Heterocycles as Chiral Auxiliaries in Asymmetric Synthesis 3030453030, 9783030453039

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Topics in Heterocyclic Chemistry  55 Series Editors: Bert Maes · Janine Cossy · Slovenko Polanc

Manfred Braun   Editor

Heterocycles as Chiral Auxiliaries in Asymmetric Synthesis

55 Topics in Heterocyclic Chemistry

Series Editors: Bert Maes, Antwerp, Belgium Janine Cossy, Paris, France Slovenko Polanc, Ljubljana, Slovenia

Editorial Board Members: D. Enders, Aachen, Germany S.V. Ley, Cambridge, UK G. Mehta, Bangalore, India R. Noyori, Nagoya, Japan L.E. Overman, Irvine, CA, USA A. Padwa, Atlanta, GA, USA

Aims and Scope The series Topics in Heterocyclic Chemistry presents critical reviews on present and future trends in the research of heterocyclic compounds. Overall the scope is to cover topics dealing with all areas within heterocyclic chemistry, both experimental and theoretical, of interest to the general heterocyclic chemistry community. The series consists of topic related volumes edited by renowned editors with contributions of experts in the field. All chapters from Topics in Heterocyclic Chemistry are published OnlineFirst with an individual DOI. In references, Topics in Heterocyclic Chemistry is abbreviated as Top Heterocycl Chem and cited as a journal.

More information about this series at http://www.springer.com/series/7081

Manfred Braun Editor

Heterocycles as Chiral Auxiliaries in Asymmetric Synthesis With contributions by S. Baskaran
R. K. Boeckman, Jr.
M. Brauns
J. A. Cody
C. Czekelius
H. Kunz
W. Maison
M. Mantel
A. K. Mourad
J. Pietruszka
A. Srivastava
A. Stoye
K. D. Veeranna

Editor Manfred Braun Institute of Organic and Macromolecular Chemistry Heinrich-Heine-University Düsseldorf Düsseldorf, Germany

ISSN 1861-9282 ISSN 1861-9290 (electronic) Topics in Heterocyclic Chemistry ISBN 978-3-030-45303-9 ISBN 978-3-030-45304-6 (eBook) https://doi.org/10.1007/978-3-030-45304-6 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

This volume is dedicated to the memory of Professor Dieter Enders

Preface

Asymmetric synthesis, considered the most elegant method for obtaining enantiomerically pure compounds, has been a major challenge in organic chemistry for decades. Whereas today’s synthetic chemists direct their efforts towards the development of enantioselective catalysis, it must not be ignored that, chronologically, the breakthrough in asymmetric synthesis was provided by covalently bound chiral auxiliaries – the tools that led for the first time to excellent degrees of enantioselectivity in the conversion of achiral precursors into chiral products. Is it so that the auxiliary concept is yesterday’s technique, mature and no longer developing? I am sure the contributions in this volume on “Heterocycles as Chiral Auxiliaries in Asymmetric Synthesis” will convince the reader of the opposite. Indeed, the majority of the chiral auxiliaries that were produced over the years are based upon heterocyclic skeletons. Among the large multitude of heterocyclic auxiliaries, those are treated in this volume that proved themselves as particularly efficient, reliable, and widely applied in the past but are, nevertheless, developing continuously. Fortunately, leading experts were ready to present the respective area in a highly competent manner. Since the very early days of asymmetric synthesis and the seminal contributions of Emil Fischer, carbohydrates have been important “privileged” structures. Their outstanding role as chiral auxiliaries is treated in the first chapter by Horst Kunz and Alexander Stoye. Boron-containing auxiliaries, discussed in the second chapter by Jörg Pietruszka, Marvin Mantel, and Marcus Brauns, might appear as “less traditional” heterocycles, but are rapidly developing and valuable tools enabling a multitude of enantioselective transformations. The following two chapters focus on two heterocycles that became true classics in asymmetric synthesis: oxazolidinones and pyrrolidines. In both chapters, “Oxazolidinones and Related Heterocycles as Chiral Auxiliaries/Evans- and Post-Evans Auxiliaries” by Constantin Czekelius and Asmaa K. Mourad and “Pyrrolidines as Chiral Auxiliaries,” written by Wolfgang Maison, the authors demonstrate that those auxiliaries, although introduced decades ago, are continuously applied in novel transformations, not only were their utility and versatility enhanced in recent years but also deeper vii

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Preface

insight into the mechanisms of “asymmetric induction” was obtained. Terpenes, at a glance, do not seem to fit in a series devoted to heterocyclic compounds. However, Robert K. Boeckman, Jr. and Jeremy A. Cody demonstrate in their chapter that cyclic and bicyclic terpene skeletons, when converted into suitable heterocyclic derivatives, provide a variety of chiral auxiliaries enabling manifold applications. The acid test for the various methods of auxiliary-based asymmetric synthesis is documented in the final chapter by Sundarababu Baskaran, Akriti Srivastava, and Kirana D. Veeranna: The authors convincingly demonstrate that, in the syntheses of complex natural products, the different heterocyclic auxiliaries function as indispensable tools. This chapter with well-chosen targets clearly underlines the advantages of the auxiliary concept in asymmetric synthesis: broad applicability, versatility, and predictability of the individual methods. I am sincerely indebted to the authors for having written excellent overviews of the different aspects of this volume. Their achievements are highly appreciated. I am also grateful to the members of the Springer staff, Judith Hinterberg, Elisabeth Hawkins, Abinay Subramaniam, Shanti Ramamoorthy, and Alamelu Damodharan for their valuable advice and patience. Everybody who is familiar with chiral auxiliaries will undoubtedly recognize the seminal contributions Professor Dieter Enders made to this field. I remember very well the sensation his first publications on the RAMP- and SAMP reagents caused in the 1970s – with degrees of enantioselectivity never reached before. Highly impressed by his achievements and thankful for his input to Organic Chemistry, the authors and editor dedicate this volume to the memory of Dieter Enders who was a great, gifted chemist. Düsseldorf, Germany 2020

Manfred Braun

Contents

Carbohydrates as Stereodifferentiating Auxiliaries . . . . . . . . . . . . . . . . . Horst Kunz and Alexander Stoye

1

Boron-Containing Chiral Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . Marvin Mantel, Marcus Brauns, and Jörg Pietruszka

73

Oxazolidinones and Related Heterocycles as Chiral Auxiliaries/Evans and Post-Evans Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 Asmaa Kamal Mourad and Constantin Czekelius Pyrrolidines as Chiral Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157 Wolfgang Maison Synthesis and Utility of Hetero- and Non-heterocyclic Chiral Auxiliaries Derived from Terpenes: Camphor and Pinene . . . . . . . . . . . . . . . . . . . . 193 Robert K. Boeckman Jr. and Jeremy A. Cody Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 Akriti Srivastava, Kirana D. Veeranna, and Sundarababu Baskaran Correction to: Carbohydrates as Stereodifferentiating Auxiliaries . . . . . 311 Horst Kunz and Alexander Stoye Correction to: Oxazolidinones and Related Heterocycles as Chiral Auxiliaries/Evans and Post-Evans Auxiliaries . . . . . . . . . . . . . . . . . . . . . 313 Asmaa Kamal Mourad and Constantin Czekelius Correction to: Pyrrolidines as Chiral Auxiliaries . . . . . . . . . . . . . . . . . . 315 Wolfgang Maison Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317

ix

Top Heterocycl Chem (2020) 55: 1–72 DOI: 10.1007/7081_2017_7 # Springer International Publishing AG 2017, corrected publication 2020 Published online: 12 December 2017

Carbohydrates as Stereodifferentiating Auxiliaries Horst Kunz and Alexander Stoye

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 [4 + 2] Cycloaddition Reactions: Diels-Alder Reactions and 1,3-Diploar Cycloadditions Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 [2 + 2] Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 [2 + 1] Cycloaddition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Reactions of Glycosylamines: Mannich-Type Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Strecker and Ugi Reactions for the Synthesis of Amino Acids . . . . . . . . . . . . . . . . . . . . . . . 3.2 Aminophosphonic Acid Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Mannich Reaction with Silylketene Acetals or Bis-Silylketene Acetals; β-Amino Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Homoallylamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Mannich-Type Reaction of Aromatic Compounds and Electron-Rich Alkenes . . . . . 3.6 Reactions with Silyl Dienol Ethers: Domino Mannich-Michael Cascades . . . . . . . . . . 3.7 Stereocontrolled Transformations of N-Glycosyl Dehydropiperidinones . . . . . . . . . . . . 3.8 Stereoselective Total Syntheses of Alkaloids Using Glycosylamines as the Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.9 Are 2,6-trans-Disubstituted Piperidines Stereoselectively Accessible via Glycosylamines? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 N-Glycosylation in Order to Induce Reactivity and Stereodifferentiation . . . . . . . . . . . . . . . . . 4.1 Glycosylation for Stereodifferentiation of Enantiotopic Sides of Aromatic NHeterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Glycosylation-Induced Stereoselective Reactions of Achiral Imines . . . . . . . . . . . . . . . . 4.3 Properties of the O-Pivaloyl Group in Carbohydrate Auxiliaries . . . . . . . . . . . . . . . . . . . . 5 Carbohydrate Auxiliaries in Conjugate Addition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Carbohydrate Auxiliaries in Diastereoselective Michael Addition of Ester Enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

The correction to this Chapter is available at https://doi.org/10.1007/7081_2020_37. H. Kunz (*) Johannes Gutenberg-Universita¨t Mainz, Institut fu¨r Organische Chemie, Mainz, Germany e-mail: [email protected] A. Stoye Corden Pharma International GmbH, Frankfurt/M, Germany

2 5 5 19 22 24 24 28 29 30 34 35 39 47 56 57 58 61 63 64 64

2

H. Kunz and A. Stoye

5.2 Bicyclic Carbohydrate Oxazolidinones as the Auxiliaries in Conjugate Addition Reactions of Organoaluminum Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 6 Conclusion and Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

Abstract Carbohydrates are inexpensive natural products. Although they contain numerous functional groups and stereogenic centers in one molecule, carbohydrates were recognized as stereodifferentiating auxiliaries much later than other classes of natural products as for example amino acids or terpenes. Apart from their polyfunctional nature carbohydrates are characterized by the anomeric and exo-anomeric effects which have distinct influence of the spatial orientation of substituents linked to the anomeric position. Based on these stereochemical properties carbohydrates were used as stereodifferentiating auxiliaries in numerous diastereoselective reactions, such as aldol addition, alkylation reactions, conjugate addition, and cycloaddition reactions with dienes, ketenes, or carbenes. Furthermore, dipolar cycloaddition reactions proceeded with high diastereoselectivity affording heterocycles. In particular, glycosylamines proved to be efficient auxiliaries in stereoselective Strecker syntheses of α-amino nitriles and Ugi reactions yielding α-amino acid amides. Mannich-reactions of glycosyl imines with silyl ketene acetals resulted in the formation of β-amino acid derivatives with high diastereoselectivity. N-Glycosyl imines exert their high stereodifferentiating potential in stereoselective MannichMichael reaction sequences with 2-silyloxy-butadiene derivatives furnishing 2-substituted piperidinones with excellent diastereomeric ratios. The efficient stereodifferentiation on glycosyl imines allowed the synthesis of enantiomerically pure alkaloids of the piperidine, indolizine, quinazoline, and decahydro-quinoline series. Even diastereoselective protonation of enolates has been demonstrated under the control of carbohydrate auxiliaries, for example, in the formation of cisannelated perhydro-quinoline alkaloids typical for toxins of Dendrobates pumilio or, alternatively, trans-annelated perhydro-quinolines characteristic for toxins from Dendrobates histrionicus. In addition to the use of carbohydrates as chiral auxiliaries the application of carbohydrate derivatives as stereoselective reagents and as chiral ligands in enantioselective catalysis is briefly outlined on selected examples. Recently, carbohydrates were also shown to be efficient organocatalysts in enantioselective reactions. Keywords Alkaloids • Carbohydrate auxiliaries • Carbohydrate organocatalysts • Cycloaddition reactions • Mannich reactions • Strecker and Ugi reactions

1 Introduction The development of stereochemistry and carbohydrate chemistry had been intensely interlinked from the very beginning when Emil Fischer elucidated the absolute configuration of the sugars, the major aldopyranoses and ketohexoses [1], on the basis of van’t Hoff’s concept (For the fundamental discoveries of J H van’t

Carbohydrates as Stereodifferentiating Auxiliaries

3

Hoff, see [2].) of the spatial structure of aliphatic carbon compounds. Actually, the Killiani-Fischer cyanohydrin formation from L-arabinose to afford L-mannono- and L-glucono-nitrile was carried out on a natural carbohydrate substrate [3, 4]. It constituted an important step in the clarification of the molecular structure of the carbohydrates, and at the same time the first asymmetric synthesis. Later on, carbohydrates played a major role as inexpensive, readily accessible starting materials in these types of ex-chiral pool syntheses in which the stereogenic centers present in a chiral substrate serve for the stereochemical steering of a reaction at a prochiral functional group in order to achieve the preferred formation of one among the possible diastereomers of the product. Quite a number of enantiomerically pure natural products were successfully synthesized starting from carbohydrates as enantiomerically pure starting materials [5]. These stereoconservative processes will not be in the focus of the present review article. Instead, methods of stereodifferentiation will be discussed in which the carbohydrates serve as chiral auxiliaries, but are not a partial structure of the chiral target molecule. Despite their high content of chiral information, carbohydrates had been underestimated as stereodifferentiating tools in asymmetric synthesis for a long time. This disregard is astonishing since a simple monosaccharide as for example D-glucose contains a number of functional groups to which shielding substituents and reacting groups can be linked in a specified arrangement required for a stereoselective conduction of a certain reaction. In addition, the polyfunctional carbohydrates offer ample opportunities for coordinating effects which stabilize stereodiscriminating effects in the neighborhood of a considered reaction center and influence the reactivity of the carbohydrate-linked functional group. This influence was illustrated, for example, by the reactivity of the xylose-derived amino acid ester 1 [6]. While the xylosyl N-allyloxy-(Aloc)-glycinate 1 did not react in dichloromethane with tert-butyl phenylalaninate, its aminolysis proceeded in the presence of two equivalents of lithium bromide to furnish the dipeptide ester 2 in high yield (Scheme 1). H N O H2N

O

O

O

O O

O O 1

OtBu

H2N

H N

O

O

O

O

CH2Cl2/ 2 eq. LiBr 3 d, 20 oC, 1 d, 40 oC

81% without LiBr 0%

OtBu

N H

O 2

tBuO

O

H N

H2N O H2N

Li O

O

O

O O A

O O

Scheme 1 Conversion of amino acid carbohydrate esters to active esters through coordination to lithium ions [6]

4

H. Kunz and A. Stoye

Obviously the coordination to the lithium ion A converts the carbohydrate from a protecting into an activating group. The principle of coordination illustrated in A constitutes a special feature carbohydrates offer for spatial discrimination in chemical transformations. Other particular properties of carbohydrates result from their nature as cyclic acetals. The anomeric and exo-anomeric effects (Fig. 1) not only influence the reactivity of functional groups positioned at the anomeric carbon, but also increase the rotational barrier of these functions, in particular, if they carry a lone-pair or are part of a π-system. In this sense, Vasella [7] explained the diastereoselectivity of the 1,3-dipolar cycloaddition of an N-α-mannofuranosyl formylnitrone to methyl methacrylate (Scheme 2) in terms of a prevailing O-endo conformation of the nitrone and a methyl-endo geometry (as is shown in 3a, in contrast to 3b) during the approach of the methacrylate from the backside which is favored by the stabilizing delocalization of the developing N-lone-pair of the isoxazolidine 4 into the σ*-orbital of the ring C–O bond. Thus, this increasing exo-anomeric effect lowers the transition state of the ene attack from the backside compared to the alternative front-side approach (Scheme 2). After reactions of an analogous spirocyclic nitrone with phosphites as the nucleophiles and analysis of the occurring stereochemistry, the authors revised this interpretation [8]. They now assumed that the O-endo conformation of the nitrone stabilized by a π-σ* delocalization is attacked by the methacrylate from the

Fig. 1 Stereoelectronic effect typical for carbohydrates: anomeric and exo-anomeric effect

O

O O

O

O

O

N Me O

O 3a

MeO

O O O

O o

N O

neat, 70 C O

O O

O

O

N MeOOC O 3b Me

98% 4

Me MeOOC (5S) / (5R) = 87.5 : 12.5

Scheme 2 1,3-Dipolar cycloaddition of N-mannofuranosyl nitrone with methyl methacrylate directed by the exo-anomeric effect

Carbohydrates as Stereodifferentiating Auxiliaries

5

front-side. Probably, an initial HOMO-nitrone/LUMO dipolarophile interaction favors the exo-methyl orientation of the methacrylate. Regarding the relatively high reaction temperature, the overall stereodifferentiating effect of the carbohydrate due to its stereoelectronic properties is impressive. The example also shows that the interpretation of these effects raises interesting mechanistic questions. It is rather astonishing in view of these results that the carbohydrates being readily available, cheap carriers of stereochemical properties have been ignored as tools in stereoselective transformations for a long time. This situation changed about 30 years ago, and a number of reviews reported on the progress made in using carbohydrate as the stereodifferentiating factors in stereoselective syntheses of chiral target molecules including building blocks, natural products, and drugs in enantiomerically pure form [9–14]. In this chapter, the focus will be on the application of carbohydrates as chiral auxiliaries being covalently linked to prochiral substrates. For some types of reactions, recent developments of carbohydrate-derived reagents and enantioselective catalysts [13, 14] will be outlined, while the role of carbohydrate ligands, for example in enantioselective hydrogenations (For a recent review on carbohydrate ligands in enantioselective hydrogenations, see [15, 16].), will only briefly be summarized at the end of the chapter.

2 Cycloaddition Reactions Asymmetric cycloaddition reactions had been an area in which carbohydrate auxiliaries were successfully applied very early as depicted in Scheme 2. Reactions that are demonstrating the typical characteristics of carbohydrates shielding, complexation and stereoelectronic effects, will be discussed. For further examples, the cited reviews [9–14] may be consulted.

2.1 2.1.1

[4 + 2] Cycloaddition Reactions: Diels-Alder Reactions and 1,3-Diploar Cycloadditions Reactions Carbohydrate-Linked Dienophiles

Dienophiles can simply be coupled to carbohydrates as esters. The 2-O-acrylate 5 of the benzyl L-arabinopyranoside reacted under Lewis acid catalysis at low temperature with dienes such as isoprene, to afford the cycloadduct 6 with moderate diastereoselectivity (~ 78:22). However, after formation of the ƞ6-chromium complex of the benzyl substituent the diastereoselectivity was distinctly enhanced (Scheme 3) [17]. In this case the increased steric crowding in the active complex with the Lewis acid certainly is the reason for the more efficient stereodifferentiation between the si- (preferred) and the re-side attack of the diene. The activating EtAlCl2

6

H. Kunz and A. Stoye (OC)3Cr

O

O O O O

O

(OC)3Cr

O

O

O O O

EtAlCl2, CH2Cl2 – 78 oC

5

6

O H

77 % 1'R : 1'S = 95 : 5

in absense of the chromium complex: 60 %, 1'R : 1'S = 78 : 22

Scheme 3 Diastereoselective Diels-Alder reaction based on steric shielding Cl

Cl Me3SiO

Ti

OSiMe3O

O

O

O O

TiCl 4 O

7

OH O

CH2Cl2, –78 oC

O

HO

1.

O O

O

O

2. H2O

7a

O O 8 82% R : S = 93 : 7

Scheme 4 Diels-Alder reaction under chelate activation and stereocontrol

coordinates to the ester carbonyl, but finds no oxygen of the carbohydrate favorably positioned for chelation. The stereodifferentiating effect of the carbohydrate auxiliary is increased if chelation of the activating Lewis acid is possible. The 5,6-bis-trimethylsilyl ether groups of the 1,2-O-isopropylidene-3-acryloyl-glucofuranose 7 (Scheme 4) reacted with titanium tetrachloride in dichloromethane at low temperature to afford the titanium chelate complex 7a. The thus activated dienophile underwent the cycloaddition with cyclopentadiene to give the adduct 8 with high stereoselectivity [18]. Bicyclic auxiliaries often provide the advantage of an exo versus endo differentiation during reactions. Such bicyclic frameworks, as shown in the D-alditol acrylate 9, can readily be obtained from carbohydrates [19]. The thermal DielsAlder reaction of 9 with cyclopentadiene gave the endo-cycloadduct with low diastereoselectivity (~ 67:33). However, the analogous process promoted by EtAlCl2 at –60
C afforded the pure R-configured cycloadduct 10 almost quantitatively. The authors attributed the dramatically enhanced diastereoselectivity to the chelating effect of ethylaluminum-dichloride. It coordinates to the carbonyl oxygen thus activating the dienophile and chelates with one of the dioxane oxygens resulting in an almost perfect shielding of the re-face of the acrylate (Scheme 5). A reversal of the re-/si-face differentiation was observed in Diels-Alder reactions of anhydrosorbitol acrylate 11 when different Lewis acid catalysts in different solvents were applied [20, 21]. While 11 reacted with cyclopentadiene in diethyl ether in the presence of ethylaluminum dichloride at room temperature to give the R-configured cycloadduct 12 with moderate selectivity, its corresponding reaction in dichloromethane promoted by tin tetrachloride prevailingly produced the Sconfigured cycloadduct 13 with high diastereoselectivity (Scheme 6). The reversal

Carbohydrates as Stereodifferentiating Auxiliaries

7

O O

Et AlCl2 O O O CH2Cl2, – 60 oC

O

99%, pure R-diastereomer COOR* 10 without EtAlCl2 under thermal conditions: R : S = 67 : 33

9

Scheme 5 The chelating and activating effect on the diastereoselectivity of Diels-Alder reactions [19]

12

O O EtAlCl2 Et2O

O

R : S = 87 : 13

O O

O O O

OBn

20 oC OBn

11

SnCl4 CH2Cl2

13 O

R : S = 4 : 96

O O O

OBn

Scheme 6 Reversal of diastereoselectivity of Diels-Alder reactions by changing the promoting Lewis acid [20, 21]

PivO HO

OPiv O

14

O

CH3 OPiv OH 15

Fig. 2 Pseudo-enantiomeric auxiliaries derived from D-glycal and L-rhamnal

of the asymmetric induction may be due to the different coordination properties of the Lewis acids in the different solvents. Stereodifferentiation is enhanced if carbonyl oxygens of the auxiliary are involved in coordination of Lewis acids. In these cases, even the pseudoenantiomeric deoxy sugars derived from D-glucose 14 and L-rhamnose 15 are efficient chiral auxiliaries (Fig. 2). Both compounds are readily accessible from the corresponding glycals by catalytic hydrogenation [22]. The 3-O-acrylate 16 of 14 reacted with butadiene in dichloromethane in the presence of isopropoxy titaniumtrichloride 0
C to preferentially form the R-configured cyclohexene-3-carboxylate 17. In contrast, the

8

H. Kunz and A. Stoye

reaction of acrylate 18 obtained from 15 with butadiene promoted at 30
C by titanium tetrachloride prevailingly afforded the S-configured cyclohexenecarboxylate derivative 19 (Scheme 7). Optimal stereoselectivity is given if one equivalent Lewis acid per acyl group is applied. With sterically more demanding dienes, as for example anthracene, almost complete diastereoselectivity is achieved at 0
C [22]. Tetra-O-pivaloyl-β-galactopyranosyl acrylate 20 also induced high stereoselectivity in the Diels-Alder reaction with cyclopentadiene promoted by an excess of di-isopropoxy-titanium dichloride [9, 23]. Five equivalents of the Lewis acid were used. After 1 h at 20
C the cycloadduct 21 was obtained with an endo/ exo diastereoselectivity of 96:4. The R-diastereomer of the endo-product was formed preferentially in a diastereomeric ratio of 96:4 (Scheme 8). The strong stereodifferentiation certainly is caused by the orientation of the acrylate substituent due to the exo-anomeric effect and by the shielding through to 2-pivaloyl group enlarged by coordination to the titanium ligand. It should be noticed that the reaction of the corresponding α-galactosyl acrylate proceeded much slower (8 h) and with low diastereoselectivity (70:30) in favor of the S-diastereomer of the adduct [23]. Ti O

OPiv Ti(OiPr)Cl 3

O

PivO

OPiv O

O

O

O

CH2Cl2

CH2Cl2 0 oC, 6 h

16

O

PivO H O

OPiv O

O

O Ti 17 90%, R : S = 92 : 8

O

CH3

TiCl4

OPiv O

CH2Cl2

O

O

CH3

O Ti

O O

Ti O

O CH2Cl2 –30 oC, 4 h

CH3

OPiv O H

O 19 68%, R : S = 5 : 95

18

Scheme 7 Dienophil linked to pseudo-enantiomeric carbohydrate auxiliaries in Diels-Alder reactions; increasing shielding of acyl groups through coordination effects

PivO

OPiv O

1. 5 eq. Ti(OiPr) 2Cl2 CH2Cl2

O

PivO OPiv

O 20

o

–20 C, 1 h

PivO

OPiv O O

PivO OPiv

O

21 95% ratio endo : exo = 96 : 4 endo-product: R : S = 96 : 4

Scheme 8 Stereoselectivity in Lewis acid promoted Diels-Alder reaction of glycosyl acrylate caused by the exo-anomeric effect and steric shielding

Carbohydrates as Stereodifferentiating Auxiliaries

9

The marked influence of the exo-anomeric effect was evidently demonstrated in the Diels-Alder reaction of the glucosyl-juglone 22 (Scheme 9) [24]. At room temperature the single cycloadduct 23 was isolated in a yield of 83%. The exo-anomeric effect is responsible for the orientation of the naphthoquinone in a fashion in which the front-side of the large conjugated dienophile is efficiently blocked by the 2-O-acetyl group. Bicyclic carbohydrate derived oxazolidinone and oxazinone auxiliaries [25, 26] also proved efficient in asymmetric syntheses. Diastereoselective Diels-Alder reactions using N-crotonoyl-oxazinone 24, prepared from L-gulonic acid, promoted by diethylaluminum chloride proceeded with excellent endo/exo selectivity and diastereoselectivity to give the prevailing 5S-configured norbornene-carboxylate 25 (Scheme 10) [26]. Bicyclic oxazolidinones derived from D-glucosamine, D-arabinosamine, or Dgalactosamine [27] were also shown to be efficient in diastereoselective DielsAlder reactions [28]. It is noteworthy that the oxazolidinones derived from Dgalactosamine 26 and D-arabinosamine 27 again represent a pair of pseudoenantiomers (Fig. 3). Their reactions with dienes provide access to both series of enantiomers of the corresponding cycloadducts. The N-crotonoyl derivatives of both auxiliaries 28 and 29 reacted with excess of cyclopentadiene in dichloromethane in the presence of three equivalents of diethylaluminum chloride at 78
C to yield the cycloadducts with high endoand excellent diastereofacial selectivity (Scheme 11). The products 30 and 31 contain the opposite enantiomers of the 6-methylnorbornen-5-yl-carboxylic acid. Their configuration was confirmed after detach-

AcO

OAc O

AcO

AcO

O O

OAc O

O O

AcO

O

O

O CH3

benzene room temp.

O

O

O CH3 23

22

Scheme 9 Thermal Diels-Alder reaction of glucosyl juglone stereocontrolled by the exoanomeric effect [24]

O O O O O

N

O O

O

O O

O

O O

Et2AlCl CH2Cl2, –20oC

N

O O

O

24 25

exo : endo = 98 : 2 d.r. = 98 : 2

Scheme 10 Diastereoselective Diels-Alder reaction of a dienophile coupled to an oxazinone derived from L-gulonic acid [26]

10

H. Kunz and A. Stoye PivO

OPiv O

OAc O

PivO

OAc O

HN 26

NH

O

27

O

O

Fig. 3 Pseudo-enantiomeric auxiliaries derived from D-galactosamine and D-arabinosamine [28]

PivO

PivO

OPiv O

PivO O

O

4h

PivO

O

N

OPiv

O

O

N

O

O 30 5R : 5S = 98 : 2

28

77%

exo : endo > 95 : 5 3 eq. Et2AlCl in CH2Cl2, –78 oC OAc

OAc

O

O N

O

OAc O

N

O

1h

OAc O

5R : 5S = 4 : 96

O

O 29

31

79%

Scheme 11 Stereoselective syntheses of enantiomers of norborn-2-ene-5-carboxylates using carbohydrate oxazolidinone pseudo-enantiomers O MeS S OSiMe3

O O

O

O

O O

benzene, room temp. O O

32

S

MeS O O

O O O O 33 d.r. = 90 : 10

Scheme 12 Thiocarbonyl dienophiles in hetero-Diels-Alder reactions [29]

ment from the auxiliary either by iodolactonization or hydrogenolysis and subsequent hydrolysis with aqueous lithium hydroperoxide [28]. Carbohydrate auxiliaries were also applied to stereoselective cycloaddition reactions on heterodienophiles, as for example thiocarbonyl compounds (Scheme 12). Carbohydrate-linked thiocarbonyl compounds usually undergo hetero-DielsAlder reactions with low diastereoselectivity [30]. However, in the reaction of the galactose-derived dithiooxalate 32 with 2-trimethylsilyloxy butadiene to give 33, a

Carbohydrates as Stereodifferentiating Auxiliaries

11

significant stereoselectivity was achieved although no coordinating promoter was used [29]. The absolute configuration of the products was not reported in this case. Highly stereoselective hetero-Diels-Alder reactions were described by Vasella et al. [31]. Mannono-hydroximino-lactone 34 was oxidized with tert-butyl hypochlorite. The formed chloro-nitroso compound 35 was susceptible to a highly diastereoselective cycloaddition at low temperature, for example with cyclohexa1,3-diene. The bicyclic isoxazine 36 arising from the intermediate adduct during the reaction or the subsequent work-up was obtained in almost enantiomerically pure form. The high stereoselectivity of this reaction certainly arises from the high reactivity of this dienephile allowing for the low temperature of the non-catalyzed reaction and from the exo-anomeric effect adjusting 35 is an endoconformation [31] (Scheme 13). Analogous stereoselective ene reactions on ribofuranosyl cloronitroso compounds were also achieved [32]. N-Glycosyl imines proved to be efficient in a number of diastereoselective syntheses [12]. For their application as hetero-dienophiles in 1,4-cycloaddition reactions, the activation with zinc chloride in dichloromethane is necessary [33, 34]. Under these conditions the reaction of N-galactosyl imines derived from aromatic aldehydes 37 with isoprene at 4–20
C yielded the 2-aryl-piperidine derivatives 38. Although the diastereoselectivity of these concerted Diels-Alder reactions is moderate due to the relatively high reaction temperature, the method offers a viable route for the synthesis of chiral piperidines since the pure major diastereomers often can be isolated after flash-chromatography (Scheme 14) [33, 34]. While these reactions with dienes of low polarity probably proceed via the concerted [4πs + 2πs] pathway (review see [35]), corresponding conversions with

O

O O O O

t BuOOH

NOH

O

O

O O O N O Cl

34

1.

O + N H2

–70 oC 2. H2O

35

O

36

Cl- ee > 96%

O O O O

O

Scheme 13 Glycosyl nitroso dienophiles in stereoselective hetero-Diels-Alder reactions [31] PivO

PivO

OPiv O Ar

N

PivO PivO

H 37

ZnCl2, CH2Cl2 4–20 °C

OPiv O N

PivO PivO

Ar 38 d.r. = 70 : 30 to 90 : 10 pure diastereomer Ar = 4-F-Ph 52% Ar = 4-Cl-Ph 60% Ar = 3-pyridyl 48%

Scheme 14 Hetero-Diels-Alder reactions on N-galactosyl imines [33, 34]

12

H. Kunz and A. Stoye

silyloxy dienes (vide infra) take their course as domino Mannich-Michael reaction sequences [36].

2.1.2

Carbohydrate-Linked Dienes and 1,3-Dipoles

In early investigations of diastereoselective Diels-Alder reactions between butadien-1-yl carbohydrate ether and glyoxylic esters a significant stereoselectivity was observed. The 3-O-butadienyl ether of 1,2,5,6-diisopropylidene-glucofuranose (diacetone glucose), for example, reacted with an endo/exo differentiation of 80:20 and a diastereofacial selectivity of 75:25 to afford the β-L-configured tetrahydropyrane-2-carboxylic ester with an amount of 60% among the four diastereomers [37]. Later on, Lubineau et al. (For review see [38].) applied unprotected butadien-1-yl glycosides in Diels Alder and hetero-Diels-Alder reactions in water in order to enhance the rate of the conversions due to the hydrophobic effect. This intrinsic pressure on hydrophobic reaction components favors ordered endo transition states in the reaction between glucosyloxy-butadiene 39 and methyl acrylate (Scheme 15) [39]. However, the diastereofacial selectivity was low in these conversions. Stoodley et al. [40] used the per-O-acetylated glucopyranosyl butadienyl derivative 41 in hetero-Diels-Alder reactions. In particular with di-tert-butyl azodicarboxylate as hetero-dienophiles they achieved a highly stereoselective formation of the cycloadduct 42 (Scheme 15), which was isolated as a single diastereomer after flash-chromatography (Scheme 16). Since the product has been characterized after purification, the exact stereofacial differentiation during the reaction cannot be quoted. However, it is remarkably efficient for the reaction of an acyclic dienophile that proceeds without the influence of a coordinating component. Actually, Diels-Alder reactions of glycosyl OH

COOMe

OH O

HO HO

O

HO HO

O OH

COOMe

OH

o

H2O, 60 C, 18 h

O

40

39

(1'R, 2'R) : (1'S, 2'S) = 75 : 25

Scheme 15 Glycosyl diene in Diels-Alder reaction in water [42]

AcO AcO

COOtBu

OAc O

N O

AcO

COOBn

t

BuOOC

AcO AcO

N o

41

toluene, 85 C 5d

OAc O

COOtBu O

N

AcO 42 76% , single diastereomer

Scheme 16 Glycosoxyl-butadiene in stereoselective hetero-Diels-Alder reaction [40]

N

COOtBu COOBn

Carbohydrates as Stereodifferentiating Auxiliaries

13

analogues of Danishefsky’s diene with benzoquinone derivatives at room temperature resulted in diastereomeric ratios of about 7:1 [41]. The enantiomerically pure piperazine carboxylic acid, a constituent of antimicrobic peptides, was easily detached from the carbohydrate by acidolysis with trifluoroacetic acid [40]. This example illustrates a further advantage of carbohydrates as chiral auxiliaries: the diastereomers often can simply be separated and purified. In addition, the enantiomerically pure target compounds can readily be detached from the carbohydrate, in particular if the prochiral substrate was coupled to the carbohydrate as an ester or in anomeric position. However, the cleavage of the glycosyl amide linkages usually is difficult [42]. A stereoselective formation of dihydro-1,2-oxazines from 3-O-propenyl ethers 43 of di-isopropylidene-glucofuranose was reported by Reissig et al. (Scheme 17) [43]. The authors observed that the E-enol ether reacts much faster than the Z-enol ether and with complete face-selectivity. The limitation of this reaction lies in the unsatisfying access to pure E- or Z-enol ethers. N-Glycosylated nitrones as 1,3-dipoles provide attractive properties in stereoselective cycloaddition reactions as already was shown in Scheme 2. Vasella et al. utilized their stereodifferentiating potential in the stereoselective synthesis of enantiomerically pure natural imino sugars as for example (+)-nojirimycin [44]. The cycloaddition of the N-ribofuranosyl nitrone 45 with the S-vinylglycine derivative 46 in boiling chloroform yielded isoxozolidine 47, a precursor of the anti-tumor antibiotic acivicin, almost as a single diastereomer (Scheme 18) [45]. The authors explained the excellent diastereoselectivity with a matched double asymmetric induction. Ph O

O

N

OO O O

O

O OO

O

t Bu-O-Me,

o

20 C

(Na2CO3)

43 Z : E = 20 : 80

O

O

O

N Ph

44, 52%, 98 (from E) : 2 (from Z)

Scheme 17 [4 + 2]-Cycloaddition of a glycosyl enol ether with nitroso-alkene [43] O

O C

O TrtO

N

O

N CH2

O

O

O

O MeOOC 45

CHCl3

C

+ N 46

H

reflux 1.5 d

TrtO

N

O

COOMe

O 47 93%

O

O d.r. > 95 : 5

Scheme 18 Matched stereofacial differentiation in a 1,3-dipolar cycloaddition of a ribofuranosyl nitrone to a vinylglycine derivative [44]

14

H. Kunz and A. Stoye

Dipolarophiles linked to carbohydrate auxiliaries as for example 48 are also useful in 1,3-dipolar cycloaddition reaction. The reaction with benzonitrile oxide in tetrahydrofuran gave the isoxaziline 49 in acceptable yield and diastereoselectivity (Scheme 19) [28]. Highly enriched or pure diastereomers of Δ2-isoxazilines of type 49 were obtained after flash-chromatography or re-crystallization from dichloromethane/ light petroleum ether. Stereoselective syntheses of chiral five and six-membered N-heterocycles were successfully performed using α-metallated alkoxyallenes in reactions with nitrones (review see [46]). Although these conversions proceed via a step-wise pathway, they lead to products which formally can be considered cycloadducts. Reissig et al. reacted the nitrone 50 derived from D-glyceraldehyde with lithiated methoxy-allene 51 and isolated the syn-configured adducts 52 of the formal [3 + 3]-cycloaddition in enantiomerically almost pure form (Scheme 20) [47]. As by-products butadienes formed by a retro-Diels-Alder reaction (elimination of formaldoxime) were isolated. The reaction certainly belongs to the ex-chiral pool type and starts with a nucleophilic attack at the nitrone C ¼ N double bond under chelation control. However, the potential of stereodifferentiation in this process through the carbohydrate structure is convincing. Recently, glycosyl nitrones derived from L-erythrose 53 were also applied to these oxazine syntheses (Scheme 21) [48]. The diastereofacial differentiation in this auxiliary-directed stereoselective oxazine formation is lower than in the stereoconservative fashion (Scheme 20). But the products can be purified, further converted and finally detached from the auxiliary to afford, for example, interesting amino-polyol components [48]. New methods for the preparation of N-glycosyl nitrones [49] will certainly support further developments in this area.

PivO PivO

N

OPiv O Cl O

N

O

OH

OPiv O

PivO PivO

Cl

O

0–20 oC, 8 h

O

O

N

O

NEt 3, THF O N

Cl

48

49 74%

d.r. = 86 : 14

Scheme 19 Cycloaddition of a nitrile oxide to a glyco-conjugated dienophile

O H

O

OMe

Li C

-

O 50

N+ Me

O

o

THF, –78 C 2h

OMe

O N

CH2

Me

51

52 53% d.r. > 98 : 2

O

Scheme 20 Carbohydrate nitrones in formal [3 + 3]-cycloaddition reactions [47]

Carbohydrates as Stereodifferentiating Auxiliaries

O

O -

O

room temp.

51

O

15

O

O

THF –130 oC to –80 oC

N+

O

O

O

+ N

Ph

O

O

O

OMe

OMe

53

Ph

Ph

N

(S)-54 49%

(R)-54 22%

Scheme 21 Carbohydrate auxiliary-directed reaction of nitrones with lithiated allenes [48]

H3C O S NH2 + O O O O

OO

55

O S ONa OMe

H O HCOOH

O THF, –50 to –20 °C

O 2 eq. + Li

C H2C

Tos

5h

OMe

Tos NH

O C H2C

1. AgNO3/K2CO3 CH3CN 16 h 2. prep. HPLC

56

O

OO 57, 41%

O

O

O

(2R : 2S = 71 : 29) +

N

3. HCl/THF N

Tos

Tos

58a

58b OMe

OMe

Scheme 22 Reaction of α-lithiated allene with imines and subsequent ring closure – a formal [3 + 2] cycloaddition of an allyl anion to imines [50]

Carbohydrate-derived lithiated allenes were successfully applied to the diastereoselective synthesis of pyrrolidin-3-ones [50]. For example, the α-lithiated di-isopropylidene-protected D-fructopyranose allenyl ether 55 and the N-protected phenylacetaldehyde imine, because of its rapid tautomerization in situ formed from the α-amino-sulfon precursor 56, yielded in THF at low temperature the α-allenylbenzyl-amine 57, which cyclized under strongly basic conditions to afford the pyrrilidinones 58 (Scheme 22). Stereoselectivity of the nucleophilic addition in the first step (R:S ¼ 5:2) was not changed under the basic condensation of the cyclization. After separation and acidolytic detachment from the fructose auxiliary, the enantiomeric pyrrolidones were isolated in the ratio of 71:29.

