.), Amino Acids, Peptides and Proteins in Organic Chemistry (Vol. 4, pp. 78, 79). WILEY-VCH Verlag & Co. KGaA. Rubiales, G., Alonso, C., Martínez De, M. E., & Palacios, F., (2014). Nucleophilic trifluoromethylation of carbonyl compounds and derivatives. ARKIVOC, (ii), 362–405. doi: 10.3998/ark.5550190.p008.340. Ma, X., Zhang, X., Qiu, W., Zhang, W., Wan, B., Evans, J., & Zhang, W., (2019). One-pot synthesis of triazolobenzodiazepines through decarboxylative [3 + 2] cycloaddition of nonstabilized azomethine ylides and Cu-free click reactions. Molecules, 24(3), 601/1–601/7. doi: 10.3390/molecules24030601. Coe, D. M., Perciaccante, R., & Procopiou, P. A., (2003). Potassium trimethylsilanolate induced cleavage of 1,3-oxazolidin-2- and 5-ones, and application to the synthesis of (R)-salmeterol. Organic & Biomolecular Chemistry, 1(7), 1106–1111. doi: 10.1039/ b212454h. Aurelio, L., & Hughes, A. B., (2009). Synthesis of N-alkyl amino acids. In: Hughes, A. B., (ed.), Amino Acids, Peptides and Proteins in Organic Chemistry (Vol. 1, pp. 245–289). Wiley-VCH Verlag & Co. KGaA.

Oxazolidin-5-ones 375

9.

10.

11.

12. 13. 14.

15. 16. 17.

18.

19. 20. 21. 22.

Hughes, A. B., & Sleebs, B. E., (2006). Effective methods for the synthesis of N-methyl β-amino acids from all twenty common α-amino acids using 1,3-oxazolidin-5-ones and 1,3-oxazinan-6-ones. Helvetica Chimica Acta, 89(11), 2611–2637. doi: 10.1002/ hlca.200690235. Casimir, J. R., Tourwe, D., Iterbeke, K., Guichard, G., & Briand, J. P., (2000). Efficient synthesis of (S)-4-phthalimido-1,3,4,5-tetrahydro-8-(2,6-dichlorobenzyloxy)-3-oxo2H-2-benzazepin-2-acetic acid (Pht-Hba(2,6-Cl2-Bn)-Gly-OH). Journal of Organic Chemistry, 65(20), 6487–6492. doi: 10.1021/jo000530d. Seebach, D., & Fadel, A., (1985). N,O-Acetals from pivalaldehyde and amino acids for the α-alkylation with self-reproduction of the center of chirality. Enolates of 3-benzoyl2-(tert-butyl)-1,3-oxazolidin-5-ones. Helvetica Chimica Acta, 68(5), 1243–1250. doi: 10.1002/hlca.19850680521. Doull, J. L., Ayer, S. W., Singh, A. K., & Thibault, P., (1993). Production of a novel polyketide antibiotic, Jadomycin B, by Streptomyces venezuelae following heat shock. Journal of Antibiotics, 46(5), 869–871. doi: 10.7164/antibiotics.46.869. Syvitski, R. T., Borissow, C. N., Graham, C. L., & Jakeman, D. L., (2006). Ring-opening Dynamics of Jadomycin A and B and dalomycin T. Organic Letters, 8(4), 697–700. doi: 10.1021/ol052814w. Ayer, S. W., McInnes, A. G., Thibault, P., Walter, J. A., Doull, J. L., Parnell, T., & Vining, L. C., (1991). Jadomycin, a novel 8H-benz[b]oxazolo[3,2-f]phenanthridine antibiotic from Streptomyces venezuelae ISP5230. Tetrahedron Letters, 32(44), 6301–6304. doi: 10.1016/0040-4039(91)80152-V. Jakeman, D. L., Dupuis, S. N., & Graham, C. L., (2009). Isolation and characterization of Jadomycin L from Streptomyces venezuelae ISP5230 for solid tumor efficacy studies. Pure & Applied Chemistry, 81(6), 1041–1049. doi: 10.1351/PAC-CON-08-11-08. Rix, U., Zheng, J., Rix, L. L. R., Greenwell, L., Yang, K., & Rohr, J., (2004). The dynamic structure of Jadomycin B and the amino acid incorporation step of its biosynthesis. Journal of the American Chemical Society, 126(14), 4496, 4497. doi: 10.1021/ja031724o. Tibrewal, N., Pahari, P., Wang, G., Kharel, M. K., Morris, C., Downey, T., Hou, Y., et al., (2012). Baeyer-Villiger C-C bond cleavage reaction in Gilvocarcin and Jadomycin biosynthesis. Journal of the American Chemical Society, 134(44), 18181–18184. doi: 10.1021/ja3081154. Li, L., Pan, G., Zhu, X., Fan, K., Gao, W., Ai, G., Ren, J., et al., (2017). Engineered Jadomycin analogues with altered sugar moieties revealing jads as a substrate flexible O-glycosyltransferase. Applied Microbiology and Biotechnology, 101(13), 5291–5300. doi: 10.1007/s00253-017-8256-y. MacLeod, J. M., Forget, S. M., & Jakeman, D. L., (2018). The expansive library of Jadomycins. Canadian Journal of Chemistry, 96(6), 495–501. doi: 10.1139/ cjc-2017-0573. Borissow, C. N., Graham, C. L., Syvitski, R. T., Reid, T. R., Blay, J., & Jakeman, D. L., (2007). Stereochemical integrity of oxazolone ring-containing Jadomycins. ChemBioChem, 8(10), 1198–1203. doi: 10.1002/cbic.200700204. Zheng, J. T., Rix, U., Zhao, L., Mattingly, C., Adams, V., Chen, Q., Rohr, J., & Yang, K. Q., (2005). Cytotoxic activities of new Jadomycin derivatives. Journal of Antibiotics, 58(6), 405–408. doi: 10.1038/ja.2005.51. Forget, S. M., Robertson, A. W., Overy, D. P., Kerr, R. G., & Jakeman, D. L., (2017). Furan and lactam Jadomycin biosynthetic congeners isolated from Streptomyces venezuelae

376

23.

24.

25. 26.

27.

28. 29.

30.

31.

32.

33. 34.

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

ISP5230 cultured with Nε-trifluoroacetyl-L-lysine. Journal of Natural Products, 80(6), 1860–1866. doi: 10.1021/acs.jnatprod.7b00152. Dupuis, S. N., Veinot, T., Monro, S. M. A., Douglas, S. E., Syvitski, R. T., Goralski, K. B., McFarland, S. A., & Jakeman, D. L., (2011). Jadomycins derived from the assimilation and incorporation of Norvaline and Norleucine. Journal of Natural Products, 74(11), 2420–2424. doi: 10.1021/np200689w. Robertson, A. W., Martinez-Farina, C. F., Smithen, D. A., Yin, H., Monro, S., Thompson, A., McFarland, S. A., et al., (2015). Eight-membered ring-containing Jadomycins: Implications for non-enzymatic natural products biosynthesis. Journal of the American Chemical Society, 137(9), 3271–3275. doi: 10.1021/ja5114672. Jakeman, D. L., Farrell, S., Young, W., Doucet, R. J., & Timmons, S. C., (2005). Novel Jadomycins: Incorporation of non-natural and natural amino acids. Bioorganic & Medicinal Chemistry Letters, 15(5), 1447–1449. doi: 10.1016/j.bmcl.2004.12.082. Dupuis, S. N., Robertson, A. W., Veinot, T., Monro, S. M. A., Douglas, S. E., Syvitski, R. T., Goralski, K. B., et al., (2012). Synthetic diversification of natural products: Semisynthesis and evaluation of triazole Jadomycins. Chemical Science, 3(5), 1640–1644. doi: 10.1039/c2sc00663d. Martinez-Farina, C. F., Robertson, A. W., Yin, H., Monro, S., McFarland, S. A., Syvitski, R. T., & Jakeman, D. L., (2015). Isolation and synthetic diversification of Jadomycin 4-amino-L-phenylalanine. Journal of Natural Products, 78(6), 1208–1214. doi: 10.1021/ np5009398. Jakeman, D. L., Graham, C. L., & Reid, T. R., (2005). Novel and expanded Jadomycins incorporating non-proteogenic amino acids. Bioorganic & Medicinal Chemistry Letters, 15(23), 5280–5283. doi: 10.1016/j.bmcl.2005.08.047. Hall, S. R., Blundon, H. L., Ladda, M. A., Robertson, A. W., Martinez-Farina, C. F., Jakeman, D. L., & Goralski, K. B., (2015). Jadomycin breast cancer cytotoxicity is mediated by a copper-dependent, reactive oxygen species-inducing mechanism. Pharmacology Research & Perspectives, 3(2), 110/1–110/16. doi: 10.1002/prp2.110. Cottreau, K. M., Spencer, C., Wentzell, J. R., Graham, C. L., Borissow, C. N., Jakeman, D. L., & McFarland, S. A., (2010). Diverse DNA-cleaving capacities of the Jadomycins through precursor-directed biosynthesis. Organic Letters, 12(6), 1172–1175. doi: 10.1021/ol902907r. Fan, K., Zhang, X., Liu, H., Han, H., Luo, Y., Wang, Q., Geng, M., & Yang, K., (2012). Evaluation of the cytotoxic activity of new Jadomycin derivatives reveals the potential to improve its selectivity against tumor cells. Journal of Antibiotics, 65(9), 449–452. DOI:10.1038/ja.2012.48. Wang, W., Ji, J., Li, X., Wang, J., Li, S., Pan, G., Fan, K., & Yang, K., (2014). Angucyclines as signals modulate the behaviors of streptomyces coelicolor. Proceedings of the National Academy of Sciences of the United States of America, 111(15), 5688–5693. doi: 10.1073/ pnas.1324253111. Martinez-Farina, C. F., & Jakeman, D. L., (2015). Jadomycins, put a bigger ring in it: Isolation of seven- to ten-membered ring analogues. Chemical Communications (Cambridge, United Kingdom), 51(78), 14617–14619. doi: 10.1039/c5cc05571g. Jakeman, D. L., Borissow, C. N., Graham, C. L., Timmons, S. C., Reid, T. R., & Syvitski, R. T., (2006). Substrate flexibility of a 2,6-dideoxyglycosyltransferase. Chemical Communications (Cambridge, United Kingdom), (35), 3738–3740. doi: 10.1039/ B608847C.

Oxazolidin-5-ones 377

35. Wang, L., White, R. L., & Vining, L. C., (2002). Biosynthesis of the dideoxysugar component of Jadomycin B: Genes in the jad cluster of Streptomyces venezuelae ISP5230 for L-digitoxose assembly and transfer to the angucycline aglycone. Microbiology (Reading, United Kingdom), 148(4), 1091–1103. doi: 10.1099/00221287-148-4-1091. 36. Shan, M., Sharif, E. U., & O’Doherty, G. A., (2010). Total synthesis of Jadomycin A and a carbasugar analogue of Jadomycin B. Angewandte Chemie (International Edition in English), 49(49), 9492–9495. doi: 10.1002/anie.201005329. 37. Forget, S. M., Na, J., McCormick, N. E., & Jakeman, D. L., (2017). Biosynthetic 4,6-dehydratase gene deletion: Isolation of a glucosylated Jadomycin natural product provides insight into the substrate specificity of glycosyltransferase JadS. Organic & Biomolecular Chemistry, 15(13), 2725–2729. doi: 10.1039/C7OB00259A. 38. Yang, X., & Yu, B., (2013). Total synthesis of Jadomycins B, S, T, and ILEVS1080. Chemistry - A European Journal, 19(26), 8431–8434. doi: 10.1002/chem.201301297. 39. Tajima, T., Akagi, Y., Kumamoto, T., Suzuki, N., & Ishikawa, T., (2012). Synthesis of Jadomycin A and related Jadomycin aglycons: Structural re-examination of jadomycins S and T may be needed. Tetrahedron Letters, 53(4), 383–387. doi: 10.1016/j. tetlet.2011.10.160. 40. Robertson, A. W., Forget, S. M., Martinez-Farina, C. F., McCormick, N. E., Syvitski, R. T., & Jakeman, D. L., (2016). JadX is a disparate natural product binding protein. Journal of the American Chemical Society, 138(7), 2200–2208. doi: 10.1021/jacs.5b11286. 41. Rohr, J., & Thiericke, R., (1992). Angucycline group antibiotics. Natural Product Reports, 9(2), 103–137. doi: 10.1039/NP9920900103. 42. Kuntsmann, M. P., & Mitscher, L. A., (1966). The structural characterization of Tetrangomycin and Tetrangulol. Journal of Organic Chemistry, 31(9), 2920–2925. doi: 10.1021/jo01347a043. 43. Kharel, M. K., & Rohr, J., (2012). Delineation of Gilvocarcin, Jadomycin, and Landomycin pathways through combinatorial biosynthetic enzymology. Current Opinion in Chemical Biology, 16(1, 2), 150–161. doi: 10.1016/j.cbpa.2012.03.007. 44. Abdalla, M. A., Helmke, E., & Laatsch, H., (2010). Marine bacteria. XLIV. Fujianmycin C, a bioactive angucyclinone from a marine derived Streptomyces sp. B6219. Natural Product Communications, 5(12), 1917–1920. doi: 10.1177/1934578X1000501216. 45. Sezaki, M., Kondo, S., Maeda, K., Umezawa, H., & Ono, M., (1970). The structure of Aquayamycin. Tetrahedron, 26(22), 5171–5190. doi: 10.1016/S0040-4020(01)98726-5. 46. Uchida, T., Imoto, M., Watanabe, Y., Miura, K., Dobashi, T., Matsuda, N., Sawa, T., et al., (1985). Saquayamycins, new aquayamycin-group antibiotics. The Journal of Antibiotics, 38(9), 1171–1181. doi: 10.7164/antibiotics.38.1171. 47. Wang, K. K. A., Ng, T. L., Wang, P., Huang, Z., Balskus, E. P., & Van, D. D. W. A., (2018). Glutamic acid is a carrier for hydrazine during the biosyntheses of Fosfazinomycin and Kinamycin. Nature Communications, 9(1), 1–11. doi: 10.1038/s41467-018-06083-7. 48. Kusumi, S., Tomono, S., Okuzawa, S., Kaneko, E., Ueda, T., Sasaki, K., Takahashi, D., & Toshima, K., (2013). Total synthesis of Vineomycin B2. Journal of the American Chemical Society, 135(42), 15909–15912. doi: 10.1021/ja407827n. 49. Abdelfattah, M. S., Kharel, M. K., Hitron, J. A., Baig, I., & Rohr, J., (2008). Moromycins A and B, isolation and structure elucidation of C-glycosylangucycline-type antibiotics from Streptomyces sp. KY002. Journal of Natural Products, 71(9), 1569–1573. doi: 10.1021/np800281f.

378

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

50. Hoffmeister, D., Draeger, G., Ichinose, K., Rohr, J., & Bechthold, A., (2003). The C-glycosyltransferase UrdGT2 is unselective toward D- and L-configured nucleotidebound rhodinoses. Journal of the American Chemical Society, 125(16), 4678, 4679. doi: 10.1021/ja029645k. 51. Henkel, T., Rohr, J., Beale, J. M., & Schwenen, L., (1990). Landomycins, new angucycline antibiotics from Streptomyces sp. I. Structural studies on landomycins A-D. The Journal of Antibiotics, 43(5), 492–503. doi: 10.7164/antibiotics.43.492. 52. Koo, B., & McDonald, F. E., (2007). Fischer carbene catalysis of alkynol cycloisomerization: Application to the synthesis of the altromycin B disaccharide. Organic Letters, 9(9), 1737–1740. doi: 10.1021/ol070435s. 53. Fei, Z., & McDonald, F. E., (2005). Synthesis of the aglycones of Altromycins and Kidamycin from a common intermediate. Organic Letters, 7(17), 3617–3620. doi: 10.1021/ol0509742. 54. Wada, S. I., Sawa, R., Iwanami, F., Nagayoshi, M., Kubota, Y., Iijima, K., Hayashi, C., et al., (2017). Structures and biological activities of novel 4’-acetylated analogs of Chrysomycins A and B. Journal of Antibiotics, 70(11), 1078–1082. doi: 10.1038/ ja.2017.99. 55. Krohn, K., & Vitz, J., (2004). Total synthesis of Premithramycinone H and related Anthrapyran antibiotics. European Journal of Organic Chemistry, (1), 209–219. doi: 10.1002/ejoc.200300451. 56. Bruntner, C., Binder, T., Pathom-Aree, W., Goodfellow, M., Bull, A. T., Potterat, O., Puder, C., et al., (2005). Frigocyclinone, a novel angucyclinone antibiotic produced by a streptomyces griseus strain from antarctica. Journal of Antibiotics, 58(5), 346–349. doi: 10.1038/ja.2005.43. 57. Paananen, P., Patrikainen, P., Kallio, P., Mantsala, P., Niemi, J., Niiranen, L., & MetsaKetela, M., (2013). Structural and functional analysis of Angucycline C-6 ketoreductase LanV involved in Landomycin biosynthesis. Biochemistry, 52(31), 5304–5314. doi: 10.1021/bi400712q. 58. Jones, K. D., Rixson, J. E., Skelton, B. W., Gericke, K. M., & Stewart, S. G., (2015). The total synthesis of Heraclemycin B through β-ketosulfoxide and aldehyde annulation. Asian Journal of Organic Chemistry, 4(9), 936–942. doi: 10.1002/ajoc.201500184. 59. Kalyon, B., Tan, G. Y. A., Pinto, J. M., Foo, C. Y., Wiese, J., Imhoff, J. F., Suessmuth, R. D., et al., (2013). Langkocyclines: novel angucycline antibiotics from Streptomyces sp. Acta 3034. Journal of Antibiotics, 66(10), 609–616. doi: 10.1038/ja.2013.53. 60. Takahashi, T., Sakamoto, Y., Yamada, H., Usui, S., & Fukazawa, Y., (1995). Synthesis of a dynemicin A analog and its Bergman-type cycloaromatization. Angewandte Chemie, International Edition in English, 34(12), 1345–1348. doi: 10.1002/anie.199513451. 61. Noinaj, N., Bosserman, M. A., Schickli, M. A., Piszczek, G., Kharel, M. K., Pahari, P., Buchanan, S. K., & Rohr, J., (2011). The crystal structure and mechanism of an unusual oxidoreductase, GilR, involved in Gilvocarcin V biosynthesis. Journal of Biological Chemistry, 286(26), 23533–23543. doi: 10.1074/jbc.M111.247833. 62. Wessels, P., Goehrt, A., Zeeck, A., Drautz, H., & Zaehner, H., (1991). Metabolic products of microorganisms. 260. Naphthgeranines, new naphthoquinone antibiotics from Streptomyces sp. Journal of Antibiotics, 44(9), 1013–1018. doi: 10.7164/ antibiotics.44.1013. 63. Kitamura, K., Ando, Y., Matsumoto, T., & Suzuki, K., (2014). Synthesis of the Pluramycins 1: Two designed anthrones as enabling platforms for flexible

Oxazolidin-5-ones 379

64. 65.