16

H. Kunz and A. Stoye TBSO TBSO

OTBS O

Tos

TBSO

+ O 59

H

OTBS O

TBSO 1. n-BuLi, LiCl, THF, –78 oC

N Ph

O

2. AgNO3 /toluene 60

C CH2

Ph

N Tos

75%, d.r. = 96 : 4

Scheme 23 Glycosyl allenyl ethers with imines to afford pyrroline and pyrrolidinone derivatives [51] O H3C O TBSO

O

Ph C N O

TBSO OMe

CH2Cl2 room temp.

N Ph

O

O H3C O O TBSO TBSO 62

OMe

61 96%, d.r. = 96 : 4

Scheme 24 Cycloaddition of benzonitrile oxide to the acrylate of a deoxyglucofuranose auxiliary [52]

Liu et al. reported the reaction of a lithiated tert-butyl-dimethylsilyl-(TBS)protected glycosyl allenyl ether 59 with N-tosyl imines of not enolizable aldehydes (Scheme 23) [51]. The cyclization was achieved best with silver nitrate in toluene. The glycosylooxy-pyrrolines, as for example 60, were obtained with high diastereoselectivity and isolated in good yield. Due to the anomeric linkage the auxiliary can readily be removed from the products by treatment with boron trichloride and thiophenole. Thus, enantiomerically pure 2-stubstituted pyrrolidin3-ones were isolated in high yield. Excellent diastereoselectivity was achieved by Tadano et al. [52] in 1,3-dipolar cycloaddition reactions of nitrile oxides to acryl esters 61 linked to O-4 of a TBS-protected methyl 6-deoxyglucopyranoside (Scheme 24). The reaction with benzonitrile oxide afforded the isoxazoline 62 with remarkable regio- and almost complete stereoselectivity. The ester linkage to the auxiliary allowed the solvolytic detachment from the auxiliary. Thus, the method provides an efficient access to enantiomerically pure isoxazolines and hydroxy acid derivatives. Tadano et al. have applied this type of auxiliary to a number of other stereoselective reactions (vide infra) [53]. In the context of carbohydrate auxiliary-directed reactions of allenyl ethers a two-step reaction sequence of lithiated glycosyl allenyl ethers, as for example 63, with α,β-unsaturated carboxamides 64 is of interest [54]. The charge-controlled nucleophilic attack of 63 at the carboxamide carbonyl in THF at low temperature results in the formation of intermediate 65 which after protonation by HCl in hexafluoroisopropanol and elimination of the amine (ammonium salt) undergoes a stereocontrolled conrotatory Nazarov cyclization and release from the carbohydrate to give the cyclopentenone derivative 66 with high enantioselectivity (Scheme 25).

Carbohydrates as Stereodifferentiating Auxiliaries

TBSO TBSO

OTBS O

Me

Ph

O N

C

O

64

CH2

TBSO TBSO

OTBS O

O LiO

O

N

O

Me

65

63

THF, –78 oC; –30 oC 1 h; –78 oC.

Li

TBSO TBSO

17

C CH2 HFIP/TFE/HCl –78 oC, 30 min

HO

OTBS O

Ph

Me OH

H

O 66

+

+ H2C

N H Cl

Ph

O

84%, 86% ee

Scheme 25 Diastereoselective formation of chiral cyclopentenones through reaction of metallated glycosyl allenyl ethers with carboxamides – a formal [3 + 2] cycloaddition reaction [54]

F3C

O

C N O

67

O

O OH

F3C OMe

O

+

69a 8% ee

COOMe

N

COOMe

Yb(OTf) 3, CH2Cl2, rt O Ph O HO 68

CH3

N

OMe

Me

F3C

69b 70% ee

yield 65%; 69a: 69b = 89 : 11

Scheme 26 Enantioselective catalysis of the 1,3-dipolar cycloaddition of aryl nitrile oxides to α,β-unsaturated esters using carbohydrate ligands [55]

Enantioselective catalysis of 1,3-dipolar cycloaddition reactions of aryl nitrile oxides to α,β-unsaturated esters was recently achieved using Lewis acid complexes of carbohydrate ligands [55]. Methyl crotonoate 67 served as a model dipolarophile. Its reaction with in situ generated 4-trifluoromethyl-benzonitrle oxide in DMF promoted by Yb(OTf)3 in the presence of the glucopyranose-derived diol 68 afforded the isoxazoline in good yield and remarkable regioselectivity. It is noteworthy that the minor regioisomer 69b was formed with 70% ee (Scheme 26). The authors applied a series of other chiral catalysts to this reaction including further carbohydrates and nucleosides. Relatively high amounts of the Lewis acid and the chiral ligands were used. The absolute configuration of the products was assigned by comparison with literature data, but is not given in the experimental section. The explanation of the stereodifferentiation given, e.g., for the related reaction of 67 catalyzed by the BiBr3 complex of 68 remains unclear.

18

2.1.3

H. Kunz and A. Stoye

Carbohydrate-Derived 1,3-Dipoles

Instead of N-glycosyl nitrones, carbohydrate-derived nitrones were recently used in asymmetric Kinugasa reactions [56] which provide an attractive access to pharmacologically important β-lactam antibiotics [57]. Although the carbohydrates were applied in these syntheses as chiral substrates the close mechanistic relation to the 1,3-dipolar cycloaddition justifies a brief description of these conversions in this context, even more as the obtained β-lactam products constitute a link to the fourmembered ring compounds reported in the following section. The cyclic nitrone 70 of L-arabinofuranose configuration, misleadingly addressed as D-xylose-derived because of its synthesis thereof, reacted with the Dxylose-derived alkyne 71 in dry acetonitrile in the presence of copper iodide and trimethylamine to afford the β-lactam 70 in high yield and diastereoselectivity. After chromatography, 72 was isolated as a single diastereomer in 85% yield (Scheme 27) [58]. The reaction obviously proceeds via an initial regio- and diastereoselective 1,3-dipolar cycloaddition followed by an electrophile(protonation-) induced rearrangement (review see [59]). The suppression of the accompanying Glaser coupling of the alkyne strongly depends upon the amine coordinating to the copper. The Kinugasa reaction of nitrone 73 obtained from 2-deoxy-ribofuranose [60] with alkyne 74 accessible from D-lactic acid was successfully applied to the synthesis of thienamycin derivatives (Scheme 28) [61]. The reaction of both, the di-O-benzyl-protected nitrone 73 and the mono-Obenzyl-deprotected nitrone 73a, afforded a mixture of cis/trans isomers of the β-lactams 75 or 76, respectively, prevailingly the desired trans-isomer in a ratio of 3:1. The separated trans-isomer 76b was subjected to a two-step oxidation and subsequent esterification with diazomethane to give 77. Hydrogenolytic debenzylation and oxidation with Dess-Martin periodinane produced the β-ketoester 78. Formation of its phosphoenolate, Michael addition of N-acetylcysteamine and phosphate elimination gave the precursor of thienamycin 79. A retro-Claisen ring opening occurred as a side reaction in the final step.

O O O BnO

CuI, 3 eq. NEt3 MeCN

OBn O

N +

O

BnO

OBn 70

O 71

0 oC (20 min), rt, 5 h

O O BnO BnO 72

OBn H

N H OBn

85%

Scheme 27 Diastereoselective Kinugasa reaction of a carbohydrate-derived cyclic nitrone with a carbohydrate-derived alkyne to give a β-lactam [58]

Carbohydrates as Stereodifferentiating Auxiliaries OTBS O

CuI

N OBn +

73

NMe2

Me2N

OBn

19

TBSO

NH MeCN 0 oC to 20 oC 12 h

74

H

TBSO

H

OBn N O

H

H

OBn

+

N O

OBn

OBn

75a

75b 55%

50% : 75a : 75b = 25 : 75 o

KHMDS, THF, –50 C 74, CuI TBSO 73

BCl3⋅SMe2

O

OBn

CH2Cl2, 0 oC 73a

OH

H

NMe2

Me2N

N

NH MeCN 0 oC to 20 oC 12 h

TBSO

H

H

OBn +

N O

OBn N

O

OH 54% (25 : 75)

76a

H

OH 76b oxidation

NHAc

TBSO

H

H

O 1. EtO P Cl EtO

TBSO

H

H

H

O

N

OBn

N COOMe

79

TBSO

H

DiPEA, DMAP

S O

CH2N2

2.

HS

NHAc

O

44%

78

N COOMe

O 77

COOMe

Scheme 28 The use of the diastereoselective Kinugasa reaction for the total synthesis of thienamycin derivatives [61]

2.2

[2 + 2] Cycloaddition Reactions

The stereoselective formation of β-lactams through [2 + 2] cycloaddition of carbohydrate-derived imines is well elaborated and has been reviewed in this series in 2006 [62]. Preferentially, the imines have been used as chiral substrates. Therefore, this review focusses on examples where the carbohydrate auxiliary can be removed from the cycloadduct. The [2 + 2] cycloaddition of 3-O-vinyl-glucofuranosyl derivatives, as for example 80, with chlorosulfonyl isocyanate (CSI) in toluene at low temperature stereoselectively afforded β-lactams (Scheme 29) [62]. Due to the high reactivity of CSI the reaction proceeds at low temperature with complete regioselectivity. The N-chlorosulfonyl group was removed by reduction with Red-Al [63]. While the glucofuranose-derived vinyl ether afforded the β-lactam 81 with high diastereoselectivity, the related 3-O-vinyl-xylofuranose 82 underwent the cycloaddition with CSI to give the diastereomeric lactams 83 with low stereodifferentiation. The mixture was subjected to intramolecular N-alkylation under Finkelstein conditions to form the cephams 84 which were separated by chromatography [63, 64]. The strong influence of the bulkiness of the substituents in 5-(and 6-) position of these vinyl ethers became evident in the reaction of the 5-O-triphenylsilyl analogue of 82 which reacted with high selectivity via its si-face.

20

H. Kunz and A. Stoye TsO 1. O C NSO2Cl toluene, –40 oC, 1.5 h

OTs OO

TsO

2. Red-Al

O

O

81 60%

80

TsO

O

NH

O

O

OTs OO

H

TsO 1.O C NSO2Cl H toluene, –40 oC, 1.5 h

OO O

O

2. Red-Al

O

TsO H

OO O

NH

O

83b

83a

82

O

NH

O

O

OO

50% 67 :33 NBu4Br H

O

CH3CN H

O

H

O

N

O

O

H

O

O O

O

H 84a 55%

N

O

H 84b 35%

Scheme 29 Stereoselective synthesis of β-lactams through cycloaddition of chlorosulfonyl isocyanate to carbohydrate-linked vinyl ethers AcO

OAc O

MeO

OAc H 85

Cl O

Ph

N

AcO

O

NEt 3 CH2Cl2 room temp.

AcO AcO

OAc O

O

OPMP

N

+

OAc

AcO AcO

Ph 86a

75% (60 : 40)

OAc O

O OPMP N

OAc

Ph

86b

Scheme 30 Glycosyl imines in [2 + 2] cycloaddition reactions with ketenes [67, 68]

Similar stereoselective [2 + 2] cycloadditions of CSI were also achieved with 5-O-vinyl gluco-and allofuranose-derivatives related to 80 [65]. The release of the stereodifferentiating carbohydrate from the products, however, was not demonstrated for the obtained β-lactams. Glycosyl imines related to 37 [33, 34], as for example 85 [66–68] reacted with ketenes to stereoselectively give the corresponding β-lactam 86 in good yields (Scheme 30) [67, 68]. In contrast to preliminary observations [67] the diastereoselectivity of the reactions was only low. Nevertheless, hydrolysis resulted in the release of the carbohydrate auxiliary and gave valuable β-amino-α-hydroxy acids [68]. High diastereoselectivity was achieved in [2 + 2] cycloaddition reactions of ketenes derived from xylofuranosylamine. The ketene 87a obtained by treating the oxazolidinone derivative of N-(α-xylofuranosyl)glycine 87 with Mukaiyama condensing reagent methyl-(2-chloropyridinium)-iodide and N-phenyl imines of aromatic aldehydes yielded the azetidinones 88 with excellent stereoselectivity (Scheme 31) [69]. The bicyclic nature of the xylo-oxazolidinone auxiliary obviously is responsible for the efficient stereodifferentiation. An O-linked 2,3-dideoxy-glucopyranosyl

Carbohydrates as Stereodifferentiating Auxiliaries

21 Ph

MeO

OMe O O

N Cl Me

N

OMe O O

CH2Cl2

O

87

MeO

COOH

O

N

N

OMe

H

O

OMe O

MeO

C

Ph

C

O

N

N

O 88 69% d.r. = 99 : 1

87a O

OMe

Scheme 31 Glycoconjugated ketenes in [2 + 2] cycloaddition reactions with imines [69]

Cl3COCl BnO

OBn O

Cu-Zn

CH3 Cl2C

O

BnO OBn

H

C

O

BnO

OBn O

BnO OBn

Et 2O, room temp.

BnO

CH3 O 3

Cl

O

+

OBn O

BnO

Cl Cl O3 H3C

OBn

H Cl

89

90-3S

O

H

90-3R NaBH4 in isopropanol

BnO

OBn O

BnO OBn

BnO

CH3 O 1

OH Cl

+

OBn O

BnO

Cl OH Cl O1 H3C

OBn

H Cl

44 %

91-1S

d.r. = 80 : 20 (HPLC)

H

91-1R

Scheme 32 Asymmetric [2 + 2] cycloaddition of ketenes to glycosyl enol ethers [70]

ketene applied to Staudinger reactions with imines afforded the cis-substituted lactams with a diastereoselectivity of about 89:11 [69]. Only a few examples are known for asymmetric syntheses of chiral cyclobutanones through [2 + 2] cycloaddition of ketenes. The O-benzyl-protected β-galactopyranosyl propenyl ether 89 obtained from the corresponding allyl galactopyranoside by isomerization with potassium tert-butanolate (KOtBu) in DMSO reacted with dichloroketene, in situ formed from trichloroacetyl chloride and zinc-copper couple in anhydrous diethyl ether, to give the diastereomeric cyclobutanones 90 with preference of the 3S-configured diastereomer 90-3S (Scheme 32) [70]. Due to the instability of these compounds, the cyclobutanones were reduced with NaBH4 and complete stereoselectivity to the corresponding cyclobutanol derivatives 91. HPLC analysis displayed the prevailing formation of the (1S,3R,4S)-cyclobutanol diastereomer 91-1S. The diastereomers 91 were separated by chromatography. X-ray analysis of the benzoate of the major diastereomer 91-1S revealed that the ketene preferentially attacked the enol ether 89 from its re-face [70]. As an acidolytic detachment of the synthesized aglycon would result in achiral cyclobutane diole, a stereoselective mono-dechlorination with tri-nbutylstannane/AIBN or O-benzylation was carried out first.

22

H. Kunz and A. Stoye

O

Ph O

O

Ph

O

O

O hν

O

Ph O

O

O 92

O

O

93a

+ O

Ph

Ph

O

Ph O

O O

O

O O

yield 80% O d.r. = 90 : 10

93b

Scheme 33 Diastereoselective Paterno-Büchi reaction of carbohydrate esters of phenyl glyoxylic acid [71]

It is noteworthy that the analogous reaction of the monochloroketene with galactosyl enol ether 89 and subsequent reduction prevailingly gave the all-cis galactosyl cyclobutane-diol derivatives in a ratio of 80:20 [70]. As early as in 1989 an asymmetric Paterno-Büchi reaction on a carbohydrate ester 92 of phenylglyoxylic acid was described. Irradiation of this compound in furan gave the diasteromeric byclic oxetanes 93. The products were obtained in a ratio of diastereomers of 90:10 (Scheme 33) [71]. Although the absolute configuration was not assigned, it was deduced from the discussion of the transition states that diastereomer 93a arising from attack of furane at the less shielded re-face of the glyoxylic ester constitutes the major product. A number of other carbohydrate esters have also been investigated in this work.

2.3

[2 + 1] Cycloaddition Reactions

Allyl glycopyranosides were successfully used by Charette et al. [72] in asymmetric Simmons-Smith cyclopropanation reactions. For example, the substituted allyl glycoside 94 of O-benzyl-protected glucopyranoside underwent Simmons-Smith conversion with diiodomethane/diethylzinc at 30
C in high yield and excellent stereoselectivity to afford the cyclopropane derivative almost as a single diastereomer 95 (Scheme 34) [73]. For detachment of the acid-sensitive cyclopropylmethanol from the carbohydrate auxiliary, 95 was transformed to the O-trifluoromethanesulfonate (triflate) and subjected to a pinacol-type rearrangement in DMF/pyridine/water at 160
C. The obtained free cyclopropylmethanol obviously was configurationally sufficiently stable and was subsequently converted to ()-coronamic acid in a few steps [73]. It is noteworthy that the Z-isomer of the allyl galactoside 94 served for the synthesis of (+)-coronamic acid in an analogous, slightly modified route. Kang et al. used acetals of α,β-unsaturated aldehydes with carbohydrate vicinal diols in asymmetric Simmons-Smith cyclopropanations [74]. The products were obtained in good diastereoselectivity, and readily released from the auxiliary by mild acidolysis and subsequent reduction. More recently, Vega-Pe´rez et al. described a similar strategy based on acetals of α,β-unsaturated aldehydes with 1,2-isopropylidene-xylofuranose [75].

Carbohydrates as Stereodifferentiating Auxiliaries

BnO BnO

OBn O

23

OTIPS BnO BnO

CH2I2/Et2Zn

O CH3

94

O OH

–30 oC

OH

OTIPS

OBn O

CH3

95, 93 %, d.r. > 99 : 1

Scheme 34 Stereoselective Simmons-Smith cyclopropanation of allyl glucosides [73] O

O

O

N O O O Ph + N2

O H

N

O O 96, 1 mol%

H

O O O

Ph

CuOTf (1 mol%) CH2Cl2

COOEt

Ph 95 % 97a, 95%

+ COOEt

Ph

(71 : 29)

COOEt 97b, 94%

Scheme 35 Enantioselective cyclopropanation using carbohydrate-derived (glucoBox) ligands [76]

BnO

OBn O

O

O

BnO

Ph 98

O OH

NaOH

O Ph

toluene, room temp. 99

100, 98%, 85% ee

Scheme 36 Enantioselective epoxidation using glycosyl hydroperoxides [78]

It should be noticed in this context that distinct progress has been achieved during the past decade in the field of enantioselective cyclopropanation reactions using carbohydrate ligands. For example, the copper-catalyzed (1 mol-%) reaction of styrene with ethyl diazoacetate in the presence of the glucosamine-derived bis-oxazoline (glucoBox) ligand 96 (1 mol-%) gave both the trans and the cis-diastereomer of the cyclopropanes 97 with excellent enantioselectivity (Scheme 35) [14, 76]. A major problem in these cyclopropanation reactions with excellent enantio-face differentiation remains the insufficient trans/cis selectivity. Epoxidation reactions (Prilezhaev reactions) are concerted [2 + 1] cycloaddition reactions closely related to non-linear cheletropic cyclopropanations. The enantioselective Shi epoxidation [77] using Oxone® by catalyzed 1,2-5,6diisopropylidene-glucofurano-3-ulose is efficient and well documented [14]. Recently, glycosyl hydroperoxides as sufficiently stable, stereodifferentiating agents have been introduced [78]. For example, the α-2-deoxygalactopyranosyl hydroperoxide 98 reacted with enone 99 in toluene in the presence of NaOH to give the epoxide 100 with high yield and remarkable enantioselectivity (Scheme 36). The glycosyl hydroperoxides are described as sufficiently stable for the separation of the anomers [79]. Different anomers can preferentially produce opposite

24

H. Kunz and A. Stoye

enantiomers of the epoxides [78]. Also, the complexing properties of the alkali ion have marked influence on the enantioselectivity of the reaction which probably proceed via a two-step pathway, nucleophilic attack at the double bond followed by intramolecular nucleophilic substitution at the oxygen. The glycosyl heroperoxides are of interest as potential anti-malaria agents [80].

3 Reactions of Glycosylamines: Mannich-Type Reactions A few reactions of N-glycosyl imines have already been mentioned in the stereoselective cycloaddition chapter, e.g. as dienophiles, dipolarophiles or in the case of N-glycosyl nitrones as 1,3-dipoles. Now their characteristics as diastereotopic electrophiles in carbohydrate auxiliary-controlled reactions will be discussed.

3.1

Strecker and Ugi Reactions for the Synthesis of Amino Acids

Glycosylamines proved to be very useful templates in Strecker syntheses of αamino nitriles [81]. O-Acyl-protected glucopyransyl- and galctopyranosylamines were used in the first experiments. The O-acetyl-protected compounds are susceptible an O ! N acyl-shift. Therefore, and because of the more efficient stereodifferentiation and the enhanced tendency towards crystallization, Opivaloyl-protected glycosylamines were preferably used. This applies in particular to the 2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosylamine 101. The compound is readily accessible from the corresponding O-pivaloyl-protected galactosyl azide 102 which was obtained either directly from penta-O-pivaloyl-galactopyranose, pathway A [81, 82] or from penta-O-acetyl-galactopyranose via reaction with trimethylsilylazide promoted by hydrogen chloride-free SnCl4 in dry dichloromethane, subsequent removal of the O-acetyl groups in dry methanol/cat. NaOMe to give 102a and following treatment with pivaloyl chloride in dry pyridine, pathway B (Scheme 37) [83, 84]. Actually, the yield of 102 usually was higher on the longer pathway B. It depends on the Lewis acid-catalyzed introduction of the azide in which the β-O-acyl hexopyranosides are much more reactive than the corresponding α-anomers. It should be considered that the Raney-nickel used for hydrogenation of 102 to give the glycosylamine is carefully washed neutral (pH 8), because otherwise anomerization of the glycosylamine will occur. The α-glycosylamine is not reactive in most of the conversions described below. The galactosylamine 101 already underwent a stereoselective Strecker reaction with aldehydes and NaCN in isopropanol/acetic acid (25:2). However, the conversion was slow. The diastereoselectivity ranged from 3 to 7:1 [82]. It revealed much

Carbohydrates as Stereodifferentiating Auxiliaries PivO

AcO

OPiv O NH2

PivO PivO

PivO

OPiv O

H2

OPiv

PivO PivO A

Me3SiN3 PivO

SnCl4 in CH2Cl2

25

AcO

Raney-Ni (neutral !) in MeOH HO

O

N3

HO pyridine

B OAc O N3

AcO mp 97 oC,

OH

102

SnCl4 in CH2Cl2

AcO MeOH cat. MeONa AcO

OH

t BuCOCl

N3 PivO

OAc

AcO

101 Me3SiN3

OPiv O

PivO

OAc O

102a mp 149 oC,

23

[α]D = –16.9 (CHCl3)

Scheme 37 Synthesis of 2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosylamine 101

Cl O

PivO PivO

R H

101

OPiv O N

PivO

R

ZnCl2

OPiv O

Cl Zn

O

PivO

PivO

R

N H

O H

103

103A

PivO PivO

OPiv O

PivO PivO

Me 3SiCN H N R

(R)-104

N C H

Me 3SiCN o

i) ZnCl2, isopropanol, 0 C or alternatively ii) SnCl4, THF, –18 oC

o

OPiv O

PivO

ZnCl2, CHCl3, 20 C d.r. (S / R) = 75 : 25 – 90 : 10

PivO

H N H

N C R

(S)-104

d.r. (R : S) = 80 : 20 – 98 : 2

Scheme 38 Stereoselective Strecker reactions using pivaloyl-protected galactosyl-amine 101 as the chiral auxiliary [81]

more efficient to pre-form the galactosyl imine and run the Strecker reaction in the presence of a Lewis acid. Galactosylamine 101 reacted with aromatic aldehydes in 2-propanol or in n-heptane in the presence of catalytical amounts of acetic acid under formation of N-galactosyl imines 103. The reaction of 103 with trimethylsilyl cyanide promoted either by ZnCl2 in 2-propanol or by SnCl4 in tetrahydrofuran prevailingly yielded (R)-amino nitriles (R)-104 (Scheme 38) [81, 82]. The diastereoselectivity was now distinctly higher, obviously due to the efficient shielding of the re-face in complex 103A. The cyanide ion set free from TMSCN in the polar solution preferably attacks this complex from the si-face. Usually, the reaction promoted by SnCl4 at 18
C was more stereoselective than the analogous process promoted by ZnCl2 at 0
C. In many cases, pure D-amino nitrile diastereomers (R)-104 were obtained by re-crystallization from n-heptane or by flashchromatography. Acidolytic cleavage of the N-glycosidic bond released enantiomerically pure amino nitriles or amino acids from the galactose auxiliary.

26

H. Kunz and A. Stoye

The method is particularly valuable for syntheses of enantiomerically pure phenylglycine derivatives which are prone to racemization under basic conditions. It is remarkable that the analogous reaction promoted by ZnCl2 in chloroform as the solvent predominantly resulted in the formation of (S)-amino nitriles (S)-104 [85]. In chloroform, the latent nucleophilicity of TMS-cyanide must be enhanced by an interaction of its silyl group with a chloride ligand of complex 103A. As a consequence, the nucleophile now is introduced to the re-side of the imine. The stereofacial differentiation given in complex 103A suggests that nucleophiles larger than the slim cyanide will react with the galactosyl imines 103 even more stereoselectively. In fact, Ugi four-component reactions of galactosylamine proceed with excellent diastereoselectivity. In a simple one-pot mode, galactosylamine 101 stirred at low temperature in THF with an aromatic or aliphatic aldehyde, formic acid, and an isocyanide in the presence of ZnCl2 gave the corresponding N-galactopyranosyl-(R)-amino acid amides (R)-105 in excellent yield and diastereoselectivity (Scheme 39) [66, 86]. Pure (R)-amino acid amides (R)-105 were obtained in high yield by stirring with n-heptane or by recrystallization or by flash-chromatography. The N-formyl group is removed from the galactopyranosyl-(R)-amino acid amides (R)-105 by treatment of compounds with HCl/methanol. Subsequent hydrolysis with aqueous hydrochloride acid gave pure (R)-amino acids (R)-106 (Scheme 40) [61.80]. It is noteworthy that N-glycosyl carboxamides usually are quite stable towards acidolysis [42]. Therefore, the easy removal of the N-formyl group by proton-catalyzed methanolysis is a pre-requisite for the acidolytic cleavage of the N-glycosidic bond. This is why formic acid is used most advantageously for the asymmetric Ugi reactions with glycosylamines according to Scheme 39. O R PivO

OPiv O

PivO

PivO 101

OPiv O O

PivO

aliphatic aldehydes: –78 °C aromatic aldehydes: –25 °C p-nitrobenzaldehyde: 0 °C

NH2

PivO

t Bu N C ZnCl2 H HCOOH / THF

H

O

N PivO (R)-105

R

N H

tBu

d.r. (R : S) > 95 : 5

Scheme 39 Diastereoselective Ugi reactions using a galactosylamine auxiliary [66]

O PivO

H3 N

OPiv O O

H N

PivO PivO

R (R)-105

O

1. HCl/MeOH N H

tBu

2. H2O

Cl

O NHtBu

H3 N

COOH

ion exchange Cl R

R +

PivO

6N HCl

(R)-106

OPiv O

PivO PivO

OH

Scheme 40 Detachment of enantiomerically pure D-amino acids from the carbohydrate auxiliary

Carbohydrates as Stereodifferentiating Auxiliaries

27

Regarding the great potential of the Ugi four-component reactions in producing molecular diversity (review see [87]), the galacosylamine auxiliary was linked to a polymer support in order to enable combinatorial asymmetric Ugi reactions on solid phase [88]. The coupling of carbohydrate auxiliary to the polymer support starting from galactosylamine 102a required a number of synthetic steps (Scheme 41). The Ugi reaction carried out on the polymer-linked galactosylamine 107 in THF at low temperature proceeded with high stereoselectivity to give the immobilized carboxamides 108. After acidolytic release from the polymer support, the galactosyl amino acid amides 109 were isolated in satisfying yield and in good diastereomeric ratio. Further separation and detachment reactions were carried out as described above [88]. As already pointed out, the reason for the high stereodifferentiation in the Ugi reactions to prevailingly give D-amino acid amides is to be traced back to the preferred nucleophilic attack on the si-face of the zinc coordinated N-glycosyl imine 103A shown in Scheme 38. In order to selectively obtain the interesting Lamino acid derivatives, the asymmetric Ugi reaction was carried out using Darabinopyranosylamine 110 as a pseudo-enantiomer of D-galactosylamine 101 [89]. Although both glycosylamines belong to the D-sugar series, compound 110 almost represents a mirror image of the galactosylamine 101 (Scheme 42).

O HO OH O N3 HO OH 102a

O

PivO O

6 steps

O

PivO

O

107

O

O O

PivO O PivO

NHtBu R

COOH

O

CHO O N

R-CHO, tBuN=C HCOOH, ZnCl2 THF, –40 to 0°C

NH2

PivO

O

PivO

O

108

TFA/CH 2Cl2 (1:9) PivO anisole, rt, 12 h PivO

O

CHO O N

PivO

NHtBu

109

R

Scheme 41 Diastereoselective Ugi synthesis of amino acids on solid-phase [88]

PivO PivO

OPiv O PivO 101

Scheme 42

D-Galactosylamine

OPiv NH2

H 2N

O

OPiv

PivO 110

and D-arabinopyranosylamine as pseudo-enantiomers

35–59 % 90:10 – 94:6

28

H. Kunz and A. Stoye PivO

PivO

OPiv O

OPiv NH2

R-CHO, tBuN=C HCOOH, ZnCl2 THF, –78 to –25°C

110

OPiv O

111

OPiv

CHO N

CONHtBu

R d.r. = 96 : 4 – 97 : 3

Scheme 43 Ugi reactions on a D-arabinopyranosyl auxiliary to give D-amino acid derivatives with high stereoselectivity [89, 90]

Actually, one pot reactions of 110 with aldehydes, tert-butylisocyanide and formic acid in the presence of zinc chloride in tetrahydrofuran gave more rapidly at lower temperature the corresponding N-arabinosyl N-formyl L-amino acid amides 111 (Scheme 43) [89, 90]. Again, pure N-arabinosyl L-amino acid amides are obtained by recrystallization or flash-chromatography. The efficient access to enantiomerically pure L- and D-amino acids is not only important for the synthesis of biologically interesting peptides or peptidomimetics, but also for the conversion to α-hydroxy carboxylic acids and the construction of depsipeptides and peptolides [90].

3.2

Aminophosphonic Acid Derivatives

Due to their close relation to α-amino acids enantiomerically pure aminophosphonic acids receive increasing interest as constituents of ligands or inhibitors of enzymes or receptors. In phosphorous-analogous Strecker reactions, galactopyranosyl- (101) and arabinopyranosylamine 110 react with aldehydes in tetrahydrofuran to give the corresponding glycosyl imines which with diethylphosphite in the presence of tin tetrachloride afford the (S)- or alternatively (R)-aminophosphonic ester derivatives in remarkable diastereoselectivity [91] (Scheme 44). Acid-catalyzed anomerization after the nucleophilic reaction forms α-anomers to some extent. The reactions with galactosylamine 101 (as well as with Lfucopyranosylamine) proceed at 0
C, while the more reactive arabinopyranosylamine 110 already reacts at even lower temperature. In a number of cases the major diastereomer can be isolated in good yield by recrystallization or chromatography.

Carbohydrates as Stereodifferentiating Auxiliaries

3.3

29

Mannich Reaction with Silylketene Acetals or Bis-Silylketene Acetals; β-Amino Acids

The Mannich reaction of N-glycosyl imines with C2-nucleophiles such as ester enolates or silylketene acetals offers an efficient diastereoselective access to enantiomerically pure β-amino acid derivatives [92, 93]. This class of compounds is of particular interest for the synthesis of peptide and β-lactam antibiotics and cytostatics [94]. In particular, the reactions of glycosyl imines, e.g. of N-galactosyl imine 103, with bis-silyl ketene acetals 113 in THF in the presence of ZnCl2 give β-amino acid derivatives with excellent diastereoselectivity [93] (Scheme 45). The analogous reactions with the unsubstituted bis-silyl- as well as with the methyl-silyl ketene acetal are less successful because they suffer from a ready O ! C silyl rearrangement. In the case of alkyl-silyl ketene acetals the dimethyl substituted reagents (isobutyrate derivatives) reacted with high diastereoselectivity [92]. However, due to a mistake in an optical rotation sign, the assignment of the absolute configuration of the products is probably wrong. It is considered particularly attractive that the Mannich reactions with the prochiral bis-silyl ketene acetals 113 shown in Scheme 45 result in β-amino acids 114 which contain two newly formed chiral centers. As a rule, out of four possible diastereomers of the products only two are observed, and one of them is obtained in high diastereoselectivity [93]. If one keeps in mind that the appropriate use of an Lfucopyranosyl- or D-arabinopyranosylamine provides access to the corresponding enantiomers of the β-amino acids, it becomes obvious that a wide variety of interesting, enantiomerically pure molecules is available via this methodology.

O PivO

R

OPiv O

SnCl4

NH2

PivO

PivO

HO P(OEt) 2 H

OPiv O O

H

PivO

THF, 0 °C

O P OEt OEt

N PivO

PivO

(S)-112

101

R

for example: R = 4-Me-C6H4: yield 78% b S 91% b R 6.2% a S 2.0% a R 0.8% O PivO

Ph

OPiv O

OPiv NH2

PivO OPiv

HO P(OEt) 2 H

SnCl 4

O

OPiv

CHO N

PO(OEt)2

THF, –15 to 15 °C Ph

110

(R)-112 94 %, a R 68% a S 13% b R 16% b S 3%

Scheme 44 Diastereoselective synthesis of α-aminophosphonic acid derivatives [91]

30

H. Kunz and A. Stoye

PivO OPiv O N R PivO PivO H 103

R1

COOSiMe3

H

COOSiMe3

113 ZnCl2 / THF

PivO OPiv R1 O H N PivO COOH PivO R 114

114a R = 3-Cl-Ph, R1 = Me, temp. –30 oC, time 48 h, yield 94%, d.r. > 95 : 5 : 0 : 0 114b R = n-pentyl, R1 = Ph, temp. –30 oC, time 96 h, yield 72%. d.r. = 94 : 6 : 0 : 0

Scheme 45 β-Amino acids with two new chiral centers through Mannich reaction of N-galactosyl imines 103 with bis-silyl ketene acetals 113 [93]

3.4

Homoallylamines

Glycosyl imines of aromatic aldehydes, as for example 103, react with trimethylallylsilane 115 as C3-nucleophiles (review see [95]) in tetrahydrofuran in the presence of tin tetrachloride to afford homoallylamines 116 with high diastereoselectivity [96, 97] (Scheme 46). Tin tetrachloride obviously not only coordinates the galactosyl imine (103B), but also activates the allylsilane through nucleophilic attack of its chloride ligands to the silicon center. The reaction requires 0
C to proceed with sufficient rate. Under these conditions, the Lewis acid SnCl4 also induces some anomerization of the glycosyl imine 103, and the α-N-glycosyl imines only slowly reacts with the allylsilane. Therefore, yield and diastereoselectivity of imines of electron-rich aromatic aldehydes are low. N-Glycosyl imines of aliphatic aldehydes more readily undergo anomerization under these conditions. Their stereoselective conversion to the corresponding homoallylamines 118 is only achieved using the more reactive (analogously to 103B) allyl-tri(n-butyl)stannane 117 at 78
C in shorter reaction time, but then also proceeds with high diastereoselectivity. The profit of these stereoselective syntheses of homoallylamines is further expanded as the compounds with opposite enantiomeric configuration can efficiently be obtained starting from O-pivaloylated L-fucopyranosyl imines 119 [97, 98] (Scheme 47). As for the corresponding N-galactosyl imines, the analogous reactions of N-Lfucosyl imines 119 require the use of allylstannes at low temperature and then diastereoselectively yield aliphatic homoallylamines of type 120. The chiral homoallylamines, as for example 121, can readily be obtained from the N-glycosyl homoallyl derivatives (after purification by chromatography or recrystallization) through acidolytic cleavage with HCl in aqueous methanol. After introduction of the N-tert-butyloxycarbonyl-(Boc)-group and oxidative cleavage of the C ¼ C double bond, β-amino acid derivatives, as for example Boc-β-phenyl-β-alanine 122, are obtained in enantiomerically pure form [96] (Scheme 48). From the corresponding N-fucosyl homoallylamines 118/120 the opposite enantiomers of the β-amino acids are accessible analogously.

Carbohydrates as Stereodifferentiating Auxiliaries PivO OPiv O N PivO PivO

SiMe3 R

PivO

115

H

103 R = Aryl Si Cl PivO

Cl

O

PivO

H N

PivO Aryl 116a Aryl = Ph, yield 65%. d.r. = 93 : 7 116b Aryl = 2-Cl-C6H4, yield 82%. d.r. = 96 : 4 116c Aryl = 4-MeOOC-C6H4, yield 44%. d.r. = 94 : 6

Sn Cl

OPiv O O

PivO

OPiv O

SnCl4 / THF, 0 oC, 2–3 d

Cl

31

R

N H

103B PivO OPiv O N PivO PivO

PivO OPiv O H N PivO

Sn(n-Bu)3 117 R SnCl4 / THF, –78 oC, 7 h

H

PivO

Alkyl

118a Alkyl = n-propyl, yield 32%. d.r. > 96 : 4 118b Alkyl = n-nonyl, yield 37%. d.r. = 89 : 11

103 R = Alkyl

Scheme 46 Homoallylamines from N-glycosyl imines and allylsilanes [96, 97]

PivO

OPiv

H3 C

O

119

PivO

SiMe3

OPiv N

115 H3 C

R H

OPiv O

OPiv H N

SnCl4 / THF, 1. 0 o C, 2 h; 2. room temp. 3–4 d

R

120a R = Ph, yield = 44%, d.r. = 96 : 4 120b R = 4-NO2-C6H4, yield 68%, d.r. = 95 : 5

Scheme 47 Homoallylamines with opposite enantiomeric configuration starting from fucopyranosylamines [98]

PivO OPiv O H N PivO PivO

+

HCl in aq. MeOH

H3N

Cl-

room temp. quant.

116a

L-

1. Boc2O, NaOH

BocHN in tBuOH, room temp. 2. NaIO4, KMnO4 H2O, room remp.

121

122

COOH

88%

Scheme 48 Conversion of the chiral homoallylamines to β-amino acids

N-Glycosyl homoallylamines proved also useful starting materials for the synthesis of enantiomerically pure chain-extended carbohydrates. For example, the Ngalactosyl imine of cinnamic aldehyde 103a reacted with allyltrimethylsilane to afford the homoallylamine 116d with excellent diastereoselectivity (19:1). Treatment of 116d with BF3OEt2 in xylene at room temperature did not induce the

32

H. Kunz and A. Stoye

PivO OPiv O N PivO PivO 103a

PivO OPiv H OH N PivO PivO

SiMe3 SnCl4 / THF

115

PivO OPiv O H N PivO PivO

BF3⋅ OEt2 xylene, 0 oC

116d, d.r. = 95 :5

PivO OPiv OH N PivO PivO 123, yield 99%, d.r. > 94 : 6

Scheme 49 Stereoselective chain extension of carbohydrates by Cope rearrangement of Nglycosyl homoallylamines [99]

expected Cope rearrangement resulting in a 1,5-diene. Instead glycoside ring opening took place, and the intermediate iminium species underwent the Cope rearrangement to afford the chain-extended C9-carbohydrate derivative 123 with complete stereoselectivity [99] (Scheme 49). O-Acetylation and hydrazinolytic cleavage of the imine give a C9-carbohydrate precursor which through oxidation at the C ¼ C double bond provides access to biologically interesting analogues of neuraminic acid. This process constitutes an ex-chiral-pool synthesis as the carbohydrate remains part of the chiral product. Another intramolecular transformation of the N-glycosyl homoallylamines, however, results in an auxiliary-controlled diastereoselective synthesis of chiral pyrrolidines. This is shown for an N-D-arabinopyranosyl homoallylamine obtained from N-D-arabinopyranosyl imine 124 formed from O-pivaloylated Darabinopyranosylamine 110 and pyridine-3-carbaldehyde according to lit [83]. Reactions of arabinosyl imines with allylsilanes and –stannanes under conditions given in Schemes 46 and 47 usually suffer from a rapid anomerization in the presence of the strong Lewis acid SnCl4. The resulting β-anomers (with axial imino group) do not react with the organometallic allyl reagent under these conditions. To suppress the undesired anomerization, the reaction temperature must strictly be kept below 10
C [100] (Scheme 50). The thus realized conversion of 124 with allyltributylstannane 117 afforded the 3-pyridyl-substituted homoallylamine 125 with high diastereoselectivity. Electrophile-induced cyclization using mercury-bistrifluoroacetate followed by reduction of the organomercury intermediate afforded N-arabinosyl pyrrolidine 126 as a single diastereomer. Treatment with HCl in aqueous methanol yielded enantiomerically pure (R)-nornicotine 127 [100]. The opposite enantiomer of 127 can be prepared when the O-pivaloylated Dgalactopyranosyl- (103) or D-glucopyranosylamine is used instead of arabinopyranosylamine 110 [100]. An interesting alternative synthesis of (S)-nornicotine was reported by Loh et al. [101]. They took advantage of the fact that the tetra-O-pivaloylated galactosylamine selectively reacts with aldehydes in the presence of ketones. 3-Nicotinoyl-propanal 128 and galactopyanosylamine 103 in dichloromethane in presence of molecular sieves selectively gave the glycosyl imine 129. Its treatment

Carbohydrates as Stereodifferentiating Auxiliaries CHO

PivO

OPiv

N

PivO

N

OPiv

SnBu3 117

OPiv N

O

110

33

O

OPiv H N

SnCl4 / THF, 1. –78 oC, 2. < 10 oC

H 124

N 125 yield 45 %, isolated; d.r. > 95 : 5

PivO

OPiv

1. Hg(OOCCF3)2 CH3CN

O

OPiv

2.NaBH4, NaOH, H2O

⋅ 2 HCl

N

aq. HCl/MeOH

N

HN

N

126, yield 74 %, after recrystallization 44 %

127, quant.

Scheme 50 Electrophile-induced formation of pyrrolidines from N-glycosyl homoallylamines [100] O O PivO

OPiv O

H NH2

PivO PivO

CH2Cl2 molecular sieves

101

NaCNBH3 AcOH

N

PivO OPiv O PivO

PivO OPiv O N PivO PivO H 129

aq. HCl/MeOH N

O

N

HN ⋅ 2 HCl

PivO 130, 45%

N N

131, 95%

Scheme 51 Stereoselective cyclizing reductive amination of glycosyl imines of 4-ketoaldehydes – synthesis of nornicotine [101]

with sodium cyanoborohydride in acetic acid led to a cyclizing reductive amination (Scheme 51). The N-galactopyransyl pyrrolidine 130 was obtained as a single diastereomer. Acidolysis of 130 with 1 M HCl in methanol effected the release of enantiomerically pure nornicotine 131 from the carbohydrate auxiliary [101] (Scheme 51). Other 4-ketoaldehydes, for example the 2-pyridyl regioisomer, have also been successfully applied to this synthesis. A further interesting stereoselective cyclization controlled by the O-pivaloylated galactosyl auxiliary can be described in this context, although it could also be considered a [2 + 2] cycloaddition. It consists of the reaction of N-galactosyl imines 103 with ethyl diazoacetate promoted by BF3OEt2in dichloromethane at low temperature [102] (Scheme 52). Also in this process the sterically less hindered si-face of the imine is preferentially attacked. In this case the Lewis acid-induced carbene binds to the imine nitrogen forming intermediate 132A as the authors suggest. Intramolecular

34

H. Kunz and A. Stoye COOEt

PivO OPiv O N R PivO PivO H 103

F3 B O H OPiv PivO OEt O R N PivO

N2 H BF3·OEt2, CH2Cl2

PivO

H

132A

PivO OPiv EtOOC O N PivO PivO R

H

COOEt Me

SH

· H BF3 OEt2, CH2Cl2

132, R = 4-NO2-C6H4 , yield 80% , d.r. = 99 : 1

S

H2N

Me

R 133 62%

Scheme 52 Diastereoselective synthesis of aziridines from N-glucosylamines [102]

nucleophilic attack at the former imine carbon results in a highly stereoselective formation of the aziridine carboxylic acid derivative 132 [102] (Scheme 52). BF3OEt2-promoted ring opening through nucleophiles provides a highly stereoselective access to β-substituted α-amino acid derivatives 133 [102].

3.5

Mannich-Type Reaction of Aromatic Compounds and Electron-Rich Alkenes

Aminoalkylation reactions generally afford interesting pharmacophoric structures. The imines 103 of O-pivaloylated galactosylamine were used in this sense for diastereoselective Mannich reactions on indoles [103]. Meng et al. mixed the 2,3,4,6-O-pivaloyl-galactopyranosyl imine 103 with indium trichloride (20 mol%) and molecular sieves under nitrogen atmosphere in dichloromethane. To this stirred suspension at 40
C, an excess of the indole was added. The galactosyl imine underwent Mannich reaction to yield the 3-aminoalkyl-indole 134 with excellent diastereoselectivity [103] (Scheme 53). The detachment of the acidsensitive indoles from the N-glycosyl compounds 134 was achieved using Na/MeOH followed by treatment with aq. acetic acid [103]. InCl3 induced higher diastereoselectivities in this process than MgBr2, ZnCl2, SnCl4 or FeCl3. The obtained diastereomers were not separable by flashchromatography. Similar to these Mannich reactions proceeded Povarov-like reactions of imines 103 of O-pivaloylated galactopyranosylamine with cyclic enol ethers and alcohols [104]. Chloroform turned out to be the optimal solvent and scandium triflate the best Lewis acid. At 40
C the β-aminoalkyl acetals 135 were obtained in high yield and with high diastereoselectivity [104] (Scheme 54).

Carbohydrates as Stereodifferentiating Auxiliaries PivO OPiv O H N PivO

R' PivO OPiv O N PivO PivO

R H

103

35

N H

PivO

InCl3 CH2Cl2. –40 oC molecular sieves

R R'

N H 134, R = 4-NO2-C6H4 , R' =H , yield 80%, d.r. > 95 : 5

Scheme 53 Stereoselective Mannich aminoalkylation of indoles

PivO OPiv O R N PivO PivO H 103

+ MeOH O Sc(OTf) 3 CHCl3, –40 oC

PivO OPiv MeO O H PivO N PivO R

O

135, R = 4-NO2-C6H4 , yield 82%, major isomer 83.6%

Scheme 54 Stereoselective Povarov-like aminoalkylation of cyclic enol ethers [104]

While the stereochemistry at the β-C of the enol ether certainly is controlled by the galactosylamine auxiliary favoring the Si-site attack at the imine, the preferred cis-configuration of the products 135 obviously is due to the anomeric effect emerging from the thermodynamically stabilized axial position of the alkoxy group.

3.6

Reactions with Silyl Dienol Ethers: Domino MannichMichael Cascades

The reactions of N-glycosylamines with silyl dienol ethers provide an efficient stereoselective access to enantiomerically pure substituted piperidines and, thus, to a variety of interesting natural products as well as their structural modifications (review see [9, 12, 105, 106]). In particular, the conversions of glycosyl imines with 1-methoxy-3-trimethylsilyloxy-buta-1,3-diene (Danishefsky’s diene 136) [107], were originally considered Diels-Alder cycloaddition reactions closely related to analogous reactions of isoprene (see Sect. 2.1, Scheme 14 [33, 34]). However, the outcome of these conversions turned out to be strongly dependent from the work-up conditions. The reactions of N-galactosyl imines 103 with Danishefsky’s diene 136 in tetrahydrofuran promoted by ZnCl2 proceeded at 20
C with high diastereoselectivity [36, 108] (Scheme 55). While the reaction of the imine of aliphatic butyraldehyde 103b yielded the 2-substituted dehydropiperidinone 137a with excellent diastereoselectivity independent of the work-up procedure, the corresponding 3-pyridyl imine 103c after work-up with aqueous ammonium chloride solution gave the open-chain Mannich product 138, also with high

36

H. Kunz and A. Stoye MeO

PivO OPiv O N PivO PivO 103b

136

OSiMe3 ZnCl2 / THF –20 oC work-up: aq. NH4Cl or dilute HCl

H

PivO OPiv O N PivO PivO

O

137a yield 96%, d.r. = 97.5 : 2.5 MeO PivO OPiv O N PivO PivO 103c

N

H

136 OSiMe3 PivO OPiv ZnCl2 / THF O H N PivO –20 oC PivO work-up: aq. NH Cl 4

PivO OPiv O

OMe aq. HCl PivO O

N

PivO N

N 138 yield 57% d.r. = 96 : 4

O

137b yield 90% d.r. = 96 : 4 (from 103c)

Scheme 55 Domino Mannich-Michael reactions of N-galactosyl imines 103 with Danishefky’s diene 136 to give 2-substituted piperidines 137 [36, 108]

diastereoselectivity. In this case, treatment of 138 with dilute aqueous hydrochloride prompted the cyclizing Michael addition and subsequent elimination of methanol to furnish the 2-substituted 2-(3-pyridyl)-piperidinone 137b for which the identical ratio of diastereomers was found as for the intermediate 138 (Scheme 55). It seems that the corresponding Mannich intermediate formed from the aliphatic imine 103b is more reactive and already undergoes intramolecular Michael addition and elimination of methanol under weakly acidic conditions. The pure diastereomer 137a was obtained by crystallization from n-hexane in a yield of 81%. Owing to a wrong sign for the optical rotation value of the hydrochloride of natural coniine in a reference literature [109], the wrong assignment of configuration of product 137a was originally published [36]. However, crystal structure analyses of the coniine precursor 137a (Fig. 4, [110]) and of its isopentylidene analogue unequivocally proved true the R-configuration at the C2 of the piperidinone ring [108, 110]. Based on this X-ray analysis and on the conversion of 137a to enantiomerically pure R-coniine, the absolute configuration of natural coniine was unequivocally confirmed to be S [111]. This result is in agreement with earlier assignments of the configuration for natural coniine based on comparison of optical rotation values (see, for example, [111, 112]). The synthesis of enantiomerically pure 2-substituted piperidines from N-glycosyl dehydro-piperidinones 137 is exemplarily displayed in Scheme 56 for the preparation of R-coniine. It starts with the 1,4-addition of hydride to the enone system using lithiumtri-sec-butylborohydride. The obtained piperidinone 139 was treated with ethane-dithiol/BF3OEt2 and the formed 1,3-ditholane 140 was desulfurized with hydrogen over Raney-nickel to yield the N-glycosyl piperidine 141 as a pure diastereomer. Acidolysis of 141 with dilute HCl in methanol yielded the hydrochloride of enantiomerically pure R-coniine [108].

Carbohydrates as Stereodifferentiating Auxiliaries

37

Fig. 4 Crystal structure of N-galactosyl piperidinone 137a (precursor of R-coniine) [108, 110]

Scheme 56 Enantiomerically pure R-coniine from N-galactosyl piperidinone 137a [108]

During work-up, the auxiliary tetra-O-pivaloyl-galactose can almost quantitatively be recovered by simple extraction with n-pentane. The O-pivaloyl groups of the auxiliary not only provide the advantage that the compounds are often prone to crystallization. They are also stable during reactions

38

H. Kunz and A. Stoye

with numerous nucleophiles (borohydrides, thiols, methanol). The methodology shown in Scheme 56 can successfully be applied to the preparation of other 2-substituted piperidines. For example, enantiomerically pure tobacco alkaloid Sanabasine was obtained from precursor 137b in likewise high yield [108]. As it has been shown for the stereoselective syntheses of amino acids and amino phosphonic acids the opposite enantiomers of the chiral piperidines are also accessible by this methodology if one starts from the corresponding D-arabinopyranosyl imines. For example, the arabinosyl imine of butyraldehyde 124a reacted with Danishefsky’s diene 136 under the described conditions to furnish the dehydropiperidinone 143 in good yield and high diastereoselectivity (Scheme 57) [113]. The ratio of diastereomers was determined by analytical HPLC of the crude product. Pure diastereomers were isolated by flash-chromatography or by crystallization. The absolute configuration of 143, which is the precursor of (natural) S(+)-coniine, was confirmed by crystal structure analysis (Fig. 5) [113, 114]. The use of substituted 2-silyloxy-butadienes offers further extensions of the scope of these stereoselective Mannich-Michael reaction cascades [105, page 17]. For example, the O-pivaloylated galactosyl imines 103d and 103e reacted with 1-methoxy-2-methyl-3-trimethylsilyloxy-buta1,3-diene 136a [115, 116] in THF in the presence of ZnCl2 to give the 5-methyl derivatives of the 2-substituted piperidinones 144 in acceptable yields and high diastereoselectivity (Scheme 58). PivO

MeO OPiv O

136 OSiMe 3 ZnCl2 / THF, –78 oC, then –20 oC

OPiv N H

PivO

O

OPiv O

OPiv N

work-up: dilute HCl

124a 143, yield 75%, d.r. = 98.9 : 1.1

Scheme 57 Synthesis of the precursor of S-coniine via Mannich-Michael reaction of N-Darabinosyl imine 124a [113]

Fig. 5 Crystal structure of N-arabinosyl dehydro-piperidinone 143 [113, 114]

Carbohydrates as Stereodifferentiating Auxiliaries

39

MeO

PivO OPiv O N PivO PivO H 103d

136a

OSiMe3

ZnCl2/ THF, 30 min –78 oC, 40 h –20 oC

PivO OPiv O N PivO PivO

O

work-up: dilute HCl 144a yield 49% d.r. > 95 : 5

R1 OPiv R2

PivO

O PivO

O

MeO 136a

N H

103e R1 = OPiv, R2 = H 145 R1 = H, R2 = OPiv

OSiMe3

ZnCl2 / THF, 30 min –78 oC, 30 h –20 oC

R1 OPiv R2 O N PivO PivO

O

O

work-up: dilute HCl R1 =

R2 =

OPiv, H, yield 58%, d.r. > 95 : 5 144b 144c R1 = H, R2 = OPiv, yield 54%, d.r. > 95 : 5

Scheme 58 Mannich-Michael reactions of N-glycosyl imines with substituted Danishefsky’s diene [110]

It should be mentioned in this context that the O-pivaloylated glucopyranosyl imine 145 of furan-3-aldehyde corresponding to 103e under these conditions yielded the N-glucosylated piperidinone derivative with the same high diastereoselectivity [105, p. 17]. In Strecker [82] and Ugi syntheses [86] of D-amino acid derivatives the glucosylamine auxiliary in comparison the galactosylamine had displayed a slightly lower diastereoselectivity by a factor of about 1.3. The given ratios of diastereomers were measured by 400 MHz 1HNMR spectroscopy after isolation by chromatography (144a) or crystallization from dichloromethane/light petroleum ether (Scheme 58) [105, p. 17]. The potential of these diastereoselective syntheses of 2-substituted piperidines carrying an additional substituent in 5-position becomes obvious if one keeps in mind that the according use of the D-arabinosylamine provides access to the opposite enantiomers (Scheme 57) and that reductive transformations allows for the conversion to the corresponding piperidinones and piperidines (Scheme 56). Further options for the stereoselective synthesis of enantiomerically pure polysubstituted mono- and polycyclic piperidine derivatives arise from stereocontrolled transformations of the N-glycosyl-dehydropiperidinones, as for example 137 or 143.

3.7

Stereocontrolled Transformations of N-Glycosyl Dehydropiperidinones

The diasteroselectively formed N-glycosyl dehydropiperidinone products 137, as well as the pseudo-enantiomers of type 143, can be subjected to multifarious modifications due to their numerous reactive groups. The substituent in 2-position can be varied by the choice of the starting aldehyde. Substituents in 6-position can

40

H. Kunz and A. Stoye conjugate addition electrophilic substitution PivO PivO

OPiv O

O N

PivO 137A

reduction and derivatization enolate reactions

PivO OPiv R O N PivO

O

PivO

R variation of the original aldehyde

137B

Scheme 59 Multiple variation of the structure of chiral piperidines starting from MannichMichael condensation products obtained from N-glycosyl imines and their preferred conformation

be introduced by conjugate addition (see, for example, in 137A, Scheme 59). Side chains in 3-position can be introduced through enolate chemistry. The 5-position can be varied via electrophilic substitution (or through Ballys-Hillman reactions). Finally, reduction or enol triflate formation open the way for substitution in 4-position (Scheme 59). Owing to the exo-anomeric effect, in this case the delocalization of the enaminone electrons into the σ*-orbital of the C-O ring bond, the N-glycosyl dehedropiperidinones adopt a preferred conformation as illustrated in 137B (Scheme 59, see also crystal structures in Figs. 4 and 5). In this conformation, any repulsive interaction between substituent R and the 2-pivaloyloxy group is minimized. Thus, the stereocontrolled attack of a nucleophile at the β-C of the enone is expected to proceed from the si-side preventing the hindrance by the pivaloyl group in 2-position of the sugar.

3.7.1

Synthesis of 2,6-Substituted Piperidines

Actually, the addition of the Gilman-type cuprate lithium-dimethylcuprate (Me2CuLi) to dehydropiperidinone 137a occurred with high stereoselectivity. At 78
C in tetrahydrofuran after trapping of the intermediately formed metalloenolate with trimethylchlorosilane (TMSCl), the (2S,6R)-configured 2-methyl-6propyl-piperidinone derivative 146a was obtained in good yield [108]. The silylenol ethers primarily formed in these TMSCl-promoted reactions were cleaved with tetrabutylammonium fluoride (TBAF). Applying the sequence of dithioketal formation, desulfurization, and acidolytic release from the carbohydrate auxiliary (see Scheme 56) the crude N-galactosyl piperidone 146a was converted to enantiomerically pure ()-dihydro-pinidine in good overall yield (Scheme 60) [108]. It should be noticed that 2-isopropyl- and 2-aryl-substituted N-galactosyl dehydro-piperidinone 137 also reacted with Yamamoto complexes [117] obtained from Grignard compounds, copper salts and BF3OEt2 to give the corresponding 2,6-disubstituted pipridinones of type 146 with high diastereoselectivity [108, 110]. In contrast to the dihydro-pinidine synthesis, the TMSCl-promoted addition of the functionalized magnesium cuprate to enaminone 137a proceeded with only

Carbohydrates as Stereodifferentiating Auxiliaries

PivO OPiv O N PivO PivO

PivO OPiv O PivO PivO

1. Me2CuLi / Me3SiCl O THF, –78 oC 2. TBAF

O N

146a, yield 71%, d.r. > 91 : 9 OEE

1.

137a

41

EEO

CuMgBr

2

Me3SiCl THF, –78 oC 2. TBAF

PivO OPiv O PivO PivO

O N

146b, yield 82%, d.r. > 75 : 25

Scheme 60 Conjugate addition of organocuprates to N-glycosyl dehydro-piperidinones [108] O

O dil. HCl

HS

OH

Ph3P/CCl4

146b MeOH

N H

NEt3, MeCN

147, 87%, cis: trans = 75 : 25

SH

BF3⋅OEt2/CH2Cl2 N

H2/Raney-Ni

N

iPrOH,70 oC

148 , 64%, pure cis

149 , 88%

Scheme 61 Enantiomerically pure gephyrotoxine 167B from N-galactosyl piperidinone 146b [108]

moderate stereoselectivity probably because of an interfering coordinating influence of the 1-ethoxy-ethyl (EE) ether group. The 2,6-disubstituted piperidinone 146b served as the starting material for a short synthesis of gephyrotoxine 167B, a minor alkaloid from the skin of the South American frog Dendrobates pumilio [118]. To this end, acidolysis with dilute HCl simultaneously released the piperidone from the carbohydrate and the EE protecting group. The 2.6-disubstituted piperidinone 147 was obtained as a mixture of the cis/trans isomers of the same ratio (75:25) as was given in 146b (Scheme 61). Activation of the alcoholic side chain function of 147 using Appel’s reagent [119] resulted in cyclizing N-alkylation and yielded indolizidinone 148, which surprisingly was isolated as the pure cis stereoisomer. It is tempting to speculate that the trans isomer does not undergo the Appel reaction and/or the cyclization under the applied conditions. Subsequent formation of the dithioketal and desulfurization gave the enantiomerically pure gephyrotoxine 167B 149 (Scheme 61) [108]. Pursuing an analogous strategy, the quinolizidine alkaloid ()-lasubin II 150 was synthesized from the disubstituted N-galactosyl piperidinone 146c (Scheme 62) [120]. In this case, the quinolizidinone corresponding to 148 was not subjected to the deoxygenation procedure, but to the stereoselective reduction using lithium-tri-secbutylborohydride to yield the enantiomerically pure alkaloid 150 as an example of a tri-substituted piperidine.

42

H. Kunz and A. Stoye

OEE PivO OPiv O PivO PivO

OH

O N

OMe

N

OMe 146c

150

OMe OMe

Scheme 62 ()-Lasubin II from disubstituted piperidone [120]

PivO

O

OPiv O

OPiv N

"PhCu⋅BF3" THF, –78 °C

143a

PivO

O

OPiv O

OPiv N

151 , 72%, d.r. = 99 : 1 Cl

Cl

Scheme 63 Diastereoselective synthesis of N-D-arabinosyl 2,6-disubstituted piperidinones 151 [114]

Opposite enantiomers of these piperidine compounds can principally be synthesized starting from the D-arabinosyl dehydropiperidinones of type 143. As an example of aryl-substituted compounds, the D-arabinosyl dehydropiperidinone 143a obtained from the reaction of p-chlorobenzaldehyde with the Yamamoto complex “PhCuBF3” in tetrahydrofuran at low temperature to afford the Narabinosyl 2,6-diaryl-piperidinone 151 with excellent diastereoselectivity (Scheme 63) [114]. The product 151 was isolated after flash-chromatography in good yield and showed a diastereomeric ratio of 99:1. Its absolute configuration was ascertained by X-ray crystallography [114]. Stereoselective syntheses of 2- and 2,6-substituted piperidines were also achieved in a combinatorial strategy on solid-phase. To this end, the azido precursor 152 of the O-pivaloylated galactosylamine auxiliary was immobilized by reaction with a cross-linked polystyrene equipped with chlorosilane functions. After reduction of the polymer-linked galactosyl azide using propane-1,3-dithiol the immobilized auxiliary 153 was installed (Scheme 64) [121]. This reduction proceeded quantitatively as was monitored by the disappearance of the azide band in the FT-IR-spectrum. In separate reaction tubes under optimized conditions the polymer-linked galactosylamine 153 was condensed with 22 aromatic or aliphatic aldehydes (5 equivalents) in toluene in the presence of 10 equivalents of acetic acid at room temperature to yield the polymer-bound N-galactosyl imines as is shown for example 154 [121, 122]. Subsequent Mannich-Michael domino reactions of the immobilized galactosyl imines with Danishefsky’s diene in tetrahydrofuran in the presence of ZnCl2 (10 equiv.) at room temperature resulted in the

Carbohydrates as Stereodifferentiating Auxiliaries

43 iPr

O

(CH2)6OH

PivO

O

+

O

PivO

N3

iPr Cl Si iPr

1. imidazole CH2Cl2 2. MeOH

O PivO

O O

PivO

PivO

(CH2)6 O Si iPr

HS

NEt3, DMF room temp.

N3

PivO

152

SH

iPr iPr O PivO

(CH2)6 O Si iPr

O O

PivO

NH2

PivO

153

O R H toluene AcOH

PivO PivO 155

O Bu2Cu(CN)Li2 BF3⋅OEt2 /THF

O O

N

–78 to –15 oC, within 14 h

PivO

yield 81% purity 97% d.r. = 98 : 2 (see text)

PivO

O O

PivO

Me3SiO

O Si iPr

PivO

H

O PivO PivO

nBu O O

ZnCl2(5 eq.), THF room temp. 154

OH O N TBAF⋅3 H2O THF, AcOH room temp.

PivO 156

CF3

OMe 10 eq.

CF3

N

iPr iPr O Si

iPr O Si iPr

O

O

CF3

O PivO PivO

nBu O O

O N

PivO 157 yield 76% purity 61% d.r. = 93 : 7

CF3

Scheme 64 Diastereoselective domino Mannich-Michael reactions of polymer-linked N-galactosyl imines [121, 122]

formation of the corresponding polymer-bound dehydropiperidinones as shown, for example 155, in Scheme 64 [122]. The diastereoselectivity of these reactions was determined for the crude products by HPLC after fluoride-induced cleavage of the auxiliary-polymer silyl ether linkage. Although the reactions on the polymer support were conducted at room temperature, the observed diastereoselectivities were comparable to those found for the corresponding reactions in solution [36, 108] performed at quite lower temperature [121, 122] (Scheme 64). It should be kept in mind that the mild acidolytic release from the galactose auxiliary only is possible after reduction of the C ¼ C double bond (see Scheme 56). The further conjugate addition of cuprates to the polymer-linked dehydropiperidinones 155 needed higher temperatures compared to the corresponding reactions in solution (see Schemes 60 and 62). Accordingly, the use of Gilman cuprates/TMSCl or Yamamoto cuprates gave insufficient results because of their lower stability at higher temperature. Cyano-modified organocuprates [123] are more stable and showed the required reactivity. Their 1,4-addition to the immobilized enaminones of type 155 proceeded at 60 to 15
C with sufficient rate and with high diastereoselectivity forming the 2,6-disubstituted piperdinones of type 156 prevailingly as the cis-diastereomers. The diastereoselectivity of these 1,4-addition reactions on solid-phase was determined by HPLC analysis of the crude products 157 obtained after fluoride-induced detachment from the polymer (Scheme 64). After purification and acidolytic cleavage of the N-glycosidic bond, pure 2,6-cis-substituted piperidinones can be isolated.

44

H. Kunz and A. Stoye

It should be mentioned in this context that trapping of the intermediate copper enolates formed by 1,4 addition onto 137 (Scheme 60), 143 (Scheme 62) or 155 offers a viable route for the stereoselective synthesis of tri-substituted pipridinones [110].

3.7.2

Stereoselective Synthesis of 3-, 4- and 5-Substituted Piperidine Derivatives

The stereoselective introduction of a 3-stubstituent can be achieved via the enolate of the N-glycosyl dehydropiperidinone as shown in Scheme 65 for the N-arabinosyl derivative 143a [114]. Deprotonation was carried out without affecting the ester protection using lithium hexamethylsilazane (LiHMDS) in THF. Alkylation at low temperature prevailingly yielded the 2,3-trans-disubstituted product 158, obviously due to the directing effect of the 2-substituent. The ratio of diastereomers and the configuration 158 were determined by 1HNR spectroscopy [114]. Opposite enantiomers of these piperidine derivatives are accessible with high diastereoselectivity using the galactosylamine 101 as the auxiliary [110]. Reaction of 2-substituted N-D-arabinosyl dehydropiperidinones 143 [114], N-Dgalactosyl dehydropiperidnones 137 or their N-D-glucopyranosyl analogues [124] with electrophiles selectively proceeds in 5-position. For example, N-galactosyl-2-isopropyl-dehydropiperidinone 137c was selectively attacked by N-bromo-succinimide (NBS) at C-5 giving the 5-bromodehydropiperidinone derivative 159a which was stereoselectively reduced by 1,4-hydride addition to preferentially form the 2,5-trans-substituted bromopiperidinone 160a (Scheme 66) [124]. Similarly, the 2-phenyl-dehydropiperidinone 137d was regioselectively brominated, and the 5-bromo derivative 159b stereoselectively underwent 1,4 addition of the methyl Yamamoto cuprate to furnish the 2,6-cis-5-trans trisubstituted piperidinone 160b. The product contains three stereogenic centers. Of the 8 possible diastereomers, only two can be detected with a high preference of the given major product [124]. A nitrogen substituent can be introduced in 5-position of the dehydropiperidinones of type 137 and 143 by treatment with nitronium tetrafluroborate [114]. Particularly versatile modification of the 5-position is PivO

O

OPiv O

OPiv N

1. LiHMDS 2. methyliodide THF, –78 °C

143a Cl

PivO

O

OPiv O

OPiv N

158 , 73%, d.r. > 95 : 5

Me

Cl

Scheme 65 Stereoselective synthesis of 2,3-trans-substituted piperidine derivatives

Carbohydrates as Stereodifferentiating Auxiliaries

45

Br PivO OPiv O N PivO PivO

O

Br

PivO OPiv NBS O N PivO THF, –78 oC PivO

137c

O

Li(sec-Bu)3BH THF, –78 oC

PivO OPiv O N PivO PivO

159a 95%

PivO OPiv O N PivO PivO

O

160a, 94% d.r. = 94 : 6 : 0 : 0

Br O

PivO OPiv NBS O N PivO THF, –78 oC PivO

137d

Br O

"MeCu⋅BF3" THF–78 oC

Ph

159b 89%

PivO OPiv O PivO PivO

O N Ph

160b, 50%, d.r. = 89 : 11 : 0 : 0

Scheme 66 2,5-Substituted N-galactosyl piperidinones [124] OMe OMe I PivO

PivO

O

OPiv OPiv N

O

NIS

143

Pd(PPh3)2Cl2 aq. Cs2CO3 THF, 65 oC

162a 69%

I

O

OPiv N

163a 40%

MgX

PivO OPiv O

O

OPiv

B(OH)2

OPiv N

O

THF, –78 oC

PivO

O

OPiv

O OPiv N

PivO iPrMgBr

O

OPiv O

o

THF, –30 C

PivO

OPiv N

OPiv N

O 164

162b CuCN/2 LiCl

166, quant. CuCN/ 2 LiCl Br

Ph-COCl o

–30 C to room temp.

O

O

OPiv

–30 °C to room temp.

PCy3 Cl Cl Ru CHPh PCy3

O PivOOPiv

OPiv N O

PivO

O 163b, 63%

O

OPiv OPiv N

163c, 79%

"allyl-Cu·BF3" PivO OPiv o

THF, –30 C

O

O OPiv N

165, 60%

Scheme 67 Organometallic coupling reactions of N-arabinosyl 5-iodo-dehydropipdinones [114, 125]

possible after iodination using the mild N-iodosuccinimide as is shown for 143 in Scheme 67 [114, 125]. The 5-iodo-substituent can be exchanged for C-substituents, e.g. aryl, alkyl, alkenyl, acyl or formyl groups, via organometallic intermediates. Both, Stille [126] and Suzuki coupling reactions [127] were achieved with the 5-iodo derivative 162a of 143 (Scheme 67).

46

H. Kunz and A. Stoye

Despite the elevated temperature required for the Suzuki reaction, a pure 5-aryl dehydropiperidinone 163a was isolated [114]. Alternative C-C couplings can be achieved through halogen-magnesium exchange [128]. Thus, for example, the 2-isopropyl analogue of 143 was iodinated to give the 5-iodo derivative 162b which reacted with isopropyl-Grignard in THF at low temperature to furnish organomagnesium intermediate 164. Treatment of this intermediate with dimethylforamide (DMF) then gave the 5-formyl derivative, while reaction with copper cyanide/lithium chloride and benzoyl chloride afforded the 5-acyl derivative 163b or, alternatively, with allyl chloride the 5-allyl dehydrpiperidinone 163c [125]. Exchange of magnesium of 164 for zinc using zinc bromide allowed Negishi couplings with aryl iodides [125]. The 2-isopropyl-5-allyl-dehydropiperidinone 163c was subjected to 1,4-addition of Yamamoto organocopper complex “allyl-CuBF3”. The obtained trisubstituted piperdinone 165 surprisingly showed 2,5-cis and 2,6-trans configuration which was unequivocally proven by X-ray analysis [125]. This is in contrast to the formation of 160b (Scheme 66) and displays the only example so far for which the 1,4 addition to an N-glycosyl dehydropiperidinone resulted in a 2,6-trans stereochemistry. Ring-closing metathesis using a Grubbs I ruthenium catalyst quantitatively afforded the trans-octahydroquinolinone 166 [125] (Scheme 67). For completion, the synthesis of 2,4-substituted N-glycosyl piperidinones should be outlined [129]. The 2-(3-pyridyl)-dehydropiperdinone 137b, as an example, was treated with L-Selectride® and the resulting lithium enolate trapped with N,N-bis (trifluoromethanesulfonyl)aniline (Comins’ reagent) to give the enol triflate 167. Compounds of type 167 were used in Suzuki couplings with aryl or hetaryl boronic acids and gave 2,4-disubstituted 4,5-dehydropiperidinones as shown for compound 168 containing three heterocycles [129] (Scheme 68). Similar results were achieved with 2-alkyl and 2-benzyl substituted dehydropiperidinones 137 [129]. The methodology displayed in Scheme 68 constitutes the first step of a cascade of organometallic coupling reactions which provides a short stereoselective access to tricyclic compounds of the benzomorphan series [130]. The 2-benzyl substituted dehydropiperidinone 137e, bromo- and alkoxy-substituted in the phenyl ring was treated with L-Selectride® and N,N-bis-triflylaniline as outlined in Scheme 68. The formed enol triflate 169 was then treated with 3-pyridylboronic acid. The thus obtained 4-substituted 4,5-dehydropiperidine was immediately subjected to a subsequent intramolecular Heck coupling (Scheme 69). In the course of this synthesis N PivO OPiv O N PivO PivO 137b

N

OPiv O 1. Li(sec-Bu)3BH PivO O THF, –78 °C N PivO PivO 2. PhNTf2 –78 oC to N room temp. 167

OTf B(OH)2 aq. Cs2CO3 Pd(PPh3)2Cl2 (5 mol-%) ThF, reflux

Scheme 68 2,4-Disubstituted piperidine derivatives [129]

PivO OPiv O N PivO PivO 168 79%

N

N

Carbohydrates as Stereodifferentiating Auxiliaries

47 N

PivO OPiv O N PivO PivO

O

Br 137e

PivO OPiv 1. Li(sec-Bu)3BH O N THF, –78 °C PivO PivO 2. PhNTf2 –78 °C to room temp. Br OMe 169

OTf B(OH)2

OMe OBn

OBn

aq. Cs2CO3 Pd(Ph3P)2Cl2 (cat.) DMF, traces of water

OMe microwave, hν 20 min 80 oC, then 20 min at 100 oC

PivO OPiv O N PivO PivO

OBn N

170, 32% after purification

Scheme 69 Synthesis of the benzomorphan framework through a Suzuki-Heck coupling cascade on an N-galactosyl dehdropiperidinone [130]

two organometallic coupling reactions were combined in a domino sequence. This is in so far remarkable as the Suzuki reaction requires the presence of water while the Heck coupling usually is moisture-sensitive and escapes into the formation of by-products. In the absence of water, no conversion occurred since the initial Suzuki reaction did not take place. Best results were obtained using dimethylformamide as solvent in the presence of traces of water. Support by microwave irradiation reduced the reaction time (Scheme 69) [130]. The outcome of this reaction cascade strongly depends on the halogen present in the enol triflate (169). While the corresponding iodo compound underwent a second Suzuki reaction instead of the Heck coupling, the analogous chloro derivative showed only the Suzuki, but no Heck reaction. The process, however, illustrates that the stereoselective formation of the N-glycosyl dehydropiperidinones through domino Mannich-Michael reactions (Schemes 55, 57, and 58) opens up attractive opportunities for the synthesis of natural products and their structural modifications.

3.8

Stereoselective Total Syntheses of Alkaloids Using Glycosylamines as the Auxiliaries

As shown for the stereoselective synthesis of benzomorphan-type compounds, the glycosylamines can be applied for stereoselective total syntheses of natural products or their biologically interesting stereochemical or structural variants. The examples outlined in the following schemes also disclose stereodirecting effects of the carbohydrate auxiliary, which arise from stereoelectronical effects typical for carbohydrates and exert differentiation even on stereochemically undemanding processes, as for example the protonation of an enolate.

48

H. Kunz and A. Stoye

Alkaloids with cis- or trans-Annelated Decahydroquinoline Structure

3.8.1

South-American frogs of the family Dendrobates secrete toxic decahydroquinoline alkaloids on their skin. Interestingly, decahydroquinoline from Dendrobates pumilio exclusively have a cis-annelated ring system, while the toxins from Dendrobates histrionicos have a trans-annelated structure [131]. Efficient syntheses of compounds from both series can start from galactosylamine 101 (Scheme 70). Depending upon the aldehyde which forms the N-galactosyl imine 103, the subsequent domino Mannich-Michael process yielded the side-chain functionalized dehydropiperidinone 137f or, alternatively, 137a already known from the coniine synthesis. The 1,4-addition of propyl Yamamoto complex PivO

OPiv

PivO

O

PivO

RCHO

NH2

OPiv O

PivO

OPiv 101

OSiMe3 OPiv

PivO

O

O

PivO

MeO

R

N

OPiv 103 R = (CH2)3-CH=CH2

H

103 R = (CH2)2-CH3

ZnCl2·OEt2 THF, –20°C OPiv

PivO

N

OPiv

THF, –78 °C d.r. > 91 : 9

EtO

O

Me3SiCl

MgCl

Me

CuBr·SMe2 NaIO4 K2OsO4cat.

d.r. = 90 : 10

aq. dioxane 2. TPAP, CH2Cl2

1. pyridine ·TsOH PivO

N

OPiv

137a 68%, d.r. > 97 : 3

n-PrMgCl, CuCl, BF3·Et2O

O

O

PivO

137f 68%, d.r. > 98 : 2

OPiv O

O

PivO

PivO

N

OPiv

PivO

O

OPiv O

O N

OPiv 171a overall 61%

O

171b overall 40%

NaOH dibenzo-18-crown-6 PivO PivO

OPiv O

N OPiv

172a 81%

benzene O

PivO PivO

OPiv O

O N

OPiv 172b 73%

Scheme 70 Synthesis of both series of hydroquinoline enantiomers on a unique galactosylamine auxiliary [132, 133]

Carbohydrates as Stereodifferentiating Auxiliaries

49

occurred with high diastereoselectivity [132]. The analogous 1,4-addition of the functionalized Gilman cuprate to 137a was of slightly lower selectivity. The functionalized side-chain of both compounds was converted to the terminal aldehydes 171a or 171b, respectively (Scheme 70). These compounds represent enantiomers of a 2,6-disubstituted piperidone which are linked to the galactosamine as the common auxiliary [133]. Crown-ether supported intramolecular aldol condensation in benzene transformed these compounds to the diastereomeric Ngalactosyl octahydroquinolinones 172a and 172b. The stereodirecting influence of the carbohydrate on the conjugate addition shows that either the trans- or the cisannelated decahydroquinolines can be constructed along this strategy [133]. The 1,4-addition of methyl Gilman cuprate/trimethylsilylchloride (TMSCl) to diastereomer 172a and subsequent cleavage of the resulting silyl enol ether gave the trans-annelated decahydroquinolinone 173a (Scheme 71). Two new stereogenic centers were built in this conversion. Of the four possible diastereomers only two were formed, among them the trans-annelated with a high diastereoselectivity. The second of the stereogenic centers obviously originates from protonation of the intermediate enolate suggesting that even a protonation at an enolate carbon apart from the auxiliary is sterically controlled by the carbohydrate. This conclusion was confirmed by the fact that the conjugate methyl cuprate addition to the dehydroquinolinone 174 obtained from 172a through detachment from the carbohydrate and introduction of a non-differentiating phenoxycarbonyl group actually yielded prevailingly the cis-annelated

PivO

OPiv O

O

PivO

N OPiv

OPiv

PivO 1. Me2CuLi TMSCl PivO THF, –78 oC

O H

O

N OPiv H

O O

N H

2. PhCH2OCOCl aq. NaHCO3 Ph

2. TBAF, –20 oC

172a

1. 0.15M HCl

O H

173a 81%, d.r. = 94 : 6 : 0 : 0

176, 88% 1. 0.15M HCl

2. PhOCOCl aq. NaHCO3

2. PhOCOCl aq. NaHCO3

1. 0.15M HCl

O N

O O Ph 1. Me2CuLi TMSCl

O

174, 60 %

N H

O H

O Ph trans-175, 82%

THF, –78 oC

O Ph

O

N H

HS

SH

BF3·Et2O

S

O N O H

HS

Ph 177, 64% Raney-Ni / H2

O H

NEt3, THF, 2 min d.r. = 75 : 25 : 0 : 0

cis-175, 67% d.r. = 82 : 18 : 0 : 0

Scheme 71 Synthesis of trans-4a-epi-pumiliotoxin C [132, 133]

H

178, 22%

N H H ·HCl

50

H. Kunz and A. Stoye

decahydro-quinolinone cis-175. This cis-annelated decahydroquinolinone is thermodynamically preferred since the hydrogen at C-4a is equatorially positioned and less acidified by the neighboring carbonyl group. To confirm this conclusion, the galactose auxiliary was detached from the trans-annelated product 173a and substituted by the phenoxycarbonyl group. The thus obtained trans-175 upon treatment with triethylamine actually resulted in an equilibrium with prevailingly cis-annelated cis-175 (middle and left wing of Scheme 71). From this compound leads a described way [134] to enantiomerically pure pumiliotoxin C. The exchange of the N-galactosyl group in 173a for a benzyloxycarbonyl group to give 176, followed by installation of the dithiolane (177) and the concluding treatment with Raney-nickel/H2 finally afforded enantiomerically pure trans-4aepi-pumiliotoxin C as the hydrochloride salt. Its structure was confirmed by crystal structure analysis [133]. The stereoselective protonation of the intermediate enolate arising from the 1,4-addition of the cuprate to 172a to afford the thermodynamically less favored, since more C-H acidic, trans-annelated 173a was explained by a hindered movement of the homocyclic ring of 173a towards the 2-pivaloyloxy group of the auxiliary. If this interpretation is correct, an analogous 1,4 cuprate addition and subsequent enolate protonation at compound 172b (Scheme 70) which contains the enantiomeric N-heterocycle linked to the identical galactose auxiliary should preferably give the cis-annelated analogue of 173a. To prove this conclusion and to synthesize an epimer of alkaloid cis-perhydro-219A the propylmagnesiumcuprate (Normant cuprate) was added to 172b (Scheme 72). The reaction again proceeded with high diastereoselectivity. As expected and predicted, the cis-annelated decahydroquinolinone 179 is now the major diastereomer. Protonation of the enolate β-carbon (C-4a) from the front side (formula 179) prompts a movement backwards, that is away from the 2-pivaloyloxy group of the auxiliary. The

PivO PivO

OPiv O

O

N OPiv

1. Pr2CuMgBr TMSCl THF, –78 oC

PivO PivO

o

2. TBAF, –20 C

OPiv O

N OPiv H

O H

NaHMDS, –78 oC Cl

172b 179, 43%, d.r. > 91 : 9 : 0 : 0

PivO PivO

OPiv O

N OPiv H

OTf H

1. H2/Pd Li2CO3, MeOH 2. 1N HCl

180, 41% , minor regioisomer separated by chromatography

N

N(SO2CF3)2

H

N H H ·HCl 181, 74%

Scheme 72 Thermodynamically controlled enolate protonation – synthesis of cis-perhydro-219A

Carbohydrates as Stereodifferentiating Auxiliaries

51

introduced hydrogen finally is in an equatorial position. Its C-H bond is more or less in the σ-plain of the neighboring carbonyl group. Base-induced enolate formation prevailingly gives the 3,4-enolate which was trapped as the enole triflate 180. The minor regioisomer was separated by chromatography. Hydrogenation of 180 and aidolytic cleavage yielded cis-perhydro 219A [133]. If one keeps in mind that using D-arabinopyranylamine as the auxiliary allows for the stereoselective synthesis of the enantiomers, that the choice of primarily used aldehyde and that the option whether the 1,4 cuprate addition and enolate protonation is carried out on the N-glycosylated or non-glycosylated enone intermediate, then the potential of this concept for the synthesis of enantiomerically pure cis- and trans-annelated hydroquinolines becomes evident.