66.

67.

68. 69. 70. 71.

72. 73.

74.

75. 76.

bis-C-glycosylation. Angewandte Chemie, International Edition, 53(5), 1258–1261. doi: 10.1002/anie.201308016. Parker, K. A., & Koh, Y. H., (1994). Methodology for the regiospecific synthesis of bis C-aryl glycosides. Models for Kidamycins. Journal of the American Chemical Society, 116(24), 11149, 11150. doi: 10.1021/ja00103a037. Cai, X., Ng, K., Panesar, H., Moon, S. J., Paredes, M., Ishida, K., Hertweck, C., & Minehan, T. G., (2014). Total synthesis of the antitumor natural product Polycarcin V and evaluation of its DNA binding profile. Organic Letters, 16(11), 2962–2965. doi: 10.1021/ol501095w. Kitamura, K., Maezawa, Y., Ando, Y., Kusumi, T., Matsumoto, T., & Suzuki, K., (2014). Synthesis of the Pluramycins 2: Total synthesis and structure assignment of Saptomycin B. Angewandte Chemie, International Edition, 53(5), 1262–1265. doi: 10.1002/ anie.201308017. Rixson, J. E., Abraham, J. R., Egoshi, Y., Skelton, B. W., Young, K., Gilbert, J., Sakoff, J. A., et al., (2015). The synthesis and biological activity of novel anthracenone-pyranones and anthracenone-furans. Bioorganic & Medicinal Chemistry, 23(13), 3552–3565. doi: 10.1016/j.bmc.2015.04.032. Kharel, M. K., Zhu, L., Liu, T., & Rohr, J., (2007). Multi-oxygenase complexes of the Gilvocarcin and Jadomycin biosyntheses. Journal of the American Chemical Society, 129(13), 3780, 3781. doi: 10.1021/ja0680515. De Koning, C. B., Ngwira, K. J., & Rousseau, A. L., (2020). Biosynthesis, synthetic studies, and biological activities of the Jadomycin alkaloids and related analogues. Alkaloids (San Diego, CA, United States), 84, 125–199. doi: 10.1016/bs.alkal.2020.02.001. Lipinski, C. A., (2016). Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions. Advanced Drug Delivery Reviews, 101, 34–41. doi: 10.1016/j.addr.2016.04.029. Barka, E. A., Vatsa, P., Sanchez, L., Gaveau-Vaillant, N., Jacquard, C., Clement, C., Meier-Kolthoff, J. P., et al., (2016). Taxonomy, physiology, and natural products of actinobacteria. Microbiology and Molecular Biology Reviews: MMBR, 80(1), 1–43. doi: 10.1128/MMBR.00019-15. Wang, J., Zhou, B., Ge, R., Song, T. S., Yu, J., & Xie, J., (2018). Degradation characterization and pathway analysis of chlorotetracycline and oxytetracycline in a microbial fuel cell. RSC Advances, 8(50), 28613–28624. doi: 10.1039/C8RA04904A. Jakeman, D. L., Bandi, S., Graham, C. L., Reid, T. R., Wentzell, J. R., & Douglas, S. E., (2009). Antimicrobial activities of Jadomycin B and structurally related analogues. Antimicrobial Agents and Chemotherapy, 53(3), 1245–1247. doi: 10.1128/ AAC.00801-08. Forget, S. M., Robertson, A. W., Hall, S. R., MacLeod, J. M., Overy, D. P., Kerr, R. G., Goralski, K. B., & Jakeman, D. L., (2018). Isolation of a Jadomycin incorporating L-ornithine, analysis of antimicrobial activity and Jadomycin reactive oxygen species (ROS) generation in MDA-MB-231 breast cancer cells. Journal of Antibiotics, 71(8), 722–730. doi: 10.1038/s41429-018-0060-0. Hatok, J., Babusikova, E., Matakova, T., Mistuna, D., Dobrota, D., & Racay, P., (2009). In vitro assays for the evaluation of drug resistance in tumor cells. Clinical and Experimental Medicine, 9(1), 1–7. doi: 10.1007/s10238-008-0011-3. Issa, M. E., Hall, S. R., Dupuis, S. N., Graham, C. L., Jakeman, D. L., & Goralski, K. B., (2014). Jadomycins are cytotoxic to ABCB1-, ABCC1-, and ABCG2-overexpressing

380

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

MCF7 breast cancer cells. Anti-Cancer Drugs, 25(3), 255–269. doi: 10.1097/ CAD.0000000000000043. 77. www.promega.com (accessed on 03 March 2022). 78. Hall, S. R., Toulany, J., Bennett, L. G., Martinez-Farina, C. F., Robertson, A. W., Jakeman, D. L., & Goralski, K. B., (2017). Jadomycins inhibit type II topoisomerases and promote DNA damage and apoptosis in multidrug-resistant triple-negative breast cancer cells. Journal of Pharmacology and Experimental Therapeutics, 363(2), 196–210. doi: 10.1124/jpet.117.241125. 79. Martinez-Farina, C. F., McCormick, N., Robertson, A. W., Clement, H., Jee, A., Ampaw, A., Chan, N. L., et al., (2015). Investigations into the binding of Jadomycin DS to human topoisomerase IIb by water LOGSY NMR spectroscopy. Organic & Biomolecular Chemistry, 13(41), 10324–10327. doi: 10.1039/C5OB01508A. 80. Monro, S. M. A., Cottreau, K. M., Spencer, C., Wentzell, J. R., Graham, C. L., Borissow, C. N., Jakeman, D. L., & McFarland, S. A., (2011). Copper-mediated nuclease activity of Jadomycin B. Bioorganic & Medicinal Chemistry, 19(11), 3357–3360. doi: 10.1016/j. bmc.2011.04.043. 81. Fu, D. H., Jiang, W., Zheng, J. T., Zhao, G. Y., Li, Y., Yi, H., Li, Z. R., et al., (2008). Jadomycin B, an aurora-B kinase inhibitor discovered through virtual screening. Molecular Cancer Therapeutics, 7(8), 2386–2393. doi: 10.1158/1535-7163. MCT-08-0035. 82. Robertson, J., & Stafford, P. M., (2003). Selective hydroxyl protection and deprotection. In: Osborn, H. M. I.,(ed.), Carbohydrates (pp. 9–68). 83. Deagostino, A., Prandi, C., & Venturello, P., (2003). α,β-Unsaturated acetals in synthesis. Current Organic Chemistry, 7(9), 821–839. doi: 10.2174/1385272033486666. 84. Palecek, J., & Svoboda, J., (1989). Protection of the carbonyl group. Chemicke Listy, 83(4), 372–387. 85. Ciaccio, J. A., Saba, S., Bruno, S. M., Bruppacher, J. H., & McKnight, A. G., (2018). Probing the reactivity of cyclic N,O-acetals versus cyclic O,O-acetals with NaBH4 and CH3MgI. Journal of Chemical Education, 95(6), 1045–1049. doi: 10.1021/acs. jchemed.7b00734. 86. Saigal, Khan, S., Rahman, H., Shafiullah, & Khan, M. M., (2019). Nitroketene N,S-acetals: Synergistic building blocks for the synthesis of heterocycles. RSC Advances, 9(25), 14477–14502. doi: 10.1039/C6NJ01170E. 87. Janni, M., Arora, S., & Peruncheralathan, S., (2016). Double heteroannulation of S,N-acetals: A facile access to quinolone derivatives. Organic & Biomolecular Chemistry, 14(37), 8781–8788. doi: 10.1039/C6OB01568A. 88. Ganganella, R., (1939). Comparison of the disinfecting powers of phenol and of formaldehyde. Chimie et Industrie (Paris), 43, 147. 89. Crusos, A., (1978). Monomer-polymer equilibrium in polyoxymethylenes subjected to degradation by vibratory grinding. Materiale Plastice (Bucharest, Romania), 15(3), 160–162. 90. Caterina, M. C., Perillo, I. A., Villalonga, X., Amiano, N., Payes, C., Sanchez, M. L., & Salerno, A., (2013). New green synthesis and antineoplastic activity of bis(3arylimidazolidinyl-1)methane. Open Journal of Medicinal Chemistry, 3(4), 121–127. doi: 10.4236/ojmc.2013.34014. 91. Ben-Ishai, D., (1957). Reaction of acylamino acids with paraformaldehyde. Journal of the American Chemical Society, 79(21), 5736–5738. doi: 10.1021/ja01578a042.

Oxazolidin-5-ones 381

92. Gonzalez, A., Lavilla, R., Piniella, J. F., & Alvarez-Larena, A., (1995). Protected derivatives of (R)-cysteine and (R)-cysteinol. Tetrahedron, 51(10), 3015–3024. doi: 10.1016/0040-4020(95)00032-4. 93. Blaskovich, M. A., & Kahn, M., (1998). Mild conditions for oxazolidin-5-one formation. Synthesis, (4), 379, 380. doi: 10.1055/s-1998-4486. 94. Paleo, M. R., Castedo, L., & Dominguez, D., (1993). Synthesis of 2-[N-(9-phenylfluoren9-yl)amino]-1-indanones by anionic cyclization of phenylalanine-derived oxazolidinones. Journal of Organic Chemistry, 58(10), 2763–2767. doi: 10.1021/jo00062a018. 95. Aurelio, L., Brownlee, R. T. C., Hughes, A. B., & Sleebs, B. E., (2000). The facile production of N-methyl amino acids via oxazolidinones. Australian Journal of Chemistry, 53(5), 425–433. doi: 10.1071/ch99082. 96. Aurelio, L., Box, J. S., Brownlee, R. T. C., Hughes, A. B., & Sleebs, M. M., (2003). An efficient synthesis of N-methyl amino acids by way of intermediate 5-oxazolidinones. Journal of Organic Chemistry, 68(7), 2652–2667. doi: 10.1021/jo026722l. 97. Cipens, G., Slavinskaya, V. A., Sile, D., Korchagova, E. K., Katkevich, M. Y., Grigor’eva, V. D., (1992). Synthesis of N-benzyloxycarbonyl-N-methyl amino acids from oxazolidin5-one derivatives. Khimiya Geterotsiklicheskikh Soedinenii, (5), 681–683. 98. Reddy, G. V., Rao, G. V., & Iyengar, D. S., (1999). A novel, simple and rapid protocol for N-protected oxazolidin-5-ones. Synthetic Communications, 29(23), 4071–4077. doi: 10.1080/00397919908085881. 99. Tantry, S. J., Kantharaju, & Suresh, B. V. V., (2002). Microwave accelerated efficient synthesis of N-fluorenylmethoxycarbonyl/t-butoxycarbonyl/benzyloxycarbonyl5-oxazolidinones. Tetrahedron Letters, 43(51), 9461, 9462. doi: 10.1016/ S0040-4039(02)02257-8. 100. Kusuda, A., Kawai, H., Nakamura, S., & Shibata, N., (2009). Solkane 365mfc is an environmentally benign alternative solvent for trifluoromethylation reactions. Green Chemistry, 11(11), 1733–1735. doi: 10.1039/b913984b. 101. Flynn, G. A., Burkholder, T. P., Huber, E. W., & Bey, P., (1991). An acyliminium ion route to cis and trans anti Phe-Gly dipeptide mimetics. Bioorganic & Medicinal Chemistry Letters, 1(6), 309–312. doi: 10.1016/S0960-894X(01)80814-3. 102. Lai, B., & Kulkarni, B. K., (1991). Synthesis of Penicillin N. Indian Journal of Chemistry, 30B, 230–232. 103. Olsen, R. K., & Ramasamy, K., (1985). Synthesis of retrohydroxamate analogs of the microbial iron-transport agent ferrichrome. Journal of Organic Chemistry, 50(13), 2264–2271. doi: 10.1021/jo00213a013. 104. Katkevich, M., Sile, D. E., Slavinska, V. A., Liepina, I. M., & Popelis, Y. Y., (1993). Synthesis of oxazolidin-5-one derivatives. Khimiya Geterotsiklicheskikh Soedinenii, (1), 115–117. 105. Allevi, P., Olivero, P., & Anastasia, M., (2004). Controlled synthesis of labeled 3-L-chlorotyrosine-[ring-13C6] and of 3,5-L-dichlorotyrosine-[ring-13C6]. Journal of Labelled Compounds & Radiopharmaceuticals, 47(13), 935–945. doi: 10.1002/jlcr.882. 106. Aurelio, L., Brownlee, R. T. C., Dang, J., Hughes, A. B., & Polya, G. M., (2006). Determination of the complete absolute configuration of Petriellin A. Australian Journal of Chemistry, 59(6), 407–414. doi: 10.1071/CH06148. 107. Calmes, M., & Escale, F., (1999). Stereoselective borane reduction of acetophenone using 1,3,2-oxazaborolidine derived from (R)-4-(diphenylhydroxymethyl)-1,3-thiazolidine. Synthetic Communications, 29(8), 1341–1347. doi: 10.1080/00397919908086109.

382

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

108. Thompson, M. J., Mekhalfia, A., Hornby, D. P., & Blackburn, G. M., (1999). Synthesis of two stable nitrogen analogs of S-adenosyl-L-methionine. Journal of Organic Chemistry, 64(20), 7467–7473. doi: 10.1021/jo9907742. 109. Shirude, P. S., Kumar, V. A., & Ganesh, K. N., (2004). (2S,5R/2R,5S)-Aminoethylpipecolyl aepip-aegpna chimera: Synthesis and duplex/triplex stability. Tetrahedron, 60(42), 9485–9491. doi: 10.1016/j.tet.2004.07.080. 110. Banner, E. J., Stevens, E. D., & Trudell, M. L., (2004). Stereoselective synthesis of the cis-275B decahydroquinoline ring system. Tetrahedron Letters, 45(22), 4411–4414. doi: 10.1016/j.tetlet.2004.03.191. 111. Lawandi, J., Toumieux, S., Seyer, V., Campbell, P., Thielges, S., Juillerat-Jeanneret, L., & Moitessier, N., (2009). Constrained peptidomimetics reveal detailed geometric requirements of covalent prolyl oligopeptidase inhibitors. Journal of Medicinal Chemistry, 52(21), 6672–6684. doi: 10.1021/jm901013a. 112. Licato, N. J., Coward, J. K., Nimec, Z., Galivan, J., Bolanowska, W. E., & McGuire, J. J., (1990). Synthesis of N-[N-(4-deoxy-4-amino-10-methylpteroyl)-4-fluoroglutamyl]γ-glutamate, an unusual substrate for folylpoly-γ-glutamate synthetase and γ-glutamyl hydrolase. Journal of Medicinal Chemistry, 33(3), 1022–1027. doi: 10.1021/ jm00165a021. 113. Whitten, J. P., Baron, B. M., Muench, D., Miller, F., White, H. S., & McDonald, I. A., (1990). (R)-4-Oxo-5-phosphononorvaline: A new competitive glutamate antagonist at the NMDA receptor complex. Journal of Medicinal Chemistry, 33(11), 2961–2963. doi: 10.1021/jm00173a009. 114. Jackson, R. F. W., Fraser, J. L., Wishart, N., Porter, B., & Wythes, M. J., (1998). Synthesis of α-amino acids using amino acid γ-anion equivalents: Synthesis of 5-oxo α-amino acids, homophenylalanine derivatives and pentenylglycines. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry, 1903–1912. doi: 10.1039/A802142B. 115. Chollet, J. F., Miginiac, L., Rudelle, J., & Bonnemain, J. L., (1993). A convenient method of protection and mild deprotection of α-amino acid group for the synthesis of functional α-amino acids. Synthetic Communications, 23(15), 2101–2111. doi: 10.1080/00397919308018603. 116. Branca, M., Pena, S., Guillot, R., Gori, D., Alezra, V., & Kouklovsky, C., (2009). Memory of chirality of tertiary aromatic amides: A simple and efficient method for the enantioselective synthesis of quaternary α-amino acids. Journal of the American Chemical Society, 131(30), 10711–10718. doi: 10.1021/ja9039604. 117. Izzo, I., Avallone, E., Della, C. L., Maulucci, N., & De Riccardis, F., (2004). Asymmetric synthesis of N,O-diprotected (2S,3S)-N-methyl-δ-hydroxyisoleucine, noncoded amino acid of halipeptin A. Tetrahedron: Asymmetry, 15(7), 1181–1186. doi: 10.1016/j. tetasy.2004.02.008. 118. DagerAlbalawi, M. A., (2016). Synthesis of some hydroxamic acids linked-naturals amino acid. IOSR Journal of Environmental Science, Toxicology and Food Technology, 10(9), 72–74. doi: 10.9790/2402–1009037274. 119. Albalawi, M. A., (2017). Evaluation of antibacterial and antifungal effects of novel hydroxamic acids linked-natural amino acids. Egyptian Journal of Chemistry, 60(4), 613–618. doi: 10.21608/EJCHEM.2017.908.1042.