3.8.2

Diastereotopic Protonation and Deprotonation Directed by the Carbohydrate Auxiliary: Total Synthesis of Indolizidines from Castoreum

Castoreum, an extract of the dried scent glands of beavers, contains aromatic components, such as phenols, aromatic aldehydes, and carboxylic acids. Additionally, several basic compounds were isolated and identified including seven quinolizidines and one minor alkaloid identified as indolizidine [135]. Due to the very small amounts of this indolizidine only a mass spectrum was measured and, therefore, the absolute configuration remained ambiguous [135]. Based on the absolute configuration of the quinolizidines found in Castoreum, two diastereomeric structures (186 and its C8-epimer) can be assumed for the natural product. Stereoselective total syntheses of enantiomerically pure diastereomers with indolizidine structure started from the N-galactosyl dehydropiperidinone 144b (Scheme 58) obtained via domino Mannich-Michael cascade on the N-galactosyl imine 103e of 3-furfural. The 1,4-addition of an organocopper/Lewis acid complex to enone of 144b afforded the all-cis-configured trisubstituted N-galactosyl piperidone 182 [136] (Scheme 73). The reason for the preferred formation of the all-cis configured piperidinone 182 lies in this case in the thermodynamic control of the enolate protonation. Since the two large substituents at C-2 and C-6 prefer equatorial positions, the C-H bond of the protonated enolate of the all-cis compound 182 adopts an equatorial orientation in which it is not acidified by overlap with the π* of the neighboring carbonyl group. Logically, this configuration is thermodynamically preferred and, thus, stereoselectively formed. This conclusion was confirmed by the regioselective deprotonation using lithium diisopropylamide (LDA), which attacks the axial C-H at C-3. Trapping with bis-triflyl-aminopyridine regioselectively yielded the enol triflate 183. Hydrogenation afforded the N-galactosyl 2,5,6-trisubstututed piperidine 184. Conversion of the side-chain function to the alkylchloride 185, subsequent acidolytic detachment from the auxiliary and treatment with base at elevated temperature furnished the all-cis substituted nupharamine indolizidine 186 [136] (Scheme 73). Its mass spectrum was identical with that of the published [135] minor component contained in Castoreum. It

52

H. Kunz and A. Stoye OTIPS

PivO

OPiv O

PivO

O N

CuMgBr TIPSO BF3·OEt2

PivO

THF, –78 oC

O

PivO OPiv O N PivO PivO

1. LDA, THF, –78 oC Cl O

O 144b

N

N(SO2CF3)2

182 82% d.r. = 86 : 14 : 0 : 0

OTIPS

OTIPS

PivO PivO

OPiv O

OTf N

H2, Pd/C MeOH

PivO 183, 65%

184, 70%

O

1. TBAF, THF room temp.

PivO OPiv O N PivO PivO

2. Ph3P/NCS CH2Cl2 –40 oC to room temp.

O

Cl

PivO OPiv O N PivO PivO 185, 69%

1N HCl, MeOH

N

then Na2CO3, EtOH reflux O

186, 60 %

O

Scheme 73 Total synthesis of all-cis indolizidine 186 [136]

should be mentioned that a changed strategy, along which the piperidone of 182 was released from the carbohydrate and the side-chain modification and cyclization performed on the non-glycosylated piperidone led to an indolizidinone with a translocated methyl group at C-8 (¼ C-5 of the piperidinone). Reduction of the carbonyl of this product furnished the cis-trans epimer of 186 which showed a slightly different fragment pattern in the mass spectrum compared to 186 [136]. However, it cannot be excluded that the observed difference is influenced by the fact that the mass spectrum of 186 was recorded from its hydrochloride, while the free base was used in the case of its epimer.

3.8.3

Total Synthesis of Tetraponerines T8 and T7: The Matched/ Mismatched Cases

Middle-sized tropical ants Tetraponera punctulata living in Papua-New Guinea defend themselves against larger sympatric ants by smearing a toxic secretion on the enemies. The paralyzing effect originates from a group of tricyclic alkaloids, the tetraponerines 1–8, which differ in the length of the side-chain (propyl or amyl), in the ring size of the parent heterocycle (pyrrolidine or piperidine) and in the stereochemistry, in particular at C-9 [137]. The major component was identified as T8. Its epimer at C-9, T7, is also an effective factor (Scheme 74).

Carbohydrates as Stereodifferentiating Auxiliaries H

H

1

R

11 9 4 N 5 N H

6

53 H

H

N

N

R

H

T7 R = n-C5H11

T8 R = n-C5H11

Scheme 74 Tetraponerine T8 and T7, toxic components of the tetraponera venome OPiv OPiv O

OPiv OPiv OPiv N

TBDPSO (S)-187

O O

N O

Ph

OPiv N

TBDPSO (R)-187

N

O

Ph

O

Scheme 75 Epimeric N-D-arabinopyranosyl imines for the synthesis of tetraponerines T8 and T7 [138]

Both compounds constitute 2-substituted piperidines with opposite stereogenic centers in the side-chain. According to the strategy based on domino MannichMichael reactions of N-glycosylamines their synthesis was designed starting from the N-arabinopyranosyl imines 187 of two enantiomeric β-amino-octanals [138] (Scheme 75). The use of the D-arabinopyranosyl imines 187 in the Mannich-Michael reactions should ascertain the R-configuration at C-11 of the produced dehydropiperidinones required for both tetraponerines. The configuration of the aminoaldehyde, on the other hand, reflects the opposing stereochemistry at C-9 of the target compounds, (S)-187 in T8, (R)-187 in T7. The comparison of the Mannich-Michael reactions with Danishefky’s diene illustrates the influence of stereogenic center in the aldehyde-derived moiety (Scheme 76). The Mannich-Michael reaction of arabinosyl imine (S)-187 with Danishefsky’s diene proceeded with excellent diastereoselectivity and gave practically only one product (S,S)-188 which could directly be used for further conversions on the way to tetraponerine 8. This process doubtless is the matched case in which the auxiliary and the stereochemistry in the aldehyde-derived portion cooperate. In contrast, the Mannich-Michael reaction of arabinosyl imine (R)-187 with Danishefsky’s diene resulted in the formation of two diastereomers with only low distereoselectivity (ratio of diastereomers 2:1). Fortunately, the desired stereoisomer (R,S)-188 was the major product. It was separated from the minor component (R,R)-188 by flash-chromatography. It was further used for the synthesis of tetraponerine T7. This Mannich-Michael reaction of (R)-187 obviously constituted the mis-matched case in which the auxiliary and the stereogenic center in the aldehyde-derived structure have opposing influence on the diastereofacial differentiation of the initial Mannich reaction of the silyl dienol ether with the Narabinosyl imine 187.

54

H. Kunz and A. Stoye OPiv OPiv

OPiv OPiv O

OPiv N

O N

TBDPSO

Ph

O

N

TBDPSO

O

(S)-187

OPiv N Ph

O O

(R)-187 OSi(CH3)3

1. H3CO

136

ZnCl2, THF, –20 °C 2. 1M HCl OPiv OPiv

OPiv OPiv O

O

OPiv N

O

Z

(R,S)-188

Z OPiv OPiv

N (S,S)-188 59% d.r. = 98 :1 : 1 : 0

O

OPiv N

O

OPiv N

O

N

Cbz (R,R)-188

OTBDPS

OTBDPS

N

58% d.r. [(R,S)-188: (R,R)-188] = 67 : 33 OTBDPS

Scheme 76 Matched and mismatched Mannich-Michael cascades with N-D-arabinopyranosyl imines 187 [138] Cl OPiv OPiv O

Cl Zn

OPiv

C5H11

N N

O Ph

OTBDPS

O

R-187/Zn

Fig. 6 Mismatched influence of coordinating groups of the side-chain

The reason of the mismatching effect in the reaction of (R)-187 lies in the coordinating potential of its β-acylamido-alkyl side-chain (R)-187/Zn towards the promoting zinc chloride (Fig. 6) [138]. Thus, not only the 2-pivaloyloxy group, but also the benzyloxycarbonylamino group hinders the nucleophilic attack at the imine. The further conversion of the almost selectively formed major diastereomer of the matched reaction cascade (Scheme 76, left wing) to the natural alkaloid is briefly illustrated in Scheme 77 [138].

Carbohydrates as Stereodifferentiating Auxiliaries OPiv OPiv O

1. NaBH4EtOH, room temp. OPiv OPiv 66% O O DMAP 2. H3C S Cl

O

OPiv N

55

Z N

OPiv N

O pyridine, room temp. 98%

(S,S)-188

> 72% 189

OTBDPS

O

OPivN

O

H2/ Pd(OH)2/C

THF

190

56% rel. to 189

OPivN H N

TBAF

H N

PrOH

OTBDPS

OPiv OPiv

OPiv OPiv

i

O CH3 O S O 1: NaI, Zn Z N DME, Δ

66%

191

OH

OTBDPS OPiv OPiv O

OPiv

HN +

OH 1M HCl

1. TPAP, NMO, CH2Cl2 H N

mol sieves (4 Å) room temp.

quant.

MeOH

2. 0.01M NaOH 93%

192

OH

13%

H

H

N

N

H 193

Scheme 77 Total synthesis of alkaloid tetraponerine 8 [138]

The reduction of the enone system with sodium borohydride and the mesylation yielded 189. Subsequent elimination and the following hydrogenation removed the functionalities of the piperidine and the benzyloxycarbonyl (Z) group. The product 190 was desilylated using tetrabutylammonium fluoride. The N-glycosidic bond of this product 191 was acidolytically cleaved to afford the arabinose auxiliary and the unprotected piperidine 192. Its selective oxidation with tetrapropyl perruthenate (TPAP) [139] was low yielding but the aldehyde generated gave enantiomerically pure tetraponerine 8 [138]. It is known that the oxidation with TPAP in the presence of primary and secondary amines is problematic. Therefore, in the total synthesis of the epimer tetraponerine T7 from the epimer (R,S)-188, the oxidation (with Dess Martin periodinane) was performed right at the beginning, and the formed aldehyde was protected as a dioxolane. Then the following reaction proceeded with high yield [138]. It should be noticed that analogous syntheses of tetraponerines using the Dgalactopyranosylamine 101 led to the enantiomers. Here the Mannich-Michael cascade proceeded with low diastereoselectivity for ent-T8, but with high selectivity for the synthesis of ent-T7.

56

3.9

H. Kunz and A. Stoye

Are 2,6-trans-Disubstituted Piperidines Stereoselectively Accessible via Glycosylamines?

The 1,4-addition of organocuprates to N-glycosyl dehydropiperidinones stereoselectively afforded 2,6-cis-disubstituted piperidinones (see 3.61, Schemes 60 and 62). The only exception concerned a corresponding 1,4-addition to a dehydropiperidinone carrying two larger substituents in 2,5-position (163c, Scheme 67). The question arose, is there any chance to stereoselectively arrive at 2,6-transdisubstituted piperidines via these Mannich-Michael cascade strategy using Nglycosyl imines? A solution of this problem was deduced from the stereoselective protonation reactions of enolates of N-glycosyl piperidinones (for example in the nuphar alkaloid inolizidine synthesis, Scheme 73). This stereoselectivity is to be traced back to the exo-anomeric effect, i.e. the delocalization of the nitrogen lone pair into the σ*-orbital of the glycan ring C-O bond. This effect stabilizes a conformation in which the N-heterocycle is nearly orthogonally oriented to the glycan. However, this exo-anomeric effect also has the consequence that the nitrogen is stabilized in a pyramidal (chiral) configuration in which the nitrogen lone pair points away from the glycan ring C-O bond. If this stereoelectronic feature also applies to the Mannich bases (see 138, Scheme 55) initially formed in the course of the domino Mannich-Michael reaction affording the N-glycosyl dehydropiperidinones 137 (Fig. 7), then the attack of the electrophilic enone at the glycosylamine nitrogen in the ring-closing nitrogen-analogous Michael addition should occur from the side where the lone-pair is located, i.e. the front side of 138A in Fig. 7. Ring-closure brings R1 in the trans-position to R. If R is positioned equatorially, then R1 is in axial position. If R1 is a methoxy group, as for example in Danishefsky’s diene, a rapid elimination does occur as it was the case in the Mannich-Michael cascades described so far. If R1, however, constitutes an alkyl group, then this group should remain in the 2,6-trans position of the piperidone. A preliminary proof of this hypothesis was conducted by reaction of N-galactosyl imine 103f with 2-trimethylsilyloxy-octa1,3-diene 194 in THF in the presence of zinc chloride [140] (Scheme 78). After work-up with dilute hydrogen chloride, crude product mixture among others contained the free tetra-O-pivaloyl-galactose indicating that ring closure

PivO

OPiv O

PivO PivO

O

R1 H N R

138A

Fig. 7 Stereoelectronic pathway of the ring-closing N-analogue Michael addition during the domino Mannich-Michael reactions of N-glycosyl imines

Carbohydrates as Stereodifferentiating Auxiliaries

PivO OPiv PivO

O PivO

Cl N H

57

194 OSiMe3 ZnCl2 /THF –78 °C, 30 min, then –30 °C

PivO OPiv PivO

O H N PivO O

work-up: aq. 1N HCl

103f Cl

Me3SiOO2SCF3 (TMSOTf)

PivO OPiv O N PivO PivO

O

NEt3, THF, –30 °C

138x yield 46% d.r. > 98 : 2

195, 40%, only one diastereomer Cl

Scheme 78 Stereoselective access to 2,6-trans substituted piperidinones via Mannich-Michael reactions of N-glycosyl imines [140]

and cleavage of the N-glycoside bond already took place. In this case, the Nglycoside bond is not stabilized by elimination of methanol to result in a vinylogous amide bond as present in the dehydropiperidinones 137. Of the product mixture, the primarily formed Mannich base 138x was isolated by flash-chromatography in a moderate yield, but excellent diastereoselectivity. Its cyclization via Michael addition required electrophilic activation at the carbonyl oxygen. As aqueous HCl prompted undesired follow-up processes, trimethylsilyl trifluoromethanesulfonate (TMSOTf) was used to induce the Michael cyclization. During work-up the silyl enol ether was (partly) hydrolyzed and the 2,6-trans disubstituted piperidinone 195 was isolated by flash-chromatography [140] (Scheme 78). The 2,6-trans configuration was unequivocally confirmed by 2D NMR experiments showing that H-6 (at the butyl-substituted C-6) of 195 only showed small coupling constants, i.e. is in an equatorial position.

4 N-Glycosylation in Order to Induce Reactivity and Stereodifferentiation N-Glycosylation of N-heterocycles which contain a C ¼ N double bond or of openchain imines provides a further opportunity to perform stereoselective reactions which are related to the strategy using glycosyl imines. However, in these cases either N-glycosyl iminium compounds with enhanced reactivity are obtained in the first step or these are formed as reactive intermediates. The two versions of glycosylation-induced stereodifferentiation will be illustrated on examples.

58

4.1

H. Kunz and A. Stoye

Glycosylation for Stereodifferentiation of Enantiotopic Sides of Aromatic N-Heterocycles

The potential of concomitant activation and stereodifferentiation through glycosylation was demonstrated at 4-pyridone as a symmetrical compound. After Osilylation, the obtained 4-silyloxy-pyridine was reacted with O-pivaloylated galactopyranosyl fluoride 196a or O-pivaloylated L-arabinopyranosyl fluoride 196b to furnish the N-D-galactosyl (197a) or, respectively, the N-L-arabinosyl 4-pyridone 197b in high yield [141] (Scheme 78). The N-glycosylation allows for the differentiation of the four equivalent sides at C-2 and C-6 of 4-pyridone and slightly activates the parent compound. Nevertheless, this activation was not sufficient for reactions of the N-glycosyl pyridines 197 with propylmagnesium chloride or n-butyllithium. In order to properly activate the N-glycosyl pyridines 197 O-silylation with triisopropylsilyl trifluoromethanesulfonate (TIPSOTf) was carried out. The formed 4-silyloxy-pyridinium salts willingly reacted with solutions of Grignard compounds in THF or diethyl ether. The 2-substituted N-glycosyl dehydropiperidinones 198 were obtained in high yield and with high diastereoselectivity (Scheme 79). The absolute configuration was ascertained for one of the major diastereomers (equivalent to 198a, but R1 ¼ Ph) by X-ray analysis [142]. It is interesting to note that in molecules 198 the dehydropiperidinone part has opposite configuration compared to molecules 137 although D-galactopyranose served as the auxiliary in both synthetic strategies. As a consequence of this relationship, N-galactosyl dehydropiperidinones 198 constituted the mismatched substrates compared to acceptors 137 (see Schemes 60 and 70) in 1,4-addition reactions with organocuprates. The corresponding 2,6-cis disubstituted N-galactosyl piperidinones were obtained with only low diastereoselectivity (2–3:1) [142]. However, once the enolates, formed in Grignard addition to N-galactosyl 4-pyridones, are trapped by alkylation or enolates generated from dehydropiperidinones 198a were alkylated, the 2,3-trans disubstituted

PivO R

OSiMe3

PivO

O

PivO

+ PivO

1,2-dichloroethane 70 °C

N

F

196a R = CH2OPiv 196b R = H

i) iPr3SiOTf ii) R1MgX THF or Et2O

R

TiCl4

O

O N

PivO PivO

197a R = CH2OPiv, almost quant. 197b R = H, 92%

PivO R

O

O N

PivO PivO

198a R1= n-Pr, R = CH2OPiv, 84%, d.r. > 90 : 10 198b R1= Ph, R = H, 96%, d.r. > 99: 1

R1

Scheme 79 Desymmetrization of 4-pyridone by glycosylation [141]

Carbohydrates as Stereodifferentiating Auxiliaries PivO OPiv O PivO N PivO

59 PivO OPiv O PivO N PivO

1. LiHMDS, THF –78 oC

O

2. Me-I, –10 oC

198a

O

199, 69%, single diastereomer

Scheme 80 Stereoselective enolate alkylation of compounds 198a [142]

PivO

OPiv O

PivO PivO

PivO

TiCl4 + F

N

OSiMe3

1,2-dichloroethane 70 °C

196a

2. 2,6-lutidine i PrMgBr, Et2O, 25 oC

N

PivO PivO

O

200, 95%

PivO 1. TMSOTf, CH2Cl2 25 oC

OPiv O

OPiv O N

PivO PivO

O

201, 88%, d.r. > 99 : 1

Scheme 81 Stereoselective addition of nucleophiles to N-galactosyl 2-pyridone 200 [143]

dehydropiperidinones 199 were formed with excellent stereoselectivity (Scheme 80) [142]. The absolute configuration of the product 199 was confirmed by crystal structure analysis [142]. Similar to 4-pyridone, 2-pyridone, after O-silylation, can be converted to the Ngalactopyranosyl derivative 200 (Scheme 81) [143]. Due to carbonyl dipole repulsion between the pyridine and the 2-pivaloyl group, the conformation shown in formula 200 is strongly preferred. After activation of compounds of type 200 with trimethlylsilyl triflate and reaction with Grignard reagents at room temperature the 40 -adducts were furnished with complete regioselectivity and excellent diastereoselectivity as displayed for the example 201. The absolute configuration was confirmed by crystal structure analysis for the adduct analogous to 201 carrying a 40 -n-propyl group [143]. Corresponding reactions with long-chain or branched alkyl, alicyclic, benzyl or aryl Grignard compounds gave quite similar results [142, 143]. N-Galactosylated dihydropyridone-2 201a obtained from 200 and benzylGrignard with almost complete diastereoselectivity was susceptible to an electrophilic activation of the enamido group by hydrogen chloride/tin tetrachloride at low temperature (Scheme 82). The thus generated acyl iminium ion initiated an intramolecular aminoalkylation of the phenyl ring which resulted in the formation of the tricyclic benzazocinone 202 with complete cis-stereoselectivity. The absolute configuration of this 7,8-benzomorphan was confirmed by crystal structure analysis [130]. The use of benzyl Grignard reagents substituted in the aryl ring yielded substituted 7,8-benzomorphan derivatives with high diastereoselectivity [130].

60

H. Kunz and A. Stoye PivO OPiv O N PivO OPiv O

1. TIPSOTf, 2,6-lutidine 200

2. RMgX, 20 oC

HCl, SnCl4 CH2Cl2, –78 oC to –20 oC

201a, 73%, R : S > 99 : 1 PivO

PivO

OPiv

OPiv

PivO O

PivO N

O

O

O

N

O

OPiv

O

202, 85%

Scheme 82 Stereoselective synthesis of 7,8-benzomorphans from N-galactosyl 2-pyridone [130]

PivO OPiv O N PivO OPiv O 201b

1.) LiHMDS 2.) PhCHO/ BF3.OEt2 THF, –78 °C to –30 °C

PivO OPiv O PivO PivO

nPr N

Ph O

OH

R1 PivO OPiv 2 R O O H N PivO O O Li O

203, 81%, d.r. = 99 : 1 : 0 : 0

203X

Scheme 83 Stereoselective synthesis of 3,4-disubstituted 2-piperidinones [145]

It should be mentioned at this point that the release of the heterocycle from the carbohydrate auxiliary in this compounds is only possible after reduction of the amido function. This was demonstrated, for example, for N-galactosyl dihydropyridones-2 substituted in 4-position after their conversion to the corresponding pyridinethions using Lawesson’s reagent [144] and treatment with Raney-nickel [145]. The regioselectively formed 4-substituted dihydropyridines-2 201 can be stereoselectively substituted in 3-position. To this end, the 4-n-propyl derivative 201b was deprotonated using LiHMDS, and the generated enolate was reacted with an aldehyde at low temperature [145] (Scheme 83). The aldol reaction with benzaldehyde supported by BF3-etherate yielded one of the four possible 3,4-disubstituted dehydropiperidinone-2 derivatives 203 with excellent stereoselectivity (Scheme 83). The efficient stereodifferentiation certainly is also caused by the coordinating properties of the aldehyde 203X in this aldol addition [145]. Related alkylation reactions of the intermediate enolate proceeded with lower diastereoselectivity.

Carbohydrates as Stereodifferentiating Auxiliaries

4.2

61

Glycosylation-Induced Stereoselective Reactions of Achiral Imines

N-Glycosylation of achiral aldimines can initiate stereodifferentiating Mannichtype reactions of aldimines with nucleophiles. This strategy was demonstrated in the stereoselective synthesis of β-amino acid esters from aldimines and silyl ketene acetals (Scheme 84) [146]. For example, p-nitrobenzaldimine 204 activated by galactosylation to the Nglycosyliminium salt reacted with silyl ketene acetals 205 to stereoselectively furnish the β-amino acid ester 206. As a rule, the diastereomers can be separated by chromatography or preparative HPLC. Crystal structure analysis of the major diastereomer 206 confirmed the configuration of the products [146]. Open-chain aldimines including N-allyl and N-benzyl compounds usually display moderate distereoselectivity. Cyclic imines, as for example dihydroisoquinoline, yielded the corresponding β-amino acid esters with high stereoselectivity. Detachment of the enantiomerically pure β-amino acid esters from the carbohydrate auxiliary was readily achieved by mild acidolysis. Similar to Mannich reactions N-glycosylation also induces reactivity and stereodifferentiation in Pictet-Spengler cyclization reactions. In this sense, the benzaldimine of dopamine dimethyl ether 207 was subjected to N-galactosylation at low temperature. The thus induced Pictet-Spengler reaction afforded the tetrahydroisoquinoline 208 with excellent diastereoselectivity (Scheme 85) [147].

O2N N

Et

OMe

Et

OSiMe3

Et+

H 204

PivO OPiv O PivO PivO Br

PivO OPiv Et O N PivO OPiv

AgOTf, 2,6-lutidine CH2Cl2, –40 to –20 oC

205

Et

Et COOMe

206 NO2 d.r. = 89 : 11 yield 2'R 53%, 2'S 7 %

Scheme 84 Glycosylation-induced stereoselective Mannich synthesis of β-amino acid esters [146]

OMe N

OMe

PivO OPiv O PivO PivO Br

PivO

OMe

OPiv O

PivO

N

OPiv AgOTf, 2,6-lutidine CH2Cl2, –40 oC

207

208, 74%, d.r. = 99 : 1

Scheme 85 Glycosylation-induced stereoselective Pictet-Spengler cyclization [147]

OMe

62

H. Kunz and A. Stoye PivO OPiv O PivO PivO Br 1.

OMe PivO OPiv OMe O N dil. HCl HN AgOTf, 2,6-lutidine PivO aq. MeOH CH2Cl2, 0 oC PivO aq. NaHCO3 2. OMe MeO CH2 Zn 2 –20 oC 211, 76% 210, 70%, d.r. > 99 : 1

OMe N

OMe 209

OMe OMe

OMe

Scheme 86 Stereoselective syntheses of 1-benzyl-tetrahydroisoquinolines [147] PivO OPiv O PivO PivOBr 1.

MeO

H N

212

OMe

AgOTf, 2,6-lutidine CH2Cl2, 0 oC

1. 1N HCl MeOH

2. Et2Zn

2. Ce(NH4)2(NO3)6 (CAN)

PivO OPiv O N PivO OPiv

Cl-

+ H3N H

214 213, 79%, d.r. > 95 : 5

Scheme 87 Glycosylation-induced stereoselective reaction of aldimines with organometallic compounds [148]

An alternative stereoselective access to the important class of 1-substituted tetrahydroisoquinolines provides the glycosylation-induced reaction of 3,4-dihydroisoquinoline 209 with organozinc compounds (Scheme 86) [147]. The iminium salt obtained from 209 by N-galactosylation reacted with di-(4-methoxybenzyl)zinc to furnish the 1-benzyl-tetrahydroisoquinoline derivative 210 with almost complete stereoselectivity. It is noteworthy that the N-heterocycle generated in this process has opposite configuration compared to the product of the Pictet-Spengler cyclization. Mild acidolytic cleavage of the Nglycosidic bond gave the enantiomerically pure benzyl-tetrahydroisoquinoline 211 [147]. The strategy displayed in Scheme 86 can also be applied to open-chain aldimines. For example, N-(4-methoxyphenyl)benzaldimine 212 was subjected to N-galactosylation. The intermediate N-galactosyl, after E/Z-isomerization, reacted with diethylzinc and yielded the N-galactosyl 1-phenylpropylamine derivative 213 with high diastereoselectivity (Scheme 87) [148]. Similar conversions were achieved with Grignard reagents and organotin and organolithium compounds. The diastereomers 213 were separated by preparative HPLC (yield of major Sdiasteomer 79%). Mild acidolytic detachment from the carbohydrate and oxidative removal of the methoxyphenyl group using cerammonium nitrate gave enantiomerically pure (S)-1-phenylpropylamine 214 [148].

Carbohydrates as Stereodifferentiating Auxiliaries

4.3

63

Properties of the O-Pivaloyl Group in Carbohydrate Auxiliaries

It is characteristic for both, the activating glycosylating reagents and the glycosylamine auxiliaries, that they contain O-pivaloyl protecting groups. Due to their steric demand [149] the pivaloyl esters are not prone to trans-acylation reactions. Thus, the O-pivaloylated glycosylamines are stable. The stability of the O-pivaloyl protection, in particular towards nucleophiles, was a precondition for many of the reactions described in the afore-outlined chapters. This stability was illustrated in a stereoselective synthesis of arylazocan-2-ones [149]. In a vinylogous Mannich reaction, the O-pivaloylated N-galactosyl imine 103g was treated with 1-silyloxy-butadiene 215 (Scheme 88). The stereoselectively obtained secondary glycosylamine 216 was reacted via its aldehyde function with a Wittig reagent to furnish the chain-extended carboxylic ester 217. The basic reaction conditions, that have not been applied in any synthesis with O-pivaloylated glycosylamine auxiliaries described so far, did not affect the structure of the auxiliary [149]. The C ¼ C double bonds in the Wittig-product 217 were selectively hydrogenated in the presence of the aromatic nitro function. The final treatment with methanolate in methanol probably converted the ethyl to the methyl ester, which after treatment with acid causing cleavage of the N-glycosidic bond cyclized to yield eight-membered lactam 218 [149] (Scheme 88). The reliable stability of the O-pivaloyl group even to methanolate is considered important for the practical value of this type of auxiliaries. Thus, the complexing properties and the sterical hindrance by this group can be exploited as has already been demonstrated for glycosylation reactions [150].

PivO OPiv O N PivO PivO H

NO2 OSiMe3 215 AlCl3/THF –50 oC, 35 h

103g

PivO OPiv O CO2Et PivO Ph3P PivO EtOH 217 90%

PivO OPiv O PivO PivO 216 88% d.r. = 99 : 1

H N

CO2Et 1. H2/ Pd-C 2. NaOMe MeOH NO2

H N

H O

NO2

PivO OPiv O + PivO PivO OH

O HN

218 60%

NO2

Scheme 88 Pivaloylated galactosylamine auxiliary is stable during Mannich and Wittig reactions

64

H. Kunz and A. Stoye

5 Carbohydrate Auxiliaries in Conjugate Addition Reactions Michael addition reactions of ester enolates have successfully been steered by carbohydrate auxiliaries [151]. In fact, reactions of carbohydrate ester enolates with electrophiles were investigated early, but reached rather limited stereoselectivity [152]. On the other hand, in alkylation reactions of ester enolates of 1,2-5,6-diisopropylidene-glucofuranose distinct stereodifferentiation was achieved when the reactions were carried out at low temperature and conditions that prevented intermediate elimination of a ketene [153]. While these ketene elimination reactions shone light on the complexing potential of carbohydrates towards cations [6], they interfered with the desired stereoselective conversions of the ester enolates.

5.1

Carbohydrate Auxiliaries in Diastereoselective Michael Addition of Ester Enolates

Promising results were obtained in with ester enolates 219 in which the carbohydrate primarily effected steric rather than complexing properties, as for example in ester enolates of type 219-enol derived from methyl 6-deoxyglucopyranoside [154] (Scheme 89). The addition to methyl crotonoate proceeded with high diastereoselectivity due to the strong stereodifferentiation caused by the marked steric difference of the groups in 3- and 6-position of the carbohydrate. The anti-adduct 220 was formed with high anti/syn selectivity and diastereoselectivity (side differentiation). This stereodifferentiation is also efficient in alkylation reactions of the enolates of type 219-enolate [151], but the observed side-differentiation strongly depends on the involved cation. Excellent stereoselectivity was also achieved in Michael addition reactions in which the acceptor is bound to the carbohydrate. For example, the crotonoate 221 of the 6-deoxyglucofuranose auxiliary reacted in copper-promoted Grignard addition to give the corresponding re-side 1,4-adduct re-222, while the analogous addition of organolithium compounds attacked selectively at the si-side to form 1,4-adducts si-222 also with excellent stereoselectivity [151] (Scheme 90). The authors explain O

Me OO

Si TBS

O

NaHMDS

TBSO OMe

THF –78 oC

219

ONa Me O O TBSO TBSOOMe 219-enolate

O

O OMe MeO –78 to 0 oC

Me O

Me O O TBSO Me TBSO OMe

220 64% anti : syn > 95 : 5 d.r. (anti) > 95 : 5

Scheme 89 Stereoselective Michael addition of carbohydrate-linked ester enolate [154]

Carbohydrates as Stereodifferentiating Auxiliaries

65 Ph O

Ph O PhMgX, CuBr-Me2S o

THF/Me2S, - 78 to 0 C

O O TBSO 221

O TBSO

O

Me-I

TBSOOMe trapping with

TBSOOMe

Ph O o

PhLi, THF, - 78 C

O TBSO

O TBSOOMe

222Si , 92 %, d.r. = 97 : 3

O TBSOOMe

222Re , 85 %, d.r. = 95 : 5

O

O TBSO

Me-I

223syn, 52 % syn : anti = 94 : 6, d.r. > 96 : 4

Ph O O TBSO

O TBSOOMe

223anti, 92 % anti: syn > 95 : 5, d.r. > 96 : 4

Scheme 90 Stereoselective 1,4-addition of organometallic compounds to Michael acceptors linked to carbohydrate auxiliaries [151]

this complementary behavior by the different reacting conformations of the enoate acceptor 221 in the presence of the complexing reagents. In case of the larger organomagnesium cuprate the enoate is forced to adapt an s-trans,syn conformation which is then attacked from its re-side. In reactions with the less demanding organolithium compounds, the enoate 221 preferably reacts in its s-cis,syn conformation. In this case, the re-side of the crotonoate is shielded, and hence the nucleophile prevailingly attacks from the si-side [151]. The authors expanded the scope of the carbohydrate auxiliary by trapping the enolates, formed after 1,4-addition to the crotonoate, with methyl iodide (Scheme 90). In these one-pot procedures they obtained with excellent stereoselectivity synconfigured 2,3-syn-disubstituted carboxylic esters syn-223. In contrast, after 1,4-addition of organolithium compounds the 2,3-anti-disubstituted carboxylic esters anti-223 were isolated with excellent yield and stereochemical purity [151] illustrating the immense stereodiscriminating potential of carbohydrates in conjugate addition reactions.

5.2

Bicyclic Carbohydrate Oxazolidinones as the Auxiliaries in Conjugate Addition Reactions of Organoaluminum Compounds

Experiments into stereoselective Diels-Alder reactions on α,β-unsaturated N-acyl derivatives coupled to a xylofuanose-derived oxazinone catalyzed by diethylaluminum chloride unexpectedly yielded the stereoselectively formed adduct of an ethyl group to the dienophile as the major product [155]. Investigations of this unprecedented reaction in greater detail [156] showed that, in particular in reactions of diorganylaluminum chlorides with N-enoyl acceptors linked to the Evans auxiliary [157], that there is a fundamental difference between dimethylaluminum chloride and higher dialkylaluminum chlorides in these conversions [156]. While the 1,4-addition of higher dialkylaluminum (and diarylaluminum)

66

H. Kunz and A. Stoye

chlorides proceeded at low temperature under polar conditions, the reactions of dimethylaluminum chloride required activation by UV light or radical initiation to proceed [156, 158, 159]. High stereoselectivity in these 1,4-addition reactions of dialkylaluminum chlorides was achieved in particular with bicyclic oxazolidinones derived from glycosamines. For example, reaction of di-npropylaluminum chloride with the N-cinnamoyl derivative 224 of the Opivaloylated oxazolidinone derived from galactosamine proceeded at 40
C in toluene within 5 h to give the β-branched adduct 225a with excellent diastereoselectivity (Scheme 91) [159]. Diethylaluminum chloride reacted similarly, diisobutylaluminum chloride much more slowly. But its 1,4-addition was markedly accelerated by dimethylaluminum chloride. Characteristically, dimethylaluminum chloride itself did not react with 224 under identical conditions. It required irradiation for 5 h, then its 1,4-addition run to completion within additional 25 h in the dark [158]. The 1,4-addition to the carbohydrate-linked acceptors needs at least two equivalents of the diorganylaluminum chlorides for complete conversion. It was concluded from this observation that two equivalents of the reagent are involved in the reactive intermediate during this process [159] (Scheme 92). The first equivalent of the diethylaluminum chloride coordinates the more nucleophilic urethane carbonyl (226), the second to the N-acyl carbonyl. In addition, a chloride bridge from the first

PivO OPiv O PivO N O Ph O 224

O

PivO OPiv O PivO

(n-Pr)2AlCl (4 eq.) toluene, –40 oC, 5 h

225a, 74%, d.r. = 97.5 : 2.5

N O Ph O

O

PivO OPiv O PivO

Me2AlCl (4 eq.) toluene/n-hexane –40 oC, 5 h hν(254 nm), then 25 h in the dark

225b, 82%, d.r. = 98 : 2

N O Ph O

O

Scheme 91 Stereoselective 1,4-addition of dialkylalumium chlorides to N-α,β-unsaturated acyl derivatives of bicyclic oxazolidinone derived from galactosamine [158, 159] PivO

OPiv O

H

PivO Ph

N

H

H

O

O O Et Al Et Al Cl Et Cl Et

H

H Al Cl Et

226a

226

Scheme 92 Mechanistic rationalization of the polar 1,4-addition of diorganyl-aluminum chlorides to α,β-unsaturated N-acyl oxazolidinones 224 derived from glycosamines [158, 159]

Carbohydrates as Stereodifferentiating Auxiliaries

67

to this second diethylaluminum chloride enhances the nucleophilicity of the latter. Thus, the ethyl group is transferred from the front (exo) side to stereoselectively give the 1,4-adduct of type 225a. In agreement with this explanation, diorganylaluminum bromides are much less reactive in these processes than the corresponding chlorides. The nucleophilic transfer of the ethyl and higher alkyl groups is decisively supported by the delocalization of the σ-electrons of a β-C-H bond into the empty p-orbital of aluminum (on the way to ethylene). Dimethylaluminum chloride does not have such a β-C-H bond. Therefore, its 1,4-addition is much less favored and needs promotion by irradiation or radical initiation. The different behavior of ethyl- and methylaluminum in Ziegler-Natta polymerizations can be traced back to the same properties. In agreement with the given explanation, the primarily formed aluminum enolate formed after ethyl or n-propyl transfer under polar conditions can be trapped with Davis oxirane [160] as a polar oxidizing reagent to give a β-branched α-hydroxy acid derivative [156], while the intermediate formed during the photochemically promoted methyl transfer from dimethylaluminum chloride favorably was trapped by molecular oxygen to afford the β-methyl-branched α-hydroxyacyl compounds [156]. The trapping of the polar aluminum enolate intermediates offers a further extension of the preparative utility of these 1,4-addition reactions of diorganylaluminum compounds to acceptors of type 224. In this second step of the reaction sequence, the bicyclic oxazolidinone which in the first step induced a highly selective exo-attack to form the enolate (see 226, Scheme 92) causes a mismatched interaction between the auxiliary and the newly built stereogenic center in the β-position. Therefore, not the bicyclic oxazolidinone 224 derived from galactosamine, but the analogue 227 obtained from glucosamine exhibited the best stereodifferentiation in these difunctionalizations of the C ¼ C double bond [27] (Scheme 93). After stereoselective 1,4-addition of the diethylaluminum chloride (dr 9:1) the attack of N-bromosuccinimide (NBS) also preferentially occurred from the front (exo) side to yield the (2R,3S)-stereoisomer of the α-bromoacyl-derivative 228 with high diastereoselectivity [27]. The release of the stereoselectively formed carboxylic acid derivatives from the carbohydrate oxazolidinones was achieved using lithium hydroxide solutions in the presence of hydrogen peroxide as the α-nucleophile.

Ph

PivO PivO O PivO N O O 227

O

1. Et2AlCl, –40 oC toluene 2. NBS, –40 oC to rt Ph

PivO PivO O PivO Br N O Et

O

O

228, 51%, d.r.=90 : 5 : 5

Scheme 93 Sequence of 1,4-addition of dialkylaluminum chloride and halogenation of the enolate on α,β-unsaturated N-acyl oxazolidinones 227 derived from glucosamines [27]

68

H. Kunz and A. Stoye

The 1,4-addition reactions can also be carried out with mixed methyl-tertbutylaluminum chlorides to selectively transfer the tert-butyl group [161]. It should be noted that the performance of these reactions on oxazolidinone auxiliaries derived from D-arabinopyranose provides the analogous stereoselective access to the series of opposite enantiomers of β-branched carboxylic acid derivatives [162].

6 Conclusion and Outlook The types of reactions that are stereoselectively directed by carbohydrate auxiliaries described in this chapter give evidence that a broad spectrum of interesting chiral compounds can be obtained in enantiomerically pure form with the aid of these tools readily accessible from renewable resources. In addition, reports from other isolated investigations, for example on the dynamic kinetic resolution during SN2-type reactions on α-halocarboxylic esters of carbohydrates [163] or samarium diiodide promoted additions of carbonyl compounds to methacrylates of carbohydrates [164], have shown that there is still room for further explorations of carbohydrates as the stereodifferentiating auxiliaries in the synthesis of enantiomerically pure products. Recent developments have aimed at the application of carbohydrates as chiral ligands or enantioselective organocatalysts in stereoselective synthesis and were summarized in a number of reviews [13, 16, 165]. It is remarkable that structures which are important in carbohydrate auxiliaries also play a major role in enantioselective organocatalysts. This applies in particular to the O-acylated glycosylamines (see Sects. 3.1–3.6). They were successfully used in form of urea derivatives [166] or imines (as long as equimolar free hydrogen cyanide is present [167]) for the enantioselective catalysis of Strecker reactions, or as thiourea derivatives to catalyze conjugate addition reactions of acetylacetone [168] or cyclohexanone to nitroolefines [169] as well as for the enantioselective catalysis of MoritaBaylis-Hillman reactions [170]. Enantioselective catalyses certainly will attract more attention from the scientific community in future investigations. However, the enantiomeric excess in many of these processes is below 90% and therefore, optically pure enantiomers are only available by subsequent separation processes. In these terms, the asymmetric synthesis of enantiomerically pure compounds via auxiliary-directed stereoselective reactions as described in this chapter offers the advantage that enantiomerically pure compounds often are accessible by simple purification techniques such as re-crystallization (see Sects. 3.1 and 3.5). It should be noted that molecules covalently linked to O-pivaloyl protected carbohydrate auxiliaries are prone to readily crystallize. Therefore, the use of chiral auxiliaries is frequently the method of choice for the synthesis of preparative amounts of enantiomerically pure compounds. Carbohydrate auxiliaries have additional benefits: They show conformational preferences, e.g. chair versus boat, are characterized through organizing stereoelectronic effects, i.e. the anomeric and the exo-anomeric effects, and offer a great variety for

Carbohydrates as Stereodifferentiating Auxiliaries

69

arranging shielding groups relative to the reacting function. They are available from renewable resources, are cheap, and can be recovered in many cases in high yield.

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85. Kunz H, Sager W, Pfrengle W, Schanzenbach D (1988) Tetrahedron Lett 29:4397 86. Kunz H, Pfrengle W (1988) Tetrahedron 44:5487 87. Ugi I (1997) J Prakt Chem 39:499 88. Oertel K, Zech G, Kunz H (2000) Angew Chem Int Ed 39:1431 89. Kunz H, Pfrengle W, Sager W (1989) Tetrahedron Lett 30:4109 90. Mathieu T (2013) Dissertation, Universita¨t Mainz, Germany, pp 65–70 91. Laschat S, Kunz H (1992) Synthesis 90 92. Kunz H, Schanzenbach D (1989) Angew Chem Int Ed 28:1068 93. Kunz H, Burgard A, Schanzenbach D (1997) Angew Chem Int Ed 36:386 94. Mathew S, Bea H, Nadarajan Sn P, Chung T, Yun H (2015) J Biotechnol 196–197:1 95. Alvaro G, Savola D (2002) Synlett 651 96. Laschat S, Kunz H (1990) Synlett 51 97. Laschat S, Kunz H (1991) J Org Chem 56:5883 98. Laschat S, Kunz H (1990) Synlett 629 99. Deloisy S, Kunz H (1998) Tetrahedron Lett 39:791 100. Deloisy S, Tietgen H, Kunz H (2000) Coll Czech Chem Commun 65:816 101. Loh T-P, Zhou J-R, Li X-R, Sim K-Y (1999) Tetrahedron Lett 40:7847 102. Zhao Y, Wang G, Zhou S, Li Z, Meng X (2014) Org Biomol Chem 12:3362 103. Li B-Y, Li Z-J, Meng X-B (2010) Carbohydr Res 345:1708 104. Wang G, Li B-Y, Lou Q, Li Z, Meng X (2013) Adv Synth Catal 355:303 105. Pleuss N, Zech G, Furman B, Kunz H (2006) In: Levy DE, Fügedi P (eds) The organic chemistry of sugars. CRC Taylor & Francis, Boca Raton, USA, pp 427 106. Kunz H, Strassnig I, Mathieu T, Bull JA (2012) In: Carrera E, Yamamoto H (eds) Comprehensive chirality, vol 3; Boeckman JR Jr (ed) Synthetic methods II chiral auxiliaries, e-Book, Amsterdam, p 359 107. Danishefsky SJ (1974) J Am Chem Soc 96:7807 108. Weymann M, Pfrengle W, Schollmeyer D, Kunz H (1997) Synthesis 1151 109. Tallent WH, Hornung HC (1956) J Am Chem Soc 78:4467; see Beilstein S EIII/IV 20:1611 110. Weymann M (1996) Dissertation, Universita¨t Mainz, Germany, p 15 111. Yue C, Ryer J, Husson H-P (1990) J Org Chem 55:1140 112. Enders D, Tiebes J (1993) Liebigs Ann Chem 173 113. Kranke B, Hebrault D, Schultz-Kukula M, Kunz H (2004) Synlett 672 114. Kranke B, Kunz H (2006) Can J Chem 84:625 115. Diels O, Pflaumer K (1916) Chem Ber 51:158 116. Sugasawa S, Yamada SI, Harahashi M (1951) J Pharm Soc Jpn 71:1345 117. Muruyama K, Yamamoto Y (1977) J Am Chem Soc 99:8068 118. Aronstam RS, Daly SW, Spande TF, Narayanan TK, Albuquerque EX (1986) Neurochem Res 11:1227 119. Appel R (1975) Angew Chem Int Ed 14:801 120. Weymann M, Kunz H (2008) Z Naturforsch 63b:425 121. Zech G, Kunz H (2003) Angew Chem Int Ed 42:787 122. Zech G, Kunz H (2004) Chem A Eur J 10:4136 123. Lipshutz BH, Ellsworth EL, Siahan TJ (1988) J Am Chem Soc 110:4834 124. Knauer S, Weymann M, Kunz H (2009) Z Naturforsch 64b:1639 125. Kranke B, Kunz H (2007) Org Biomol Chem 5:349 126. Stille JK (1986) Angew Chem Int Ed 25:508 127. Miyaura N, Suzuki A (1995) Chem Rev 95:2457 128. Abarbri M, Knochel P (1999) Synlett 1577 and work cited therein 129. Knauer S, Kunz H (2005) Tetrahedron Asymmetry 16:529 130. Klegraf E, Knauer S, Kunz H (2006) Angew Chem Int Ed 45:2623 131. Tokuyama T, Nishimori N, Karle H, Edwards NW, Daly JW (1987) Tetrahedron 43:643 132. Weymann M, Schultz-Kukula M, Kunz H (1998) Tetrahedron Lett 39:7835 133. Weymann M, Schultz-Kukula M, Knauer S, Kunz H (2002) Monatsh Chem 133:571

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134. Comins DL, Deghani (1993) J Chem Soc Chem Commun 1839 135. Maurer B, Ohloff G (1976) Helv Chim Acta 59:1169 136. Stoye A, Quandt G, Brunnh€ofer B, Kapatsina E, Baron J, Fischer A, Weymann M, Kunz H (2009) Angew Chem Int Ed 48:2228 137. Braekman JC, Daloze D, Pasteels JM, Vanhecke P, Declercq JP, Sinnwell V, Francke W (1987) Z Naturforsch 42C:627 138. Strassnig I, K€ orber K, Hünger U, Kunz H (2015) Synthesis 2299 139. Ley SV, Norman J, Griffith WP, Marsden SP (1994) Synthesis 639 140. Stoll J (2011) Diplomarbeit (diploma work) Universita¨t Mainz 141. Follmann M, Kunz H (1998) Synlett 989 142. Klegraf E, Follmann M, Schollmeyer D, Kunz H (2004) Eur J Org Chem 3346 143. Follmann M, R€ osch A, Klegraf E, Kunz H (2001) Synlett 1569 144. Scheibye S, Pederson BS, Lawesson SO (1978) Bull Soc Chim Belg 87:229 145. Klegraf E, Kunz H (2012) Z Naturfosch 67b:389 146. Allef P, Kunz H (2000) Tetrahedron Asymmestry 11:375 147. Allef P, Kunz H (2007) Heterocycles 74:421 148. Allef P, Kunz H (2009) Z Naturforsch 64b:646 149. Cui B, Hou G, Cai Y, Miao Z (2013) Carbohydr Res 374:1 150. Kunz H, Harreus A (1982) Liebigs Ann Chem 41 151. Totani K, Takao K-I, Tadano K-I (2004) Synlett 2066 152. Heathcock CH, White CT, Morrison JJ, Derveer V (1981) J Org Chem 46:1296 153. Kunz H, Mohr J (1988) J Chem Soc Chem Commun 1315 154. Asano S, Tamai T, Totano K, Takao K-I, Tadano K-I (2003) Synlett 2252 155. Kunz H, Pees K-J (1989) J Chem Soc Perkin Trans I 1168 156. Rück K, Kunz H (1991) Angew Chem Int Ed 30:694 157. Evans DA, Britton TC, Dorow RL, Dellaria JF (1986) J Am Chem Soc 108:6395 158. Rück K, Kunz H (1992) Synlett 343 159. Rück K, Kunz H (1993) Synthesis 1018 160. Davis FA, Sheppard AC (1989) Tetrahedron 45:5729 161. Maas S, Kunz H (2000) J Prakt Chem 342:396 162. Elzner S, Maas S, Engel S, Kunz H (2004) Synthesis 2153 163. Kim HJ, Shin E-K, Chang J-Y, Kim Y, Park YS (2005) Tetrahedron Lett 46:4115 164. Huang L-L, Xu M-H, Liu G-Q (2005) J Org Chem 70:529 ¨ züduru G, Grugel H, Albrecht F, Telligmann S, Boysen MMK (2011) 165. Lehnert T, O Synthesis 2685 166. Becker C, Hoben C, Kunz H (2007) Adv Synth Catal 349:417 167. Negru M, Schollmeyer D, Kunz H (2007) Angew Chem Int Ed 46:9339 168. Pu X-W, Peng F-Z, Zhang H-B, Shao Z-H (2010) Tetrahedron 66:3655 169. Lu A, Gao P, Wu Y, Wang Y, Zhou Z, Tang C (2009) Org Biomol Chem 7:3141 170. Gergelitsova I, Tauchman J, Cisarove I, Vesely J (2015) Synlett 2690

Top Heterocycl Chem (2020) 55: 73–112 DOI: 10.1007/7081_2017_6 # Springer International Publishing AG 2018 Published online: 11 January 2018

Boron-Containing Chiral Auxiliaries Marvin Mantel, Marcus Brauns, and J€org Pietruszka

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 2 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75 3 Diastereoselective Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 3.1 Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 3.2 Matteson Homologations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 3.3 SN2’ Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 3.4 Carbonyl Allylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 3.5 [3,3]-Sigmatropic Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93 3.6 Remote-Controlled Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 4 Applications in Asymmetric Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

Abstract Organoboron chemistry has proven its general versatility over the last century. In this chapter, the focus is on boron-containing auxiliaries. First, a short overview of commonly used cyclic compounds is provided, followed by their diastereoselective synthesis in the main part. In six subsections, from cycloadditions to remote-controlled reactions are discussed in detail. Finally, arguably the most prominent transformation of one group of synthesized reagents – the allyl addition – is used to exemplify the broad applicability in asymmetric synthesis and in natural product synthesis in particular.

M. Mantel and M. Brauns Institut für Bioorganische Chemie, Heinrich-Heine-Universita¨t Düsseldorf im Forschungszentrum Jülich Stetternicher Forst, 52426 Jülich, Germany J. Pietruszka (*) Institut für Bioorganische Chemie, Heinrich-Heine-Universita¨t Düsseldorf im Forschungszentrum Jülich Stetternicher Forst, 52426 Jülich, Germany Institute for Bio- and Geosciences 1 (IBG-1): Biotechnology, Forschungszentrum Jülich, 52428 Jülich, Germany e-mail: [email protected]

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Keywords Allyl addition • Boron • Diastereoselective synthesis • Natural products

1 Introduction Among the chemical elements utilized in organic chemistry, boron has proven to be the dexterous answer to a large number of challenging synthetic problems. Thus, last decades’ Nobel Prizes for boron-based works in 1976, 1979, and 2010 underline with undoubtable convincement the early recognized importance of substances employing the versatile element [1–4]. Not only a broad variety of reagents but also the excellent synthetic properties, embodied, for example, by high stereoselectivities in allylic addition reactions, have made boron-bearing compounds an indispensable part of modern organic synthesis [5–9]. In this article it is intended to show how boron auxiliary reagents have been utilized during the last decades addressing several synthetic problems by a more than sufficient reactivity paired with excellent stereoselectivity. However, over the bygone half-century relentlessly conducted research on boron chemistry has spawn a sheer endless variety of reagents and applications, making it impossible to give a complete treatise of the topic within the following pages. Thus, the compounds dealt with in this article were needed to be edged suiting the book series’ title. All reagents mentioned are united by a heterocyclic character with a boron atom and chirality located within the ring system. Also, the elaborated moieties are categorized as auxiliaries, which is why further chemistry takes place on another residue attached to the boron exclusively. An overview of chiral auxiliaries used on this occasion is depicted. Anyway, a complete list of all boron species fitting the criteria mentioned would still not only be too big but also unrewarding in respect of clarity and comprehensibility. Therefore, the presented examples were ultimately chosen by relevance and obviously from personal perspective. According to the given parameters, boron species for catalytic applications as well as methods using (even stoichiometric amounts of) chiral modifiers and/or chiral boron-based Lewis acids have been excluded. To structure the chosen scope of compounds, sorting has been conducted by assigning the different chiral auxiliaries to the reaction type they have been utilized for. Again, reactions have been divided into three types: (I) Initial generation of a boron species bearing a chiral auxiliary (II) A diastereoselective step resulting in, if stability provides it, theoretically separable stereoisomers (III) Application in target molecule synthesis For the initial step (I), a reagent bearing a cyclic boron auxiliary and a non-auxiliary side chain attached to the boron needs to be formed. In many cases

Boron-Containing Chiral Auxiliaries

XR + B Y XR R2

R2

75 ∗

R2 Y R2

XR B XR

HZ ZH -2 HXR

R2 Y R2

B Z

Z ∗

Scheme 1 Synthesis of boron species bearing cyclic, chiral auxiliaries via a hydroborationcondensation sequence (double-bond configuration not specified in scheme)

this is realized by hydroboration of unsaturated aliphatic systems followed by condensation reactions with a chiral compound (Scheme 1). Occasionally, the procedure of generating the desired species differs from this general route, which will be indicated briefly within the respective subsection. Intrinsically this step does usually not provide any asymmetric synthesis and will therefore not be dealt in detail. Subsequently advantage of the chiral information just added is taken. In detail, a diastereoselective step (II) at the non-auxiliary side chain is affiliated, forming, if general stability provides it, in principle separable diastereomers. As a variety of reactions have been employed on this behalf within the history of boron chemistry, those regularly applied will be introduced, only. For every reaction type, a general overview will be followed by one of the most fruitful outcomes of the respective technique. To underline the practical relevance, applications in total synthesis will be attached at last. Finally, numerous boron reagents synthesized under (II) are meant to enable another stereoselective reaction before cleaving off the boron atom. Providing excellent synthetic properties, the allylic addition reaction is one of the most popular applications among those target molecule syntheses [6, 7]. Due to its excellent vividness for high stereoselectivities possible when using boron reagents in asymmetric synthesis, it was conclusively chosen to illustrate (III) representatively.

2 Overview Within the following (Table 1), a general compilation of the most prominent boron auxiliaries shall be given. Assorted to the different compounds, reaction types they have been employed for are emphasized as well as relevant literature describing the aforementioned use. Thus, it is intended to provide an easy-to-apply reference work, which connects structure, reactivity, and literature comprehensively. To complete the information given here, later chapters may be consulted in order to get deeper insight into the issues introduced.

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Table 1 Classes of heterocycles used as chiral boron auxiliaries and compound structures assigned to reaction types and corresponding literature

R2

R2

B R1 Boracycles

O

O B R1 1,3,2-Dioxaboracycles

Auxiliary I

B R II

TMS

R2 N 3 B R R1 Oxazaborolidine O

R2 R3N B N R3 R1 Diazaborolidine

Reaction • Allyl addition to aldehydes • Aldol reaction

References [10–14]

• Allyl addition to aldehydes

[15]

• Asymmetric aldol reaction

[16, 17]

• Allyl addition to aldehydes and ketones • Hydroboration

[18–24]

• Reduction • Allyl addition

[25–34]

• Allyl addition to aldehydes • Matteson homologation

[34–53]

• Matteson homologation

[54]

B R III

Ph B R

IV

R R B

V

∗

OMe O B R MeO O

VI

O B R O VII

O O O

O B R O

O (continued)

Boron-Containing Chiral Auxiliaries

77

Table 1 (continued) Auxiliary VIII

O B R

Reaction • Matteson homologation • Allyl addition to aldehydes • Reduction

References [32, 34, 55– 58]

• Cyclopropanation

[34, 59, 60]

• Cyclopropanation

[61]

• Allyl addition to aldehydes • Diels-Alder reaction • Cyclopropanation

[34, 62–75]

• Allyl addition to aldehydes • Carbonyl allylation • Cyclopropanation, epoxidation • Diels-Alder • [3,3]-Sigmatropic rearrangement • Hydroboration • Nucleophilic additions • Allyl addition to aldehydes, ketones • SN2’ reaction

[34, 59–61, 76–81]

• Allyl addition to aldehydes

[85, 86]

• Cyclopropanation

[87–92]

O IX

Ph

O B R O

Ph Ph X

NMe2 O B R O NMe2

XI

O R R

O

O

O

O

B R O

XII

Ph Ph O O B R O O Ph Ph

XIII

Ar Ar

R

O B

O O

B O

R

[82–84]

Ar Ar XIV

R O N N R O

XV

O B R O

N O

O

O

O

B R

N (continued)

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M. Mantel et al.

Table 1 (continued) Auxiliary XVI

Ph Ph O O B R1 O O Ph Ph

R2 R2

XVII

Reaction • 1,3-Dipolar cycloaddition • Cyclopropanation

References [34, 61, 93]

• Allyl addition to aldehydes

[34, 94– 100]

• Allyl addition to imines, aldehydes

[101–105]

• Matteson homologation • Preparation of allylic boronates • Diels-Alder reaction, 1,3-dipolar cycloaddition • Nucleophilic addition • Matteson homologation • Cyclopropanation

[34, 76, 93, 106–113]

• Hydroboration

[116]

• Allyl addition to aldehydes, ketones

[117]

O B R O Ph XVIII

O B R O Ph

XIX

O B R O

XX

XXI

O B R O ∗

O B R O

XXII

CF3

[34, 59, 114, 115]

O B R O CF3 XXIII

R2 a N O B 1O R

• 1,3-Dipolar cycloaddition, Diels-Alder reaction [118–120]

a

R3

R3

a = (CH2)n XXIV

O

Ts N B R O

• Enantioselective aldol reaction of silyl ketene acetals with aldehydes

[121]

(continued)

Boron-Containing Chiral Auxiliaries

79

Table 1 (continued) Auxiliary XXV

Ph

O

Reaction • Hydroboration

References [122]

• Allyl addtion to imines

[123]

B R N XXVI

O O

B R

N Ts

O XXVII

• Allyl addition [124–130] • Asymmetric sequential allylic transfer reaction

SO2R N B R N SO2R

Ph Ph

3 Diastereoselective Synthesis As mentioned afore, the utilization of boron-containing auxiliaries may be categorized by different reaction types proven to be suitable for the successful employment in asymmetric synthesis. Within the category “diastereoselecive synthesis” outlined in the very introduction of this treatise, various different name reactions can be affiliated, on which light is shed within this chapter. Again, a quick overview shall be given first, shortly describing the various reactions possible. Later on, elucidations that are more detailed can be found, whereas the overview refers to the details by section numbers given in each bullet point. • Cycloaddition (see Sect. 3.1) Various cycloadditions have been reported, in which boron-containing auxiliaries found employment on behalf of asymmetric synthesis. Not only stereoselective epoxidations and cyclopropanations have been investigated extensively, but also more classical Diels-Alder-type reactions as well as [3 + 2] cycloadditions were subjected to comprehensive research. • Epoxidation, Cyclopropanation (Sect. 3.1.1) R3 *

O

R3

O B

*

R1 R2

O

O X B *

R1

R2

X = CH2, O

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M. Mantel et al.

• [4 + 2]-Cycloaddition (Sect. 3.1.2) R *

O

O B

Dienophile

R *

R *

O

O B

O

O B

DA-product

Diene

• [3 + 2]-Cycloaddition (Sect. 3.1.3) Ar R1 R2

N R2 1 B O O R

N

R3

O

*

Ph

Ph

O N

R3

• Matteson Homologation (see Sect. 3.2) During the 1980s Matteson and co-workers introduced one of the earliest high-selectivity methodologies in organic boron chemistry. Providing impressive yields and stereoselectivities, the method is rightfully adjunct to its inventor’s name ever since. Matteson homologations have found their appliance in various total syntheses on behalf of the construction of α-chiral boranes and boronates, enabling ultimately the efficient construction of multi-stereogenic center moieties. R2

X X B R1 *

CH2Cl2 n-BuLi

R2

X * X B

*

R1

Cl

X = O, C

• SN2’ Reaction (see Sect. 3.3) Among the construction of α-stereogenic boronates, enantioselective catalysis has proven to be a valuable tool for the selective construction of the desired moieties independently from the stereogenic information given by the chiral protecting group. Shown on advanced boron-containing systems, copper catalysis offers highly selective access to excellent yields of allyl boronates suitable for allylic addition reactions without any stereomeric purification. R2

O * B O

R1MgBr Cl

[Cu]

R2 *

O

O B

*

R1

• Carbonyl Allylation (see Sect. 3.4) Alcoholic derivatives of allylic boronates offer a synthetically valuable supplement in the field of starting materials for allylic addition reactions.

Boron-Containing Chiral Auxiliaries

81

Starting from hydroboration products, carbonyl allylation reactions grant convenient access to the compounds by a method employing either tin or boron as a second metal component. R2

R2

[H+]

O * B O

*

O

OR1

O B

*

HO

*

R3

R1 = H, TBS

• [3,3]-Sigmatropic Rearrangement (see Sect. 3.5) Famously known in “classical” carbon chemistry, [3,3]-sigmatropic rearrangements proved to be suitable for the construction of α-chiral boronates as well. The method conveniently offers allylic species simultaneously bearing ester and amide functionalities in one step from hydroboration products.

R2

R2

O * B O

OH

O * B O

R1

O *

R1 = OEt, NMe2

• Remote-Controlled Reactions (see Sect. 3.6) On behalf of remotely controlled reduction and aldol reactions, boronates could be shown capable of controlling stereochemistry significantly over up to 1,7-interactions. Not least, high selectivities and yields underline the potential of the method established. R1

R1 R2

O

*

B

reduction

O

R2

Y

*

B

R3

R4

R3

O

O YH *

R4

Y = O, NR5 R1

R1 R2

O

*

B

O H

R3 O

Me3SiO

OEt

R2 R3

O

*

B

O

* CO2Et OSiMe3

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M. Mantel et al.

3.1

Cycloadditions

3.1.1

Epoxidation, Cyclopropanation

It was not until last centuries’ 1990s when first progresses on the field of asymmetric cyclopropanation using chiral boronate-auxiliaries were made. The transfer of stereogenic information from an auxiliary to the newly formed moiety was first described by Imai et al. in 1990 [87]. Using fairly accessible, optically pure tartaric esters and amides, vinylboronic species such as 1 could be formed as intermediate. Subsequent application of Simmons-Smith conditions to the alkene system afforded the corresponding boron-cyclopropanes 2 in moderate yields with good enantiomeric excesses independently from the residue R attached to the double bond (Scheme 2). Various transformations of the cyclopropanated boron species were feasible1 of which well-known removal of the boron auxiliary by oxidative workup allowed access to the corresponding cyclopropanols. Analogous to cyclopropanations, epoxidations were intended as a reaction performable using vinylic boron species. Factual, few have been reported on this field so far; exemplary work on non-stereoselective variants was provided by the beginning of the millennium [131]. However, it almost took a decade until asymmetric versions could be established. In 2010 the group of Pietruszka published the first known synthesis of enantiomerically pure oxiranylborane compounds by using diol XII as an auxiliary [79]. The desired, air-stable epoxides could be formed using different agents such as meta-chloroperoxybenzoic acid (m-CPBA), VO(acac)2/ tert-butyl hydroperoxide (TBHP), or Murray’s reagent (dimethyldioxirane, DMDO) of which the last one provided yields >95% (Scheme 3). Further methods based on the same principle but using auxiliaries with the chirality located at a residue attached to the cyclic system have been established as well [132, 133]. While Imai’s method could not be significantly improved with respect to selectivity, yields notably left space for an increase. Thus, Pietruszka et al. provided a

R

B O

O

O NMe2

O

NMe2

1 R = n-butyl, benzyl, phenyl

R

CH2I2, Zn-Cu

B O

O

O NMe2

Et2O, reflux, 24 h O

NMe2

2 yield: 46-67% ee 89-94%a

Scheme 2 Asymmetric cyclopropanation by Imai et al. [87]. aDetermined after cleavage of the boron auxiliary with H2O2/KHCO3

1

For example, Matteson homologation by treatment with CH2ClI/n-butyllithium (n-BuLi).

Boron-Containing Chiral Auxiliaries

R

B O

Ph

O

83

Ph

Methoda

R

O O

Ph

Ph

O

Ph

Ph

Ph

O

B O O

O Ph

4

3

R = n-pentyl, phenyl, CH2OH

yield: 35->95% dr 53:47-37:63%b

Scheme 3 Asymmetric epoxidation of vinylboronic esters 3 by Pietruszka et al. [79]. aMethod A: m-CPBA, CH2Cl2, 0 C, 3 h. Method B: DMDO, rt., 4–8 h. Method C: VO(acac)2, TBHP, CH2Cl2, 40 C, 4 h. bDiastereomers can be obtained as analytically pure compounds

R

B O

Ph

O

Ph

O

Ph

Pd(OAc)2 (5mol%)b, CH2N2 (2ml/h)

O Ph

3

R = n-pentyl, n-butyl, t-butyl, phenyl, TPSaO(CH2)3

Et2O, 0 °C

R

B O

Ph

O

Ph

O

Ph

O Ph

5

yield: 89-99% dr 86:14-95:5c

Scheme 4 Cyclopropanation of vinylboronic esters 3 by treatment with diazomethane in the presence of catalytic amounts of Pd(OAc)2 [60]. aTPS ¼ tert-butyldiphenylsilyl. bCatalyst was pretreated in an ultrasonic bath. cDiastereomers are readily separable by medium-pressure liquid chromatography (MPLC)

method giving a convenient combination of yield, selectivity, and reagent stability [60]. Air-stable vinylboronic esters 3 could therefore be formed either by the common hydroboration-condensation protocol, direct hydroboration, or via a nucleophilic attack of a vinyllithium species to a borate followed by condensation of the formed ate complex with the desired boron-protecting group [60, 134– 142]. Either way, by treatment of vinylboronates 3 with diazomethane in the presence of catalytic amounts of Pd(OAc)2, the desired cyclopropanes 5 were obtained in excellent yields (89–99%). To ensure sufficient stereoselectivities (dr ¼ 86:14–95:5), careful adjustment of the addition rates of the cyclopropanation agent proofed to be crucial (Scheme 4). Ultimately, the established method was found to be valuable for a variety of natural product’s total syntheses [34, 92]. Exemplary exploitation of the excellent yield and stereo- as well as regioselectivity (diene 6 to cyclopropane 7: yield >95%, dr > 98:2) provided by the use of diazomethane and Pd(OAc)2 could be shown for the construction of ambruticin’s 8 cyclopropane system (Scheme 5) [34, 143].

84

M. Mantel et al. a

a

TBSO

Ph

Ph O

MeO MeO

TBSO

Pd(OAc)2 (5 mol%), CH2N2, Et2O B O

95% dr (cyclopr.) >98:2 dr (methyl) >98:2

Ph Ph 6

Ph MeO

MeO

H

HO

O O

Ph O

H B O

H

Ph Ph 7

O OH

H

Ambruticin 8

OH

Scheme 5 Application of highly selective, boron auxiliary controlled cyclopropanation (diene 6 to cyclopropane 7) as usable for the total synthesis of ambruticin A 8 [34, 143]. aTBS ¼ tertbutyldimethylsilyl

3.1.2

[4 + 2]-Cycloadditions

Both dienes and dienophiles attached to cyclic boron auxiliaries have been utilized to perform enantioselective Diels-Alder-type reactions since the early 1990s (Scheme 6). In 1991 Wang published the first examples of diene-containing boronate-auxiliaries used for the asymmetric synthesis of cyclohexene derivatives. While showing the general feasibility of the intended Diels-Alder reactions, enantioselectivity could not be achieved using threefold coordinated boron species (protecting group XIX). Utilization of ate complexes (protecting group XXIII, R3 ¼ Me, n ¼ 2) not only improved the reaction’s speed but yielded products with a notable diastereomeric excess (dr 69:31) [118]. Half a decade later, Renard and Lallemand were able to show an improved procedure based on tartrate auxiliaries (protecting group XI). While yields remained unsatisfyingly low, enantiomeric excesses of 70% could be shown [65]. Even though Matteson and Waldbillig already busied themselves on the field of boronate dienophiles in the early 1960s, Bonk and Avery were the first to employ chiral boron auxiliaries on this subject in 1997 [66, 144]. Albeit yields and enantiomeric excesses of the preferred endo-products remained low (37–76%, 7–33% ee), the general feasibility of using formal vinyl alcohol equivalents could be shown using the diethyl ether of protecting group XI. After the conduct of basic research, C–C-bond forming Diels-Alder reactions using chiral boron auxiliaries unfortunately turned out to be a hard task in stereochemical matters, even though good to very good yields could be obtained [34, 66, 76, 118, 145]. One fruitful attempt was provided by Zhang et al. in 2001, switching to dienophiles other than ethylene-based ones [110]. By employing azo-compounds such as 10, boron-diene 9 could be converted into the corresponding Diels-Alder product 11 not only with satisfying yields but moreover almost perfectly stereoselectively (Scheme 7). However, introduction of a methyl group in γ-position to the boron atom already increased the system’s reactivity to a level where allylic addition of the newly formed boron species 11 to the Michael system of 10 occurs. Despite its high potential, the scope of this method may therefore be limited and has to be further investigated.

Boron-Containing Chiral Auxiliaries R *

O

O B

85

Diene Dienophile

R *

R *

O

O B

O

Dienophile

O B

DA-product

Diene

Scheme 6 Feasible [4 + 2]-cycloadditions on boron auxiliary-bearing systems

N N O

O

B O 9

N Ph

O

O 10

84% single stereoisomer

B O

N N O

N Ph

O 11

Scheme 7 Highly stereoselective hetero-Diels-Alder reaction of chiral diene-boronate 9 with triazolidinedione 10 to form product 11 [110]

3.1.3

1,3-Dipolar Cycloadditions

1,3-Dipolar cycloadditions on vinylboronates have been under investigation for quite a while [146–152]. Due to the lack of catalytic variants, auxiliary chemistry has proven its point in the field and could be established in chiral variants during the late 1990s. Wallace and Zong showed in 1999 how TADDOL-based vinyl boronates could, among others, be used for the asymmetric synthesis of Δ2isoxazolines in general (Scheme 8) [93]. While diastereoselectivities remained unpleasantly low for the vinylic systems 12 employed initially (dr 69:31–75:25), introduction of a methyl group in α-position to the boron atom increased the dr to 89:11 with yields of 85%. Furthermore, the protecting group could be recovered without major loss of substance (>90%). An interesting continuation of earlier works concerning 1,3-dipolar cycloadditions to vinyl boronates was published by Davies et al. in 2000 (Scheme 9) [119, 120]. Introducing a chiral amino diol, solid-state studies support an intramolecular Lewis acid-base adduct formed within the vinyl-boron species 15, causing chirality at both heteroatom bridgeheads. Thus, additional chiral information can be installed relatively close to the center of reactivity in comparison to other boronprotecting groups. In detail, the rigid auxiliary backbone caused conformers with the noncyclic hetero-substituents in pseudo-axial positions, therefore shielding one side of the dipolarophile sufficiently. Additional installation of a carbon-stereogenic center next to the nitrogen atom proofed to increase the reaction’s stereoselectivity. The designed and investigated reagents were reacted with nitrile oxides as well as nitrones, whereas bad to moderate yields and moderate enantiomeric excesses of up

86

M. Mantel et al.

Ar

Ar O B O

R1 O R2 O Ar

N

O 13a

R3

dr 69:31-75:25b

Ar

Ar

R1 = H, methyl, R2 = metyhl, phenyl R3 = phenyl, t-butyl Ar = 1/2-naphtyl,

R3

O B O

R1 O R2 O

Ar 12

Ar

N O

Ar 14

3,5-(Me)2Ph

Scheme 8 1,3-Dipolar cycloaddition of 2,2-dimethyl-α,α,α0 ,α0 -tetraphenyldi-oxolane-4,5dimethanol (TADDOL)-protected vinylboronates 12 and nitrile oxides 13. aPrepared in situ from N-hydroxyimidoyl chlorides. bYields not given. Due to the water sensitivity of 14, dr’s were determined by 1H-NMR after transesterification to pinanediol [93]

N R2

13a

THF, rt

O N

Ph

O Ph

N O B O

R3

Bn

17

Ph

THF, rt

R1 R2

15

N O

R1 = phenyl, CO2Me R2 = phenyl, CO2Me

HO

R1 16

Bn N O

R3

Yield: 31-65% ee = 59-70%b

R1 = CO2Me R3 = H, CO2Me

R1 18

Yield: 20-42% ee = 65-74%c

Scheme 9 1,3-Dipolar cycloaddition of nitrile oxides 13 and nitrones 17 to tertiary amino diolprotected vinyl boronates 15 [120]. aPrepared in situ from N-hydroxyimidoyl chlorides. bBoronyl cleaved off during workup. cAfter removal of the boron auxiliary by treatment with NaOH/H2O2

to 74% could be achieved. Conveniently, all isoxazolines are obtainable without much effort. In case of the disubstituted products 16, the boronyl group was even cleaved off during workup. For trisubstituted products 18, standard oxidative treatment with NaOH/H2O2 could be employed in order to remove the auxiliary reliably.

3.2

Matteson Homologations

At the beginning of the 1980s, Matteson and co-workers lay the foundation of a method, which should become one of the most successful diastereoselective syntheses in the field of boron auxiliary chemistry. Treating chiral boronic esters 19 with the readily available nucleophile LiCHCl2 at 100 C, they accomplished to form an ate complex, which undergoes 1,2-metallate rearrangement upon increasing the reaction’s temperature. Presumably, due to the direct involvement of the boron atom located closely to the chiral moiety of the molecule, the rearrangement

Boron-Containing Chiral Auxiliaries

O B R O 19

LiCHCl2 THF -100 °C - rt

87

R

O B O

Cl

Yield: 87-99% dr = 98:2->99:1a

20

R = phenyl, benzyl, methyl, propyl, sec-butyl, 2-pentanone ethylene ketal

Scheme 10 Homologation of boronic esters 19 with LiCHCl2 toward chlorinated products 20 as introduced by Matteson and co-workers [153, 155]. aR ¼ phenyl: yield 94%, dr ¼ >98:2, no additive; for every other example, addition of 0.5–0.65 equivalents ZnCl2

step took place with high diastereoselectivities. As a result, “elongated” species 20 were provided in high optical purities [153, 154]. By the addition of substoichiometric amounts of ZnCl2 not only an improvement of the already high selectivities could be observed, but moreover an increase of the yield of up to 99% was achieved [155] (Scheme 10). Upon submitting species 20 to further transformations such as treatment with Grignard reagents, the resulting alpha-substituted boronic esters were again obtained in high selectivities due to the underlying SN2-mechanism [154, 156]. In conclusion, almost perfect synthetic utilities were acheived at quite early states of research. Thus, it comes as no surprise that Matteson’s homologation became popular among the chemical society very quickly and was used extensively in various synthetic projects. Feasible applications were, e.g., the construction of α-chiral allylic boronates [35, 36, 38, 56, 106], the asymmetric synthesis of multisubstituted alkyl chains [44, 45, 53, 55, 57], introduction of heteroatom (bearing) residues [47, 48, 115, 157], the preparation of sugars [107], generation of isotopically labeled chiral compounds [50, 51, 158], and even the buildup of target molecules bearing a boron atom within the final structure [53, 108, 112–114, 159]. A key step in the further development of Matteson’s method was the variation of the nucleophiles used. Beginning with the homologation step, C1-fragments other than LiCHCl2 showed to be suitable for the established procedure. Despite LiCH2Cl or LiCH2Br generated from ICH2Cl or H2CBr2, respectively, LiCHBr2 from dibromomethane turned out to be a worthwhile surrogate for the usually chlorinated reagents [106, 107, 160]. While the first reagents are an interesting option for a C1-elongation of alkyl chains, albeit lacking additional stereochemical information, the latter’s additional value lays in the extension of nucleophiles usable for the second step. In particular, satisfying employment of enolates was enabled, which α-chlorinated species failed to provide. The resulting aldol-like substitution patterns are not only an interesting motive in organic synthesis but attract attention within the presented method due to the creation of a second stereogenic center upon addition of the second nucleophile. As Matteson and Michnick pointed out, diastereomeric ratios from 89:11 up to >98:2 for broronate 24 were achievable in favor of the 2S,3S-isomer (R ¼ n-butyl, iso-propyl)/2S,3R-isomer (R ¼ phenyl) and depending on the boronate’s residue. However, even after adding ZnCl2, the yields provided by the procedure are disappointingly low in comparison to similar reaction sequences described (see above) (Scheme 11) [57]. Nonetheless, the described

88

M. Mantel et al.

approach points out the opportunity of boronate 22 being used as an aldehyde synthon in matters of very classical aldol chemistry. This should, in combination with the stereochemical control provided, be recognized as an interesting extension of the method’s capabilities. As already mentioned, Matteson’s method has been applied in total synthesis regularly. While many examples focus on the preparation of starting materials for allyl addition reactions [35, 39, 40, 46, 52], sequential homologation steps have proven to be a valuable tool in establishing (multi-)substituted alkyl chains with high selectivity [161]. An interesting example is presented in Scheme 12. Not only Y Y

Y

Y

O

B R

Y

OLi

a) CH2Br2, LDAa THF, -78 °C

O

Y

23b OtBu O

b) 1.9 equiv ZnCl2 -78-20 °C

B

O

O

THF, -78 °C

B

O

R R

21

Br

t

BuO

22

O

24 Yield: 57-61% over 2 steps dr = 89:11->98:2

R = n-butyl, iso-propyl, phenyl Y = H, OMe

Scheme 11 Use of α-chiral boronic esters as aldehyde synthons: Matteson homologation followed by nucleophilic substitution of bromine by lithium ester enolates [57]. aLithium diisopropylamide (LDA). bPrepared from propionic acid tert-butyl ester and LDA

OTBS O Cy

B

O

a

1a) LiCHCl2, THF, -100 °C 1b) ZnCl2, -70-25 °C 2) PhCH2ONa, THF, ref lux

Cy

O

B

O

Cy

Cy 26 Yield 97% (over 2 steps)

25 Y N R=

OTBS BnO

O Y = H, F, I

2b) ZnCl2/Et2O -78-25 °C 3) AllylMgBr, THF, -70-25 °C

or

N

O

NH2

O

B

single d O isomer

27

Re

N O HO

28a-c

OTBS BnO

Yield 69% (over 3 steps) HO

O NH

1) pinanediolb Et2O/H2O, rt 2a) LiCHBr2c, THF, -78 °C

28d

B

OH

28

Scheme 12 Matteson homologation-based key steps in the total syntheses of several 1-(30 dihydroxyboryl-20 ,30 -dideoxyribosyl)-pyrimidines 28a–d [53]. aTert-butyldimethylsilyl (TBS). bPrepared from (+)-α-pinene. cPrepared from H2CBr2 and LDA. dBy 1H- and 13C-NMR for all species from 25 to 27. eMajor isomer for 28a–c after purification

Boron-Containing Chiral Auxiliaries

89

a “multi-Matteson” sequence with even different homologation agents and boronprotecting groups is shown, but also a target molecule containing boron as part of its final structure is included in the depicted total synthesis [53]. Thus, a nice summary of last decades’ progresses in the field is given. Starting material 25 was provided via a multistep sequence from boric esters B (OR)3. Upon addition of one equivalent of LiCH2Br, the corresponding boronate is formed, which upon transesterification with the desired chiral diol and nucleophilic substitution of the halogen atom by a benzyl alcoholate yielded a boronate that was transferred into species 25 by hydration and subsequent TBS protection [48, 160, 162]. A first homologation followed by replacement of the introduced chlorine atom by a benzyl alcoholate provided boronate 26 in almost quantitative yields with only one stereoisomer detectable by 1H- and 13C-NMR. After change of the chiral protecting group toward the more stable though still highly selective pinanediol [159], another homologation step was utilized to introduce an allylic side chain. In this case, brominated homologation agents were employed, which are known to be more stereoselective for the intended synthesis from α-alkoxy boronates 26 [107]. Boronate 27 was once again obtained in good yields over three steps from species 26 as a single stereoisomer according to NMR analysis. Further transformations finally yielded four derivatives of the desired 1-(30 -dihydroxyboryl20 ,30 -dideoxyribosyl)-pyrimidines 28 reliably.