Oxazolidin-5-ones 383

120. Polonski, T., (1985). Optical activity of lactones and lactams-III. Circular dichroism spectra of 5-oxazolidinones. Tetrahedron, 41(3), 603–609. doi: 10.1016/ S0040-4020(01)96506-8. 121. Satsumabayashi, K., Nomoto, Y., Numanami, K., & Satsumabayashi, S., (1981). Stereochemistry of organic compounds (2): Conformation of oxazolidinone derivatives; Bulletin of Nippon Dental University. General Education, 10, 137–152. doi: 10.14983/00000203. 122. Draper, R. W., Hou, D., Iyer, R., Lee, G. M., Liang, J. T., Mas, J. L., & Vater, E. J., (1998). Novel stereoselective syntheses of the fused benzazepine dopamine D1 antagonist (6aS,13bR)-11-chloro-6,6a,7,8,9,13b-hexahydro-7-methyl-5H-benzo[d]naphth[2,1-b] azepin-12-ol: 2. L-homophenylalanine-based syntheses. Organic Process Research & Development, 2(3), 186–193. doi: 10.1021/op970122k. 123. Paleo, M. R., Calaza, M. I., & Sardina, F. J., (1997). Enantiospecific synthesis of N-(9-phenylfluoren-9-yl)-α-amino ketones. Journal of Organic Chemistry, 62(20), 6862–6869. doi: 10.1021/jo9707646. 124. Cheng, Z., Li, Y., Yue, Z., Yang, G., & Jiang, Y., (1997). A facile synthesis of α-aspartylpeptide via 5-oxazolidinone. Hecheng Huaxue, 5(2), 109–112. 125. Zhang, Y., Feng, X. M., Chen, Z. Y., & Yang, G. S., (1999). A facile synthesis of L-alanylpeptides from 5-oxazolidinone. Hecheng Huaxue, 7(2), 125–127. 126. Altmann, E., Nebel, K., & Mutter, M., (1991). Versatile stereoselective synthesis of completely protected trifunctional α-methylated α-amino acid starting from alanine. Helvetica Chimica Acta, 74(4), 800–806. doi: 10.1002/hlca.19910740414. 127. Konstantinov, I. A., & Broadbelt, L. J., (2010). The role of oxazolidinones in L-prolineassisted Aldol-type reactions. Topics in Catalysis, 53(15–18), 1031–1038. doi: 10.1007/ s11244-010-9527-3. 128. Cueva, J. P., Cai, T. B., Mascarella, S. W., Thomas, J. B., Navarro, H. A., & Carroll, F. I., (2009). Synthesis and in vitro opioid receptor functional antagonism of methyl-substituted analogues of (3R)-7-hydroxy-N-[(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl1-piperidinyl]methyl}-2-methylpropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (JDTic). Journal of Medicinal Chemistry, 52(23), 7463–7472. doi: 10.1021/jm900756t. 129. Hsiao, Y., & Hegedus, L. S., (1997). Synthesis of optically active imidazolines, azapenams, dioxocyclams, and bis-dioxocyclams. Journal of Organic Chemistry, 62(11), 3586–3591. doi: 10.1021/jo962343e. 130. Kelly-Basetti, B. M., Mackay, M. F., Pereira, S. M., Savage, G. P., & Simpson, G. W., (1994). Asymmetric synthesis of a homochiral δ2-isoxazoline amino acid derivative. Heterocycles, 37(1), 529–539. doi: 10.3987/COM-93-S49. 131. Pyne, S. G., Dikic, B., Gordon, P. A., Skelton, B. W., & White, A. H., (1992). Asymmetric synthesis of chiral cyclic amino acids by Diels-alder reactions of (2S)- and (2R)-4-methyleneoxazolidin-5-ones. Australian Journal of Chemistry, 46(1), 73–93. doi: 10.1071/CH9930073. 132. Pyne, S. G., Safaei-G, J., Hockless, D. C. R., Skelton, B. W., Sobolev, A. N., & White, A. H., (1994). Exo diastereoselective Diels-Alder reactions of (R)-2phenyl-4-methyleneoxazolidin-5-one. Tetrahedron, 50(3), 941–956. doi: 10.1016/ S0040-4020(01)80808-5. 133. Chinchilla, R., Najera, C., Garcia-Granda, S., & Menendez-Velazquez, A., (1993). Synthesis of (R)- and (S)-2,3-methanovaline from (2S)-N-benzoyl-2-tert-butyl-

384

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

4-methylene-1,3-oxazolidin-5-one. Tetrahedron Letters, 34(36), 5799–5802. doi: 10.1016/S0040-4039(00)73864-0. 134. Acton, J. J. III., & Jones, A. B., (1996). Synthesis and derivatization of a versatile α-substituted lactam dipeptide isostere. Tetrahedron Letters, 37(25), 4319–4322. doi: 10.1016/0040-4039(96)00835-0. 135. Abell, A. D., Oldham, M. D., & Taylor, J. M., (1995). Synthesis of phenylalaninebased cyclic acylated enamino ester dipeptide analogs: Inhibitors of α-chymotrypsin. X-ray molecular structure of (2’S,4’R)-4’-benzyl-3’-benzyloxycarbonyl-5’-oxo-2’phenyloxazolidin-4’-ylacetic acid. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry, (7), 953–961. doi: 10.1039/P19950000953. 136. Tonn, O., (1933). Reaction mechanism in the purification by the sodium method of anesthetic ether decomposed by autoxidation. Pharmazeutische Zentralhalle fuer Deutschland, 74, 765–769. 137. Neuberg, C., & Gorr, G., (1925). The dismutation between aldehyde and ketone. Biochemische Zeitschrift, 166, 444–449. 138. O’Donnell, M. J., Fang, Z., Ma, X., & Huffman, J. C., (1997). New methodology for the synthesis of α,α-dialkylamino acids using the “self-regeneration of stereocenters” method: α-ethyl-α-phenylglycine. Heterocycles, 46, 617–630. doi: 10.3987/COM-97-S83. 139. Seebach, D., Sting, A. R., & Hoffmann, M., (1996). Self-regeneration of stereocenters (SRS) - applications, limitations, and abandonment of a synthetic principle. Angewandte Chemie, International Edition in English, 35(23, 24), 2708–2748. doi: 10.1002/ anie.199627081. 140. Fadel, A., & Salaün, J., (1987). α-Alkylation of acyclic amino acids with self-reproduction of the center of chirality. A new route to (S)-(+)-α-alkylated aspartic acids. Tetrahedron Letters, 28(20), 2243–2246. doi: 10.1016/S0040-4039(00)96091-X. 141. Alonso, F., Davies, S. G., Elend, A. S., & Haggitt, J. L., (1998). Enantiospecific alkylations of alanine. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry, (2), 257–264. doi: 10.1039/A705764D. 142. Nebel, K., & Mutter, M., (1988). Stereoselective synthesis of isovaline (IVA) and IVA-containing dipeptides for use in peptide synthesis. Tetrahedron, 44(15), 4793–4796. doi: 10.1016/S0040-4020(01)86182-2. 143. Eriksson, M., Napolitano, E., Xu, J., Kapadia, S., Byrne, D., Nummy, L., Grinberg, N., et al., (2006). The formation of a crystalline oxazolidin-5-one from (L)-alanine and its use as a chiral template in the practical synthesis of α-substituted alanine esters. CHIMIA, 60(9), 566–573. doi: 10.2533/chimia.2006.566. 144. Long, Y. Q., Huang, S. X., Zawahir, Z., Xu, Z. L., Li, H., Sanchez, T. W., Zhi, Y., et al., (2013). Design of cell-permeable stapled peptides as HIV-1 integrase inhibitors. Journal of Medicinal Chemistry, 56(13), 5601–5612. doi: 10.1021/jm4006516. 145. Zydowsky, T. M., De Lara, E., & Spanton, S. G., (1990). Stereoselective synthesis of α-alkyl α-amino acids. Alkylation of 3-substituted 5H,10bH-oxazolo[3,2-c][1,3] benzoxazine-2(3H),5-diones. Journal of Organic Chemistry, 55(20), 5437–5439. doi: 10.1021/jo00307a008. 146. Goodman, M., Zhang, J., Gantzel, P., & Benedetti, E., (1998). The stereocontrolled synthesis of orthogonally protected (R)-α-methyltryptophan. Tetrahedron Letters, 39(52), 9589–9592. doi: 10.1016/S0040–4039(98)02302–8.

Oxazolidin-5-ones 385

147. Chantegrel, B., Deshayes, C., & Faure, R., (1993). Reaction of trifluoroacetic anhydride with N-(2-hydroxybenzyl)-α-amino acids: An entry in the new [1,3]oxazolo[2,3-b][1,3] benzoxazine ring system. Heterocycles, 36(12), 2811–2818. doi: 10.3987/COM-93-6525. 148. Hiskey, R. G., & Jung, J. M., (1963). Azomethine chemistry. II. Formation of peptides from oxazolidin-5-ones. Journal of the American Chemical Society, 85, 578–582. doi: 10.1021/ja00888a021. 149. Walter, M. W., Adlington, R. M., Baldwin, J. E., & Schofield, C. J., (1998). Reaction of (trifluoromethyl)trimethylsilane with oxazolidin-5-ones: Synthesis of peptidic and nonpeptidic trifluoromethyl ketones. Journal of Organic Chemistry, 63(15), 5179–5192. doi: 10.1021/jo980443+. 150. Aitken, R. A., McGill, S. D., & Power, L. A., (2006). Synthetic applications of chiral 1,3-dioxolan-4-ones and 3-acyloxazolidin-5-ones. ARKIVOC, (vii), 292–300. doi: 10.3998/ark.5550190.0007.721. 151. Smith, A. B. III., Benowitz, A. B., Favor, D. A., Sprengeler, P. A., & Hirschmann, R., (1997). A second-generation synthesis of scalemic 3,5,5-trisubstituted pyrrolin-4-ones: Incorporation of functionalized amino acid side-chains. Tetrahedron Letters, 38(22), 3809–3812. doi: 10.1016/S0040-4039(97)00752-1. 152. Crossley, M. J., & Tansey, C. W., (1992). A convenient method for the synthesis of β-substituted α-amino acids. Diastereoselective conjugate addition of nitronates to a chiral dehydroalanine derivative. Australian Journal of Chemistry, 45(2), 479–481. doi: 10.1071/CH9920479. 153. Beck, A. K., & Seebach, D., (1988). Large-scale preparation of (S)-α-methylmethionine from the parent amino acid. Chimia, 42(4), 142–144. 154. Beck, A. K., Blank, S., Job, K., Seebach, D., & Sommerfeld, T., (1995). Synthesis of (S)-2-methylproline: A general method for the preparation of α-branched amino acids. Organic Synthesis, 72, 62. doi: 10.15227/orgsyn.072.0062. 155. Seebach, D., Boes, M., Naef, R., & Schweizer, W. B., (1983). Alkylation of amino acids without loss of the optical activity: Preparation of α-substituted proline derivatives. A case of self-reproduction of chirality. Journal of the American Chemical Society, 105(16), 5390–5398. doi: 10.1021/ja00354a034. 156. Grigg, R., Idle, J., McMeekin, P., & Vipond, D., (1987). The decarboxylative route to azomethine ylides. Mechanism of 1,3-dipole formation. Journal of the Chemical Society, Chemical Communications, (2), 49–51. doi: 10.1039/c39870000049. 157. Zhang, L., & Finn, J. M., (1995). A facile method for the asymmetric synthesis of α-methyltryptophan. Journal of Organic Chemistry, 60(17), 5719–5720. doi: 10.1021/ jo00122. 158. Sting, A. R., & Seebach, D., (2001). (2S,4S)-3-Benzoyl-2-t-butyl-4-methyl-1,3oxazolidin-5-one. Encyclopedia of Reagents for Organic Synthesis, 308–309. 159. Gander-Coquoz, M., & Seebach, D., (1988). Synthesis of enantiomerically pure, α-alkylated lysine, ornithine, and tryptophan derivatives. Helvetica Chimica Acta, 71(1), 224–236. doi: 10.1002/hlca.19880710124. 160. Seebach, D., Müller, S. G., Gysel, U., & Zimmermann, J., (1988). Preparative chromatographic resolution of synthetically useful cyclic acetals. Helvetica Chimica Acta, 71(5), 1303–1318. doi: 10.1002/hlca.19880710541. 161. Alonso, F., & Davies, S. G., (1995). Enantiospecific conversion of (S)-alanine to (R)-α-methyl phenylalanine. Tetrahedron: Asymmetry, 6(2), 353–356. doi: 10.1016/0957-4166(95)00011-D.

386

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

162. Alonso, F., Davies, S. G., & Smethurst, C. A. P., (1998). Synthesis and reactivity of a range of 2-ferrocenyl-3-pivaloyl-1,3-oxazolidin-5-ones. Journal of Organometallic Chemistry, 553(1, 2), 463–468. doi: 10.1016/S0022-328X(97)00652-9. 163. Tanyeli, C., & Sezen, B., (2001). Enantioselective hydrolysis of potent amino acid precursors 5-oxazolidinone derivatives. Enantiomer, 6(4), 229–233. 164. Branca, M., Alezra, V., Kouklovsky, C., & Archirel, P., (2008). Accurate conformation analysis in solution: NMR and DFT/PCM study of the S-3-(1-naphthoyl)-4-isopropyl2,2-dimethyloxazolidin-5-one in CDCl3. Tetrahedron, 64(8), 1743–1752. doi: 10.1016/j. tet.2007.12.001. 165. Branca, M., Gori, D., Guillot, R., Alezra, V., & Kouklovsky, C., (2008). Tertiary aromatic amide for memory of chirality: Access to enantioenriched α-substituted valine. Journal of the American Chemical Society, 130(18), 5864, 5865. doi: 10.1021/ja801165z. 166. Weygand, F., Burger, K., & Engelhardt, K., (1966). 2,2-Bis(trifluoromethyl)-5oxazolidones. Chemische Berichte, 99(5), 1461–1469. doi: 10.1002/cber.19660990507. 167. Rühl, T., Böttcher, C., Pumpor, K., Hennig, L., Sieler, J., & Burger, K., (2004). Hexafluoroacetone as protecting and activating reagent: Site-selective functionalization of α-amino alkanedioic acids. Synthesis, (18), 3065–3069. doi: 10.1055/s-2004-834918. 168. Burger, K., Kluge, M., Koksch, B., Fehn, S., Böttcher, C., Hennig, L., & Müller, G., (2004). Hexafluoroacetone as protecting and activating reagent: A new approach to O-glycosides. Heterocycles, 64, 143–152. doi: 10.3987/COM-04-S(P)6. 169. Pumpor, K., Windeisen, E., Spengler, J., Albericio, F., & Burger, K., (2004). Hexafluoroacetone as a protecting and activating reagent. regioselective esterification of aspartic, malic, and thiomalic acid. Monatshefte für Chemie, 135(11), 1427–1443. doi: 10.1007/s00706-004-0183-9. 170. Golubev, A. S., Schedel, H., Radics, G., Fioroni, M., Thust, S., & Burger, K., (2004). Hexafluoroacetone as a protecting and activating reagent: 5,5-difluoro- and trans-5fluoropipecolic acids from glutamic acid. Tetrahedron Letters, 45(7), 1445–1447. doi: 10.1016/j.tetlet.2003.12.038. 171. Stille, J. K., (1986). Palladium-catalyzed coupling reactions of organic electrophiles with organic tin compounds. Angewandte Chemie, 98(6), 504–519. doi: 10.1002/ ange.19860980605. 172. Golubev, A. S., Sewald, N., & Burger, K., (1996). Synthesis of γ-oxo α-amino acids from L-aspartic acid. Tetrahedron, 52(47), 14757–14776. doi: 10.1016/0040-4020(96)00942-8. 173. Burger, K., Neuhauser, H., & Worku, A., (1993). Application of hexafluoroacetone as protecting and activating reagent in amino acid and peptide chemistry. N-Substituted glycine derivatives from iminodiacetic acid. Zeitschrift fuer Naturforschung, B: Chemical Sciences, 48(1), 107–120. doi: 10.1515/znb-1993-0123. 174. Böttcher, C., Spengler, J., Essawy, S. A., & Burger, K., (2004). Hexafluoroacetone as protecting and activating reagent. A new approach to N-glycosides. Monatshefte für Chemie, 135(7), 853–863. doi: 10.1007/s00706-003-0145-7. 175. Burger, K., Gold, M., Neuhauser, H., & Rudolph, M., (1991). Regiospecific reactions with ω-carboxy-α-amino acids. Part III. Aspartic acid. Chemiker-Zeitung, 115(3), 77–82. 176. Herpin, T. F., Motherwell, W. B., & Weibel, J. M., (1997). Two free radical routes for the preparation of novel difluoromethylene-linked serine-O-glycopeptide analogs. Chemical Communications (Cambridge), (10), 923, 924. doi: 10.1039/a700928c.

Oxazolidin-5-ones 387

177. Golubev, A., Sewald, N., & Burger, K., (1993). An efficient synthesis of 5-hydroxy4-oxo-L-norvaline from L-aspartic acid. Tetrahedron Letters, 34(37), 5879, 5880. doi: 10.1016/S0040-4039(00)73803-2. 178. Burger, K., Neuhauser, H., & Rudolph, M., (1990). A new, preparatively simple way to dihydroorotic acid, 1-methyl-4,5-dihydroorotic acid and their derivatives. ChemikerZeitung, 114(7, 8), 251–255. 179. Burger, K., & Rudolph, M., (1990). Regiospecific reactions with ω-carboxy α-amino acids. A simple synthesis of aspartame. Chemiker-Zeitung, 114(7, 8), 249–251. 180. Burger, K., Heistracher, E., Simmerl, R., & Eggersdorfer, M., (1992). Application of hexafluoroacetone as protecting and activating reagent in amino acid and peptide chemistry. 8. Synthesis of phosphorus-containing sarcosine derivatives via a new electrophilic sarcosine synthon. Zeitschrift fuer Naturforschung, B: Chemical Sciences, 47(3), 424–433. doi: 10.1515/znb-1992-0321. 181. Osipov, S. N., Lange, T., Tsouker, P., Spengler, J., Hennig, L., Koksch, B., Berger, S., et al., (2004). Hexafluoroacetone as a protecting and activating reagent: Synthesis of new types of fluoro-substituted α-amino, α-hydroxy and α-mercapto acids. Synthesis, (11), 1821–1829. doi: 10.1055/s-2004–829131. 182. Roberts, C. W., Travis, G. D., & Heeschen, J. P., (1967). Synthesis of a series of 1,1a,3,3a,4,5,5,5a,5b,6-decachlorooctahydro-4’-substituted spiro[1,3,4-metheno-2Hcyclobuta[c,d]pentalene-2,2’-oxazolidin]-5’-ones. Journal of Organic Chemistry, 32(10), 3194–3196. doi: 10.1021/jo01285a057. 183. Claesson, A., (1988). 1,3-Oxazolidin-5-ones, not 1,3-diazetidinones, are formed in the reaction of tryptophan with alkyl isocyanates in the presence of acetone. Heterocycles, 27(9), 2087–2090. doi: 10.3987/COM-88-4644. 184. Garrido, M., López, R. M. L., Morcillo, M. J., Peréz, G. V., & Monge, A., (1990). Unambiguous structure of the compounds in the reaction of L-tryptophan and 5-hydroxyL-tryptophan with alkyl isocyanates in acetone. Journal of Heterocyclic Chemistry, 27(5), 1513–1516. doi: 10.1002/jhet.5570270562. 185. Aly, A. A., (2003). Synthesis of novel quinazoline derivatives as antimicrobial agents. Chinese Journal of Chemistry, 21, 339–346. doi: 10.1002/cjoc.20030210324. 186. Singh, H., & Kumar, S., (1987). Synthesis of heterocycles via enamines-XIII: Steric control on the mode of reactions of β-isothiocyanatoketones with amino acids. Tetrahedron, 43(9), 2177–2180. doi: 10.1016/S0040-4020(01)86799-5. 187. Amine, M. S.; Eissa, A. M. F.; El-Sawy; Shaaban A F, A. A.; El-Sayed, R, (2005). New heterocycles having double characters as antimicrobial and surface active agents: Part 1 - nonionic compounds from fatty acid isothiocyanate. Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 44B(8), 1724–1730. 188. Airiau, E., Girard, N., Mann, A., Salvadori, J., & Taddei, M., (2009). Four-component reactions toward fused heterocyclic rings. Organic Letters, 11(22), 5314–5317. doi: 10.1021/ol902279m. 189. Isono, N., & Mori, M., (1995). Total synthesis of (-)-cephalotaxine. Journal of Organic Chemistry, 60(1), 115–119. doi: 10.1021/jo00106a023. 190. Cwiek, R., Niedziejko, P., & Kaluza, Z., (2014). Synthesis of tunable diamine ligands with spiro indane-2,2’-pyrrolidine backbone and their applications in enantioselective henry reaction. Journal of Organic Chemistry, 79(3), 1222–1234. doi: 10.1021/ jo402631u.