3.3

SN2’ Reactions

Copper-catalyzed allylic substitution reactions are a well-known method to create stereogenic centers in allylic positions selectively [163–166]. Even though examples using non-chiral boronates as nucleophiles had been established [167, 168], Carosi and Hall were the first to synthesize α-chiral allylboronic esters from electrophilic vinyl boronates bearing a leaving group in 2007 [169]. Demonstrating not only the general feasibility of SN2’ reactions on this group of substrate but also providing a stereoselective variant, the foundation was laid for the advancement of the method using chiral boron auxiliaries (Scheme 13). A recent example for the preparative value of Halls’s method was presented by Brauns et al. in 2016. Starting from readily available, air-stable vinyl boronate 31, allylic boronates 33 and 34 could be obtained in excellent yields and diastereoselectivities of up to 97% and >95:5, respectively (Scheme 14). It is noteworthy

*

O

[M]Nu Cu(I), Ligand

O B

LGa 29

- [M]LG

O B * O Nu 30 *

Scheme 13 Generation of α-chiral boronates 30 from vinylic species 29 via a SN2’ mechanism. a Leaving group (LG)

90

M. Mantel et al. RMgBr CuTc (3 mol%) 32 or ent-32 (3 mol%) CH2Cl2, -90 °C

Cl

Ph

Ph O B O

O B O 31

Cl

Ph

Ph

R B O

Ph

O Ph

Yield: 89 - 97% dr = 91:9 - >95:5

Ph

O Ph O B 33 R from 32

R = ethyl, n-pentyl

R Ph O N P O Ph 32

CuTc = S

O Cu O

B O

Ph

O Ph

Ph

O Ph O B 34 R from ent-32

Scheme 14 Copper-catalyzed SN2 reaction of vinyl boronate 31 to form allylic boronates 33 and 34 by Brauns et al. [82, 83]. The corresponding enantiomers can be obtained using ent-31 as a starting material

that the corresponding α-isomer from the competing SN2 reaction was formed in negligible amounts (γ:α > 20:1) [82, 83]. Shown in 2017, the method established could be expanded without any relevant drawbacks in stability to systems with substituted aryl systems, granting access to valuable reagents for the synthesis of tertiary homoallylic alcohols [84]. Additionally, the same method was proven applicable to an even greater extent using protecting group XII (not shown). Not only ethyl- and n-pentyl- but also n-propyl- and n-butyl residues were utilizable with similarly good outcome (dr 95:5, yield, 89–92%, γ:α ¼ >20:1, n-propyl, 10:1 n-butyl).

3.4

Carbonyl Allylation

The palladium-catalyzed, metal-mediated allylation of carbonyl compounds is a comprehensively investigated method for the preparation of homoallylic alcohols, which includes an interesting umpolung step of the allylic species [170–178]. Starting from allylic compounds 35 bearing a suitable leaving group, oxidative addition of a palladium(0) catalyst typically forms η3-allyl-palladium complexes 36. Subsequently, transmetallation accompanied by the recovery of the catalytic palladium(0) species readily provides a nucleophilic agent 37 suitable for the allylic addition to carbonyl compounds. Via a transition state such as 38, homoallylic alcohols 39 are formed with the formation of up to two stereogenic centers (Scheme 15).

Boron-Containing Chiral Auxiliaries

LGa

R1

91

R1

Pd0 - LG-

[M] - Pd0

PdII

35

R1

[M] 37

36

O R2

H

R2

O

OH ∗

R1

[M] 38

Ph Ph

O

O

O

B

O

Ph Ph

PdCl2(PhCN)2 (5 mol%) SnCl2, DMF/H2O, rt

∗

R2

R1 39

Ph Ph

O

O

O

B

Ph Ph

OH O H

∗

R3

O

O Ph Ph

B

∗

R3

O

O O Sn(OH)3 41 42 40 Yield 42: 70 - 86%; dr (α-R anti : α-S anti : syn) = 75:18:7 - 100:0:0 R3 = c-hexyl, phenyl, Ph(CH2)2, PhCHCH, Me2CH, Me2CHCH2, furfuryl, CO2Et

Ph Ph

OMsb

Scheme 15 Palladium-catalyzed generation of allylation reagents via an umpolung starting from protected allylic alcohols [170–172, 179]. Illustration by the palladium-tin-mediated carbonylation of allylic mesylates presented by Ferna´ndez et al. [80, 180]. aLeaving group (LG). bMesyl (Ms)

In 2009 the working group of Pietruszka transferred the well-known method to the objective of synthesizing α-chiral boronates bearing chiral protecting groups [180]. Starting from mesylate 40, the formation of a nucleophilic allyl-tin species 41 could be realized analogously to protocols for non-boron-containing substrates [173]. Subsequent reaction with aldehydes reliably formed homoallylic alcohols 42, which, in fact, are allylic boronates including an α-chiral carbon atom. During the formation, it turned out to be beneficial for the reaction’s progress to have certain amounts of water present, presumably due to the formation of species 41, which is more reactive than its trihalogenated counterpart generated by the coordination of SnCl3 to the allyl-palladium complex [179, 180]. Combined with a later publication in 2010, Ferna´ndez et al. showed for in total 11 examples how the applied method allows good yields from 70 to 86% [80, 180]. On top, the key feature of the striven synthesis, the stereoselectivity, could be brought into action: As it is intrinsic for the cyclic transition state 38 assumed to be favored under the conditions given [172, 180], the anti-diastereomeres (referring to the non-auxiliary part of the molecule) are formed preferably. In combination with a chiral boron auxiliary being present, further stereo-discrimination takes place and allows therefore the preparation of single anti-stereoisomers in good to excellent selectivities. For the 11 examples given, only three show formation of the syn-product at all (anti:

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M. Mantel et al.

syn ¼ 91:9 to 96:4), while the anti-isomers themselves could be prepared in diastereomeric ratios from good 81:19 to excellent 100:0 for residues other than hydrogen. Additionally, all diastereomers were separable via medium-pressure liquid chromatography (MPLC), giving sufficient access to optically pure compounds 42. An even more convenient method toward α-chiral boronates was presented by B€ ose et al. in 2014 [81]. Even though the previously introduced procedures using tin for the enantioselective preparation of boronates 42 already proofed to be quite successful [80, 180], space for improvement was clearly left. Namely, overcoming the need for highly toxic tin species and the quite unstable starting material 40, as well as a more satisfying overall stereoselectivity, were objectives valuable to realize. Based on preliminary results of Szabo´’s group [181], tetrahydroxydiborane turned out to be the solution to the problems tackled. Starting directly from the TBS-protected allylic alcohol 43, B€ose et al. were able to utilize the diboron compound under Brønsted acid catalysis as a less toxic and more stable transmetalation reagent. Therefore, not only the undesired tin species became redundant, but moreover the deprotection and activation of the allylic alcohol could be avoided, saving the whole sequence two steps. Finally yet importantly, the additional advantages of the newly introduced tin substitute were reflected in an improved stereochemical outcome. Caused by boron’s increased oxophilicity in comparison to tin, the sequential allyl addition step was expected to run by a more constricted transition state [81], thus causing excellent stereoselectivities for a broad scope of substrates (dr 91:1, >95:5). Even for the small formaldehyde, stereo-induction could be observed at all (dr 37:63). At last, all reactions did proceed reliably under the convenient conditions in satisfying to very good yields for products 44 (56–90%) (Scheme 16). The established carbonyl allylation method has proven to be a versatile tool in total syntheses. A variety of natural products 46a–c could be synthesized starting directly from hydroxyboronate 44 by allyl addition reactions to the corresponding aldehydes. After isolation of homoallylic alcohols 45 in high yields (72–99%) and excellent stereoselectivities (d. >20:1, ee ¼ 93–99%), terminal oxidation by bis (acetoxy)iodobenzene (BAIB) and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO)catalysis provided lactones 46a–c via intramolecular esterification. More complex

Ph

Ph

O

O O Ph

B O

OTBS

a

B2(OH)4, RCHO [Pd(CH3CN)4](BF4)2 (5 mol%) DMSO/MeCN (1:1), PTSAb (4 mol%), 6 °C

Ph

Ph

Ph

O

O O Ph

43 R = phenyl, 3,4-F3C6H3, C6F5, furfuryl, CO2Et, PhCHCH (E), PhCH2CH2, (CH3)2CH, (CH3)2CH2CH, C6H11, H

B O

OH R

Ph

44 Yield: 56-90% dr = 91:9- >95:5; 37:63 (R = H)

Scheme 16 Palladium and Brønsted acid-catalyzed, boron-mediated allylic carbonylation of TBS-protected vinylboronates 43 as presented by B€ose et al. [81]. atert-Butyldimethylsilyl (TBS). b para-Toluenesulfonic acid (PTSA)

Boron-Containing Chiral Auxiliaries

93

OH *

BAIBa,

OH B

O Ph Ph O

O Ph O Ph

RCHO 0 °C - rt, CH2Cl2

44

R

TEMPOb (20 mol%)

*

CH2Cl2, rt

O O

*

R

OH 45

46

9 examples, Yield: 72-99%, dr >95:5 ee = 93-99%

R=

Me: Parasorbic Acid 46a n-Pent: Massoia Lactone 46b CH=CHPh: Goniothalamin 46c CH2CH2OTBS: precursor for 47, 46d

O Rugulactone 47 Yield : 38% over 5 steps from 44 ee (based on 46d) = 96-98%

O

*

O Ph

Scheme 17 Total syntheses of various dihydro-α-pyrone-based natural products starting from carbonyl allylation-derived boronates 44 [182, 183]. aBis(acetoxy)-iodobenzene (BAIB). b(2,2,6,6Tetramethylpiperidin-1-yl)oxyl (TEMPO)

examples such as rugulactone 47 could be prepared by two additional steps, providing the natural product in an acceptable overall yield (38% over 5 steps). Finally, all compounds could be obtained in their enantiomeric form by simple variation of starting material 44’s α-carbon’s configuration (Scheme 17) [182, 183].

3.5

[3,3]-Sigmatropic Rearrangement

In 2003 Pietruszka and Sch€one showed how [3,3]-sigmatropic rearrangements can be applied to boronic esters [77]. Even though known for tin and silicon compounds since the late 1970s [184–190], those were the first reports on boron reagents undergoing this kind of pericyclic reaction. As starting materials, E- and Z-vinyl boronates E/Z-48 could be utilized successfully. While the E-configured compound was obtained directly from the alkyne via classic hydroboration followed by condensation with protecting group XII, the Z-compound needed to be generated by ruthenium-catalyzed hydroboration [191]. Subsequent transformation of both starting materials into the corresponding ester 49 by a Claisen rearrangement proceeded smoothly in good yields. However, starting from boronate E-48, stereoselectivity was not given at all and could only be improved slightly to 30:70 using the isomer Z-48 as a starting material. Still, the separation of the diastereomers of allyl boronate 49 was possible by MPLC to yield stereoisomerically pure material. Analogous, Eschenmoser-Claisen rearrangements forming amide 50 could be performed, while only the E-configured starting material granted access to yields and selectivities similar to those of the Claisen rearrangements. Boronate Z-48, however, did not undergo conversion to the desired product 50 at all (Scheme 18).

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M. Mantel et al.

HO

O Ph Ph O

B

MeC(OEt)3, cat. EtCO2H 135 °C or MeC(OMe)2NMe2 toluene, 80 °C

O Ph O Ph

49 X = OEt f rom - E-48: 71%, dr = 50:50 - Z-48: 64%, dr = 30:70

X

O

*

O

B

Ph Ph O

E/ Z-48

O Ph O Ph

49/50

50 X = NMe2 f rom - E-48: 70%, dr = 50:50 - Z-48: dif f erent product

Scheme 18 [3,3]-Sigmatropic rearrangement of vinylboronic esters as introduced by Pietruszka and Sch€ one [77]

R1 R2

HO

R3 O

B

Ph Ph O

R4 ∗

MeC(OMe)2NMe2

O

cat. EtCO2H, solvent T (MW or heat) 9 min (MW) or 3-48 h (heat)

Ph O Ph 51

1

X

O orthoester or

O Ph Ph O

R3 R1

∗

B

O

R2

Ph O Ph 52

2

3

4

A: R = Me, n-Pe, Ph; R ,R ,R = H; X = OEt, NMe2; B: R1,R2 = Me; R3,R4 = H; X = OEt, NMe2; C: R1 = Me, n-Pe, Ph; R2,R3 = H; R4 = Mea; X = OEt; D: R1, R2, R4 = H; R3 = Me; X = OEt;

63-89%, dr >99:1 51-53%, dr 46:54 - 69:31 79-89%, syn:antib up to 86:14 53%, dr 58:42

Scheme 19 Preparation of α/β-substituted allyl boronates 52 via Claisen and EschenmoserClaisen rearrangements [192–196]. aIntroduction of methyl group by EtC(OEt)3. b(2S,3R):(3R:3S)

Presumably, the lone pair of the nitrogen allowed the formation of a cyclic structure which from a different side product was formed via a Matteson-like reaction. In order to expand the established method, access to substituted allyl boronates 52 was developed from 2004 to 2010. A variety of residues could be introduced in β- and γ-positions, while yields and stereoselectivities varied depending on the position addressed. Excellent results could be obtained for singly β-substituted allyl boronates 52 in case of Claisen and Eschenmoser-Claisen rearrangements. Regardless of the residue’s structures (R1 ¼ Me, n-Pe, Ph; A, Scheme 19), the method provided moderate to very good yields (63–89%) and excellent selectivities (dr > 99:1) [192–194]. An interesting variant of the very same reaction included the utilization of propionic acid orthoester instead of acetic acid othoesters for the Claisen rearrangement. The derivative allowed the introduction of another methyl group in α-position to the boron moiety, creating an additional stereogenic center. Enabling unaltered high yields (79–89%), good stereoselectivities of up to 86:14 could be obtained (B, Scheme 19). Note that only syn- and anti-isomeres with one

Boron-Containing Chiral Auxiliaries

95

particular configuration in 3-position are formed, indicating no stereochemical impact of the different orthoester onto the buildup of the α-carbon center. Furthermore, double-γ-substituted boronates 52 could be prepared in a similar fashion in 2013. However, lower yields must be taken into account as well as a moderate stereoselective outcome (51–53%, dr ¼ 46:54–69:31, C, Scheme 19). Still, due to their outstanding stability, the diastereomeric esters and amides 52 could be purified chromatographically, providing stereoisomerically pure material conveniently [195]. Lately, Gehrke et al. completed the set of substitution patterns by introducing a residue to the β-position attached to the double bond of boronate 52. Even though yields and stereoselectivities proofed to be limited (53%, dr ¼ 58:42, D, Scheme 19), optically pure material could be obtained easily via MPLC once again [196]. Conclusively, residues other than hydrogen could be introduced successfully in all positions R1–R4 of allyl boronates 52. Synthetic drawbacks have to be recognized in some cases; however, the outstanding stability of all boronates still allows the utilization of optically pure material for further transformations. Even though access toward higher substituted derivatives is still pending, a versatile tool for the preparation of a variety of ester- and amide-containing boronic esters 52 has been established within the past one and a half decades. Boronic esters, provided by 3,3-sigmatropic rearrangements, have moreover proven to be a valuable tool in the total syntheses of various marine oxylipins [197–199]. For instance, ester 49, obtained as depicted in Scheme 18, was used in the synthesis of the constanolactones C 55 and D epi-55 [197]. After allylic addition to aldehyde 53, perfect conversion to the desired homoallylic alcohol was achieved (quant., dr > 99:1, ee > 99%). Ensuing from the obtained building block, the total synthesis of the desired constanolactones 55 and epi-55 could be realized within nine more steps and 10% overall yield (Scheme 20). Further examples of total synthesis employing the method detailed in this chapter can be found by the preparation of neohalicholactone as well as solandolactones A–I [198–201].

Ph O Ph O

O Ph Ph B

O

O

+ H

O

OPMB

a

53 O O

OH R1 R2

OH

O

PMBO

OEt

quant., dr >99:1, ee >99% 54

OEt 49

CH2Cl2 rt

constanolcatone C 55 (R1 = H, R2 = OH) constanolactone D epi-55 (R1 = OH, R2 = H)

Scheme 20 Application of boronic ester 49 provided by a [3,3]-sigmatropic rearrangement in the total syntheses of constanolactones C and D [197]. apara-Methoxybenzyl

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M. Mantel et al.

3.6

Remote-Controlled Reactions

During the 1980s the preparation of 1,3-diols flourished with a variety of methods utilizing 1,3-interactions for the stereoselective synthesis of the versatile target molecules [202–206]. Inspired by those contributions, Molander et al. began investigations on an elegant method toward similar diols in the early 1990s. Namely, δ-keto boronates 56 were intended to enable the stereoselective reduction of the prochiral keto-functionality, even though the stereodetermining moiety is placed quite remote from the newly buildup stereogenic center. After early substrate controlled approaches proved the intentions, again by 1,3-interactions, to be realizable, (Scheme 21 at lower left) [207], an auxiliary controlled version could be presented in 1993 [58]. Herein 1,7-interactions were employed to cause the desired stereoselective discrimination (Scheme 21 at lower right), making the method rightly bearing the affix “remote.” Practically, a variety of δ-keto boronates 56 was prepared by Michael addition of boronate cuprates derived from Matteson homologation products to the α,ß-unsaturated ketone of choice. Subsequently, reduction with borane dimethyl sulfide in dimethyl sulfide toward alcohol 57 was followed by direct oxidative cleavage of the boron moiety to give 1,4-diols in one pot. All products could be isolated in good to excellent yields (81–97%) and enantiomeric excesses (85 to >98% ee). Remarkably, the method established allows the highly stereoselective conversion of ketones with residues of rather

O

a

BH3*SMe2

O

O B

Me2S, 0°C O

R

OH

O B

Yield: 81-97% ee = 85->98%a

R 57

56

R = Me, n-pentyl, cyclohexyl, phenyl, (CH2)3Cl, (CH2)10CN, 2-butyl-1,3-dioxane, (CH2)4CO2CH3 former approach with β-substituted δ-keto boronates (not shown, see [104]) favoured

Nu

assumed transition state for the reaction shown above 1,7-interaction

-

unfavoured

Nu

-

H O O B

R3 R2

1,3interaction

unfavoured

Nu

-

O O B

O

R favoured

Nu

O

-

Scheme 21 Remote-controlled reduction of δ-keto boronates as introduced by Molander, Bobbitt, and Murray with mechanistic insight into the different modes of stereoinduction [58, 207]. aReferring to the diol obtained after oxidative workup with H2O2/aq. NaOH

Boron-Containing Chiral Auxiliaries

97

similar steric and/or electronic demand (e.g., R ¼ n-pentyl: ee ¼ 92%; (CH2)3Cl: ee ¼ 93%; (CH2)10CN; 97% ee). Similar results could be obtained by the group of Whiting in the following years, also accessing analogous nitrogen compounds [25–27, 29–32]. An obvious follow-up of the successful utilization of keto boronates 56 in the remote-controlled asymmetric reduction is the diversification of the nucleophiles used. In 2006 the Whiting group reported on their progress [33]: While the conversion of γ-keto boronates 56 derived from Matteson-like homologation products [208] with alkyllithium, Grignard- or cuprate-based reagents caused undesired ring-opening reactions, lithium ester enolates 59 yielded aldol products as striven. Although the chemoselectivity was high, the reaction turned out to exhibit insufficient stereoselectivity (70%, dr 29:71), which was accounted to the increased steric demand of the new nucleophile causing interactions with one of the ketone’s residues. Thus, aldehyde 58 was chosen as a less hampered substrate suitable for the intended reaction. With good yields and excellent stereoselectivities for the formation of alcohol 60 (74%, dr > 98:2), the assumptions made turned out to be true (Scheme 22). While asymmetric aldol reactions of preformed enolates bearing boron auxiliaries had already been known [11, 12, 14, 16], herein an applicable method was realized where the boron compound provides the electrophile for the very same type of reaction. The pending procedure for an efficient removal of the auxiliary does not cancel out the fact that the foundation of a complementary method within the asymmetric aldol reactions was established. Even though Molander’s and Whiting’s method has rarely been employed in total syntheses so far, precedent does exist. In 2006 Talley et al. published the preparation of a variety of heterocyclic structures 63 intended to be used for the treatment of lipid metabolism disorders such as high cholesterol levels [209]. Among them, a handful of β-sultams was accessed utilizing the remote-controlled reduction developed in the early 1990s [58]. Therefore fluorinated boronate 61 was synthesized analogous to the method described by Molander and Bobbitt [58]. Subsequent stereoselective reduction afforded diol 62, which could be utilized as a building block in the 14–15-step-lasting total syntheses of ten target molecules 63 (Scheme 23).

O O MeO

B O

OMe

H

58

OH O

LiO O t

BuO 59 -78 °C - rt, THF

MeO

OtBu

B O

OMe

60

74%, dr >98:2

Scheme 22 Remote-controlled aldol reaction of γ-carbonyl boronate 58 with lithium ester enolates 59 toward alcohol 60 as published by Mears et al. [33]

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M. Mantel et al.

OH O

O

O B

HO

b) H2O2, aq. NaOH 61

OH * *

F 62 yield and ee not given

F R

14-15 steps

a) BH3*SMe2

OH

R = OMe, OH, m-phenol,

a

N S O O

F

p-(PO3)-phenyl p-Glc-phenyl

63

Scheme 23 Total synthesis of several β-sultams 63 intended to be used for the treatment of lipid metabolism disorders published by Microbia Inc. in 2006 [209]. aSyn- and anti-isomer of each compound available via separation of the diastereomers

4 Applications in Asymmetric Synthesis Boron compounds equipped with chiral protecting groups have proven to be valuable reagents for the diastereoselective modification of the non-auxiliary residue attached to boron. However, enantioselective applications in asymmetric syntheses, one of the most important branches in boron chemistry, have barely been touched within this treatise so far. On this behalf, the allyl addition of boronates to carbonyl compounds shall be illustrated representatively due to its outstanding potential and synthetic quality. As the amount of precedence in literature is quite voluminous, the focus will rather be on the development of general concepts, mechanisms, and the assignment of this treatise’ auxiliaries to the different categories of allyl-boron reagents than on concrete synthetic examples. Conclusively, recent examples in total synthesis are shown to illustrate the method’s relevance in modern organic synthesis. In 1964 Mikhailov and Bubnov were the first to report on the reaction of triallylborane with various aldehydes [210, 211]. Two years later, similar procedures could be shown using boronates instead of boranes, followed by further investigations until 1975 [211–215]. While those early attempts did only use simple, achiral allylation reagents, they still laid the foundation for Herold and Hoffmann’s work 3 years later. In 1978, they were the first to come up with the idea of employing chiral boron-protection groups expanding the method to the field of asymmetric synthesis [94]. As a result, the influence of a chiral boron auxiliary could be shown to have a considerable effect on the stereochemical outcome of the reaction due to the rigid Zimmerman-Traxler-like transition state of the reaction proposed by Hoffmann [216–218] (TS-1, Scheme 24). Within the following years, several protecting groups were developed increasing the stereoselectivity, yield, and substrate scope of the method by different steric

Boron-Containing Chiral Auxiliaries

OR B OR

99

R1

X

+ R1

R2

R2

65, X = O, NR 3

64

XH

OR X B OR

*

R1 2 R

TS-1

66

Scheme 24 Exemplary allyl addition of carbonyl compounds 65 to boronates 64 via a cyclic transition state TS-1 [216]

R3

O

∗

Allyl-B TMS

O O

76

B-Allyl N Ts 67

O B-Allyl O Ph 68

B-Allyl 75 O R4

R4

O

O

O

O

B-Allyl O

XH ∗

74

Ph

R1 2 R

69

66 H N

O O

O

B-Allyl

B-Allyl N H

SO2R5 N B-Allyl N SO2R5

Ph

O O

O Ph

Allyl Addition

73

70 CF3 O B-Allyl O 72 CF3

OMe O B-Allyl MeO O 71

Scheme 25 Common cyclic and chiral protecting groups used as auxiliaries for the allylation of carbonyl compounds by organoboron species (for references, see below)

demand and even electronic effects [63, 219]. Next to tartaric acid ester 71, 73, 74 [28, 63, 85, 86], camphor 68, 70 [94, 97, 101, 102], and threonine derivatives 67 [123], stilbene diamine 69 [124–128, 130, 220], BINOL-72 [117], butadiene-75 [15], and 9-borabicyclo(3.3.1)nonane (9-BBN)-based compounds 76 [18, 20, 22– 24] were employed for the allylation of carbonyls (Scheme 25), each providing valuable results in mechanistic studies and total syntheses.

100

M. Mantel et al.

The complexity of allyl addition reactions was later on increased by the use of crotyl boron reagents 77 instead of allyl compounds. Hence, more complex homoallylic products 86 could be obtained, making these attempts an interesting objective to realize (Scheme 26). Historically, Hoffmann and Zeiß reported on the first diastereoselective crotylation of aldehydes via crotyl boronates in 1979, yet not employing chiral boron auxiliaries [221, 222]. However, shortly afterward terpenebased crotylation reagents provided an enantioselective variant [96, 98], on which basis the newly born crotylation method prospered within the upcoming years. Again, several chiral protection groups found employment in the optimization of yield, stereoselectivity, and applicability where the stereogenic information of tartaric acid 80, 81 [64, 68, 69, 71–75, 86], camphor 79, 84 [96, 98, 99, 102– 105], threonine 85 [123], 9-BBN 83 [18, 21], and haloalkane 82 derived compounds [10] were used (Scheme 27). Common to all are mechanistic ground rules based on Zimmerman-Traxler-like transition states [217]. In comparison to pure allylation reagents, crotyl compounds already possess stereogenic information next to the auxiliary embodied by the configuration of the double bond. This configuration is retrieved in the cyclic transition state of a subsequent allyl addition ensuing the relative configuration: For E-olefins the substituents will be oriented pseudo-equatorial (TS-2, Scheme 26), while in Z-compounds the group will be in pseudo-axial position (TS-3, Scheme 26), ultimately leading to 78 or dia-78, respectively [221]. In combination with a chiral protecting group, not only high simple diastereoselectivity is observed but also enantioselectivity [98, 99]. The allylation and crotylation compounds covered so far have proven to be valuable reagents for the synthesis of homoallylic alcohols and imines with terminal double bounds. Introduction of residues at the terminal position of alkenes obviously requires α-substituted boron species for their synthesis, which in addition will introduce another element of stereochemistry to the homoallylic system 94. The additional stereogenic center leads to two possible different chair conformations in the transition state, one bearing the α-substituent in an equatorial (TS-4, Scheme 28) and one placing it in an axial position (TS-5, Scheme 28).

OR B OR

R1

R2

(E)-77 3

R1R

77 +

OR X B OR

XH R3 R2

TS-2

X

R2 R4

R3 65, X = O, NR5

(Z)-77

R3

OR X B OR

R1 TS-3

R1 78

XH R3

R2

R1 dia-78

Scheme 26 Mechanism of the asymmetric crotylation of carbonyl compounds depicted exemplary by the allyl addition of crotyl boronates 77 via cyclic transition states [221]

Boron-Containing Chiral Auxiliaries

101

O R5

R5

O

O

O

O

82 B-Crotyl

O

R4

B-Crotyl

*

Crotyl-B

83

81

O HN

O

O B-Crotyl

N H

O Ph

* *

R1 2 R

80

O

B-Crotyl

XH

O

84

R3

86 O

O B-Crotyl

O Ph

79

B-Prenyl N Ts 85

O

'Crotylation'

O

Scheme 27 Common cyclic and chiral protecting groups used as auxiliaries for the crotylation of carbonyl compounds by organoboron species (for references, see below)

OR B OR R1 +

87

R2 R3

R3 65

OH *

R1

R2 3 R 88

TS-4

O R2

OR O BR1OR

R2

OR B OR

O R3 1 R TS-5

OH *

R2 3 R

R2

dia-88

Scheme 28 Mechanism of the asymmetric allyl addition of α-chiral allyl boronates 87 to carbonyl compounds 65 [223]

In case of nonpolar substituents, the preference mainly depends on the steric bulk of the boron protecting group and the axially or equatorially placed residue. An increasing steric bulk causes greater repulsion in TS-4, hence favoring TS-5. However, polar residues additionally put dipolar effects into play, which usually favor TS-5 due to the anti-orientation of the C–R bond to the axial B–O-bond. Consequently, every reaction has to be evaluated carefully considering the different effects [211, 223, 224]. In principle, this method already allows asymmetric synthesis without a chiral protecting group, as the discrimination of enantiomeric transition states is caused by

102

M. Mantel et al.

the reagents configuration at C-α [223]. Anyway, in practice it has proven to be advantageous to utilize chiral boron-protecting groups. One aspect is the utilization of the auxiliary for the enantioselective formation of the desired stereogenic center next to the boron moiety. As described previously (Sect. 3), highly efficient method has been established for their synthesis, also reporting on the selectivity of the allyl addition. While the additional auxiliary seems to be redundant in terms of enantioselectivity [56], cases of an increase in diastereoselectivity to excellent levels (dr > 95:5) have been reported [223]. The utilization of α-chiral boron species is intrinsically linked to more complications than their linear pendants. Next to the need of a stereoselective preparation for the proper use in asymmetric synthesis, epimerisation of the optically pure allylation and crotylation reagents can occur [36, 225]. Thus, a certain stability of the utilized compound proved advantageous, a prerequisite not often observed. Hoffmann et al., next to some more recent publications [46, 52], used hydrobenzoin and tartaric acid derivatives 89, 93, and 92 for investigations and applications in total synthesis extensively [35–43, 56]. To avoid epimerization, the reagents need to be accessed quickly and used immediately. A more stable option is given by tartrate derivatives 90 and 91, which do not only provide excellent results in allyl addition reactions but are configurationally and chemically stable enough to undergo various modifications of the allylic residue and even separation of diastereomers by liquid chromatography (Scheme 29) [34, 77, 82–84, 180]. As mentioned, the excellent synthetic properties of boron reagents have made them a valuable tool for asymmetric allylation reactions. Within the last years, for example, the groups of Zakarian [226] and Pietruszka [199] reported on sophisticated total syntheses of different natural products employing the aforementioned reagents. Additionally, Williams et al. presented their approach toward a fragment of the marine compound Perloruside A in 2012 [227], resorting to a metal-halogen exchange reaction for the generation of allyl boronate 95 that they had already R5Ph PhR5 ∗ O 1 B ∗ R O ∗ 1 R ∗ B O O 5 R Ph PhR5

91 Ph Ph R

O

O

∗

B O

R

R1

O

Ph Ph

R4 O B

90

∗

R1

O 92

R4

XH

∗ ∗

O B O 89

R2 3 R

∗

R1

Allyl

R1

O B

R4 94

O

Addition

∗

R1

93

Scheme 29 Common cyclic and chiral protecting groups used as auxiliaries for the crotylation of carbonyl compounds by α-chiral organoboron species (for references, see below)

Boron-Containing Chiral Auxiliaries

103

employed for their total synthesis of leucascandrolide A [228]. Conversion of the allylation reagent 95 with aldehyde 96 leads to the multiple protected homoallylic alcohol 97 in good yields and diastereoselectivities (80%, dr ¼ 89:11). Three additional steps in good yield (67%) granted access to the desired fragment 98 from alcohol 97 (Scheme 30). In addition to allylation reactions, the crotylation of carbonyl compounds utilizing boron reagents is also a present method in total synthesis. Recent examples are the dexterous application of diborylated reagents from Roush’s group in the preparation of the C(23)-C(40) fragment of tetrafibricin [21] or the Ley group’s impressive total synthesis of rapamycin [229]. Three years later Wohlfahrt et al. coped with the preparation of (+)-Awajanomycin, where the bicyclic structure proofed to be accessible utilizing crotyl boronate 99. Treatment with ketomalonate 100 afforded homoallylic alcohol 101 in good yield and enantioselectivity (85%, ee ¼ 92%), and, ultimately, 12 additional steps provided the desired target molecule 102 in an overall yield of 23% from 101 (Scheme 31). In conclusion, over the past five decades, a method increasing in complexity was established, which barely fails to succeed in most of the problems tackled. High O Ph

Ts a

N B

TMS

N Ts

H Ph

OTBDPS OPMBb 96

c

OH

-78 °C

OTBDPS OPMB

TMS

97 80%, dr = 89:11

95 OMe 3 steps, 67%

O

OH

O O

OTBDPS OPMB

Fragment of Perloruside A 98

OPMB

Scheme 30 Total synthesis of the Perloruside A fragment 98 by the group of Chow in 2012 [227]. a TMS ¼ trimethylsilyl. bPMB ¼ 4-methoxybenzyl, cTBDPS ¼ tert-butyldiphenylsilyl Cy O B RO

EtO2C

O OH CO2Et

a

O

Cy

100 CO2Et

TES O

rt

CO2Et

99

85%, ee = 92%

101 OH O

12 steps, 23% OH

NH O

(+)-Awajanomycin 102

O

Scheme 31 Total synthesis of (+)-awajanomycin 102 by Wohlfahrt et al. [230]. aTriethylsilyl (TES)

104

M. Mantel et al.

yields and excellent stereoselectivities for the construction of three different stereogenic elements have made the allylic addition reaction of boranes and boronates an outstandingly powerful tool in organic chemistry. Proven in various total syntheses, the reliability of the method has contributed greatly to the organic synthetic progress. Ongoing investigations have already led to more convenient and even more potent procedures, hinting to an even broader scope of applications in the future.

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Top Heterocycl Chem (2020) 55: 113–156 DOI: 10.1007/7081_2020_36 # Springer Nature Switzerland AG 2020, corrected publication 2020 Published online: 6 November 2020

Oxazolidinones and Related Heterocycles as Chiral Auxiliaries/Evans and Post-Evans Auxiliaries Asmaa Kamal Mourad and Constantin Czekelius

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Synthesis of Optically Active Oxazolidinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Optically Active Oxazolidinones as Chiral Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Diastereoselective α-Functionalization of Optically Active Oxazolidinones . . . . . . . . 3.2 Diastereoselective Aldol Reactions and Related Transformations . . . . . . . . . . . . . . . . . . . 3.3 Diastereoselective Transformations of α,β-Unsaturated Acyl-oxazolidinones . . . . . . 3.4 Diastereoselective Reactions of Vinyl-, Alkynyl-, or Allenenyl-oxazolidinones . . . 3.5 Diastereoselective C(1)-Transformations of Oxazolidinone Derivatives . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

114 115 124 125 130 136 144 148 151

Abstract The application of optically active oxazolidinones and their sulfurincorporating derivatives as chiral auxiliaries for the diastereoselective functionalization of carboxylic acids and related starting materials is described. Herein, seminal work and more recent contributions in this area covering the developments in the past 40 years are summarized. This review aims in demonstrating not only the broad and reliable, synthetic applicability of this auxiliary class but also the methodological impact on the area of diastereoselective chemistry in general. In the beginning, the preparation of the auxiliary by ex-chiral pool synthesis or enantioselective methods is reviewed. Following, the application of oxazolidinones and related derivatives in diastereoselective transformations is separately discussed for the electrophilic α-functionalization of enolates and aldol reactions. Herein, reported working models for explaining the stereochemical outcome of the transformations with respect to auxiliary structure and Lewis acid coordination are The correction to this Chapter is available at https://doi.org/10.1007/7081_2020_38.

A. K. Mourad Fayoum University, Fayoum, Egypt C. Czekelius (*) Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany e-mail: [email protected]

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presented. In addition, the stereoselective transformation of α,β-unsaturated acyloxazolidinones by either conjugate additions or pericyclic reactions is summarized in detail. The discussion is extended toward the diastereoselective, electrophilic functionalization of vinyl-, alkynyl-, or allenyl-oxazolidinones extending the scope of the auxiliary towards the transformation of carbonyl compounds. Finally, this review is complemented by examples of the employment of oxazolidinones for the stereoselective reaction of auxiliary-bound carbenium ions or carbanions. Throughout this review, references for the application of this highly useful class of chiral auxiliary in the context of natural product synthesis are provided. Keywords Aldol reaction · Chiral auxiliary · Conjugate addition · Enolate · Oxazolidinones

1 Introduction Chiral oxazolidinones belong to the most successful heterocycles for the diastereoselective transformation of carboxylic acid derivatives. Their initial employment for the generation of chiral enolates and subsequent alkylation, aldol reaction, or heterofunctionalization has later been complemented by their application in electrophilic transformations or conjugate addition reactions. Key properties of oxazolidinones for their broad application include their easy access from the chiral pool, straightforward introduction of the auxiliary in the substrate of choice and subsequent cleavage under mild conditions, as well as their high reliability with respect to diastereoselectivity and predictability of absolute configuration. Since the seminal reports by Evans and coworkers [1], the field of oxazolidinone auxiliaries has substantially broadened with respect to complementary stereoselectivities, novel transformations, and applications in asymmetric catalysis [2]. This chapter describes the preparation of optically active oxazolidinones, their employment as auxiliaries in diastereoselective reactions, and selected examples of natural product syntheses using this well-established methodology. Since the application of oxazolidinones as auxiliaries has already reviewed earlier [3–6], this chapter focusses mostly on recent developments.

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2 Synthesis of Optically Active Oxazolidinones One of the driving factors for success of oxazolidinones as chiral auxiliaries was their ready availability from (L)-amino acids. Upon reduction of the typically unprotected amino acids with lithium aluminum hydride, the corresponding 1,2-amino alcohols are obtained in high yields and enantiopurity (Scheme 1) [7]. For small amino alcohols, separation from the aluminum salts after work-up may be troublesome. In this case, also lithium borohydride in combination with trimethylsilyl chloride or sodium borohydride with iodine has been efficiently employed [8, 9]. Although there are 19 proteinogenic, chiral amino acids (except glycine without a stereocenter), (L)-valinol and (L)-phenyl-alaninol have found most widespread application in this respect. The amino alcohols are then transformed into the corresponding oxazolidinones by refluxing in diethyl carbonate and azeotropic removal of ethanol [10]. Alternatively, related carbonic acid derivatives such as phosgene, Staab’s reagent, etc. can be used [11]. For the preparation of chiral 1,2-amino alcohols, which are not directly derived from naturally occurring amino acids, numerous protocols involving resolution, diastereoselective synthesis, as well as enantioselective catalysis have been reported. For example, phenyl-glycine and tert-butyl-glycine, prepared by enantioselective Strecker reaction to benzaldehyde imines or pivaldehyde imines, respectively, followed by hydrolysis of the amino nitriles, are well available today (Scheme 2) [12–15]. Synthetically appealing for the stereoselective preparation of 4,5-disubstituted oxazolidinones from amino alcohols is the treatment with carbon dioxide in the presence of tri-n-butyl-phosphine, DBU, and dibenzyl azodicarboxylate (DBAD) [16]. Herein, presumably the free carbamic acid derivative formed in situ undergoes a Mitsunobu-type reaction with retention of configuration at 5-position, when an unprotected amine is used and inversion of configuration in the case of methyl- or benzyl-amines (Scheme 3). An enantioselective, ruthenium-catalyzed synthesis of oxazolidinones from racemic diols and urea was reported by Beller and coworkers in 2016 (Scheme 4) [17]. Therein, nucleophilic displacement generates a hydroxy-carbamate which is

Scheme 1 Preparation of oxazolidinones from (L)amino acids

Scheme 2 Enantioselective synthesis of nonnatural, chiral amino acids by Strecker reaction

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Scheme 3 Carboxylation of amino alcohols followed by Mitsunobu-type cyclization

Scheme 4 Synthesis of chiral oxazolidinones by enantioselective ruthenium catalysis

Scheme 5 Copper-catalyzed desymmetrization of di-hydroxy-carbamates

oxidized by the catalyst to the ketone. The concomitantly formed ruthenium hydride then reduces the oxazolinone which is generated by in situ condensation. In the presence of an optically active copper bis-oxazoline catalyst dihydoxycarbamates undergo a desymmetrization reaction, in which a quaternary stereocenter is formed in very high enantioselectivities (Scheme 5) [18]. The intermediately formed hydroxy-oxazolidinone is not isolated but treated with benzoyl chloride. It has been proposed that the same chiral copper catalysts promote the benzoate formation rendering the process an additional kinetic resolution in which the enantiomeric excess is increased further. A closely related catalyst has also been successfully employed for the synthesis of 4,5-disubstituted oxazolidinones by copper-mediated amination of α-ketoesters or β-ketoesters [19, 20]. The substrates are most likely bound in a bidentate fashion and the corresponding enol aminated by dibenzyl azodicarboxylate (DBAD). Upon diastereoselective reduction of the ketone by L-selectride and hydrogenation, the N-amino-oxazolidinone is obtained. Reductive cleavage of the hydrazine provides the desired product (Scheme 6). For cyclic, chiral 1,2-amino alcohols, also enantioselective aminohydroxylations of alkenes, are a straightforward pathway. Such approach also allows the introduction of additional substituents. Due to the stereospecific cis-functionalization, the alkene configuration determines the formation of either diastereomeric products (Scheme 7) [21]. Although the reaction shows medium to high regioselectivity for the amino group being introduced in the benzylic position, typically also the opposite regioisomer is formed.

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Scheme 6 Oxazolidinone formation by copper-catalyzed amination of α-ketoesters

Scheme 7 Preparation of optically active oxazolidinones by aminohydroxylation of alkenes Scheme 8 Rhodiumcatalyzed enantioselective opening of oxabicyclic alkenes

Scheme 9 Palladium-catalyzed opening of vinyl-oxiranes

A complementary approach for the preparation of 3-aryl-oxazolidinones has been disclosed by Lautens and coworkers [22]. Oxabicyclic alkenes serve as starting materials for the rhodium-catalyzed asymmetric ring opening. The chiral allyl cation formed that way is attacked by an isocyanate anion. The resulting alkyl isocyanate undergoes addition with the benzyl alkoxide forming the oxazolidinone (Scheme 8). In recent years, epoxides have evolved as highly suitable substrates for the preparation of chiral oxazolidinones. This is partly due to the fact that a plethora of reliable methods has been developed in the past for the synthesis of enantiomerically pure epoxides. In addition, epoxides provide substantial ring strain to render oxazolidinone formation thermodynamically favorable. For example, vinyl oxiranes undergo ring opening in the presence of optically active palladium complexes forming the alkoxy-allyl-palladium intermediates (Scheme 9) [23]. By addition of isocyanides, these form oxazolidinones with very high selectivity (up to

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Scheme 10 Phosphonium-mediated formation of oxazolidinones from epoxides

94% ee). The enantioselectivity is induced by the metal complex. Therefore, racemic epoxides can be employed. Suga and coworkers have presented the opening of chiral epoxides using tetraarylphosphonium salts [24, 25]. In particular, glycidol derivatives are suitable starting materials for this transformation because they are very well available in enantiomerically pure form, for example, by Sharpless epoxidation. The p-cresyl substituent in the catalyst plays the role of a Brønstedt acid for the activation of the epoxide. Then, the iodide counteranion presumably attacks forming the iodohydrin. Isocyanate addition and catalyst-supported nucleophilic displacement then close the heterocycle (Scheme 10). In addition to metal complexes or organocatalysts, also enzymes can mediate the ring enlargement of epoxides to oxazolidinones. In an enantiomer-differentiating reaction, a halohydrin dehalogenase promotes epoxide opening and subsequent heterocycle formation in the presence of sodium isocyanate in buffered solution [26]. The product is isolated with a selectivity of 69–98% ee. Also, the epoxide enantiomer, which is not consumed in the reaction, can be recovered in 78–96% ee. The kinetic resolution shows a high selectivity factor (E > 200). As suitable electrophiles in the catalytic epoxide opening, not only isocyanates have been successfully employed but also carbamates. In particular chiral metal salen complexes promote this reaction in very high selectivities (>99%). Both kinetic resolution of racemic epoxides and desymmetrization of meso-epoxides have been demonstrated [27, 28]. Depending on the specific carbamate used, either additional base is required (e.g., using H2NCO2Et) or cyclization occurs in situ (e.g., employing H2NCO2Ph). The synthetically challenging desymmetrization of small substrates such as cyclohexene oxide presumable requires double activation for high selectivity. This entropically disfavored alignment of both reaction partners can be facilitated by a dimeric catalyst system. When a monomeric chiral salen-cobalt triflate precatalyst was used, low enantioselectivities were observed (up to 33% ee). In contrast, an oligomeric catalyst system incorporating two or three salencobalt moieties provided the desired products in very selectivities (up to >99% ee) (Scheme 11). Complementing the epoxide opening with N-nucleophiles also carbonate formation offers a synthetic approach to oxazolidinones. When amino-oxiranes are treated with carbon dioxide in the presence of an aluminum triphenoxide catalyst, cyclic carbonates are formed in the presence of tetrabutylammonium iodide (Scheme 12) [29]. In contrast, oxazolidinones are produced when dimethylaminopyridine (DMAP) is used as additive. In both cases, enantiopurity is fully translated from the starting material.

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Scheme 11 Desymmetrization of meso-epoxides by chiral cobalt-salen complexes

Scheme 12 Aluminum-catalyzed carbamate formation Scheme 13 Palladiummediated carboxylation of allyl-aziridines

While aziridines are more difficult to prepare in highly enantioselective fashion when compared to epoxides, they are equally suitable for the synthesis of oxazolidinone derivatives. For example, vinyl-sulfonyl-aziridines open already at low temperatures in the presence of Pd(0)-catalysts to the amido-palladium-allyl intermediates and cyclize to the five-membered heterocycle when exposed to carbon dioxide (Scheme 13) [30]. Herein, the relative configuration at the allylic position is retained. Non-activated aziridines can be opened employing a methodology similar to the transformation of epoxides described above. Chromium-salen complexes allow for direct transformation of aziridines and carbon dioxide [31]. In this transformation, a mixture of regioisomers is obtained with the 5-substituted isomer the major one. An organocatalytic enantioselective aziridination followed by diastereoselective ring enlargement has reported by Jørgensen and coworkers [32]. In this two-step

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Scheme 14 Organocatalytic enantioselective aziridination with subsequent oxazolidinone formation

Scheme 15 Intramolecular, iron-catalyzed fluoro-carbamoylation of alkenes. XtalFluorE ¼ (Diethylamino)difluorosulfonium tetrafluoroborate

protocol, α,β-unsaturated ketones are aziridinated with BocNH-OTs in the presence of 9-epi-aminoquinine and (R)-mandelic acid. The Boc-protected aziridine is then treated with sodium iodide in acetone giving the 4,5-disubstituted oxazolidinones in 94–99% ee (Scheme 14). Allyl carbamates offer the possibility for a straightforward access to oxazolidinones upon electrophilic activation of the double-bond and subsequent nucleophilic ring closure. Depending whether O- or N-allyl carbamates are employed, different substitution patterns are built up quickly. If electrophilic halogenating agents are used, the corresponding haloalkyl-oxazolidinones are formed in typically excellent diastereoselectivities. Recent examples include the iodocarbamoylation using tert-butyl hypoiodite [33] or the iron-catalyzed fluorocarbamoylation of O-allyl-N-carboxy-carbamates in the presence of fluorides [34]. In the latter process, it has been proposed that the iron catalyst forms an ironnitrene intermediate. The occurrence of an acyl-aziridine is less likely based on control experiments. However, in relation to rhodium-catalyzed transformations in which carbamates are oxidized with hypervalent iodine compounds, aziridine formation appears to be a major pathway [35]. When optically active tetraphenyl-bisoxazolines are added as ligands for iron, the process showed in one case an enantioselectivity of 81% ee, but a medium diastereoselectivity (3.2:1) (Scheme 15). In the absence of fluoride, using a closely related reaction protocol also the corresponding acyl-benzyl alcohols can be obtained in enantioselectivities up to 71% ee [36]. A highly enantioselective bromo-carbamoylation of O-allyl-N-tosyl-carbamates has reported by Shi and coworkers in 2013 [37]. Utilizing a chiral scandium-

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Scheme 16 Scandium-mediated enantioselective bromo-carbamoylation

Scheme 17 Organocatalytic synthesis of oxazolidinones from γ-hydroxy-but-2-enones

bisamido-complex, the bromonium ion formed upon attack of N-bromosuccinimid to the C¼C double bond is opened in a nucleophilic substitution reaction (Scheme 16). The nature of the brominating agent has little effect on the observed enantioselectivity which is in line with a fast intermolecular transfer-bromination mechanism. Highest enantioselectivities are observed with Z-olefins. In the context of oxazolidinones as useful protecting groups in carbohydrate chemistry, the mechanistically related photochemical cleavage of azidoformates and following nitrene addition to electron-rich C¼C double bonds, such as enol ethers, has been reported by Rojas and coworkers [38]. A synthetically convenient way of promote nucleophilic attack of a carbamate to an olefinic double bond is by installing an electron-withdrawing group, thereby generating a Michael system [39–41]. However, the development of an enantioselective methodology is less straightforward requiring careful control of the intramolecular attack and the transition state geometry. In 2013, Fukata, Asano, and Matsubara disclosed the organocatalytic, enantioselective oxazolidinone synthesis starting from γ-hydroxy-but-2-enones and tosylisocyanates [36]. In the presence of an aminothiourea derivative prepared from cinchonine, the intermediately formed carbamate cyclizes already at low temperatures (Scheme 17). Alternatively to the molecular handle of a Michael system, the intramolecular nucleophilic attack of the carbamate can also be promoted by employing a palladium allyl intermediate. In a Tsuji-Trost-type reaction, diacylated butendiols are activated with suitable palladium complexes. Overman and Remarchuk presented an enantioselective variant of the transformation using a chiral oxazoline ligand derived from ferrocene showing very yields and enantioselectivity (Scheme 18) [42]. For this process, an aminopalladation has been proposed as the key step. In a related fashion, propargylic carbonates can be cyclized to the corresponding allenyliden-

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Scheme 18 Enantioselective Tsuji-Trost intramolecular allylation of carbamates

Scheme 19 Photochemical palladium-mediated oxazolidinone formation (TBD ¼ 1,5,7Triazabicyclo[4.4.0]dec-5-ene)

Scheme 20 Rhodium-catalyzed CH-insertion of carbamates under oxidative conditions

oxazolidinones [43]. Herein, no metal catalyst is needed, but addition of DBU at elevated temperatures is sufficient. Apart from palladium allyl intermediates, also photochemical transformations involving iridium or palladium catalysts have been reported recently [44, 45]. Herein, allyl carbamates (also generated in situ from simple amines and carbon dioxide) undergo cyclization to the double bond. A radical mechanism is likely to proceed in this case involving Ir(II) or Pd(I) intermediates, respectively. In the presence of alkyl halides, further functionalization of the former double bond can be achieved (Scheme 19) [41]. Most recently, an electrochemical methodology for radical generation has been explored [46]. A particularly attractive synthetic access to oxazolidinones is opened by transition metal-catalyzed CH-insertion into alkylcarbamates. For example, this was pioneered by the group of Du Bois using hypervalent iodine reagents and a rhodium catalyst (Scheme 20) [47]. Herein, the formation of a rhodium-nitrene intermediate is likely. Upon oxidation of the carbamate with PhI(OAc)2, acetic acid is generated which hampers catalytic turnover. Magnesium oxide was found as suitable scavenger agent. The transformation is regioselective and renders the five-membered ring oxazolidinones in racemic form. Insertion in benzylic, secondary, as well as tertiary CH-groups is equally effective. N-Sulfonyloxycarbamates have also been reported to undergo CH-insertion reactions in the presence of rhodium catalysts [48, 49]. In contrast to common carbamates, no further oxidation is required. The CH-reaction itself is stereospecific allowing access of optically active oxazolidinones starting from chiral alkylcarbamates (Scheme 21).

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Scheme 21 Stereospecific rhodium-mediated CH-insertion

Scheme 22 Palladiumcatalyzed CH-activation of homoallylcarbamates

Scheme 23 Organocatalytic kinetic resolution of oxazolidinones

In addition to rhodium-catalyzed CH-insertions, also palladium complexes are capable mediating this reaction when suitable ligands are employed. In this respect, bis-sulfoxides have been reported by White and coworkers for the ring closure of Ohomoallylcarbamates (Scheme 22) [50, 51]. The diastereoselectivities of the transformation vary substantially, but predominantly the trans-isomer in racemic form is obtained. It has been proposed that allylic CH-activation results in a palladium allyl species which is regioselectively attacked by the nucleophilic carbamate. The methodology has been extended toward the related transformation of Nhomoallylcarbamates [52]. The straightforward synthesis of racemic oxazolidinones calls for the development of kinetic resolution in order to isolate oxazolidinones in high optical purity. While a desymmetrization of 1,3-difluoropropan-2-carbamates has been developed by Haufe, Shibata, and coworkers [53], an organocatalytic, kinetic resolution of oxazolidinones by enantioselective N-acylation was reported in 2006 [54– 56]. Herein, both unreacted oxazolidinone enantiomer and acylated enantiomer are obtained with a selectivity factor of 170 (Scheme 23). A related kinetic resolution mediated by a chiral Brønstedt acid has recently been disclosed by Yang and coworkers [57]. Herein, a β-hydroxy-vinyl-carbamate is used as racemate for the acid-catalyzed oxazolidinone formation. The resulting alkylidene-oxazolidinone can then be hydrogenated using Raney nickel with a diastereoselectivity of >25:1 (Scheme 24). A highly enantioselective synthesis of oxazolidinones by organocatalytic α-selenenylation of aldehydes has been reported by Marini, Melchiorre, and coworkers [58]. In the presence of diaryl-prolinol derivatives, aldehydes are functionalized using PhthalN-SePh as electrophilic selenenylation reagent.

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Scheme 24 Kinetic resolution of β-hydroxy-vinyl-carbamates

Scheme 25 Organocatalytic synthesis of oxazolidinones by enantioselective α-selenenylation

The reaction most likely proceeds via the chiral enamine. Upon reduction of the configurationally sensitive product, the corresponding selenoalcohol is obtained in selectivities of 95–99% ee (Scheme 25). Addition of an isocyanate forms the carbamate. When the selenoether is oxidized using mCPBA, nucleophilic substitution leads to formation of the optically active heterocycle.

3 Optically Active Oxazolidinones as Chiral Auxiliaries Although chiral oxazolidinones have been reported for a plethora of different transformations, their main application remains without doubt the diastereoselective functionalization of carboxylic acids. Herein, they combine the good stereochemical induction of amides with the straightforward cleavability of esters. In addition, high levels of selectivity are typically observed for the functionalization of carboxylic esters in α-position (such as in enolate alkylations or heterofunctionalizations as well as aldol reactions), in β-position (in conjugate additions or pericyclic reactions), or occasionally in remote positions. The synthesis of N-acyl oxazolidinones as the starting materials for further functionalization is typically achieved by deprotonation of the oxazolidinone with bases such as n-butyl lithium and the corresponding lithium salt is then reacted with an acid chloride or a (mixed) anhydride (Scheme 26) [59, 60]. As a milder alternative, the direct acylation of oxazolidinones in the presence of triethylamine and N,N-dimethyl-4-aminopyridine (DMAP) has been reported [61]. In addition, Evans and coworkers reported the combination of titanium tetrachloride and a tertiary amine base (e.g., diisopropylethylamine, DIPEA) for soft enolization [62]. The use of an excess of strong bases should be particularly avoided in the

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Scheme 26 Preparation of N-acyl oxazolidinones

Scheme 27 Formation of enolates from N-acyl oxazolidinones

Scheme 28 Diastereoselective alkylation of a lithiated propionyl oxazolidinone

preparation of N-acyl oxazolidinones derived from ephedrine derivatives since epimerization at the benzylic position can be a problem.

3.1

Diastereoselective α-Functionalization of Optically Active Oxazolidinones

N-Acyl oxazolidinones undergo deprotonation in the α-position of the carboxylic acid derivative. Commonly, bases such as lithium diisopropylamide (LDA) or sodium hexamethyldisilazide (NaHMDS) are employed for this. Due to the strong A1,3-repulsion between the α-substituent and the heterocyclic ring, Z-enolates are formed exclusively [63–65]. Depending on the capability of the Lewis acid to extend coordination and also the polarity of the solvent, chelate formation overcomes the intrinsic dipole repulsion of the intermediate allowing for stereodivergence in the subsequent transformation (Scheme 27) [66, 67]. Upon generation of the N-acyl oxazolidinone enolate functionalization with a variety of different electrophiles is possible. For example, treatment of the lithiated ephedrine-derived propionyl-oxazolidinone with benzyl bromide results in a highly diastereoselective alkylation (Scheme 28) [59]. The described methodology can be further extended toward various alkylating agents [68] and also responds well with respect to different substituents in α-position of the acyl-oxazolidinone. For example, an alkoxy group is tolerated allowing for a stereoselective access to chiral lactic acid derivatives from glycolates (Scheme 29) [69]. Most common O-protecting groups are tolerated, and selectivities are typically >98:2 de.

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Scheme 29 Diastereoselective alkylation of oxazolidinone glycolates

Scheme 30 Synthesis of amino acids with a quaternary α-stereo center Scheme 31 Allylation of oxazolidinone bromopropionates under radical conditions

Oxazolidinones are not restricted to be used solely in the form of N-acyloxazolidinones for alkylations but can also serve as auxiliaries for the alkylation of α-amino-carbonyl compounds. This has been exemplified by Wenglowsky and Hegedus [70]. In this method, palladium-catalyzed Tsuji-Trost alkylation of oxazolidinones followed by ozonolysis and addition of a primary amine to the aldehyde formed that way gives the corresponding substituted α-N-oxazolidinonylimines (Scheme 30). Diastereoselective alkylation and subsequent hydrogenation lead to the nonnatural amino acids incorporating a quaternary α-stereocenter. Alkylation of enolates is not restricted to electrophilic reagents but can also be achieved under radical conditions. This has been pioneered by the group of Sibi [71, 72]. Using this method, α-bromo carboxylates are alkylated with an allyl tin reagent and triethylborane/oxygen as radical initiator (Scheme 31). Best selectivities are obtained employing a chiral oxazolidinone carrying a benzhydryl substituent and a coordinating Lewis acid (such as magnesium bromide or scandium triflate). When the reaction is conducted in the presence of simple alkenes instead of allyl tin reagents, insertion of the C¼C double bond into the C-Br bond is observed and the corresponding γ-bromoalkyl derivatives isolated [73]. An electrochemical carboxylation of bromopropionyl oxazolidinones was reported by Feroci, Inesi, and coworkers [74]. Using an aluminum anode and a platinum cathode and tetra-n-butylammonium tetrafluoroborate as electrolyte, the bromopropionate is reduced and carboxylated in the presence of carbon dioxide (Scheme 32). The corresponding methylmalonate was isolated as the methyl ester upon treatment with diazomethane. However, diastereoselectivities are typically low (dr 59:41) favoring the product of the non-chelated metal enolate. As was shown in

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Scheme 32 Electrosynthetic carboxylation of bromopropionyl oxazolidinones

Scheme 33 Electrophilic vinylation of acyl-oxazolidinones using alkenylselenonium salts

Scheme 34 Synthesis of sintokamide B involving a ruthenium-mediated trichloromethylation

control experiment, the reaction is at least partially under kinetic control since equilibration under basic conditions gives predominately the other diastereomers. Instead of electrophilic allylation reagents which are readily available, the introduction of a vinyl group in α-position of an acyl-oxazolidinone is less straightforward. It can be realized by using an electrophilic alkenylselenonium salt [75]. The reaction proceeds in good yields and diastereoselectivities (Scheme 33). A special challenge in the α-alkylation of carbonyl compounds is the introduction of perhaloalkyl groups. Depending on the specific halogenated compound, either the transformations are conducted under radical conditions or electrophilic reagents are employed. For example, trichloromethylation of enolates has been accomplished by treatment with BrCCl3 in the presence of a ruthenium catalyst such as [RuCl2(PPh3)3] [76, 77]. The enolate is conformationally rigidified by complexation with titanium tetrachloride. The applicability of the new methodology in the context of complex natural product synthesis has been exemplified, for example, in the total synthesis of sintokamide B (Scheme 34) [78]. The method has later been extended to the preparation of the corresponding perfluoroalkylated products [79]. Herein, titanium enolates do not form the desired products at all. In contrast, transformation of

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Scheme 35 Electrophilic trifluoromethylation of acyl-oxazolidinones with Togni’s reagent Scheme 36 Palladiumcatalyzed α-arylation of silyl enolates

Scheme 37 Total synthesis of ()bursehemin by oxidative enolate heterocoupling

the zirconium or hafnium enolates leads to effective product formation representing a remarkable case of differential homologue reactivity. While perfluoroalkylations of carbonyl compounds are commonly conducted under radical conditions, also electrophilic reagents (such as Umemoto’s reagent [80, 81] or Togni’s reagent [82]) have been successfully employed [83]. This is exemplified in the preparation of enantiopure α-trifluoromethyl-carboxylic acids (Scheme 35) [84]. As chiral auxiliary, 4-phenyl-oxazolidinone is employed. α-Arylations of acyl-oxazolidinones under mild conditions have been reported using palladium catalysts (Scheme 36) [85]. As additive, zinc fluoride or zinc tertbutoxide is added to the trimethylsilyl ethers. The method is also applicable to the functionalization of α-alkoxy-carbonyl compounds. In contrast to the electrophilic α-functionalizations discussed so far, C–C bond formation is also possible under oxidative conditions. Baran and coworkers presented enolate heterocouplings of acyl-oxazolidinones in the presence of either copper(II) or iron(III) salts (Scheme 37) [86, 87]. The products are typically isolated as diastereomeric mixtures (dr up to 2.8:1). The methodology has been applied in the context of the natural product synthesis of ()-bursehemin [83]. A special electrophile as reaction partner for enolates are Fischer carbenes derived from chromium hexacarbonyl. In a Dötz-type multicomponent reaction, the

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Scheme 38 Enantioselective Dötz-type synthesis of cyclohexenones

Scheme 39 Diastereoselective cyclopropanation of acryloyl-oxazolidinones

corresponding chiral addition product, a metalated acyl-oxazolidinone, is then attacked by a propargyl Grignard reagent [88] (Scheme 38). The bis-allenyl-intermediate formed that way then undergoes ring closure forming the corresponding cyclohexenone in excellent enantioselectivities. Optically active acyl oxazolidinones derived from dihaloacetic acid or diazoacetic acid can serve as carbenoid precursors upon metalation or in the presence of transition metal catalysis, respectively. This is exemplified in cyclopropanation reaction of acrylates [89]. Therein, the dibromofluoroacetyl imide is metalated under Reformatsky conditions with elemental zinc in the presence of lithium chloride for highest selectivity (Scheme 39). It has been proposed that the reaction proceeds stepwise via a zinc enolate intermediate. Diastereoselective heterofunctionalization of acyl-oxazolidinones in α-position is as straightforward as alkylations when suitable electrophilic or radical reagents or used. For example, α-halogenations can be achieved by the corresponding N-halosuccinimides [90] or N-halo-benzenesulfonylimides [91, 92]. Typically, brominations show higher diastereoselectivity compared to chlorinations [93]. A synthetic sequence involving α-bromination followed by SN2-discplacement under inversion of configuration allows for access to diastereomers with are difficult to prepare otherwise. This methodology has been used for the preparation of unnatural amino acids by via azidation [94, 95]. Subsequent hetero-functionalizations and alkylations lead to highly functionalized, chiral carboxylic acids with a tertiary stereo center (Scheme 40) [86]. Adapting the radical functionalization of titanium enolates by a perhaloalkyl group as described above, related methodology has been developed by Mabe and Zakarian [96] complementing the established α-hydroxylation protocols by Evans

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Scheme 40 Synthesis of fluorinated carboxylic acids with a quaternary α-stereo center

Scheme 41 α-Hydroxylation of titanium enolates

[97] or Davis [98]. Herein, strongly basic conditions or use of ruthenium complexes as catalyst are not required when TEMPO as stable radical is employed. By reductive N-O-cleavage, the free secondary alcohols are prepared (Scheme 41).

3.2

Diastereoselective Aldol Reactions and Related Transformations

There are few reactions which rival the aldol reaction when it comes to highly versatile, operationally simple, and highly stereoselective carbon–carbon bondforming transformations. Therefore, the reaction of an enol or enolate with a carbonyl compounds is employed by nature as one of the key transformations for natural products and has challenged chemists for more than a century. In order to control the specific outcome of an aldol reaction, the following aspects need to be considered: 1. Regioselectivity in the enolate formation determines the specific aldol product which is formed. Commonly, kinetic deprotonation is achieved by a sterically encumbered, strong base. This irreversible deprotonation can be effected, for example, by lithium diisopropylamide (LDA) or sodium hexamethyldisilazide (NaHMDS). In contrast, deprotonation with a weaker base under equilibrium conditions renders the thermodynamically more stable product, which typically embodies the higher substituted double bond. 2. E/Z-Stereoselectivity in the enolate formation is a precondition in most cases for stereoselective aldol reactions, since opposite stereoisomers typically lead to opposite aldol epimers as well. While secondary amides and related derivatives (such as acyl-oxazolidinones) show good Z-selectivity due to minimization of allylic A1,3-strain, esters can be more difficult substrates in this respect.

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Scheme 42 Evans syn-aldol formation employing acyl-oxazolidinones

3. Deprotonation of the carbonyl compound by the enolate and concomitant equilibrium formation hampers selective aldol formation due to lack of chemoselectivity. While this nuisance can be avoided by employment of either compounds which no α-protons or doubly activated carbonyl compounds, the more general solution is the intermediate formation of boron enolates or silyl enol ethers [99, 100], in particular in the area of diastereoselective aldol transformations. 4. Once the desired enolate is obtained in good regio- and stereoselectivity, diastereoselectivity in the aldol reaction requires diastereoface-differentiation in both the enolate and carbonyl compound. Oxazolidinones have emerged as a gold standard chiral auxiliary for aldol reactions as they combine good availability, high selectivity, and straightforward cleavability [1, 2]. This is exemplified in the aldol reaction of propionyloxazolidinones with aldehydes (Scheme 42). For this, the acyl-oxazolidinone is transformed into the boron enolate upon reaction with dibutylboron triflate in the presence of either Hünig’s base or triethylamine. The latter has been recommended for better selectivities due to a beneficial effect of the corresponding ammonium salt in the aldol transition state [101, 102]. For boron enolates, activation of the aldehyde in a closed Zimmerman-Traxler transition state requires loss of coordination to the oxazolidinone carbonyl group. Due to the dipole repulsion, the chiral auxiliary orients in a way that attack of the enolate from the Si-face is preferred (for the stereocontrolled aldol reaction of chiral amino acids, see [103]). This methodology was extended toward the formation of the other syn-aldol products (“non-Evans-syn” product) by the group of Crimmins [104, 105]. Using a slightly modified auxiliary incorporating a thiazolidinethione, both syn products are accessible when titanium enolates are formed in the presence of different equivalents of sparteine. In this stereodivergent approach, additional binding of titanium to the thiocarbonyl group results in a rotation of the chiral auxiliary exposing now the Re-side of the enolate toward attack of the aldehyde (Scheme 43). The coordination mode on titanium, its influence on reactivity, and coordination of remote donors has been addressed by in-depth DFT calculations [106, 107]. In addition to methodology accessing both syn-aldol products, the Evans group has extended the use of chiral oxazolidinones also toward the highly selective preparation of the anti-aldol products which have challenged synthetic chemists

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Scheme 43 Crimmins’ stereodivergent syn-aldol product formation

Scheme 44 Magnesium-catalyzed anti-aldol product formation

Scheme 45 Stereoselective aldol reaction of crotonyl-oxazolidinones

for a substantial time. By using of catalytic amounts of magnesium chloride and stoichiometric quantities of trimethylsilyl chloride, the “non-Evans-anti” product is formed presumably via a six-membered ring boat transition state (Scheme 44) [108]. When the corresponding thiazolidinethione is employed as chiral auxiliary, the “Evans-anti” product has been isolated in similar selectivities. The conformational analysis of enolates with alkali and earth-alkali metal countercations is typically hampered by aggregate formation and has been the subject of several computational studies [109, 110]. The acyl-oxazolidinone methodology has been extended toward the application of crotonate imide starting materials [111]. Under almost identical reaction conditions described before, deprotonation in γ-positions renders the unsaturated enolate which undergoes stereoselective aldol reactions in an analogous fashion (Scheme 45). This has been exemplified in the context of the total synthesis of the polyether antibiotic ionomycin [112].

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Scheme 46 γ-Selective addition of unsaturated enolates

Scheme 47 Diastereoselective repetitive aldol additions (Xc ¼ (S)-4-isopropyl-oxazolidione)

When the 2-position of the unsaturated enolate is additionally substituted, also attack of the γ-position on a suitable electrophile is observed. Although the stereocenter in the chiral auxiliary is very remote to exert stereochemical induction, very high diastereoselectivities can be observed. This has been exemplified in the total synthesis of oxindole alkaloids convolutamydines B and E [113]. Herein, an unsaturated silylenol ether undergoes a Mukaiyama-type aldol addition to dibromoisatin in the presence of titanium tetrachloride as Lewis acid (Scheme 46). The product is formed in remarkable diastereoselectivity via an open transition state. A particularly attractive feature of the Evans-methodology in the context of natural product synthesis, such as polyketides, is its consecutive application upon oxidation of the aldol product to the β-keto-carboxylic acid. The ketone in turn can then be deprotonated to an enolate and undergo a second aldol addition (Scheme 47) [114]. The stereocenter in 3-position between the two carbonyl moieties does not epimerize, because the required conformation – perpendicular to the amide carbonyl group – is inaccessible due to increasing A1,3-strain between the C2-substituent and the oxazolidinone ring. Application of coordinating or non-coordinating Lewis acids renders both syn-aldol products in high selectivities. Subsequently, the β-ketone is selectively reduced to the corresponding secondary alcohols by either sodium trisacetoxy-borohydride (anti-syn-product) or diisobutylaluminum hydride (syn-synproduct), respectively (Scheme 48). An example for the application of this concept is found, e.g., in the total synthesis of oasomycin A [115]. Despite the beauty and success of the Evans oxazolidinone method for the stereoselective aldol reaction of various carboxylic acids, it is not applicable in its original form to acetic acid as such since the reaction of acetyl-oxazolidinones shows

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Scheme 48 Diastereoselective reduction of β-keto-imides

Scheme 49 Anti-selective aldol reaction of 2-chloroacetyloxazolidinones

Scheme 50 Tin-mediated diastereoselective acetate aldol reaction

poor selectivity [116]. As a synthetic loophole, acetic acid derivatives with removable functional groups such as thioethers or a halogen substituent can lead to acetate aldol products in high diastereoselectivity [117, 118]. In the case of monochloroacetyl-oxazolidinones, the stereochemical outcome is highly dependent on the enolate counter cation [119–121]. High syn-selectivities are observed for boron- or tin(II)-enolates, while tin(IV)-enolate give predominantly anti-aldol products (Scheme 49). In contrast to acetyl-oxazolidinones, the corresponding oxazolidinethiones [122] or thiazolidinethiones [123] derivatives, respectively, undergo aldol reactions in a much higher diastereoselectivity in the presence of tin(II) triflate as Lewis acid as has been shown by Nagao, Fujita, and coworkers (Scheme 50). It was proposed that this can be explained by a closed transition state involving coordination of the sulfur donor by the metal ion. The applicability of this method was demonstrated in the context of natural product synthesis, e.g., for the total synthesis of (+)-phorboxazole A [124]. Using oxazolidinethiones or thiazolidinethiones with optimized substitution patterns, also boron or titanium enolates can effectively employed for acetate aldol additions with high stereoselectivity. For example, auxiliaries derived from valinol [125], diphenylvalinol [126, 127], tert-butyl-glycinol [128, 129], camphor [130], or 4-mesityl-thiazolidinethione [131] have been reported (Scheme 51). Addition of sparteine as coordinating ligand for titanium allows for fine-tuning of reactivity. Under Reformatsky-type conditions, acetate aldols are formed in high diastereoselectivities when samarium iodide is employed [132]. In the transition state, presumably the samarium (III) center is coordinated by the carbonyl oxygen atom of the auxiliary leading to the observed stereochemical outcome (Scheme 52). This has been exemplified, for example, in the stereoselective synthesis of the natural

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Scheme 51 Titanium-mediated acetate aldol reaction

Scheme 52 Stereoselective aldol reactions under Reformatsky-type conditions

product prepiscibactin [133]. In comparison, generation of chromium enolates under Reformatsky conditions lead to preferential anti-aldol products [134]. The comparison between classical enolate formation by deprotonation and under Reformatsky conditions gives rise to stereodivergence [62], as has been exemplified by Ishihara and coworkers [135]. Herein, trifluoropropionic acid derivatives carrying the same 4-benzyl-oxazolidinone are submitted to soft deprotonation and subsequent Z-titanium enolate formation which upon treatment with the aldehyde gives the non-Evans-syn product via a closed Zimmerman-Traxler transition state with additional coordination of the auxiliary as described above. In contrast, when the corresponding α-bromo-propionic acid derivative is metalated by zinc and the zinc enolate then reacted with an aldehyde in the presence of triethylaluminum, the Evans-anti product is formed. This has been rationalized by an open transition state (Scheme 53). In these studies the exclusive formation of the Evans-anti product was observed under Reformatsky-type conditions. In general, open transition states should be taken into account when an excess of Lewis acid is present and additional functional groups with donor atoms are available. This is exemplified in the anti-selective aldol reaction of titanium enolates derived from N-glycolyl-oxazolidinethiones [136]. Just by changing the order in addition of reagents, the transition state structure and therefore the stereochemical outcome can be reversed, as has been demonstrated, for example, by Hajra and coworkers (Scheme 54) [137]. The described methods have also been extended toward related Mannich-type reactions [138, 139]. An interesting case of stereodivergence has been reported by Watanabe, Yamazaki, and Kubota [140]. Herein, glutarimides with pseudo-C2-symmetry

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Scheme 53 Stereodivergent aldol reaction with open vs. closed transition states

Scheme 54 Reversal of selectivity on aldol additions by premixing

Scheme 55 Stereodivergent aldol reaction of glutarimides

form pseudoenantiomeric products depending on the nature and the amount of base employed for enolate formation (Scheme 55). It has been proposed that in the case of Hünig’s base, the adduct iPr2NEt.BBu2OTf is formed which is a stronger Lewis acid than the corresponding adduct with triethylamine. Therefore, an open transition state is favored leading to the opposite pseudoenantiomer formation compared to the normal Zimmerman-Traxler transition state responsible for stereo control in aldol reactions of boron enolates. Under the reaction conditions, direct displacement of one oxazolidinone auxiliary by the aldolate occurs rendering the corresponding lactones.