388

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

191. Vartak, A. P., & Johnson, R. L., (2006). Concerted synthesis of a spirobicyclic type-VI β-turn mimic of Pro-Pro-Pro-NH2. Organic Letters, 8(5), 983–986. doi: 10.1021/ ol0600335. 192. Humphreys, E. R., Hong, J. B., & Green, K. L., (2011). Chiral synthesis of an α-tetrasubstituted proline derivative. Synthetic Communications, 41(15), 2256–2264. doi: 10.1080/00397911.2010.501477. 193. Zou, J., Cho, D. W., & Mariano, P. S., (2010). A concise, metathesis based approach to construction of the lepadiformine/cylindricine tricyclic framework. Tetrahedron, 66(32), 5955–5961. doi: 10.1016/j.tet.2010.06.027. 194. Lucas, M. C., Weikert, R. J., Carter, D. S., Cai, H. Y., Greenhouse, R., Iyer, P. S., Lin, C. J., et al., (2010). Design, synthesis, and biological evaluation of new monoamine reuptake inhibitors with potential therapeutic utility in depression and pain. Bioorganic & Medicinal Chemistry Letters, 20(18), 5559–5566. doi: 10.1016/j.bmcl.2010.07.020. 195. Zhang, B., Zheng, W., Wang, X., Sun, D., & Li, C., (2016). Total synthesis of Notoamides F, I, and R and Sclerotiamide. Angewandte Chemie, International Edition, 55(35), 10435–10438. doi: 10.1002/anie.201604754. 196. Torbeev, V. Y., Fumi, E., Ebert, M. O., Schweizer, W. B., & Hilvert, D., (2012). Cis-trans peptide-bond isomerization in α-methylproline derivatives. Helvetica Chimica Acta, 95(12), 2411–2420. doi: 10.1002/hlca.201200483. 197. Rojas-Lima, S., Tellez-Zenteno, O., Lopez-Ruiz, H., Loubet-Gonzalez, L., & AlvarezHernandez, A., (2005). 3-Benzoyl-2-isopropyl-4-alkyloxazolidin-5-ones as efficient and inexpensive sources of enantiopure α,α-dialkyl α-amino acids and α,β-dialkyl α,β-diaminopropionic acids. Heterocycles, 65(1), 59–75. doi: 10.3987/COM-04-10214. 198. Kinkel, J. N., Gysel, U., Blaser, D., & Seebach, D., (1991). Preparative resolution of heterocyclic acetals derived from glycine, mercaptoacetic acid, β-alanine, and formylor acetylacetic acid by recycling chromatography on chiraspher and temperature dependence of separation factors. Helvetica Chimica Acta, 74(8), 1622–1635. doi: 10.1002/hlca.19910740803. 199. Fairlie, D. P., Abbenante, G., & March, D. R., (1995). Macrocyclic peptidomimetics - forcing peptides into bioactive conformations. Current Medicinal Chemistry, 2(2), 654–686. 200. Angell, Y. M., Thomas, T. L., Flentke, G. R., & Rich, D. H., (1995). Solid-phase synthesis of cyclosporin peptides. Journal of the American Chemical Society, 117(27), 7279, 7280. doi: 10.1021/ja00132a042. 201. Dong, Q. G., Zhang, Y., Wang, M. S., Feng, J., Zhang, H. H., Wu, Y. G., Gu, T. J., et al., (2012). Improvement of enzymatic stability and intestinal permeability of deuteroheminpeptide conjugates by specific multi-site N-methylation. Amino Acids, 43(6), 2431–2441. doi: 10.1007/s00726-012-1322-y. 202. Chatterjee, J., & Kessler, H., (2008). New perspectives in peptide chemistry by multiple N-methylation. Chimica Oggi, 26(Suppl.), 4, 5. 203. Li, Y., Li, W., & Xu, Z., (2021). Improvement on permeability of cyclic peptide/ peptidomimetic: Backbone N-methylation as a useful tool. Marine Drugs, 19(6), 311/1–311/18. doi: 10.3390/md19060311. 204. Aurelio, L., Brownlee, R. T. C., & Hughes, A. B., (2002). A novel synthesis of N-methyl asparagine, arginine, histidine, and tryptophan. Organic Letters, 4(21), 3767–3769. doi: 10.1021/ol026799w.

Oxazolidin-5-ones 389

205. Reddy, G. V., & Lyengar, D. S., (1999). A simple and rapid protocol for N-methyl-αamino acids. Chemistry Letters, (4), 299, 300. doi: 10.1246/cl.1999.299. 206. Reddy, G. V., Rao, G. V., & Iyengar, D. S., (1998). A practical approach for the optically pure N-methyl-α-amino acids. Tetrahedron Letters, 39(14), 1985, 1986. doi: 10.1016/ S0040-4039(98)00111-7. 207. Kurosawa, M., & Nishioka, K., (1996). An improved method for 14C-labeling of L-DOPS, A norepinephrine precursor amino acid. Radioisotopes, 45(11), 685–688. doi: 10.3769/ radioisotopes.45.11_685. 208. Makosza, M., Sulikowski, D., & Maltsev, O., (2008). Enantioselective synthesis of (R)-α(p-nitroaryl)prolines via oxidative nucleophilic substitution of hydrogen in nitroarenes. Synlett, (11), 1711–1713. doi: 10.1055/s-2008-1078483. 209. Tsuge, O., Kanemasa, S., Ohe, M., & Takenaka, S., (1987). Simple generation of nonstabilized azomethine ylides through decarboxylative condensation of α-amino acids with carbonyl compounds via 5-oxazolidinone intermediates. Bulletin of the Chemical Society of Japan, 60(11), 4079–4089. doi: 10.1246/bcsj.60.4079. 210. Araujo, R., Fernandes, F. M., Proenca, M. F., Silva, C. J. R., & Paiva, M. C., (2007). The 1,3-dipolar cycloaddition reaction in the functionalization of carbon nanofibers. Journal of Nanoscience and Nanotechnology, 7(10), 3441–3445. doi: 10.1166/jnn.2007.815. 211. Burger, K., & Burgis, E., (1970). Base induced fragmentation of (4R)-2,2bis(trifluoromethyl)-5-oxazolidinones. Justus Liebigs Annalen der Chemie, 741, 39–44. doi: 10.1002/jlac.19707410105. 212. Chu, F. L., & Yaylayan, V. A., (2009). FTIR monitoring of oxazolidin-5-one formation and decomposition in a glycolaldehyde-phenylalanine model system by isotope labeling techniques. Carbohydrate Research, 344(2), 229–236. doi: 10.1016/j.carres.2008.10.011. 213. Brown, G. A., Martel, S. R., Wisedale, R., Charmant, J. P. H., Hales, N. J., Fishwick, C. W. G., & Gallagher, T., (2001). The azomethine ylide strategy for β-lactam synthesis. An evaluation of alternative pathways for azomethine ylide generation. Journal of the Chemical Society, Perkin Transactions 1, (11), 1281–1289. doi: 10.1039/b010050l. 214. Musaev, D. G., & Morokuma, K., (1996). Potential energy surfaces of transition-metalcatalyzed chemical reactions. Advances in Chemical Physics, 95(Surface Properties), 61–128. doi: 10.1002/9780470141540.ch2. 215. Gardner-Chavis, R. A., & Reye, J., (2003). Unified explanation of catalyzed and non-catalyzed chemical reactions. Journal of Molecular Catalysis A: Chemical, 206(1, 2), 269–289. doi: 10.1016/S1381-1169(03)00419-9. 216. Jain, S., Dwivedi, J., Jain, P., & Kishore, D., (2016). Use of 2,4,6-trichloro-1,3,5-triazine (TCT) as organic catalyst in organic synthesis. Synthetic Communications, 46(14), 1155–1174. doi: 10.1080/00397911.2016.1192651. 217. Sato, K., (2010). New dimension of N-heterocyclic carbene organic catalyst. Gendai Kagaku, 468, 24–28. 218. Nagasawa, K., & Sohtome, Y., (2006). Asymmetric carbon carbon bonds formation reaction by cyclic/chain guanidine organic catalyst. In: Shibasaki, M., (ed.), Yuki Bunshi Shokubai no Shintenkai (pp. 191–203). 219. Paraskar, A. S., (2003). Pyrrolidine-2-carboxylic acid (L-proline). Synlett, (4), 582, 583. doi: 10.1055/s-2003-37536. 220. Limbach, M., 5-(Pyrrolidin-2-yl)-1H-tetrazole and 5-[(pyrrolidin-2-yl)methyl]-1Htetrazole: Proline surrogates with increased potential in asymmetric catalysis. Chemistry & Biodiversity, 3(2), 119–133. doi: 10.1002/cbdv.200690016.

390

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

221. Khandelwal, S., Tailor, Y. K., & Kumar, M., (2016). L-Proline catalyzed multicomponent reactions. Current Organocatalysis, 3(2), 176–204. doi: 10.2174/221333720266615062 4172658. 222. List, B., & Liao, S. H., (2012). The proline-catalyzed Mannich reaction and the advent of enamine catalysis. In: Ding, K., & Dai, L. X., (eds.), Organic Chemistry (pp. 367–384). 223. Cukrowski, I., Dhimba, G., & Riley, D. L., (2019). A reaction energy profile and fragment attributed molecular system energy change (FAMSEC)-based protocol designed to uncover reaction mechanisms: A case study of the proline-catalyzed Aldol reaction. Physical Chemistry Chemical Physics, 21(30), 16694–16705. doi: 10.1039/c9cp03046h. 224. Armstrong, A., & Dingwall, P., (2016). Mechanistic understanding of proline analogs and related protic lewis bases (n → π*). In: Vedejs, E., & Denmark, S. E., (eds.), Lewis Base Catalysis in Organic Synthesis (pp. 145–190). doi: 10.1002/9783527675142.ch6. 225. Lalwani, K. G., & Sudalai, A., (2016). A concise enantioselective synthesis of (+)-L733,060 and (+)-T-2328 via sequential proline catalysis. Synlett, 27(9), 1339–1343. doi: 10.1055/s-0035-1561346. 226. Tanaka, F., & Barbas, C. F. III., (2005). Organocatalytic approaches to enantioenriched β-amino acids. In: Juaristi, E., & Soloshonok, V. A., (eds.), Enantioselective Synthesis of β-Amino Acids (2nd edn., pp. 195–213). 227. Arun, D. M., & Shanmugam, S., (2017). Synthesis of chiral α-carbonyl-δ-nitro-ketene dithioacetals via L-proline-catalyzed Michael addition reaction. Research on Chemical Intermediates, 43(12), 6863–6873. doi: 10.1007/s11164-017-3025-1. 228. Choudary, B. M., Rajasekhar, C. V., Krishna, G. G., & Reddy, K. R., (2007). L-Proline-catalyzed Michael addition of aldehydes and unmodified ketones to nitro olefins accelerated by Et3N. Synthetic Communications, 37(1), 91–98. doi: 10.1080/00397910600978218. 229. Ramachary, D. B., Reddy, Y. V., Banerjee, A., & Banerjee, S., (2011). Design, synthesis and biological evaluation of optically pure functionalized spiro[5,5]undecane-1,5,9triones as HIV-1 inhibitors. Organic & Biomolecular Chemistry, 9(21), 7282–7286. doi: 10.1039/c1ob06133j. 230. Yu, P., Zhou, Y., Yang, Y., & Tang, R., (2016). Two catalytic systems of L-proline/Cu(II) catalyzed allylic oxidation of olefins with tert-butyl hydroperoxide. RSC Advances, 6(70), 65403–65411. doi: 10.1039/C6RA11784H. 231. Steiner, D. D., Mase, N., & Barbas, C. F. III., (2005). Direct asymmetric α-fluorination of aldehydes. Angewandte Chemie, International Edition, 44(24), 3706–3710. doi: 10.1002/anie.200500571. 232. Schmid, M. B., Zeitler, K., & Gschwind, R. M., (2010). The elusive enamine intermediate in proline-catalyzed aldol reactions: NMR detection, formation pathway, and stabilization trends. Angewandte Chemie, International Edition, 49(29), 4997–5003, S4997/1–S4997/11. doi: 10.1002/anie.200906629. 233. Sharma, A. K., & Sunoj, R. B., (2010). Enamine versus oxazolidinone: What controls stereoselectivity in proline-catalyzed asymmetric aldol reactions? Angewandte Chemie, International Edition, 49(36), 6373–6377, S6373/1-S6373/101. doi: 10.1002/ anie.201001588. 234. Seebach, D., Yoshinari, T., Beck, A. K., Ebert, M. O., Castro-Alvarez, A., Vilarrasa, J., & Reiher, M., (2014). How small amounts of impurities are sufficient to catalyze the interconversion of carbonyl compounds and iminium ions, or is there a metathesis

Oxazolidin-5-ones 391

through 1,3-oxazetidinium ions? Experiments, speculations, and calculations. Helvetica Chimica Acta, 97(9), 1177–1203. doi: 10.1002/hlca.201400221. 235. List, B., Hoang, L., Martin, H. J., & Trost, B. M., (2004). New mechanistic studies on the proline-catalyzed aldol reaction. Proceedings of the National Academy of Sciences of the United States of America, 101(16), 5839–5842. doi: 10.1073/pnas.0307979101. 236. Schmid, M. B., Zeitler, K., & Gschwind, R. M., (2011). NMR investigations on the proline-catalyzed aldehyde self-condensation: Mannich mechanism, dienamine detection, and erosion of the aldol addition selectivity. Journal of Organic Chemistry, 76(9), 3005–3015. doi: 10.1021/jo200431v. 237. El-Hamdouni, N., Companyo, X., Rios, R., & Moyano, A., (2010). Substrate-dependent nonlinear effects in proline-thiourea-catalyzed Aldol reactions: Unraveling the role of the thiourea co-catalyst. chemistry - A European Journal, 16(4), 1142–1148. doi: 10.1002/ chem.200902678. 238. Isart, C., Bures, J., & Vilarrasa, J., (2008). Seebach’s oxazolidinone is a good catalyst for Aldol reactions. Tetrahedron Letters, 49(37), 5414–5418. doi: 10.1016/j. tetlet.2008.07.028. 239. Kanzian, T., Lakhdar, S., & Mayr, H., (2010). Kinetic evidence for the formation of oxazolidinones in the stereogenic step of proline-catalyzed reactions. Angewandte Chemie, International Edition, 49(49), 9526–9529, S9526/1–S9526/22. doi: 10.1002/ anie.201004344. 240. Teng, H., He, Y., Wu, L., Su, J., Feng, X., Qiu, G., Liang, S., & Hu, X., (2006). A general and facile synthetic approach to Nα-Boc ureidoalanine derivatives. Synlett, (6), 877–880. doi: 10.1055/s-2006–939044. 241. Rao, R. V. R., Tantry, S. J., & Babu, V. V. S., (2006). Practical and efficient synthesis of orthogonally-protected 2,3-diaminopropionic acid (2,3-DAP), 2,4-diaminobutanoic acid (2,4-DAB), and their N-methylated derivatives. Synthetic Communications, 36(19), 2901–2912. doi: 10.1080/00397910600772827. 242. Teng, H., Jiang, Z., Wu, L., Su, J., Feng, X., Qiu, G., Liang, S., & Hu, X., (2006). Facile way to synthesize Nα-Boc-Nβ-Cbz-2,3-diaminopropionic acid derivatives via 5-oxazolidinone. Synthetic Communications, 36(24), 3803–3807. doi: 10.1080/00397910600948039. 243. Venkataramanarao, R., & Sureshbabu, V. V., (2007). An efficient synthetic route to N-glycosyl-amino acids using Nα-Fmoc-Asp/Glu-5-oxazolidinone as internal protection. Synlett, (16), 2492–2496. doi: 10.1055/s-2007-986645. 244. Gelb, M. H., Lin, Y., Pickard, M. A., Song, Y., & Vederas, J. C., (1990). Synthesis of 3-fluorodiaminopimelic acid isomers as inhibitors of diaminopimelate epimerase: Stereo controlled enzymatic elimination of hydrogen fluoride. Journal of the American Chemical Society, 112(12), 4932–4942. doi: 10.1021/ja00168a045. 245. Hughes, A. B., & Sleebs, B. E., (2005). Synthesis of new β-amino acids via 5-oxazolidinones and the Arndt-Eistert procedure. Australian Journal of Chemistry, 58(11), 778–784. doi: 10.1071/CH05199. 246. Hoffmann, M. G., & Zeiss, H. J., (1992). Natural products synthesis in agricultural chemistry. I. A novel and convenient route to L-homoserine lactones and L-phosphinothricin from L-aspartic acid. Tetrahedron Letters, 33(19), 2669–2672. doi: 10.1016/S0040-4039(00)79053-8. 247. Singh, S. P., Michaelides, A., Merrill, A. R., & Schwan, A. L., (2011). A microwaveassisted synthesis of (S)-N-protected homoserine γ-lactones from L-aspartic acid. Journal of Organic Chemistry, 76(16), 6825–6831. doi: 10.1021/jo2008093.

392

Amino Acids: Insights and Roles in Heterocyclic Chemistry, Volume 4

248. Itoh, M., (1969). Peptides. I. Selective protection of α- or side-chain carboxyl groups of aspartic and glutamic acid. A facile synthesis of β-aspartyl and γ-glutamyl peptides. Chemical & Pharmaceutical Bulletin, 17(8), 1679–1686. doi: 10.1248/cpb.17.1679. 249. Reddy, G. V., (1999). A novel, simple and practical protocol for N-protected-αamino hydroxamic acids. Synthetic Communications, 29(20), 3613–3619. doi: 10.1080/00397919908085996. 250. Dorow, R. L., & Gingrich, D. E., (1999). A novel, one-pot preparation of N-methyl-αamino acid dipeptides from oxazolidinones and amino acids. Tetrahedron Letters, 40(3), 467–470. doi: 10.1016/S0040-4039(98)02426-5. 251. Lee, K. I., Kim, J. H., Ko, K. Y., & Kim, W. J., (1991). Regioselective amidation of aspartic and glutamic acid. Synthesis, 11, 935, 936. doi: 10.1055/s-1991-26610. 252. Pirrung, M. C., Zhang, F., Ambadi, S., & Ibarra-Rivera, T. R., (2012). Reactive esters in amide ligation with β-hydroxyamines. European Journal of Organic Chemistry, 23, 4283–4286, S4283/1–S4283/39. doi: 10.1002/ejoc.201200624. 253. Pirrung, M. C., & Schreihans, R. S., (2016). Native serine peptide assembly - scope and utility. European Journal of Organic Chemistry, 34, 5633–5636. doi: 10.1002/ ejoc.201601148. 254. D’Angeli, F., Di Bello, C., & Filira, F., (1971). β-Carbonylamides in peptide chemistry. Synthesis of optically active peptides from N-acetoacetylamino acids via 2-acetonylideneoxazolidin-5-ones. Journal of Organic Chemistry, 36(13), 1818–1820. doi: 10.1021/jo00812a021. 255. Bundgaard, H., & Rasmussen, G. J., (1991). Prodrugs of peptides. 9. Bioreversible N-α-hydroxyalkylation of the peptide bond to effect protection against carboxypeptidase or other proteolytic enzymes. Pharmaceutical Research, 8(3), 313–322. doi: 10.1023/A:1015833229554. 256. Kahns, A. H., Friis, G. J., & Bundgaard, H., (1993). Protection of the peptide bond against α-chymotrypsin by the prodrug approach. Bioorganic & Medicinal Chemistry Letters, 3(5), 809–812. doi: 10.1016/S0960-894X(00)80671-X. 257. Buur, A., & Bundgaard, H., (1988). Prodrugs of peptides. III. 5-Oxazolidinones as bioreversible derivatives for the α-amidocarboxy moiety in peptides. International Journal of Pharmaceutics, 46(1, 2), 159–167. doi: 10.1016/0378–5173(88)90021-X. 258. Walter, M. W., Adlington, R. M., Baldwin, J. E., Chuhan, J., & Schofield, C. J., (1995). Reaction of Ruppert’s reagent (TMS-CF3) with oxazolidinones: Synthesis of protected α-amino trifluoromethyl ketones. Tetrahedron Letters, 36(42), 7761–7764. doi: 10.1016/0040-4039(95)01619-S. 259. Paleo, M. R., & Sardina, F. J., (1996). Enantiospecific synthesis of α-amino ketones and β-amino alcohols from the reaction of N-(9-phenylfluoren-9-yl)alanine oxazolidinone with organolithium reagents. Tetrahedron Letters, 37(19), 3403–3406. doi: 10.1016/0040-4039(96)00557-6. 260. Reddy, G. V., Rao, G. V., & Iyengar, D. S., (1999). Selective reductions of oxazolidinones: New protocol for diastereoselective synthesis of vicinal amino alcohols. Tetrahedron Letters, 40(13), 2653–2656. doi: 10.1016/S0040-4039(99)00265-8. 261. Reddy, G. V., Rao, G. V., Sreevani, V., & Iyengar, D. S., (2000). An enantioselective synthesis of (1S,2S)-pseudoephedrine. Tetrahedron Letters, 41(6), 953–954. doi: 10.1016/S0040-4039(99)02106-1.

Oxazolidin-5-ones 393

262. Allevi, P., & Anastasia, M., (2003). Mild regeneration of the carboxylic group of amino acid alkyl esters by aqueous methanolic sodium hydrogen carbonate via 5-oxazolidinones. Tetrahedron Letters, 44(41), 7663–7665. doi: 10.1016/j.tetlet.2003.08.028. 263. Reddy, G. V., & Iyengar, D. S., (1998). A new approach for chiral allyl amines via a novel dichloromethylenation of oxazolidinones. Chemistry Letters, (12), 1237, 1238. doi: 10.1246/cl.1998.1237. 264. Paleo, M. R., Calaza, M. I., Grana, P., & Sardina, F. J., (2004). Stanna-Brook rearrangement of carboxylic acid derivatives. Synthetic utility and mechanistic studies. Organic Letters, 6(6), 1061–1063. doi: 10.1021/ol049826m. 265. Van, N. T. T., Brownlee, R. T. C., & Hughes, A. B., (2009). A novel synthesis of N-but3-enyl-α- and β-amino acids. Synthesis, (12), 1991–1998. doi: 10.1055/s-0028-1088072. 266. Pumpor, K., Boettcher, C., Fehn, S., & Burger, K., (2003). Hexafluoroacetone as protecting and activating reagent: An efficient strategy for activation of pyroglutamic acid and homologs. Heterocycles, 61, 259–269. doi: 10.3987/COM-03-S34. 267. Golubev, A., Sewald, N., & Burger, K., (1995). Hexafluoroacetone as activating and protecting reagent in amino acid and peptide chemistry. 19. An efficient approach to the family of 4-substituted pipecolic acids. Syntheses of 4-oxo-, cis-4-hydroxy-, and trans-4-hydroxy-L-pipecolic acids from L-aspartic acid. Tetrahedron Letters, 36(12), 2037–2040. doi: 10.1016/0040-4039(95)00183-D. 268. Spengler, J., Schedel, H., Sieler, J., Quaedflieg, P. J. L. M., Broxterman, Q. B., Duchateau, A. L. L., & Burger, K., (2001). Asymmetric Pictet-Spengler reactions: Synthesis of 1,2,3,4-tetrahydroisoquinoline carboxylic acid (Tic) chimeras. Synthesis, 10, 1513–1518. doi: 10.1055/s-2001-16091. 269. Radics, G., Schedel, H., Heistracher, E., Sieler, J., Hennig, L., & Burger, K., (2002). Some unexpected reactions of 2,2-bis-(trifluoromethyl)-1,3-oxazolidin-5-ones. Heterocycles, 58, 213–225. doi: 10.3987/COM-02-S(M)11. 270. Tian, W., Chen, Y., Luo, Y., & Deng, X., (1991). A facile synthesis of 2-trifluoromethylpyrrole via 1,3-dipolar cycloaddition reaction of 2-trifluoromethyloxazolone and the activated carbon-carbon multiple bond. Chinese Chemical Letters, 2(3), 217–220.

Index

1

2

1,1,2-trichloroethane, 297 1,2,3,4,5-pentamethylcyclopenta-2,4-dien1-ide, 63 1,2-bis(diphenylphosphino)ethane (dppe), 54 1,2-dichloroethane, 56, 69, 81, 86, 93, 126, 143 1,2-dimethoxyethane (DME), 20, 32, 55, 168, 172, 320 1,3,5-trioxane, 295, 301 1,3-dioxazolidin-5-one, 259 1,3-dipolar cycloaddition, 6, 113, 114, 128–142, 173, 181–188, 212, 225, 227, 283, 306, 307, 325, 340, 350, 351, 374 reaction, 128 1,3-oxazolidin-5-one moiety, 260, 262, 297 1,4-benzoquinone (BQ), 201 1,4-diaminobutane, 218 cross-linked block copolymer, 218 1,4-diazabicyclo[2.2.2] octane (DABCO), 117, 150, 161, 166 1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one, 56, 105, 153 1,4-diiodobutane cross-linked microgels, 218 1,4-dithiane-2,5-diol, 178 1,5,7-triazabicyclo[4.4.0]-dec-5-ene (TBD), 90 1,5,9-cyclododecatriene, 219 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 10, 90, 130, 146, 205, 222, 306, 307, 344, 355 1-aminocyclohexane-1-carboxylic acid, 210, 219 1-azidooctane, 284 1-benzyl 4-ethyl 2-vinylidenesuccinate, 184–186 1-benzyl-3-methylimidazolium dihydrogen phosphate, 11, 17 1-naphthoyl chloride, 319, 321 1-naphthyl group, 53, 98

2-((4S)-3-formyl-5-oxo-2-(tribromomethyl) oxazolidin-4-yl)acetic acid, 304 2-(1-bromoethyl)-4,4-dimethyloxazol-5(4H)-one, 125, 218 2-(2-nitrophenyl)propyl (2-(dimethylamino) ethyl)carbamate, 209 2-(4-methoxyphenyl) 4-aryloxazol-5(4H)-ones, 97 4-phenyloxazol-5(4H)-one, 44–46, 97 2-(bromomethyl)isoindolin-1,3-dione, 306 2-(dimethylmaleimido)-N-ethyl-acrylamide, 219 2-(N-methylacetamido)-2-phenylacetic acid, 134 2-(piperidin-1-yl)ethan-1-amine, 206 2-(X-phenyl)-4-ethyloxazol-5-ol, 92 2,2,2-trichloroethylchloroformate, 299 2,2,3,3-tetrafluoropropanoic anhydride, 222 2,2,5-trimethyl-4-phenyl-3-azahexane-3oxyl, 218 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), 202 2,2-(terephthaloylbis (azanediyl))bis(3methylbutanoic acid), 212 2,2-(terephthaloylbis (azanediyl))bis(3phenylpropanoic acid), 212 2,2-bis(trifluoromethyl)-1,3-oxathiolan5-one, 322, 333 2,2-dimethyl-1,3-dioxolane, 182, 293 2,2-diphenylacetic acid, 100 2,3-dimethylmaleimde groups, 219 2,3-substituted oxazolidin-2-ones, 259 2,4-dichloro-D-phenylalanine, 263 2,4-difluorobenzaldehyde, 14 2,4-diphenylthiazol-5(4H)-one, 72 2,4-disubstituted-oxazol-5-yl carbonates, 61 2,5,6-triphenyl-2,5-dihydropyridine, 100 2,5-diketopiperazine (DKP), 34, 259, 332, 342 2,5-dimethylbenzoquinone (2,5-DMBQ), 53

396

2,5-dioxopyrrolidin-1-yl 2-phenoxyacetate, 263, 282 2,6-dideoxy D-threo-4- hexulose, 270 L-erythro-4-hexulosyl-JdA, 270 L-sugar glycosyltransferase, 270 2-acetyl-5,6,7,8-tetrahydroindolizine-1-carbonitrile, 135 2-amino-2 methylpropanoic acid, 203, 219 phenylacetic acid, 76, 82, 90, 223, 301, 302, 306, 338, 359 2-amino-3,3-dimethylbutanoic acid, 224, 301 2-aminobutanoic acid, 90, 223, 265 2-aminohexanoic acid, 90, 223, 265, 283 2-aminopentanoic acid, 223, 265, 283 2-aminopyridine, 9–11 2-benzamidocinnamic acids, 14 2-benzoylamino esters, 119 2-chloro 2-phenylacetyl)alanine, 223 4,6-dimethoxy-1,3,5-triazine (CDMT), 35, 36, 110 acrylonitrile, 135, 136, 225, 370 2-cinnamyl-2,4-diphenyloxazol-5(2H)-one, 100 2-diazo-1,1,1-trifluoroethane, 191, 192 2-ethyl-2-((methacryloyloxy)methyl)propane1,3-diyl bis(2-methylacrylate)), 205 2-ethynyl 2-acetylamino adamantane, 36 adamantan-2-ol, 35 2-hydroxyethyl methacrylate (HEMA), 205 2-hydroxyl styrenes, 153 2-iodobenzoyl chloride, 315 2-mercaptoacetaldehyde, 178, 180 2-mercaptoacetic acid, 332 2-methyl 2-(vinyloxy)propane, 99 4-(quinolin-2-yl) oxazol-5(4H)-one, 60 4-phenyloxazol-5(4H)-one, 136 5-(trifluoromethyl)-1H-pyrrole-3-carbonitrile, 225 allyltributyltin, 316 azlactones, 78 enetetrahydrofuran, 101 oxazol-5(4H)-one, 18, 25, 26, 35, 60, 109, 154, 155, 168, 172, 191, 192, 195, 212

Index

oxazolin-5(4H)-one, 60 prop-1-en-1-yl acetate, 98 2-nitrobenzaldehyde, 18 2-oxazolin-5-one, 1, 125, 154 2-phenyl-4-(quinolin-2-yl)oxazol-5(4H)one, 60 2-phenylazlactone, 60, 76–78, 83, 126 2-phenylethanal bisulfite, 18 2-phenyloxazolin-5-one, 11, 35 2-pyrrolidinone hydrotribromide, 23 2-vinyl-4,4-dimethylazlactone, 208, 213

3 3-(3-oxobutyl)-2-thioxoimidazolidin-4-one, 337 3-(4-methoxyphenyl)isoxazole-5-carbaldehyde, 6 3-(dimethylamino)propan-1-ol, 222 3,4-dichloro D-phenylalanine, 263 L-phenylalanine, 263 3,4-dihydrocoumarins, 151 3,4-dihydropyridin-2(1H)-one, 147–149 3,4-dimethoxybenzaldehyde, 24 3,4-dimethoxyphenethyl 4-nitrobenzenesulfonate, 340 3,5,6-trimethoxybenzylamine, 110 3,5-dihydro-4H-imidazol-4-one derivatives, 107 3,5-dimethoxyaniline, 103 3-amino-3,4-dihydropyridin-2(1H)-ones, 148 3-aminopropanoic acid, 267 3a-R configuration, 277, 279, 281 3-benzylidene-2-oxoindoline, 129 3-chloropropyl-trimethoxysilane, 10 3-hydroxy-2-methylpentanal, 352, 353 3-isopropyl-2,2-dimethyl-2H-azirine, 225, 226 3-methyl-2,2-bis(trifluoromethyl) oxazolidin-5-one, 331, 332 3-methylpyridine, 10

4 4-(((3-aminopropyl)amino)methyl)phenylmethanol, 209 4-((5,6-dihydropyrimidin-1(4H)-yl)methyl) phenyl-methanol, 208

Index 397

4-(4-(dimethylamino) benzylidene)2-phenyloxazol-5(4H)-one, 171 4-(4-(tert-butyl)cyclohexylidene)-2-phenyloxazol-5(4H)-one, 199 4-(isoquinolin-1-yl)-2-phenyloxazol-5(4H)one, 60 4-(naphthalen- 1-ylmethyl)-2-phenyloxazol-5(4H)-one, 117 4-(tert-butyl)-2-phenyloxazol-5(4H)-one, 41 4,4-dimethyl 2-phenyloxazolin-5-one, 123 2-vinyloxazol-5(4H)-one (DMV), 111, 202–209, 212–220, 222 azlactone ring, 209 oxazol-5(4H)-one, 202 4,5-dimethyl-2-phenyloxazole, 125 4-acyl-2,4-disubstituted oxazol-5(4H)-ones, 61 4-alkylidene azlactones, 11, 15, 18, 187, 191 4-amino D-phenylalanine, 263 L-phenylalanine, 263 4-arylidene 2-phenyl-5(4H)-oxazolones, 7 azlactones, 24, 184, 185, 187, 189, 191, 195, 198 moiety, 24, 190 4-benzhydryl-2-phenyloxazol-5(4H)-one, 162 4-benzyl-2 3,4,5-trimethoxyphenyl-oxazol-5(4H)one, 74 phenyloxazol-5(4H)-one, 23, 44, 49, 54, 55, 69, 80, 84, 86, 93, 104–106, 119, 128, 129, 139, 140, 145, 147, 150, 152 4-benzylidene-2-phenyloxazol-5(4H)-one, 9, 14, 23, 28–30, 112, 162, 163, 172, 177, 178, 181, 185, 186, 189, 191, 196, 197 4-bromo 3-methyl-2,2-bis(trifluoromethyl) oxazolidin-5-one, 332, 334 L-phenylalanine, 263 4-chloro benzaldehyde, 9, 17 L-phenylalanine, 263 4-cycloheptylidene-2-phenyloxazol-5(4H)one, 199 4-ethynyl-X-1-tosyl-1,4-dihydro2H-benzo[d][1,3]oxazin-2-one, 104

4-fluorobenzylamine, 219 4-hydroxyproline, 80, 322, 367 sulfonyl carboxamides, 80 4-isobutyl-2-phenyloxazol-5(4H)-one, 119 4-isopropyloxazol-5(4H)-one, 39, 40, 120 4-isopropyloxazol-5-olate, 39 4-isothiocyanatobutan-2-one, 337 4-methyl-2-(trifluoromethyl)oxazol-5(2H)one, 224, 225 4-methyl-2-(trifluoromethyl)oxazol-5-yl acetate, 224 4-methyl-2-phenyloxazol-5(4H)-one, 37, 48–52, 65, 66, 70–72, 74, 80, 119, 125–128, 131, 132, 136, 147–149, 155, 156, 225 4-methyl-3,5-diphenyl-4H-1,2,4-triazole, 138 4-methyloxazol-5(4H)-one, 60, 61, 89, 91, 120, 209–211 4-N,N-dimethylaminopyridine, 63, 327 4-nitrobenzonitrile, 137 4-phenyl-2-(trifluoromethyl) oxazol-5(2H)one, 372 4-substituted-2-(4-(trifluoromethyl)phenyl) oxazol-5(4H)-ones, 120

5 5-exo-dig cyclization, 35, 36 5-hydroxy-L-tryptophan, 336 5-methoxy-2,4-disubstituted oxazoles, 36, 46 5-nitro-2-thienyl, 19 5-oxo-2-phenyl-2-oxazolinium perchlorate, 13 5-phenylisoxazole, 164, 166 5-trimethylsiloxyoxazoles, 154

6 6-alkylidenecyclohexa-2,4-dien-1-one, 151, 152 6-aminohexanoic acid, 268 6-deoxy D-glucose, 270, 277 L-altrose, 270 6-phenyl-4-(propan-2-ylidene)-3,4-dihydro2H-1,3,5-oxadiazin-2-one, 173

398

Index

A Abiotic amino acids, 117 Acenaphthylene, 137 Acetaldehyde, 15, 69, 72, 302, 304, 360, 373 Acetic anhydride, 1, 2, 4, 5, 7–9, 12–17, 19–21, 25, 26, 30, 34, 37, 38, 60, 64, 69, 78, 84, 123, 135, 136, 167, 169, 176, 178, 205, 210, 219, 304 Acetonitrile, 13, 32, 35, 36, 55, 65, 69, 78, 80, 81, 113, 140, 143, 178, 191, 192, 302 Acetophenone, 14, 17, 18 Acetoxy group, 25 Acetyl chloride, 224, 303, 324, 325, 327, 367 CoA, 273 Achiral base, 146 Acid chloride, 219, 324, 325, 367 hydrolysis, 117 Acidolysis, 224, 350 Acrylonitrile, 40, 41, 131, 218 Actinobacteria, 280 Actinometer, 195 Actuator, 215 Acyclic N-acyl amino acids, 134 Acyl halide, 336 Acylation, 43, 64, 78, 124, 126, 315 Adamantane, 36, 65 Addition allenes, 104 elimination mechanism, 59 Advanced lithography, 204 Aglycone, 260, 262, 272, 280, 281 Alcoholysis, 98, 116, 119, 127, 176 Aldehyde bisulfite, 17, 18 Aldol addition, 30 condensation, 20, 38, 68, 69, 227, 352, 353, 374 reaction, 16, 42, 68–70, 75, 340, 352, 353, 355, 368 Aliphatic side chain, 191, 289 Alkene moiety, 75 Alkoxyamines, 218 Alkyl lithium, 41, 362 Alkylation, 38, 42, 43, 47, 53, 58, 96, 303, 305, 314, 316, 318, 320, 321, 340, 342, 343, 345, 346 products, 321

Alkylenediamine, 212 Alkylidene azlactones, 11, 12, 160, 192 Alkynyl (phenyl)iodonium salts, 67 moiety, 283 Alkynylation azlactones, 66 Allyl 2,4-disubstituted-oxazol-5-yl, 54, 61 chloroformate, 54, 55 Allylation, 38, 43, 47, 52–54, 56–58, 61, 100, 160, 161, 315 Allylic alkylation, 42, 48, 160 azlactones, 47 moiety, 47 Allyloxycarbonyl chloride, 314 Allyltributyltin, 315 Alpha-isomer, 194 Altromycin B, 273 Alum, 16 Alumina, 7, 11, 15, 16 Amastigotes, 3 Amidation product, 129, 148 Amidinium bicarbonate, 209 Amine containing macromolecules, 212 nucleophiles, 108, 205 Amino acid biodegradable polymers, 211 ester, 108–110, 116, 210, 304 Aminolysis, 20, 57, 60, 107–109, 114, 172, 223, 367 Aminomethylferrocene, 205 Aminosugars, 357 Ampicillin, 292 Analogous intermediate, 18 Angiotensin III, 121 Angucycline, 272–277, 280 antibiotics, 280 derived antibiotics, 272 Angucyclinone, 272, 273, 291 Anhydride, 3, 32 character, 202 Aniline, 60, 111, 115, 172, 177, 356, 359 Anisole, 126 Annexin V affinity assay, 289 Antagonist, 305

Index 399

Anthelmintic, 280 Antibacterial, 7, 166, 215, 260, 280–284, 286, 287, 292, 372 activity, 260, 280–284, 292 Antibiotic activity, 260 molecules, 260 Anticancer, 260, 280, 287–292 activities, 104, 287 Anti-coupling, 199 Antifungal, 7, 166, 280 activity, 280 compounds, 280 Antimicrobial, 280, 283, 287, 288, 292, 337, 338, 372 properties, 283 Anti-tremorine effect, 3 Antivirus, 280 Anti-yeast activities, 280 Apoptosis, 287, 289, 292 Aprotic polar solvents, 214 Aquayamycin, 273 Aromatic acyl chloride, 224 aldehyde, 5, 10, 14, 17–19, 167 amino acid functionalities, 289 Aromatization, 84, 93 Arylation, 42, 45, 60, 73, 227, 350 azlactones, 59 Arylidene moiety, 194, 195, 198 Arylmethyl amines, 59 diphenylphosphates, 58 methyl carbonates, 58 Asparaginase, 207 Aspergillus niger, 337, 338 Asymmetric benzylation, 57 cooperative catalysis, 153 cycloadduct, 196 induction, 40, 108 Atom force microscopy, 220 transfer radical polymerization (ATRP), 203, 207, 208, 218, 219 Atropisomeric equilibrium, 281 Aurora kinases, 291 Aza compound, 1 cope [3,3]-rearrangement, 100

Azetidine, 49, 316 Azlactone, 1–12, 14–30, 32, 34–49, 51–61, 63–70, 72–74, 76–84, 86, 90–98, 100, 101, 103, 105, 107–130, 132–137, 139–157, 159, 160, 162, 164, 166–170, 172, 174, 176, 181–185, 187–192, 195, 196, 198, 200–220, 222, 223, 225–227, 259 containing block copolymers, 208 polymers, 113, 115, 203, 205, 206 functionalized alkenes, 219 polymers, 206 intermediate, 35, 65, 108, 110 moiety, 24, 25, 44, 52, 66, 80, 84, 94, 96, 105, 108, 111–114, 125, 170, 205, 207–209, 214, 215, 219 polymers, 220 racemization, 109 reactivity, 210 ring, 30, 39, 47, 57, 83, 98, 107, 119, 123, 153, 154, 164, 168, 169, 182, 189, 205, 206, 214 Azlactonization, 5, 8, 9, 12, 17, 22, 35 Azodicarboxylates, 103 Azomethine imines, 139

B Bacillus cereus, 337 circulans, 338 subtilis, 281, 283, 285, 337 C971, 283, 285 Bacterial biofilms, 213 triggered acidification, 215 Bacteriophage SV1, 261 Baeyer-Villiger oxidation, 277 Benz[b]anthracene base structure, 280 Benzaldehyde, 1, 4, 5, 7–9, 13, 14, 18, 26, 30, 304–312, 314, 318, 319, 348, 353, 360, 372 dimethyl acetal, 309–312 Benzene, 12, 14–16, 18, 28, 34, 35, 45, 80, 83, 85, 92, 94, 99, 101, 123, 126, 162–164, 170, 173, 177, 186, 192, 203, 210, 223, 284, 295–299, 301, 307, 309, 314, 315, 327, 344, 347, 356, 364

400

Benzil, 365 Benzo[a]quinolizine-4-one, 112 Benzoic acid, 52, 76, 78, 80, 117, 137, 155, 282 anhydride, 78 Benzo-moiety, 129 Benzophenone, 14, 208 Benzoxazolophenanthridine, 260, 279 Benzoyl chloride, 5, 22, 24, 113, 127, 128, 224, 305, 310, 314 Benzoylation, 116 Benzoyl dl-O-methylphenylserines, 22 L-leucylglycine, 111 Benzyl (2-(benzylamino)-2-oxoethyl) carbamate, 361 (S)-5-oxo-4-(3-oxopropyl)oxazolidine3-carboxylate, 357 5-oxo-oxazolidine-3-carboxylate, 295, 360 alcohol, 111, 116, 117, 151, 299, 300, 356 diethylphosphate, 58 iodide, 320 Benzylamine, 110, 111, 129, 172, 205, 332, 360, 361 Benzylation, 58, 59 azlactones, 57 Benzylic electrophile, 58 Benzyloxycarbonyl amino acids, 210 glycine p-nitrophenyl ester, 11 group, 210, 295 peptides, 210 Benzyl-oxygen bond, 58 Benzylthio group, 177 Benzylthiol, 176, 177, 179 Bergmann rearrangement, 25 Bicyclic pyrazolidinone derivatives, 139 Bifunctional catalyst, 76 linkers, 125 squaramide organo-catalyst, 152 Bimetallic asymmetric catalysis, 77 Binaphthol, 130 Binuclear ortho-palladated cyclobutanes, 195 Bioconjugation, 202 Biohybrid, 205 Bio-inspired applications, 203

Index

Biological activities, 3, 4, 260, 280, 372 antibacterial-antimicrobial activities, 281 anticancer activity-cleavage (DNA), 287 signal molecules, 292 Bioluminescence assay, 206 NADH detection system, 288 Biosynthetic aldehyde group, 262 Biotechnologically relevant enzymes, 207 Biotin, 214 bound terpolymer, 219 Biphasic polynuclear complexes, 17 system, 43 Bis-(diphenylphosphinobenzoyl)diamine (Dppba), 58 Bis-azlactones, 212 Bis-guanidinium salt, 121, 139 Bis-metallic complex, 76 Bis-palladacycle bimetallic catalyst, 78 Bis-protected amino acid derivatives, 111 Block copolymer, 202 nanoparticles, 208 Blue light LED, 198 Boc protecting group, 344 Boric acid, 15 Boron trifluoride etherate, 309, 310, 319 Branched polyethyleneimine (BPEI), 206 Bromal, 304 Bromide end-chain functionality, 204 Brominated, 223, 314, 327, 331–333 azlactone, 22 Brønsted acid, 12, 17, 49, 52, 76, 119, 147, 148, 151, 153, 155 Butyl alcohol, 356 Butyraldehyde, 17

C Cadmium chloride, 17 Calcium acetate, 7 hydrogen phosphate, 7, 8 Camphorsulfonic acid (CSA), 80, 109, 110, 119, 155, 196, 198, 295, 298 Cancer therapeutic target, 132 Candida albicans, 282, 286, 337 Carbanion, 38, 75, 164, 224, 340, 341, 343–345, 348, 349, 364, 365

Index 401

Carbon dioxide, 37, 134, 340 Carboxyl group, 123, 168, 267, 268, 299, 300, 321, 322, 324, 325, 337, 340, 344, 350, 356–359, 363, 367, 373 Carboxylation, 42, 64, 65 azlactones, 61 Carboxylic acid, 2, 5, 32, 35–37, 40, 41, 43, 64, 76, 110, 130, 134, 136, 271, 272, 277, 303, 305, 307, 316, 325, 330, 333, 335, 344, 345, 349, 350, 367–371, 373 Carcinoma, 287, 288 Catalase, 291 Catalyst, 8–12, 16–18, 30, 39, 40, 42–44, 51–53, 56, 59, 62, 69, 71, 73, 76, 78, 86, 88–90, 93, 94, 96, 97, 99, 101, 109, 110, 117, 119, 128, 130–132, 144, 147, 157, 160, 162, 172, 181, 183, 184, 198, 199, 204, 205, 207, 213, 293, 295, 301, 312, 338, 352, 353 activity, 8, 10, 16, 17 dehydrogenative cross-coupling, 45 oxidative cross-enolate coupling reaction, 44 Cecropin B, 215 Cell culturing media, 268, 270, 280, 283 differentiation, 3 encapsulation, 215 metabolic activity, 288 Central nervous system (CNS), 3, 217, 287 Centrifugation, 10 Centrosymmetric 1,3-diazetidines, 199 Chain transfer agent (CTA), 203, 218, 219 Chalcone, 80, 130, 147 Chemoselective, 18, 156 Chiral amino acids, 116, 372 auxiliary, 33, 44 bisguanidine, 147 bisguanidinium salts, 121 catalyst, 39, 70, 76, 90, 99, 120–122, 132, 141, 151, 160, 178, 184, 185, 190 organic catalyst, 82, 89, 128, 143 phosphoric acid (CPA), 91–97, 100, 101, 103, 130, 140, 148, 149, 151–153 assisted protodepalladation, 96 phosphorus ligands, 185 stereogenic center, 157

thiourea, 74, 80, 81, 90, 101, 141, 145, 187, 188 derivatives, 81 Chloral, 302, 304 Chloramphenicol, 260, 261, 280 Chlorine-substituted phenols, 40 Chlorobenzene, 81, 162 Chloroform, 10, 105, 148, 189, 301, 312 Chlorosulfonylisocyanate, 327 Chlortetracycline, 280 Chromosome, 277 Chrysomycin A, 273 Cinchona alkaloid, 84, 142 Cinnamaldehyde, 12, 18, 19, 105, 107, 130, 147, 148, 157, 158 Cinnamoyl benzotriazole, 39, 40 Cinnamylation, 47 Cis-oxazoline, 22 Classic native chemical ligation, 359 purification processes, 73 Click chemistry, 113, 114, 125, 263, 279, 283, 286 Clinical Laboratory Standards Institute (CLSI), 281, 283, 285 Colorimetric assay, 288 Column chromatography, 7, 135 Computational study, 153, 198 Condensation agent, 20, 34, 326 Configurational purity, 110 Conformational constraint, 43 rigidity, 347 Conjugate addition, 75, 76, 91–94, 171, 172, 176, 178, 187 Contact angle measurements, 220, 221 Conventional silanized glass substrates, 213 Copolymerization, 202, 203, 205, 208, 211, 215, 217 Copper-mediated DNA cleavage, 291 Covalent cross-linked multi-layer polymer structures, 212 immobilization, 205 shell-crosslinked capsules, 215 Critical aggregation concentration, 109 micelle concentration (Cmc), 109

402

Index

Cross-link density, 205 Crotonaldehyde, 9, 15, 17, 130 Crystallization-induced dynamic resolution (CIDR), 44, 45 Culture supernatants, 272 Cyclic anhydride, 215 azlactone-functionalized oligomers, 213 Cycloaddition, 39, 125, 128, 153, 189, 193 product, 147, 150, 153, 155, 156, 196, 336 reaction, 153, 155, 198 Cycloadducts, 130, 132, 135, 140, 148, 185, 191, 194–196, 284, 307 Cyclobutane, 192, 194, 195, 199 Cyclodehydration, 15 Cyclodextrin, 205 Cycloelimination, 125 Cyclohex-1-en-1-yl-L-proline, 353 Cyclohexanethiol, 119 Cyclohexanone, 10, 12, 15, 17–19, 353, 355 Cyclohexylalanine, 301 Cyclooctene, 219 Cyclopentadiene, 114, 307 Cyclopentadienyl rings, 77 Cyclopentanone, 10, 353 Cyclopentyl methyl ether (CPME), 43, 128 Cyclopropanation, 36, 191, 192 product, 192 Cyclopropane spiro-azlactones, 192 Cystamine, 207 Cytosine, 280 Cytotoxicity, 283, 287–289

D Dakin-West reaction, 37, 64–66 Dalomycin T, 272, 273, 289 Dansylcadaverine, 214, 217 D-configuration, 108 Dean-Stark apparatus, 293, 304 Decarboxylation, 56, 64, 105, 136, 272, 277, 350 Degree of functionalization, 206, 221 Dehydrating, 30, 126, 171, 350 agent, 5, 15, 126, 167, 227 diamides, 211 reagent, 16 Dehydrogenative crosscoupling, 46

Density functional theory (DFT), 96, 131, 153, 194, 198 Deoxyribonuclease I, 207 Depalladation, 195 Deprotonation, 39, 135, 164, 320, 368, 372 Deuterolysis, 316 D-glucamine, 213 Diammonium hydrogen phosphate, 7 Diastereoisomer, 32, 191 Diastereomer, 30, 35, 43, 44, 48, 49, 98, 99, 105, 107, 155, 156, 160, 166, 198, 277, 279, 305–311, 314, 315, 318, 338, 339, 355 D-L isomer, 108 isomer, 105 ratio, 44, 73, 105, 310 Diastereoselective, 30, 41, 43, 44, 51–53, 65, 70, 71, 73, 74, 76, 78–81, 83, 84, 86, 89, 90, 93, 94, 99, 100, 105, 121, 128–130, 132, 139, 142, 145, 146, 153–156, 161, 178, 183, 186, 188, 189, 192, 225, 305–307, 314, 315, 318, 352, 353,355, 372 dimerization, 65 Diazo compounds, 42, 101, 137, 191, 358 Diazomethane, 101, 131, 325, 327, 330, 333, 340, 358 Dibenzylidene acetone (dba), 52–55, 59, 105, 185, 324 Dichloroacetic acid, 211 Dichloromethane, 11, 20, 24, 72, 187, 217 Dicyclohexylcarbodiimide (DCC), 10, 20, 23, 32–34, 63, 108, 109, 147, 168, 210, 222, 360 Dicyclohexylurea, 35, 63 Diels-Alder cycloaddition, 95, 114, 142, 144, 145, 154, 189, 190, 308 reaction, 125, 128, 153, 154 Dienophile, 142, 149 Diethyl (2-(aminomethyl)-5-(piperidin-1-yl) oxazol-4-yl)phosphonate, 169, 170 3-oxoglutarate, 164 3-oxopentanedioate, 165, 201, 202 5-benzamido-2,4-dihydroxyisophthalate, 164, 165 aminosulphur triflouride (DAST), 333 ether, 7, 51, 80, 146, 210

Index 403

Dihydrocoumarin, 93, 95, 151 moiety, 93 Dihydroisoquinoline, 112, 113 Dihydropyrimidinones, 166 Dihydroxylation, 49 Diisopropyl (E)-diazene-1,2-dicarboxylate, 101, 104 Diisopropylethylamine (DIPEA), 58, 59, 130, 157, 166 Dimethyl 3-oxopentanedioate, 201 Dimethylsilylpropyl 2-bromo-2-methylpropanoate, 207 Dimethylsulfide, 36 Diphenylphosphine oxide, 201, 202 Dipolarophiles, 130, 134, 139, 141, 142, 181, 182, 189, 340 Direct amidoalkylation, 73 Dispersion polymerization, 205 Di-tert-butyl peroxide (DTBP), 44 DMV homopolymer, 202 DNA cleaving profile, 264 damaging properties, 290 DOD inkjet printing processes, 214 D-olivose, 269–271 Domain orientation, 204 Double bond configuration, 157 dehydrohalogenation, 26 H-bonded thioureas, 101 Drug delivery, 202, 208 Dynamic equilibrium, 279, 353 kinetic resolution, 38, 108, 116, 117, 119, 121 Dynemicin A, 273

E (E)-2-benzylidene-4-methyloxazol-5(2H)one, 223 (E)-hex-3-enedioyl dichloride, 219 Escherichia coli, 3, 283, 285 C498, 283, 285 E2 elimination, 30 E-azlactones, 28–30, 199 Electrochemical probes, 205 Electron deficient alkenes, 131

aromatic compounds, 59 aromatic core, 60 dipolarophiles, 134 species, 348 demanding dienophile, 142 density requirement, 145 donating group, 4, 51, 58, 96, 97, 145, 159, 195, 304 substituent, 160 enriched enol ethers, 98 species, 75, 95 transfer, 198, 199 withdrawing carbonyl group, 38, 340 group, 40, 42, 51, 75, 96, 98, 103, 143, 151, 184, 185, 192, 194, 304 nature, 40, 224, 226 substituent, 18, 129, 159, 160, 190, 198 Electronegative, 321 elements, 38 Electronic nature, 53, 129, 365 Electrophilic, 38, 39, 66, 70, 95, 105, 107, 128, 162, 166, 168, 204, 205, 211, 339, 340, 364, 365 Electrospinning technology, 215 Electrostatic interactions, 212, 222 Ellipsometry, 206, 220 Enamide, 72, 96, 98, 178, 180 Enantiomeric, 43, 89, 96, 105, 117, 121, 297, 319 ratios, 117 Enantiopure non-proteinogenic dipeptides, 191 Enantioselective, 40, 41, 51–53, 55, 56, 58, 62, 63, 69–72, 76, 78–84, 86, 89–94, 96, 97, 100, 101, 103–105, 107, 116, 117, 119, 120, 128–132, 139, 140, 143–153, 157–160, 182, 183, 185, 186, 188, 189, 191, 320, 321, 352, 353 1,3-dipolar cycloaddition, 139 synthesis, 363 Endopeptidase, 123 Ene reactions, 95 Enolization, 78, 105, 318 Enterococcus faecalis, 281, 283, 285 C625, 283, 285 Enzymatic process, 262

404

Index

Epi-isomer, 194 Epimastigotes, 3 Epimerization, 109, 191, 310 Epsilon-isomer, 194, 195 Equimolar mixture, 4 Erlenmeyer azlactone synthesis, 1, 4, 9, 11, 12, 17, 20, 26, 28, 37 synthesis, 11 Erythro-isomers, 22 Erythromycin, 281, 292 Espicufolin, 273 Esterification, 49, 130, 131, 203, 205 Ethanol, 5, 9, 10, 16, 24, 41, 112, 115, 177, 207, 210, 261, 280, 307, 314, 318, 350 Ethyl (R)-2-amino-4-phenylbutanoate hydrochloride, 35 (S)-2-amino-4-phenylbutanoate hydrochloride, 110 (S)-2-benzamido-4-fluoro-4-methylpentanoate, 116 2-(cyanomethyl)buta-2,3-dienoate, 184 2,3-dihydro-1H-pyrrolizine-7-carboxylate, 134 2-azidoacetate, 24 3-phenylpropanoate, 69 5,6,7,8-tetrahydroindolizine-1-carboxylate, 134 buta-2,3-dienoate, 181 carbonochloridate (ClCO2Et), 18, 19, 35, 113, 125, 356, 358 carbonocyanidate, 137 chloroformate, 12, 35, 154, 317 glycinate hydrochloride, 5, 12 iodoacetate, 320 propionate, 69 Ethylenediamine, 208 Ethynyl magnesium bromide, 35 Eukaryotes, 292 Exo-approach, 131 Exocyclic double, 21, 25, 28, 162, 164, 166, 172, 176, 181 olefinic azlactone, 162, 166

F Ferric chloride, 44 Ferrocene carboxaldehyde, 318

counterpart, 77 Fibrotic overgrowth, 216 Fidelity microphase separation, 204 Flash chromatography, 307 Flow synthesis, 35, 36 Fluorescence emission, 6 Fluorinated solvents, 94 Fluorobenzene, 70, 81, 131, 132 Fluorophore, 217 Folic acid, 208 Formaldehyde, 70, 294, 295, 301, 302, 362, 368 Formalin, 294 Fractional crystallization, 14 Free radical copolymerization, 215 Friedel-Crafts acylation, 162 alkylation, 297 reaction, 126, 223 Frigocyclinone, 273 Fujianmycin A, 273 Fumarate, 132, 137 Functionalization, 42, 83, 115, 206, 209, 220, 221, 299, 300, 318, 321, 356, 357

G Galactose, 260 Gamma-isomer, 194 Gaudimycin C, 273 Gene delivery, 206 expression, 261 Gentamicin, 286 Gilvocarcin V, 273 Glucagon-like peptide-1 (GLP-1), 193, 194 receptor (GLP-1R), 193 Glucoamylase, 207 Glucose, 207, 260, 270, 271, 277 oxidase, 207 Glutamic acid, 299, 300, 321, 325, 326, 331, 333, 335, 356–359, 367, 373 Glutathione, 205, 359 Glycolaldehyde, 352 Glycosyltransferase, 270, 277 Gold nanoparticles, 208 Grafting density, 206, 221 Gram negative

Index 405

bacteria, 282, 283 strains, 283 positive bacteria, 3, 282, 283, 285 soil bacterium, 292 Graphene, 113 Green chemistry, 12 Grignard reaction, 41, 42, 127 reagent, 41, 127, 162, 163, 223, 363 Group-assisted purification (GAP), 72, 73 Guanidine, 145, 153 Guanine, 280

H Halide alkylating agent, 44 Halogenation method, 23 Hartree-Fock method, 198 Head-to-head dimeric intermediates, 198 Heat shock, 261 protein, 261 Heck reaction, 69 Hemiacetal, 293 Hemiketal, 293, 322 Henry reaction, 342 Heraclemycin B, 273 Hetero-acetals, 293 Heteroarylidene azlactones, 198 Heteroatom, 16 Heterocyclic compounds, 1, 259 moiety, 227 Heterocyclic ring, 60, 76, 329 Heterofunctional azlactone monomer, 114 Heterogeneous catalyst, 11, 16 Hetero-polyatomic structures, 16 Hexachlorocyclopentadiene, 334 Hexafluoroacetone, 321, 322, 324, 325, 327, 330–334, 367, 368, 370, 373, 374 protected L-glutamic acid, 324 Hexamethylenediamine, 211 Hexamethylphosphoramide (HMPA), 344 Hexapeptide, 210, 345 Heydamycin, 273 Hierarchical polymer brush architecture, 215 High-molecular weight polyamides, 211 Hippuramide, 13

Hippuranilide, 13 Hippuric acid, 1, 4–19, 26, 30, 34, 35, 37, 68, 78, 110, 175, 176 Holo-transferrin, 217 polymer conjugate, 217 Homochiral amino acids, 156 Homophenylalanine, 155 Host-guest supramolecular chemistry, 205 Human colon cancer cell line, 288 leukocyte elastase (HLE), 319 microvascular epithelial cells, 290 Hybridization density, 213 Hydantoin, 336 Hydrazinolysis, 174–176 Hydrazoic acid, 173 Hydroboration, 49 Hydrogel, 219 Hydrogen abstraction, 208 bonding interactions, 153 shift, 98 Hydrogenation, 61, 127, 172, 195, 223, 307, 347, 349 Hydrogenolysis, 210, 295 Hydrolysis, 2, 11, 16, 20, 21, 40, 60, 70, 103, 116, 123, 167, 168, 172, 173, 177, 208, 216, 223, 277, 297, 305, 307, 308, 312, 315, 319, 324, 325, 327, 330, 332–334, 340, 352, 361, 362, 365, 367, 372 enzymes, 123 Hydrophilic, 205, 208, 213, 279 Hydrophobic, 109, 208, 213–216, 221, 279 nanofiber scaffolds, 215 n-decyl amine, 213 Hydrous calcium aluminum silicate, 9 Hydroxylation, 272 Hydroxymethyl group, 360 Hygroscopic, 210

I Ice-bath temperature, 309 Imidazole ketone, 44, 46 Imidazolone, 172 Imide, 178 Iminophosphorane, 24, 87, 88 Immunogenicity, 218

406

Index

Implantation tests, 211 In vitro cell proliferation, 288 Indole-fused azlactones, 2 Induction behavior, 261 Inflammatory cytokine marker, 216 Infrared spectroscopy, 205, 220 Insulin, 121 Interfacial structure, 214 Intermolecular, 86, 157 Internalization, 217 Intracellular amastigotes, 3 Intramolecular, 16, 57, 81, 86, 98, 171, 173, 216, 340, 342, 367, 368, 370 attack, 81, 342 cyclization, 16, 277, 367, 368 Inverse-electron-demand hetero-Diels-Alder reaction (IEDHDA), 145, 147, 149, 151 Ionic liquid, 10, 17 Isatin, 142, 143 Isobutyraldehyde, 319 Isomeric pseudo-azlactone, 25 Isomerization quantum, 195 Isopropyl isocyanate, 336 Isopropylidenetriphenylphosphorane, 307 Isopropyltriphenylphosphonium iodide, 307 Isosbestic point, 29 Isotactic polymer, 210 Isothioureas, 62 Isotopic effect, 45, 46 Isoxazole, 6, 164

J Jadomycin, 260–264, 266–269, 271–273, 279–281, 283, 287–292, 372 alkaloids, 280 analogs, 261, 288 derivatives, 263–270, 272, 279–281, 283, 284, 288–290 dideoxysugar biosynthetic pathway, 271 metabolites, 263 shunt reaction, 272 S-phe, 264, 289 Jacomycin Ala, 262 Jadomycin A, 260–262, 264, 268, 270, 277, 279, 281 Jadomycin B, 260–262, 270, 277–279, 281, 288–293, 353 Jeffamine, 208, 209

K Kinamycin, 273

L Lactam, 51, 285, 325, 326, 352 Lactate dehydrogenase assay, 288 Lactimide, 2 Lactimone, 2 Lactone, 1, 51, 164, 359 Landomycin A, 273, 274 Langkocycline, 273 L-configuration, 108 L-digitoxose, 260, 269–271, 277 Lepadiformine-cylindricine tricyclic framework, 344 Lepadiformine A, 53 Lepadiformine B, 53 Leucine, 33, 34, 52, 59, 67, 76, 80–82, 90, 108, 167, 223, 301, 302, 313, 315, 334, 348, 359, 361, 364, 373 Leukemia, 287 Lewis acid, 12, 17, 76, 100, 126, 297, 311, 322, 366, 367 L-glutamine, 295 Light-emitting diode (LED), 194–196 Linear polyethyleneimine (LPEI), 206 Lipophilicity index, 205 Living radical polymerization, 203 L-leucine, 35, 109, 261, 269, 301, 312, 314, 321, 363 L-ornithine, 264, 265, 282, 285 L-proline methyl ester, 108 L-serine, 263, 269, 272, 295, 301, 327 L-tyrosine, 4, 269, 295 Luciferase, 193, 194, 206, 288 Luciferin, 288 Lysosomotropic agent, 217

M Macroinitiator, 204 Macromolecular amines, 208 architectures, 203 Magnesium oxide, 7 sulfate, 153 Magnetic nanoparticles, 207, 208

Index 407

Maleate, 132, 137, 154 Malonyl-CoA, 273 Mammalian cells, 213 Mannich reaction, 38, 42, 70–75, 352 Marine alkaloid, 53 Mask-less array synthesis (mas), 213 MCF-7 breast cancer cells, 288, 290 Mean molecular weight, 210, 211 Mechanochemical conditions, 5 Mesoionic azlactone, 136–138 azomethine ylides, 128 compound, 135, 136, 138 intermediate, 135, 340 Metabolic degradation, 43 Meta chlorobenzaldehyde, 12 methoxybenzaldehyde, 5 methylbenzoyl chloride, 12 Metallocene, 63 Metathesis polymerization, 219, 221 Methacrylate monolith, 208 Methacrylic acid (MAA), 215 Methacrylonitrile, 137 Methanesulfonate, 69 Methanesulfonyl chloride, 69, 84 Methicillin-resistant staphylococcus aureus (MRSA), 281–283, 286, 374 Methionine, 41, 67, 80–82, 86, 90, 211, 265, 269, 281, 295, 301, 302, 309, 321, 334, 338, 348, 359, 361, 365 Methoxy containing amines, 217 diphenylphosphane, 332 Methyl (R)-2-amino-2-methyl-3-phenylpropanoate, 304 (tert-butoxycarbonyl)-L-seryl-L-alaninate, 117 (Z)-2-benzamido-3-phenylacrylate, 196 2-iodoacetate, 37 3-((tert-butoxycarbonyl)oxy)-2-methylenebutanoate, 161 5-formyl-2-hydroxybenzoate, 7 alaninate, 103, 304 ester, 363 glycinate, 156, 168, 169 L-phenylalaninate, 191, 330, 331 hydrochloride, 191

L-tryptophanate, 338 methacrylate, 214, 218 methioninate, 304 prolinate, 304 tert-butyl ether (MTBE), 86, 107, 128 trifluoromethanesulfonate (MeOTf), 209, 320 Methylation, 168, 272, 315, 316, 347 Methylimidazole-containing oligopeptides, 65 Michael acceptor components, 78 addition, 38–42, 75–87, 89, 91, 92, 94, 132, 144–147, 149, 150, 152, 157, 158, 203, 224, 304, 316, 352, 355, 367 product, 40, 75, 76, 84, 144, 147, 150, 316 adduct, 41, 80–84, 86 reaction, 40, 41, 75, 76, 80, 82, 159, 227, 374 Microbe, 260 Microphase segregation, 208, 214 Microwave irradiation, 7–12, 17, 18, 166, 296, 338 Midazoloisoquinolin-3-one, 112 Mildly acidic aqueous environments, 212 Minimum inhibitory concentrations (MIC), 281, 282, 374 Mitosis, 292 Molecular sieves, 52, 89, 97, 144, 183, 317, 319 weights, 206, 210, 219 Molybdophosphoric acid, 16 Mono-alcohols, 293 Monoamine reuptake inhibitors, 345 Monodansylcadaverine (MDC), 217 Monometallic reaction pathway, 79 Monopalladacycle, 78 Moromycin B, 273 Multidrug resistant (MDR), 289, 374 Multi-layer polymers, 212 Multiple hybridization-dehybridization cycles, 213 response element-cAMP response element (MRE-CRE), 193 Münchnone, 139 Mutarotation, 30 Mycelial growth, 292

408

Index

N N-(1-((4-methoxyphenyl)amino)-1-oxopropan-2-yl)benzamide, 148 N-(2-formylphenyl)acetamide, 176 N-(2-oxo-2H-chromen-3-yl)benzamide, 177 N-(2-oxo-2-phenylethyl)benzamide, 162, 163 N-(3-methylbut-2-enoyl)benzamide, 178 N-(4-bromo-2-chlorophenyl)-1,1,1-trimethyl-N-(trimethylsilyl)silanamine, 343 N-(4-chlorophenyl)-benzimidamide, 166 N-(alkoxycarbonyl) amino acids, 34 N-(benzyloxycarbonyloxy)succinimide, 347 N,N,N′,N″,N″pentamethyldiethylenetriamine, 207 N,N-dimethylpyridin-4-amine (DMAP), 44, 61, 63, 150, 168, 178, 327 N,O-dialkylhydroxylamine, 73 N,O-acetal, 259, 272, 293 N-acetyl (S)-isovalyl-(S)-isovaline, 2 L-leucine, 35, 36 N-phenylglycine, 134 N-acyl amino acid, 5, 21, 32–34, 37, 64, 100, 108, 116, 121, 134, 172, 224 ester, 116 valine, 41, 321 N-acylglycine, 167 N-alkylamine, 206 Nano-imprint lithography technology, 214 Nano-templating applications, 217 Naphthalene, 58, 81, 84, 86, 103, 126 Naphthgeranine A, 273 Naphthyl distortion, 319 National Cancer Institute (NCI), 287 N-benzoyl amino acid, 83, 84, 96, 101, 108, 173, 296 arylglycinates, 59 arylglycines, 59 D-alanine, 30 dl-allothreonine, 22 DL-tert-leucine 5(4H)-oxazolone, 108 glycine, 1, 4, 8, 13, 27 O-methyl-DL-allothreonine, 21, 22 N-boc-N-methyl alanine, 168 N-bromosuccinimide (NBS), 23, 105, 332 N-butyl acrylate, 218

N-carboxyanhydride, 2, 259 N-carboxymethyl glycine, 325 N-Cbz-DL-glutamic acid, 295 N-chloroacetyl-DL-phenylalanine, 25 N-decylamine, 207 N-dichloroacetyl-DL-phenylalanine, 25 NDP-4-keto 2,6-dideoxy-5-epimerase, 277 2,6-dideoxyhexose 4-ketoreductase, 277 Necrosis, 287 N-ethyl isatin, 143 morpholine, 325, 326 Neutron reflectometry, 206 N-formylpipecolic acid, 134, 135 N-glycopeptides, 357 N-hydroxysuccinimide esters, 282 N-iodoacetyl-DL-phenylalanine, 25 N-isobutyryl-4-methoxybenzamide, 173 Nitro group, 83, 137, 350 Nitroalkene, 84 Nitrobenzene, 126, 350 Nitrogenous organo-catalyst, 178 Nitroso compounds, 137 Nitroxide-mediated polymerization (NMP), 203, 218, 219 N-methyl 1,1-diphenylmethanimine, 27 amino acid, 295, 347, 348, 366, 373, 374 asparagine, 347 morpholine (NMM), 35, 36, 110, 333, 342 N-methylmorpholine (NMM), 201, 342 N-oxide (NMO), 201 Nonanoic acid N-hydroxysuccinimide ester, 282, 283 Nonaromatic aldehydes, 9 Non-coordinating counterion, 49 Non-degradable aliphatic diamine linkers, 207 Non-leaching antibacterial surface, 215 Non-peptidic, 193, 313 Non-proteinogenic amino acids, 261 Norbornene, 219 Norleucine, 63, 67 Norvaline, 67, 155, 325, 327 Novel biosensors, 113 microcontact stamping method, 220

Index 409

N-phenylimine, 18 N-phenylmaleimide, 41, 81, 131 N-phenylmaleinimide, 154 N-protected amino acid, 295, 361 dehydroalanine derivatives, 80 serines, 117 N-substituted amino acids, 372, 373 N-terminal cysteine, 216 primary amino group, 216 N-tosyl amino acid, 296 protected oxazolidin-5-one derivatives, 348 N-trichloroacetyl-DL-phenylalanine, 25 Nucleophilic, 24, 38, 39, 42, 45, 52, 56, 57, 59, 68, 70, 76, 94, 96, 107, 111, 112, 119, 121, 123, 125, 128, 148, 156, 157, 160–162, 166, 168–170, 177, 202, 211, 213, 216, 226, 272, 316, 321, 339, 340, 342, 348, 350, 359, 360, 362, 364, 365, 372 addition, 39, 42, 112, 161, 166, 170, 177, 226, 348, 350, 362 amines, 111 attack, 38, 94, 107, 116, 123, 148, 339, 342, 360 azlactone, 52 character, 339 nature, 68, 162 substitution, 24, 42, 45, 340, 348 treatment, 156 Nucleoside, 269, 270 diphosphate, 269, 270 Nutritional environment, 280 N-vinylbenzamide, 72 Nystatin, 286 Nε-trifluoroacetyl- L-lysine (TFAL), 264, 266, 281, 282

O O-alkylation, 342 Ochromycinone, 273 O-fluorobenzoic acid, 189 O-glycotransferase, 269 Olefinic bond, 343 configuration, 157, 160

Oligonucleotide arrays, 212, 213 One-pot manner, 35 Organic aqueous binary system, 42 chemistry, 268 chiral molecules, 94 inorganic hybrid polyoxometalates, 10 Organometallic compounds, 352 Ortho-chlorobenzaldehyde, 305 Overexpressed receptors, 217 Ovotransferrin, 217 Oxa-diene precursors, 153 Oxalyl chloride, 311 Oxazol-5(4H)-one, 1, 3, 5, 12, 19, 22–27, 41, 46, 53, 68, 71, 72, 80, 81, 86–89, 91–93, 96, 98, 100, 103, 109, 111, 122, 124, 131, 135, 142, 144, 145, 157–161, 163, 164, 168, 172, 173, 177, 178, 180, 199, 201, 202, 205, 209, 211, 212, 226 Oxazole, 1, 12, 23, 54, 84, 125–127, 151, 154, 199, 367 5-(4H)-one, 1 Oxazolidin-5-one, 260, 262, 264, 266, 269, 270, 272, 280, 283, 293–295, 297, 299–308, 310–319, 321, 322, 324–328, 330–334, 337–340, 342–353, 355–373 2-one, 259 4-one, 259 5-one, 259, 260, 294–297, 299–302, 310, 312, 314, 315, 318, 319, 321–324, 329, 334, 336, 338–340, 347, 348, 350, 351, 359–361, 363, 365, 366, 368, 372, 373 derivatives, 280, 295, 302, 310, 312, 313, 315, 317, 321, 334, 347, 348, 365, 372 moiety, 266, 269, 270, 301, 310, 318, 321, 339 ring, 295, 299, 318, 332, 340, 342, 344, 347, 356–359, 363–366, 372 Oxazolidinone, 259, 281, 282, 285, 300, 301, 359 Oxazolin-5-one, 11, 20, 107, 123 Oxazolindin-5-one scaffold, 295 Oxazolinone, 11 Oxazolone, 1, 11, 34, 108, 114, 222, 223, 225, 227 Oxazolonium, 13 Oxidative addition, 58

410

Index

Oxidizing agent, 23, 44–46 Oxidoreductase, 277 Oxohexahydropyrimidine ring, 272 Oxone, 306, 307 Oxytetracycline, 280

P Paclitaxel, 289 Palladium catalysis, 51 reaction, 51 catalyst, 47, 54, 58, 59, 61, 185, 324 P-anisidine, 147 Para-chlorobenzoyl chloride, 24 Paraformaldehyde, 295–299, 301, 302, 310, 321, 347, 350, 351, 356, 360, 364, 373 Parasitic equilibrium, 352, 353, 355, 374 Para-toluenesulfonic acid (PTSA), 295 Parylene, 220 Penicillium notatum, 337 Pent-4-yn-1-ol into 2-methylenetetrahydrofuran, 100 Pentafluorophenyl, 53, 111, 113 acrylate (PFPA), 113 Pentaphenylferrocene, 78 Peptide coupling reagents, 103 ligation, 191, 359, 360 segment condensations, 120 Perchloric acid, 12, 13, 15, 29, 30 Perfluorobenzene, 59, 94 Perfluorophenyl acrylate, 111 Perfluorotoluene, 59 Performance-specific functionality, 205 Perkin reaction, 5 Petroleum ether-diethyl ether, 7 P-fluorobenzaldehyde, 4 Phage infection, 261 shock, 261, 280 Pharmacokinetics, 218 Pharmacological parameters, 347 Phenoxyacetic acid N-hydroxysuccinimide ester, 282, 283 Phenoxyformyl chloride, 26, 27 Phenyl chloroformate, 63, 64 lithium, 362 magnesium halide, 127

Phenyl((trimethylsilyl)ethynyl)iodonium) tosylate, 67 Phenylalanine, 23, 25, 26, 32–34, 44, 52, 59, 63, 76, 80, 81, 86, 90, 96, 117, 167–169, 171, 223, 224, 263, 269, 297, 301, 309, 312, 313, 315, 318, 321, 334, 338, 348, 352, 359–361, 364, 365, 368 Phenylglycine-derived azlactones, 84 Phenylhydrazine, 123, 174 Phosgene, 312, 313 Phosphine-containing indane, 201 Phosphoramidite, 52, 53 Phosphoric acid moiety, 96 Phosphorus, 16, 63, 181, 183, 184, 187, 331, 332 containing molecules, 331 Phosphoryl chloride, 17, 18 Phosphorylation, 292 Photo chemical condition, 193, 316, 332, 333 dimerization, 195, 196, 198, 199 electrocyclic reaction, 51 isomerization, 198 quantum yield, 195 dimerization, 194–196, 199, 223, 227 grafting method, 208 induced radical polymerization, 215 irradiation, 29, 195, 197, 209 isomerization, 29 mediated postfabrication modification, 209 stationary state, 195 switches, 195 Phylum, 280 Physicochemical properties, 208 Physiological media, 207 Picoline, 10, 125 Pig liver esterase (PLE), 319 Piperazine, 3 Pivalaldehyde, 303, 307, 310, 314–319, 343, 372, 373 Plasmid DNA, 206, 289 Pluramycin, 273 P-methylbenzyl diphenylphosphate, 58 P-nitro-cinnamaldehyde, 147 P-nitrophenyl hippurate, 11, 20 Polar aprotic media, 189 organic solvents, 210

Index 411

Poly(2-acrylamido-2-methylpropanoate), 222 Poly(2-vinyl-4,4-dimethylazlactone) (PDMV), 212–214, 220 Poly(acrylamides) moieties, 217 Poly(ethylene glycol), 113, 208, 214 b-poly(2-vinyl-4,4, dimethylazlactone) (PEG-b-PVDMA), 208 Poly(ethyleneimine) (PEI), 206, 212–214 Poly(glycidyl methacrylate) (PGMA), 214, 220 Poly(styrene-stat-DMV), 203–205 Polycarbonate substrates, 216 Polycarcin V, 273 Polydispersity index (PDI), 204, 205, 219 Polyelectrolyte multilayers, 212 Polyketide, 273, 374 synthase (PKS), 273, 274, 374 Poly-L-lysine-coated calcium alginate hydrogel, 215 Polymerase chain reaction, 289 Polymer bound reagents, 204 fixed thiourea, 36 scaffolds, 203 Polymerization, 113, 187, 203, 204, 206, 208, 210, 211, 216–220 process, 204 Polyphosphoric acid (PPA), 14, 15, 29, 297, 340 Polyplexes, 206 Polystyrene, 204 Post-polymerization, 216 modification, 208 Potassium acetate (KOAc), 4, 7, 83, 169 hydroxide, 36 tert-butoxide, 201 Potential post-modification of polymer, 217 Powdery polymeric materials, 210 Pregilvocarcin V, 273 Prejadomycin, 277 Preorganized optimal conformation, 43 Preparative methods, 4, 293 mechanisms (formation of azlactones), 37 oxazolidin-5-ones (α-amino acid), 294, 302, 304, 314, 318, 319, 321, 334, 336 saturated azlactones, 32 unsaturated azlactones, 4 alternative methods, 20

configuration of exocyclic double bond, 28 erlenmeyer azlactone synthesis, 4 Primary amine, 107, 110, 111, 115, 147–149, 172, 204–207, 212, 214–217, 294 amino group, 207, 214 Prochiral azlactone, 57, 90 Proline derivatives, 302 Prop-1 en-2-yl-L-proline, 353 yn-1-ylbenzene, 100, 102 Propargyl alcohol, 6, 113 Propargylation, 42 Propyl isocyanate, 336 Protein ligands, 205 Proteolysis, 218 cleavage, 360 Proteus vulgaris, 282, 286 Protonated, 16, 65, 90, 91, 222, 357 benzaldehyde, 30 Pseudo first-order kinetic, 109 Pseudoazlactone, 26, 222, 224, 226, 227 intermediate, 26 Pseudomonas aeruginosa, 213, 281–283, 285, 286, 337 H187, 283, 285 Pseudo-oxazolone, 60, 61, 222–225, 227 Pseudoxazol-5(2H)-ones, 223, 224 P-spiro-triaminoiminophosphorane, 39 P-xylene, 155, 156 Pyridine, 10, 14, 19, 21, 22, 25, 26, 28, 30, 37, 55, 60–62, 73, 104, 114, 127, 154, 155, 205, 208, 210, 223, 224, 333, 336, 344 N-oxides, 73 Pyridinium p-toluenesulfonate (PPTS), 338 Pyridoxal phosphate-dependent enzymes, 69 Pyrrole derivatives, 134, 136, 225 Pyrrolidine, 22, 80, 105, 107, 121, 149, 157, 158, 160, 189, 191, 302, 340, 342, 344, 345, 350, 352

Q Quantitative characterization, 206 Quaternary allylic amino acids, 53 amino acids, 47, 82 carbon atom, 156 Quinoline 1-oxide, 59, 60

412

Index

R Rabelomycin, 273 Racemic alkylation product, 320 amino acid azlactone, 123 products, 146 Racemization, 30, 32, 33, 38, 43, 108, 109, 116, 320, 360, 363 Radical anion, 198 cation, 198, 291 Ravidomycin V, 273 Reactions, 38, 39, 42, 107, 162, 339, 352, 361 oximes, 121 Reactive amphiphilic block copolymers, 217 azlactone graphene platform, 113 oxygen species (ROS), 289–292 dependent mechanism, 290 detection assay, 289 independent mechanism, 289 Receptor-mediated endocytosis, 217 Recombinant human aurora-B kinase, 292 Recrystallization, 5, 14, 16, 19, 73, 117, 162, 307, 320 Regioselective, 41, 49, 80, 82, 89, 134–136, 182 divergent intramolecular ene-yne reaction, 201 functionalization, 299 Renal filtration, 218 Retro-Diels-Alder reaction, 370 Retro-ene reaction, 370 Reversible addition-fragmentation chain transfer polymerization, 203, 207 addition-fragmentation transfer (RAFT), 113, 203–205, 217–219 polymerization, 219 thermal homolysis, 218 weak interactions, 212 Rhodium catalyst, 100 Rifampicin, 286 Ring closing metathesis polymerization, 219 opening metathesis polymerization (ROMP), 114, 219

product, 163, 171, 174–177, 196, 339 reaction, 38, 212 Ritter reaction, 35, 36 Robust anti-fouling behavior, 207 Ruthenocene, 77

S Staphylococcus aureus, 3, 281, 283, 285 305, 281 623, 281 C622, 283, 285 MRSA C623, 283, 285 epidermidis, 281, 283, 285 C960, 281, 283, 285 epidermis C960, 283 warneri, 282, 286 Streptomyces coelicolor, 292 species, 280 venezuelae, 260–267, 269, 277, 280 ISP5230, 260–267, 269, 277, 280 mutants, 277 Salacin, 129 Salicylaldehyde, 312, 313 Salmonella enterica typhimurium, 283, 285 C587, 283, 285 typhi, 3 Saptomycin B, 273 Saturated azlactone, 1, 2, 22, 25, 32, 39, 98, 157, 168 S-benzyl 2-benzamido-3,3-bis(benzylthio) propanethioate, 177 Scavenger, 204, 291 Schiff base, 308, 310 decarboxylation, 59 Sclerotiamide, 345 Scolecite zeolite, 9 S-configuration, 157, 172, 261 Scrutinization, 80 S-cyclohexyl (S)-2-benzamidopropanethioate, 119 Secondary amine, 105, 205, 294, 350 metabolites, 263, 265, 272, 280 Self-reproduction of chirality (SROC), 310, 311, 372, 373

Index 413

Serine, 22, 33, 67, 115, 171, 263, 272, 273, 281, 295, 302, 321, 322, 327, 348, 359 Signal-tonoise ratios, 213 Simple molecular structures, 280 S-methyl-L-cysteine, 301, 306 Sodium (S)-2-amino-2-phenylacetate, 310 (S,E)-2-(benzylideneamino)propanoate, 310 acetate, 4–7, 12, 19–21, 28, 37, 103, 115, 172, 176 azide, 173, 314, 356, 367 bicarbonate, 299 methioninate, 308, 314 S-methyl-L-cysteinate, 306, 307, 310 tetrakis[3,5-bis(trifluoromethyl)phenyl] borate, 49 Sol-gel method, 16 Solid-phase dehydropeptide synthesis, 172 Solkane®365mfc, 296 Solvation, 109 Solvent-free condition, 5, 7, 9–11, 16 Sonication, 361 Sphingofungin E, 49 Sphingofungin F, 49, 50 Spiro-azlactone moieties, 192 Spiro-compounds, 184 Spirotryprostatin A, 129 Squaramide, 117, 141 Stearoyl isothiocyanate, 338 Steglich rearrangement, 61–64 Step-growth polymerization, 211 Stereo-center, 157 Stereo-chemically homogeneous polypeptides, 210 inverted azlactone, 32 Stereo-chemistry, 148, 151, 178, 184–186, 190, 281, 307, 310, 352, 366 Stereo-determining ring-closing, 187 Stereo-induction, 96 Stereo-selectivity, 43, 49, 53, 71, 78, 101, 109, 151, 155, 160, 302, 310, 314, 318, 352 Steric hindrance, 67, 79, 110, 161, 193, 198, 200 less-hindered tertiary phosphine, 185 Stilbene, 137 Stimulus-responsive materials, 214

Stoichiometric quantity, 15 Streptavidin, 219 Streptococcus mutans, 283 Streptomycetes, 292 Structural characterization, 223 Sub-stoichiometric, 216 Succinimide, 20, 83–85 Sulfonyl, 75, 80 Sulforhodamine B assay, 290 Sulfuric acid, 13–15, 17, 29, 30, 334 Sulfuryl chloride, 23 Superhydrophobic behavior, 213 properties, 214 Superoxide, 290, 291 dismutase (SOD), 291 Supplemented minimal medium (SMM), 292 Supramolecular cluster, 39 Surface plasmon resonance sensor, 219 properties, 205, 220 Surgical pharmaceutical devices, 212 Suspension polymerization, 204 Symmetric anhydride, 108 Syndiotactic polymer, 210 Syn-enantiomer, 73 Synthon, 67

T Takemoto urea, 104, 105 Tautomers, 72 Taxol, 290 T-boc-L-serine, 283 T-butyl alcohol, 291 Tentoxin, 168 Terephthaloyl chloride, 211 Terpolymer, 216, 219 Tert-butyl (R)-5-oxo-2-phenyloxazolidine-3-carboxylate, 346 (S)-4-(isocyanatomethyl)-5-oxooxazolidine-3-carboxylate, 356 (S)-4-isopropyl-5-oxooxazolidine3-carboxylate, 359 L-phenylalaninate, 327 Tetrabutylammonium acetate, 83 iodide, 69

414

Tetracycline, 280 Tetraethyl ethene-1,1-diylbis(phosphonate), 82 Tetramethyl aminium tetrafluoroborate (TBTU), 326 guanidine (TMG), 59, 89 Tetrangomycin, 273 Tetrangulol, 273 Tetraphene, 273 Tetra-substituted azlactones, 67 Thalassotalic acid A, 178 acid B, 178 acid C, 178 Therapeutic cell encapsulation, 215 Thermal annealing, 204 decarboxylation, 100 decomposition method, 208 Thermolysis, 125, 126, 173 Thiocarbonylthio moiety, 219 Thioester functionality, 216 Thiols, 107, 119, 120, 214 Thionyl chloride, 22, 41, 311, 322, 325, 342, 358, 367, 368 Thiophene-2-carbaldehyde, 16, 18 Threonine, 20, 22, 45, 44, 263, 265, 269, 272, 273, 281, 295, 298, 301, 302, 321, 322 Threo-phenylserinates, 22 Threo-p-nitrophenyl serine methyl, 22 Toluenesulfonic acid, 18, 155, 296, 338 Toluenesulfonyl chloride, 18, 73 Topoisomerase, 289, 290 Topopyronone C, 273 Total growth inhibition concentration, 287 synthesis, 99, 340, 341, 372, 373 Trans-configurations, 345 Trans-hydration, 215 Trans-oxazoline hydrochlorides, 22 Transferrin receptor, 217 Transgene expression, 206 Transition metal-mediated living radical polymerization, 203 Trienamine, 190 Triethoxysilylpropyl chloride, 11

Index

Triethylamine, 10, 58, 69, 130, 154, 177, 218 Triethylene glycol monomethyl ether, 216 Trifluoroacetic acid, 52, 155, 210, 295, 303, 316, 340, 347, 359, 368 anhydride, 22, 41, 227, 312, 319 Trifluoroacetyl group, 32, 134, 222, 226 Trifluoromethanesulfonate, 333, 342 Trifluoromethyl ketone derivatives, 361 Trifluoromethylsulfonic acid, 297 Trimethyl phosphite, 332, 333 Trimethyl(trifluoromethyl)silane, 296, 361 Trimethylaluminum, 204 Trimethylolpropane trimethacrylate, 205 Trimethylsilyl chloride (TMSCl), 19, 23, 44, 154, 155, 182, 191 enolate, 12 Triphenylphosphine, 10, 24, 51, 132, 153, 324, 364 Tropone, 155, 156 Trypanosoma cruzi, 3 Trypomastigote, 3 Trypsin, 123, 207 Tryptophan, 25, 26, 86, 269, 295, 317, 336, 347 Tumor cell resistance, 288 Tungstophosphoric acid (TPA), 16 Type II topoisomerases, 290

U Ultrasonication, 9, 10 Ultrasound vibration, 16 Undecylprodigiosin, 293 Unsaturated azlactone, 1, 2, 4–23, 25–33, 69, 142–145, 159, 161, 162, 167–172, 174–177, 179, 181, 182, 184, 185, 187, 189, 191–196, 201, 202, 223, 224, 227 Urdamycin A, 273 UV-vis spectroscopy, 195

V Vacuum desiccator, 223 Valine, 33, 34, 41, 42, 52, 59, 67, 76, 81, 82, 86, 90, 108, 154, 155, 167, 211, 222–224, 265, 269, 297, 300–302, 315, 334, 338, 348, 359–361, 364, 365

Index 415

Vanadium, 16 Vancomycin, 281, 282, 285, 286 resistant Entrococcus faecium, 282 Vapor phase infiltration technology, 204 Verapamil, 288 Vineomycin B2, 273 Vinyl dimethyl azlactone (VDM), 113 Vinylation, 68, 69 Vinylcyclopropane azlactone, 105 Vinylidene carbene intermediate, 67 Vinylogous methyl groups, 161

W Wang resin, 203, 204 Water insoluble species, 216 LOGSY NMR spectroscopy, 290 sensitive substrates, 214 soluble substrates, 214

Web of science, 227 Western blotting, 289 Woodward-Hoffmann rule, 193 Work-up process, 5, 16

X X-ray photoelectron spectroscopy, 204

Z Z-4-benzylidene-2-phenyloxazol-5(4H)-one, 23, 180, 189, 201 Z-alkylidene azlactones, 12 Z-azlactone, 28, 30, 31 radical anion, 198 Zeolites, 9 Z-ethyl 2-benzamido-3-phenylacrylates, 177 Zinc oxide (ZnO), 7 Z-isomer, 15, 28–30, 195, 198 Zwitterionic intermediates, 211