3.3

Diastereoselective Transformations of α,β-Unsaturated Acyl-oxazolidinones

In addition to the electrophilic functionalization of enolates carrying oxazolidinones as chiral auxiliaries, also the diastereoselective conjugate addition to crotonyloxazolidinones has found broad synthetic application extending the impact of this

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Scheme 56 Diastereoselective addition of cuprates to crotonyl-oxazolidinones

Scheme 57 Lithium-mediated, stereodivergent conjugate addition of Gilman cuprates to crotonates

successful methodology. Herein, various organometallic reagents have been investigated [141–143] and the methodology applied in the context of the synthesis of natural products or biologically relevant targets [144–146]. In later studies, it was found that for organocuprate addition to crotonates, the substituent in the 4-position of the oxazolidinone plays an important role [147]. For example, opposite epimers were formed using auxiliaries with the same absolute configuration in 4-position (Scheme 56). While it is less straightforward to propose a mechanistic rational for explaining the stereochemical outcome of the conjugate addition, in general, it was found that 4-phenyl-oxazolidinones are superior auxiliaries in terms of selectivity and reliability. Later developments include, for example, the introduction of α-substituents by subsequent treatment of the intermediately formed enolate with a suitable electrophile [148–150]. Even when using the same auxiliary, the stereoselectivity in the conjugate addition of cuprates to crotonates can be reversed by changing the reaction conditions. The strong coordinating effect of lithium ions present in Gilman cuprates presumably results in a chelation involving the carbonyl group of the auxiliary (Scheme 57) [151]. This is consistent with the observation that highest selectivities are found when employing diethyl ether rather than tetrahydrofuran as solvent due to its lower cation coordination potential. Likewise, addition of 12-crown-4 leads to preferential formation of the lk-product. It was anticipated that in this reaction, the added halosilane does not interfere in any crucial reaction step. An important extension of methodology for the conjugate introduction of alkyl groups by using cuprates is the generation of alkyl radicals [152]. Due to the high reactivity of such intermediates, reactions proceed at low temperatures, but careful stereocontrol is required [153]. Sibi and coworkers reported the synthesis and application of 4-benzhydryl-oxazolidinones as suitable auxiliaries [154–156]. Radical generation is effected at low temperatures by using triethylborane in the presence of oxygen (Scheme 58). After addition of the alkyl radical to the Michael system, the enoyl radical generated is quenched by addition of tributyltin hydride. In order to lock the conformation of the acyl-oxazolidinone, addition of a Lewis acid is

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Scheme 58 Conjugate alkylation under radical condition

Scheme 59 Synthesis of fluoroalkylated acyl-oxazolidinones

Scheme 60 Lewis acid-catalyzed crotylation of crotonoyl-oxazolidinones

required. In particular, ytterbium triflate proved optimal for this purpose. The method was extended toward the addition of prochiral alkyl radicals [157]. Herein, high anti-selectivity (up to 17:1) for the β- and γ-stereocenters was observed for monohaloalkyl radicals, while dialkyl-substituted products showed low syn-selectivity (up to 2:1). The described method was further developed for the conjugate perfluoroalkylation of crotonoyl-oxazolidinones [158]. Stereoselectivities in such transformations are very difficult to control due to the very high reactivity of such non-stabilized radicals. It was found that in these reactions, the addition of tributyltin hydride, which can be tedious to remove [159], is not necessary. In its absence the same products are obtained presumably by formation of the corresponding boron enolates. Although the transformation has low selectivity, the products can be easily isolated in pure form and further transformed into fluorinated butanolides or amino acid (Scheme 59) [160, 161]. In the Lewis-mediated addition of allyl or crotyl silanes or stannanes, respectively, to crotonyl oxazolidinones, the coordination mode (monodentate vs. chelate) determines the stereochemical outcome. It was found that both scandium triflate and zirconium chloride apparently prefer monodentate activation even in nonpolar solvents such as dichloromethane (Scheme 60) [162–164]. Both allylations and crotylations proceed in very good diastereoselectivities. Intramolecular allylation

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Scheme 61 Addition of glycine enolates to crotonoyl-oxazolidinones

Scheme 62 Photocatalytic α-arylation

has also been described for doubly activated 2-alkylidene-malonoyl-imides [165]. Herein, the activation by tin(IV) chloride resulted in highest selectivities. The addition of enolates to Michael acceptors has proven challenging in terms of stereocontrol and general applicability. In 2000, Soloshonok, Hruby, and coworker reported the synthesis of 3-substituted pyroglutamic acid derivatives by addition of a nickel-glycine complex to crotonoyl-oxazolidinones (Scheme 61) [166]. Upon deprotonation of the glycine derivative, fast addition to the crotonate occurs leading to the formation of the products as single diastereoisomers. It should be noted that the optically active nickel complex apparently does not interfere in the stereochemical outcome of the transformation but only the configuration of the oxazolidinone auxiliary determines its outcome. As described so far, attack of carbon nucleophiles exclusively occurred at the β-position following the reactivity pattern of Michael systems. Under photocatalytic conditions, also α-functionalization is possible [167]. This is exemplified in the Friedel-Crafts alkylation of aniline derivatives in the presence of an iridium photocatalyst, ferrous triflate, and irradiation of visible light (Scheme 62). Although good ortho-/para-selectivity (1:10) was achieved, the reaction was not diastereoselective. Apart from C-nucleophiles, also additions of heteroatom nucleophiles to crotonoyl-oxazolidinones have been studied. Herein, high nucleophilicity can be accompanied with lower selectivity, while a good leaving group capability can result in low selectivity as well because epimer mixtures are entropically always favored. For example, the treatment of a crotonoyl-oxazolidinone with boron trichloride at low temperatures gives the β-chloro derivative with a diastereomeric ration of 3:1, while the use of isopropoxy boron dichloride renders the opposite epimer with 1:2 dr (Scheme 63) [168].

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Scheme 63 Conjugate addition of boron chlorides to crotonates

Scheme 64 Diastereoselective formation of halo aldols

Scheme 65 Enantioselective cascade Michael-aldol addition of 2-mercapto-benzaldehydes to crotonates

The conjugate addition of halides to acrylates opens the way for an in situ generation of enolates in the sense of a Baylis-Hillman reaction generating a stereocenter in α-position. This has been exemplified in the addition of acryloyloxazolidinones to aldehydes in the presence of diethylaluminum iodide (Scheme 64) [169]. It has been proposed that the reaction proceeds via an open transition state. The halo aldol products are formed in high yield and diastereoisomeric ratios >95%. Related methodology has been developed for the intermediate addition of thiols. In a cascade Michael-aldol addition 2-mercaptobenzaldehyde derivatives add to crotonyl-oxazolidinones (Scheme 65) [170]. In this report the oxazolidinone does not incorporate an additional substituent and is therefore not chiral. Chiral induction is effected by an additional organocatalyst based on a cinchona alkaloid carrying a thiourea functional group. By hydrogen bonding to both carbonyl groups of the substrate, both activation of the electrophile and conformational locking are leading to high selectivities.

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Scheme 66 Intramolecular sulfur transfer in crotonoyl-oxazolidine-2-thiones

Scheme 67 Rhodium-mediated thiiran formation from diazoacetyl-oxazolidin-thiones

The diastereoselective introduction of a mercapto group in β-position of a crotonoyl-oxazolidinone has been achieved by intramolecular sulfur transfer from the corresponding oxazoline-2-thione [171, 172]. Lewis acid addition initiates the attack of the sulfur atom at the Michael position (Scheme 66). The intermediate is then hydrolyzed giving the oxazolidinone. Using this methodology synthetically challenging tertiary stereocenters can be created in very high selectivity. It should be noted that the stereochemical outcome is independent of the double bond configuration, as also E/Z-mixtures can be submitted to the reaction conditions without any loss of selectivity. The method was extended toward the diastereoselective synthesis of thiiranes [173, 174]. Herein, diazoacetyl-oxazolidin-2-thiones were transformed into the corresponding bicyclic ylide by rhodium-mediated loss of dinitrogen. Aldehyde addition leads to the tricyclic addition product which resulted in sulfur atom transfer giving predominantly the cis-configured thiirans in excellent diastereoselectivities (Scheme 67). Optically active β-amino acids have emerged as an interesting research area complementing the picture of the naturally occurring α-amino acids in terms of conformational space and superstructure formation [175]. Apart from the classical C1-extension methodology by an Arndt-Eistert reaction, the conjugate addition of amines or amides to crotonoyl oxazolidinones is a straightforward way for generating this compound class [176]. It was found that the addition of lithium dibenzylamide gives low selectivity (58% de) which was attributed to the flexibility of the crotonate to adopt different s-cis and s-trans conformers. In contrast, when optically active lithium benzyl-α-methylbenzylamide was used by a double asymmetric induction, the diastereoselectivity in this addition was >98% de for the matched and 66% de for the mismatched case (Scheme 68). In order to obtain the free amino acids, deprotection of both benzyl groups is achieved by hydrogenation with Pearlman’s catalyst. The methodology was further extended to the preparation

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Scheme 68 Synthesis of β-amino acid derivatives by double asymmetric induction

Scheme 69 Diastereoselective Diels-Alder reactions of crotonoyl-oxazolidinones

Scheme 70 Synthesis of ()-epibatidine by diastereoselective Diels-Alder reaction

of α-substituted β-amino acids by subsequent alkylation of the intermediately formed enolate [177]. The C¼C double bond in crotonoyl-oxazolidinones is not only subject to attack of a nucleophile but can also participate in various pericyclic reactions. In such transformations, several stereocenters are concomitantly formed by induction of the auxiliary. For example, Diels-Alder reactions proceed well with the electrondeficient crotonate as dienophile [178–181]. The addition of diethylaluminum chloride has proven beneficial for activation (Scheme 69). Herein, it was found that an excess of this Lewis acids (>1.0 equiv) leads to a reversal of selectivity, which has been explained by the formation of a cationic aluminum complex which is capable in coordinating the carbonyl group of the auxiliary [147]. A related effect for Et2AlCl has also been observed in another context such as in Felkin-Anh-controlled additions to carbonyl compounds [182]. Diels-Alder reactions of crotonyl-oxazolidinones have been demonstrated for both inter- and intramolecular transformations. The Diels-Alder reaction of substituted crotonyl-oxazolidinones has been successfully applied in the context of natural product synthesis such as in the synthesis of pulo’upone [183] or ()epibatidine [184]. In the latter synthesis, an azadiene was reacted with the crotonate in the presence of dimethylaluminum chloride (Scheme 70). The bicyclic lactam generated was further transformed into the desired product by a fluoride-promoted fragmentation and Hofmann rearrangement.

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Scheme 71 Diastereoselective [3 + 2]-cycloaddition forming pyrrolidines

Scheme 72 Stereoselective aminohalogenation of crotonoyl-oxazolidinones. [Bmim][BF4] ¼ 1Butyl-3-methylimidazolium tetrafluoroborate

In addition to [4 + 2] cycloadditions such as the Diels-Alder reaction, crotonoyloxazolidinones have also been employed as starting materials in [3 + 2] dipolar cycloadditions. For example, azomethine ylides prepared in situ from silyl-aminals add to cinnamyl-oxazolidinones forming the corresponding pyrrolidines. In early studies, it was observed that transformations of acylated 4-phenyl-oxazolidinones showed limited diastereoselectivity (up to dr 66:34) [185]. Later, studies by Sibi and coworkers revealed that in fact highest yields and selectivities are observed in the absence of a Lewis acid [186]. Herein, the 1,3-dipole is formed by base-mediated elimination from chloro-imines (Scheme 71). In a related methodology, also tetrahydrothiophenes were prepared from silyl-α-chloro-thioethers via the [3 + 2]cycloaddition of thiocarbonyl ylides [187]. However, while yields in this transformation were high, selectivities remained low (dr 55:45) in contrast to the related application of Oppolzer’s sultams in which selectivities up to dr 90:10 were recorded. Diastereoselective cheletropic reactions onto α,β-unsaturated acyloxazolidinones are limited in number. An example is the stereoselective aminohalogenation of acrylic acid and substituted cinnamic acid derivatives [188]. In the presence of copper(I) triflate, N,N-dichlorotoluenesulfonamide undergoes a formal nitrene transfer. In this diastereodetermining step, presumably an aziridinium intermediate is formed which is regioselectively opened by chloride at the electronically more favored position (Scheme 72). It was found that this transformation only proceeds in ionic liquids as reaction media. The products are formed in selectivities ranging from dr 3:1 to 7:1.

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Scheme 73 Asymmetric synthesis of α-fluoro-acyl-oxazolidinones

3.4

Diastereoselective Reactions of Vinyl-, Alkynyl-, or Allenenyl-oxazolidinones

Oxazolidinones undergo straightforward condensation with aldehydes to the corresponding enamine derivatives. Such electron-rich double bonds can be transformed by using various electrophilic reagents or take action in pericyclic reactions. Due to the close proximity of the stereocenter in optically active 4-substituted oxazolidinones, high levels of stereoinduction can be achieved. Like in enolate functionalization, good control of double bond configuration and s-cis/ s-trans conformation is mandatory in most cases though. Photochemical E/Z-isomerizations of 20 ,20 -disubstituted N-vinyl-oxazolidinone in solution and in host-guest systems have been the subject of research in this respect [189, 190]. The heterofunctionalization of N-vinyl-oxazolidinones by electrophilic halogenation occurs regio- and diastereoselectively [191, 192]. The intermediately formed halonium or iminium intermediate is directly attacked by suitable electrophiles in either inter- or intramolecular reaction. This is exemplified in the stereoselective preparation of α-fluoro-acyl-oxazolidinones [173]. The intermediately formed aminal is directly oxidized to the acylimide by Dess-Martin periodinane (Scheme 73). In a related fashion, oxidation of vinyl-oxazolidinones by reagents such as dimethyldioxirane (DMDO) or meta-chloroperbenzoic acid (mCPBA) allows for the preparation of the epoxide intermediate which is typically opened under the reaction conditions giving the corresponding 1,2-difunctionalized compounds [193, 194]. In order to explain the stereochemical outcome of the reaction, the vinyl-carbamate is assumed to adopt an s-trans conformation (Scheme 74). Similar observations have been made in the context of the photooxygenation of related vinyl-oxazolidinones in the presence of a photocatalyst such as 5,10,15,20-tetrakis (pentafluorophenyl)porphine (TPFPP) [195–197]. In this UV-initiated reaction, the approach vector of ozone is governed by steric effects, while the stereochemical course of singlet oxygen addition is ruled by vibrational deactivation [198–200]. Under radical conditions, regio- and diastereoselective hydroamination of vinyloxazolidinones by N-aminated dihydropyridines has been reported by Studer and coworkers (Scheme 75) [201]. In this radical transfer reaction, selective functionalization in the β-position occurs rendering this process complementary than the electrophilic functionalizations described above. The products are formed in very high selectivities and can serve as precursors for protected vicinal diamines.

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Scheme 74 Stereoselective epoxidation of vinyl-oxazolidinones

Scheme 75 β-Selective amination of vinyl-carbamates under radical conditions

Scheme 76 Cyclopropanation of vinyl-carbamates under Simmons-Smith conditions

Cyclopropanations of the electron-rich, chiral vinyl-carbamates have been achieved both under Simmons-Smith conditions [202] as well as Doyle conditions [203]. For example, the enamine derived from the condensation of the auxiliary with cyclohexanone was treated with an excess of diethylzinc and chloro-iodomethane [182] (Scheme 76). The latter gave substantially better yields than the cheaper diiodomethane due to its higher reactivity. Using optically active syn-4,5diphenyl-oxazolidinone as auxiliary chiral cyclopropylamines were prepared which are pharmaceutically interesting building blocks. Electron-rich vinyl-oxazolidinones are highly suitable reaction partners in DielsAlder reactions, either as dienes or as dienophiles in reactions with inverse electron demand. In such transformations, the electronic nature of the substituent in 4-position of the auxiliary plays an important role. Benzhydryl groups, for example, may provide an additional π-surface effectively shielding one side of the dienes [204]. In contrast, also small ethyl substituents suffice for high levels of diastereoselectivity due to the rigid transition state geometry and their close proximity [205]. Amino-cyclohexadienes derived from the condensation of the oxazolidinone with 2-cyclohexen-1-one undergo endo-selective formation of [2.2.2]-biyclic building blocks by reaction with vinyl ketones (Scheme 77) [185]. For additional activation of the dienophile tin(IV) chloride is added. This methodology was later extended toward the reaction of amino dienes with imines [206]. In an aza [4 + 2] cycloaddition reaction, optically active isoquinuclidines are formed in diastereoselectivities up to dr >95:5. In Diels-Alder reactions with inverse electron demand, optically active vinylcarbamates form dihydropyrans with β,γ-unsaturated α-ketoesters. Depending on the

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Scheme 77 Diastereoselective Diels-Alder reaction with normal electron demand

Scheme 78 Reversal of stereoselectivity in Lewis acid-mediated hetero-Diels-Alder reactions

Scheme 79 Synthesis of chiral cyclobutanones by photochemical [2 + 2] addition

reaction conditions, the two endo products can selectively be prepared (Scheme 78) [186]. When the reaction is conducted at low temperatures in the presence of tin (IV) tetrachloride, the endo-β-product is formed, while the europium-catalyzed reaction at elevated temperatures renders the product in complete endo-α-selectivity. This remarkable reversal of selectivity was attributed to different modes of chelation. In the case of tin, five-membered ring chelation of the α-ketoester occurs, while europium is capable to extend chelation also to the carbonyl group of the auxiliary in a sandwich geometry. The applicability of this method was extended toward an asymmetric Robinson annulation [207] and exemplified in the context of natural product synthesis, e.g., in the synthesis of the Iboga-type indole alkaloid voacangalactone [208]. An example for a diastereoselective [2 + 2] cycloaddition is the reaction of vinyloxazolidinones with Fischer carbenes derived from chromium hexacarbonyl (Scheme 79) [209, 210]. By participation of an additional carbonyl ligand on the metal, optically active cyclobutanones are formed which can be further transformed into five-membered ring lactones upon oxidation with mCPBA or undergo ring opening under basic conditions forming electron-rich dienes. Similar to the synthesis of cyclobutanones also related cycloaddition reactions involving carbonylation, such as Pauson-Khand-type reactions have been investigated employing chiral allenyl-oxazolidinones (Scheme 80) [211]. Herein, the terminal allene double bond participates, together with an alkyne in the

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Scheme 80 PausonKhand-type cyclization of allenyl-oxazolidinones

Scheme 81 Electrocyclic ring closure of 2-halo-imidotrienes

Scheme 82 Torquoselective Nazarov-cyclization

intramolecular formation of a bicyclic cyclopentenone. Due to the alkyl substituent in 1-position of the allene, an s-cis conformation of the substrate is preferred. In this transformation, no additional stereocenter is created, but the bicyclic enamine generated can be further diastereoselectively functionalized. In this specific example, molybdenum hexacarbonyl is used instead of dicobalt octacarbonyl. Allenyl-oxazolidinones form 2-halo-imidotrienes upon electrophilic halogenation, e.g., by pyridinium tribromide (Scheme 81) [212]. At elevated temperatures, electrocyclic ring closure renders the optically active cyclohexadienes in a thermally allowed disrotatory motion. This is a rare case of stereochemical 1,6-induction by restricted rotation requiring a bulky substituent in 2-position of the hexatriene. Otherwise, selectivities drop substantially (dr 3:1). Torquoselectivity has also been observed in Nazarov cyclizations of oxazolidinonyl-1,4-pentadien-3-ones (Scheme 82) [213, 214]. In the presence of a Brønstedt acid, the reaction proceeds with high regioselectivity rendering the 5-oxazolidinonyl-cyclopentenones with the auxiliary at a newly formed stereocenter. Upon treatment with either lithium naphthalenide (LiNp) or samarium diiodide, it can be reductively cleaved off giving the cyclopentenone products in enantiomerically pure form. The mechanistic implications of the observed torquoselectivity have been the subject of an in-depth computational study [195]. This methodology has been applied in the context of the natural product synthesis, e.g., for the preparation of pauciflorol F [215].

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Scheme 83 Preparation of oxazolinone-derived enolates from alkynyl-oxazolidinones

Alkynyl-oxazolidinones serve as very versatile starting materials for the preparation of both vinyl-imides and acyl-imides upon addition of organocopper reagents [216, 217]. The addition occurs regioselectively with copper bound to the 1-position. These intermediates can then be oxidized, e.g., with tert-butylhydroperoxide giving the corresponding enolates, treated with acid chlorides for generation of the acylenamines, or be submitted to Simmons-Smith cyclopropanation conditions giving allyl zinc intermediates which undergo selective, closed-transition state aldol reactions (Scheme 83).

3.5

Diastereoselective C(1)-Transformations of Oxazolidinone Derivatives

The majority of applications of optically active oxazolinones as chiral auxiliaries are found in the diastereoselective transformations of carboxylic acid derivatives. Herein, most commonly, the C(2)-position (as in enolate alkylations or aldol reactions) or the C(3)-position (e.g., by conjugate additions) are functionalized. However, also functionalization of the C(1)-position by either nucleophilic or electrophilic mechanisms has been reported. The stereoselectivity of such reactions typically benefits from the close proximity to the auxiliary’s stereocenter. However, only selected auxiliaries can be chosen in order to allow for their clean cleavage after the duty is done. When acyl-oxazolidinones are reduced to the aminals, the corresponding iminium intermediates are formed upon addition of a Lewis acid [218]. Alternatively, Ntrimethylsilylmethyl-oxazolidinones can be oxidized under electrochemical conditions forming the methylene-iminium species (“cation pool” method) [219]. In addition, oxyallyl-oxazolidinone betaines are formed upon oxidation of allenyloxazolidinones (e.g., by DMDO) [220]. The iminium intermediates obtained that way undergo addition reactions with nucleophiles such as enolates, vinyl silanes, or electron-rich dienes. An example is the synthesis of β-amino acids from acyl-

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Scheme 84 Synthesis of β-amino acids by diastereoselective Mannich reaction

Scheme 85 N-Amino-oxazolidinone hydrazone alkylation under radical conditions

Scheme 86 Palladium-catalyzed, diastereoselective allylation of optically active hydrazones

oxazolidinones by a Mannich-type reaction [203]. The silyl-protected aminal is treated with boron trifluoride etherate in order to generate the iminium species. After addition of a silyl enol ether derived from ethyl acetate and deprotection under Birch conditions, the β-amino acid is obtained (Scheme 84). This methodology has been extended toward the corresponding hydrazine derivatives. When chiral N-amino-oxazolidinones are condensed with aldehydes to the corresponding hydrazones, additions of alkyl radicals and subsequent auxiliary cleavage allow for the highly selective preparation of chiral secondary amines (Scheme 85) [221]. In this reaction, choice of a suitable Lewis acid is important. Best results were obtained with zinc chloride with yields ranging from 28 to 83%. In 2015, Cook and coworkers reported the palladium-catalyzed allylation of optically active N-amino-oxazolidinone hydrazones (Scheme 86) [222]. The allyl anion equivalent is prepared in situ from allyl acetate and indium(I) iodide. So far, the method is restricted to the formation of homoallyl amines. The deprotonation or transmetalation of substituted N-alkyl-oxazolidinones renders optically active C-nucleophiles, which readily react with various electrophiles. Herein, the carbonyl group of the auxiliary provides an additional coordination site for the metal ion resulting in improved configurational and conformational stability. For example, when α-stannylated N-alkyl-oxazolidinones are lithiated at low temperatures, e.g., with n-butyl lithium, the corresponding organolithium species undergoes rapid equilibration giving the coordinated, thermodynamically most stable stereoisomer (Scheme 87) [223]. Upon addition of an electrophile such as benzaldehyde, the addition product is formed as a 1.5:1 mixture of epimers at the carbinol position.

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Scheme 87 Configurationally stable lithiated N-alkyl-oxazolidinones

Scheme 88 Addition of metallated allenyl-oxazolidinones to aldehydes

Scheme 89 Synthesis of chiral diols by lithiation of 3-methylthiomethyl-oxazolidinones

In the case of the N-propargyl oxazolidinones, deprotonation with an organolithium reagent and transmetalation to either tri-n-butyltin chloride [224] or diethylboron methoxide [225] provides the corresponding allenyltin or allenylboron intermediates, respectively. They undergo Lewis-mediated addition to epoxides or aldehydes in high diastereoselectivities. In the latter case, the corresponding synproducts are isolated (Scheme 88). In contrast, transmetalation to copper yields the trans-product in a closely related process [226]. In the presence of additional functional groups, capable of mesomerically stabilizing the carbanion, also high selectivities in electrophile additions can be observed. This is exemplified in the lithiation of 3-methylthiomethyl-oxazolidinones and subsequent reaction with aldehydes (Scheme 89) [227]. Hydrolysis of the reaction product and subsequent reduction provide access to the corresponding chiral, monoprotected diols. In addition to stereocenters which can be installed on carbon centers using oxazolidinones as auxiliaries, the described C(1)-functionalization was also extended to configurationally stable heteroatom substituents such as phosphorous [228]. Optically active oxazolidinones undergo highly diastereoselective nucleophilic displacement reaction with phosphinoyl chlorides. When the N-phosphinoyl oxazolidinone products are treated with Grignard reagents, the corresponding chiral phosphine oxides are formed with retention of configuration (Scheme 90). Summarizing, oxazolidinones and the corresponding thio-derivatives belong to the most successful chiral auxiliaries, in particular, when it comes to the highly

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Scheme 90 Synthesis of chiral phosphine oxides from N-phosphinoyl-oxazolidinones

diastereoselective functionalization of carboxylic acids. Although their primary application lies in the functionalization of enolates, also other stereoselective transformations in 3- or remote positions have been well-documented. In addition, prediction of the product’s absolute configuration can be done in a very reliable fashion, rendering this auxiliary class a valuable instrument in natural product synthesis. Even in light of the tremendous success of versatile and highly enantioselective catalytic processes, which are known today, oxazolidinone auxiliaries can be expected to remain an indispensable tool for organic chemists also in the future.

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Top Heterocycl Chem (2020) 55: 157–192 DOI: 10.1007/7081_2019_34 # Springer Nature Switzerland AG 2019, corrected publication 2020 Published online: 15 May 2019

Pyrrolidines as Chiral Auxiliaries Wolfgang Maison

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Pyrrolidine Auxiliaries in α-Alkylation Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Pyrrolidine Auxiliaries in Aldol Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Pyrrolidine Auxiliaries in Michael Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Pyrrolidine Auxiliaries in Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Pyrrolidine Auxiliaries in Nucleophilic Additions to C¼N Bonds . . . . . . . . . . . . . . . . . . . . . . . 7 Pyrrolidine Auxiliaries in Cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Pyrrolidine Auxiliaries in Birch Reductions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Pyrrolidine Auxiliaries in Organometallic Chemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 CrossLinkingellaneous Applications of Pyrrolidine Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

158 161 167 168 170 175 177 180 182 185 188

Abstract Despite the fact that various enantioselective catalytic reactions are available for many important stereoselective reactions, diastereoselective auxiliarycontrolled synthesis is still an important area of organic synthesis. Chiral pyrrolidine auxiliaries are frequently used in this context, due to good availability and efficient transfer of chirality via the rigid pyrrolidine scaffold. The following chapter focusses on recent examples and gives a brief overview of applications of pyrrolidine auxiliaries in diastereoselective syntheses. Illustrative examples were chosen to spotlight the underlying principles. Keywords Diastereoselective synthesis · Proline · Prolinol · Pyrrolidine auxiliaries · Traceless auxiliaries

The correction to this Chapter is available at https://doi.org/10.1007/7081_2020_39.

W. Maison (*) Department of Chemistry, University of Hamburg, Hamburg, Germany e-mail: [email protected]

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W. Maison

1 Introduction Chiral pyrrolidines are used frequently in asymmetric synthesis: as ligands and catalysts in catalytic stereoselective reactions, as structural motif in ex-chiral pool syntheses and as chiral auxiliaries in diastereoselective reactions. One of the major reasons for their frequent use in asymmetric synthesis is the good availability of many chiral derivatives either directly from the chiral pool of natural products or via easy preparation from readily available precursors such as proline and other amino acids. Another important factor is the rigidity of their cyclic pyrrolidine scaffold, which often allows an efficient transfer of chiral information to an attached substrate. The most prominent examples of pyrrolidine auxiliaries are depicted in Fig. 1. The first applications of proline esters as chiral auxiliaries via enamine derivatives date back to the work of Yamada et al. in the late 1960s [1]. Next to other chiral auxiliaries highlighted in this book, such as amino acid auxiliaries [2] and carbohydrate auxiliaries (Chapter “Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products”), terpene derived auxiliaries (Chapter “Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products”), oxazolidinones (Chapter “Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products”) and boron containing auxiliaries, they belong to the most powerful tools in diastereoselective synthesis. The derivatives mentioned above fulfil the most important criteria for a successful auxiliary: cheap and straightforward synthesis, easy conjugation to substrates, efficient transfer of chiral information and mild cleavage of the auxiliary from the substrate, which ideally allows recycling of the auxiliary. A good example is the particularly versatile SAMP auxiliary, developed by Enders [3, 4]. It is easily synthesized from (S)-proline as depicted in Scheme 1 via six steps. The Organic Syntheses protocol depicted is scalable and allows the reliable synthesis of SAMP in multigram quantities [5]. The final two synthetic steps from 3 to SAMP might be accomplished either via a nitroso compound or an urea, which is less toxic. Overall yields of the sequence are between 50 and 58% for large-scale preparations giving about 60 g SAMP. The optical antipode RAMP may be prepared likewise from (R)-proline. However, due to the high cost of non-proteinogenic (R)-proline, an

R N H

R

N NH2

N H

2,5-substituted pyrrolidines

SAMP

N-alkyl or acyl prolinol

N H prolinol ethers

O

proline ester

N H aminomethylpyrrolidines

OH

OR

OH N R

HN R

OR

OMe

N H prolinol

Fig. 1 Prominent chiral pyrrolidine auxiliaries employed in diastereoselective synthesis

Pyrrolidines as Chiral Auxiliaries

159 HCO2Me, CH2Cl2

OH

LiAlH4, THF

CO2H N H

OH N

N H

(S)-proline

O

H

(S)-prolinol

1 NaH, MeI, THF OMe

OMe

1. tBuONO 2. LiAlH4

N NH2

N H

or 1. KOCN 2. KOCl, KOH

SAMP overall: 50-58%

2 OMe

N NO

OH

1. EtONO, THF 2. NaH, MeI

N H (R)-prolinol

6

RAMP overall: 35%

CO2H

O

H

LiAlH4, THF

HO2C

N

3

OMe N NH2

OMe KOH, H2O

LiAlH4, THF

1. H2O, reflux 2. Ion exchange column

CH2N2, Et2O CO2H

NH2 (R)-glutamic acid

CO2Me

N H

O

O

4

N H 5

Scheme 1 Synthesis of SAMP and RAMP CO2Me CO2tBu NH 7

O

Benzene, MS 4A, reflux

CO2tBu

+

N 8

MeOH, reflux, then H3O 33%, 43% ee

CO2Me

O 9

Scheme 2 Yamada’s first example of proline ester 7 as a pyrrolidine auxiliary in stereoselective α-alkylations of carbonyls

alternative protocol starting from cheaper (R)-glutamic acid has been developed as a cost-efficient alternative providing RAMP in six steps with an overall yield of 35% [6, 7]. SAMP and RAMP auxiliaries have become standard reagents particularly for stereoselective α-alkylations of carbonyl derivatives, a highly important type of reaction in Organic Syntheses. The first application of a chiral pyrrolidine auxiliary in this context was reported by Yamada who used proline ester 7 to prepare cyclohexanone enamine 8, which was applied to a Michael reaction with methyl

160

W. Maison

n-PrI MeO SAMP, 60 °C

O

N N

1. LDA, Et2O, 0°C 2. n-PrI, -110°C

87%

N Et2O N Et2O Li H3CO Et

3-pentanone 10

11

recycling: LiAlH4

n-PrI 90%, d.r. > 99:1

MeO

O

O3, CH2Cl2

MeO

+ N 14

58%

N

N

NO 13, ee > 97% Z-12

Scheme 3 Illustrative example of a SAMP-mediated α-alkylation of 3-pentanone

acrylate to give ketoester 9 after acidic hydrolysis (Scheme 2) [1]. However, yield and selectivity of this pioneering reaction were only moderate. Diastereoselective α-alkylations of carbonyl compounds were later improved by using chiral azaenolate intermediates, derived from acyclic or cyclic amino acid hydrazines [3, 8]. Chiral hydrazines like SAMP and RAMP are ideal auxiliaries because they are easily converted to the corresponding hydrazones with various carbonyl derivatives. An illustrative example from Organic Syntheses is depicted in Scheme 3 [9]. Aldehydes may be converted to the SAMP hydrazones at low temperature (typically 0 C). The reaction with ketones, such as 3-pentanone, in turn, needs higher temperature to give complete conversions to the corresponding hydrazones such as 10. It should be noted that hydrazones like 10 can be formed as mixtures of E and Z isomers, if unsymmetric carbonyl compounds are used as starting materials. The E/Z ratio is dependent on the substitution pattern. However, this unselective hydrazine formation does not compromise the stereochemical outcome of the following alkylation. Subsequent deprotonation of hydrazone 10 with LDA gives azaenolate 11, which is alkylated at low temperature to give substituted hydrazone Z-12 with excellent diastereoselectivity. It should be noted that not only the newly formed stereogenic centre but also the geometry of the hydrazone N¼N double bond in 12 is determined (Z in this case) by the well-organized transition state. This outcome is important for the regioselectivity of an eventual second alkylation step, if hydrazones like 10 are treated with an additional equivalent of base and nucleophile (for an example, see Scheme 9b). In a last step, the chiral auxiliary is cleaved via ozonolysis to give the α-alkylated ketone 13 in excellent enantiomeric purity. The additionally formed nitroso compound 14 may be recycled by reduction with LiAlH4 to SAMP as mentioned before (Scheme 1). The reaction works reliably even on a large scale. Chiral ketone 13 is an important insect pheromone, which has been found in different species. Additional recent

Pyrrolidines as Chiral Auxiliaries

161

applications of the SAMP/RAMP methodology in natural product synthesis may be found in Chapter “Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products” by Baskaran. The final cleavage of SAMP and RAMP with ozone has some drawbacks with respect to the high toxicity of ozone and the nitroso derivative 14. Alternatively, a number of other variants, such as acidic hydrazone hydrolysis or quaternarization with MeI and following hydrolysis, have been developed for racemization-free cleavage of the auxiliary, and the reader is referred to an excellent account on this topic for additional details [10]. The following chapter gives a brief overview of applications of pyrrolidine auxiliaries in diastereoselective syntheses. Illustrative examples were chosen to spotlight the underlying principles. Applications of pyrrolidines in organocatalysis and as ligands in catalytic stereoselective conversions will also not be treated. Applications of pyrrolidine auxiliaries in natural product synthesis are covered by Baskaran in Chapter “Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products”. This chapter covers only the recent literature and is not comprehensive. The reader is referred to excellent reviews for a comprehensive survey of the earlier literature [11–13]. At this point, the author apologizes in advance to all researchers whose work is not mentioned or cited. The sheer quantity of material makes it impossible to include all the fine work available on pyrrolidine auxiliaries.

2 Pyrrolidine Auxiliaries in α-Alkylation Reactions The installation of carbon-carbon or carbon-heteroatom-bonds adjacent to carbonyl groups is of great importance in various fields of organic synthesis. However, the direct conversion of carbonyl enolates is often accompanied by side reactions and limited selectivity. These problems may be addressed by the use of nitrogen analogues of carbonyls and enolates such as imines, enamines and azaenolates. As mentioned above, Enders SAMP/RAMP auxiliaries have become standard tools for the diastereoselective α-alkylation of aldehydes [14] and ketones. The reader is referred to earlier reviews for a more comprehensive summary of applications [12, 13]. The intermediate SAMP or RAMP hydrazones like 16 and 19 are routinely prepared from ketones 15 and aldehydes 18 (Scheme 4). However several other methods for hydrazone synthesis may also be used [15]. A recent example is the rhodium-catalysed conversion of SAMP and RAMP with terminal alkynes [16]. As outlined in Scheme 4, the sequence of hydrazone formation and subsequent alkylation to 17 and 20 gives reliably good results for various carbonyl compounds with high yields and, in most cases, very good diastereoselectivities, which are a consequence of the highly ordered transition state, depicted in Scheme 3. The resulting α-alkylated hydrazones 17 and 20 are highly versatile intermediates, which may be transferred to other functionalities. Next to the previously mentioned conversion to α-alkylated carbonyls 22 via quaternarization/hydrolysis or ozonolysis, they may also be reduced to amines 23 [17], hydrolysed and oxidized

162

W. Maison MeO O R2

R1 15

SAMP, 60-80 °C

1. LDA, Et2O, 0°C 2. R3X, -110°C

N

MeO N

N 16

R2

MeO O R2

H

17

1. LDA, Et2O, 0°C 2. R3X, -110°C

N

75-95%

N

70-95% 19

R2

2

N R3

H

H

1

R2

MeO

N

18

R3

R1

R1

SAMP, 0 °C

N

20

3

R = H, alkyl, aryl; R = H, alkyl, aryl; R = alkyl, benzyl, allyl, alkoxy

R2

d.r. = 65:35 - 99:1

Scheme 4 Stereoselective α-alkylations of aldehydes and ketones with Enders’ SAMP auxiliary O R1

HO R2 24

1. MeI, HCl 2. Ag2O

O R1

H

HS(CH2)3SH BF3 x OEt2

MeI, HCl or O3

R2 22

S H

S

R1

R2 26

MeO 1. LiAlH4 2. Raney Ni, H2

N R1

H

MMPP, oxy-Cope type elimination

R2 21

NH2 R1

O reduction

R1

H R2

R2

R2 23

R1

NC 25

27

Scheme 5 Different types of conversions of alkylated hydrazones 21. MMPP magnesium monoperoxyphthalate

to carboxylic acids 24 [18, 19], transferred to nitriles 25 [20, 21] or converted to dithianes 26 as depicted in Scheme 5 for an aldehyde-derived hydrazone 21 [22]. The oxy-Cope-type elimination to nitriles 25 and subsequent reduction to aldehydes 27 is a particularly useful method for epimerization-sensitive α-alkylated aldehydes, which are frequently used intermediates in natural product synthesis. Unfortunately this method is restricted to aldehyde-derived hydrazones. With ketone-derived hydrazones like 28, many of the above-mentioned cleavage

Pyrrolidines as Chiral Auxiliaries

163

Table 1 Cleavage conditions for epimerisation-sensitive SAMP hydrazone 28 MeO

O

N N H OH

conditions O

HetAr

OH

HetAr

28

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14

O H

29

Conditions Oxalic acid, Et2O, rt., 15 h CuCl2, THF, H2O, rt., 15 h SnCl2, Pd(OAc)2, DMF, H2O, rt., 15 h SnCl2, Pd(OAc)2, DMF, H2O, 50 C, 15 h SnCl2, DME, H2O, rt., 15 h SnCl2, DME, H2O, 50 C, 15 h O3, CH2Cl2, 78 C NaBO3, AcOH, rt., 2 h NaBO3, phosphate buffer, pH 7, rt., 5 h MMPP, phosphate buffer, pH 7, rt., 24 h 30% H2O2, phosphate buffer, pH 7, rt. to 70 C, 19 h NaIO4, phosphate buffer, pH 7, rt., 15 h 30% H2O2/SeO2, MeOH, rt., 48 h 30% H2O2/SeO2, phosphate buffer, pH 7, rt., 24 h

Fig. 2 Sterically hindered SAMP and RAMP derivatives

Observations Epimerization Epimerization No reaction Epimerization No reaction Epimerization 21% 29 Decomposition Decomposition No reaction Decomposition Decomposition 76% 29 91% 29

MeO

MeO

MeO

N

N

N

NH2

SADP

NH2

SAEP

Ph Ph

NH2

SAPP

MeO

N

NH2

RAMBO

conditions to sensitive ketones like 29 lead to epimerization (Table 1). Smith and coworker have developed a mild and epimerization-free method for SAMP cleavage with H2O2/SeO2 [23]. This method works most likely via initial formation of peroxyselenous acid, which oxidizes the pyrrolidine nitrogen, activating the hydrazone towards hydrolysis. Next to applications in natural product synthesis, this cleavage method has also been used in the synthesis of loxoprofen and similar anti-inflammatory drugs [24]. In some cases, more sterically demanding derivatives of SAMP and RAMP have been found to give superior results in diastereoselective alkylations. Examples are the SAMP analogues SADP, SAEP and SAPP (Fig. 2), which have been prepared according to a modified SAMP protocol from proline [25]. The even more sterically demanding derivative RAMBO is also readily available from the corresponding azabicyclooctane carboxylic acid [26–30].

164

W. Maison R1

R1

N

N

R2

LDA, THF, R2X, -90 °C

N

R1 N

44-53%

MeO

4

32

31, dr >96:4

30

R2

N H

OMe

R1 = alkoxy, H; R2 = alkyl, benzyl, aryl; R3 = alkyl, benzyl, aryl 3

R Li, THF, -78 °C to rt R1

R1 R3 HN

N

MOMCl, AcOH, reflux 47-50%

OMe

N N

53-58% R3

MeO 33, dr >96:4

R1

R1 BH3, THF, then NaOH N H

3

35

R R3

1 N H 36

34

Scheme 6 Asymmetric synthesis of 1-, 3- and 4-substituted benzo[c]azepines 32, 35 and 36

Alkylation of SAMP hydrazones 30 gave α-alkyl hydrazones 31 in good yields and excellent selectivities (Scheme 6) [31]. These compounds are versatile synthetic intermediates and have been converted to 4-substituted benzoazepines 32 in three steps via reduction of the hydrazone, cyclomethylenation and subsequent reductive cleavage of the auxiliary. Alternatively, 3-substituted benzoazepines 35 were synthesized starting from the same SAMP hydrazones 30 by a highly diastereoselective nucleophilic addition of lithium organyls to the hydrazone moiety. The resulting α-alkylated hydrazines 33 were then cyclized with MOMCl under acidic conditions to SAMP benzoazepines 34 in moderate yields. Reductive cleavage of the auxiliary gave 3-substituted benzoazepines 35 with a free amino group. The strategy of nucleophilic addition to chiral SAMP hydrazones in combination with a following ring-closing metathesis was used by the same authors for the stereoselective synthesis of 1-substituted benzoazepines of type 36 [32]. The products were again obtained with excellent diastereoselectivity (d.r. > 95:5). A useful application of the alkylation of ketones with SAMP has recently been reported by Enders within a synthesis of fluorinated triols [33]. The alkylation of a chiral azaenolate generated by tBuLi treatment of SAMP hydrazone 37 (Scheme 7) with various alkyl halides and subsequent SAMP cleavage with ozone gave ketones 38 in good yields and with excellent enantioselectivity. Following treatment with TMSCF3 and acidic acetal cleavage with DOWEX 50 gave the final triols 39 in excellent stereochemical purity. It should be noted that this method is also applicable to the synthesis of higher alkylated trifluoromethyl triols simply by repeated addition of base and electrophile to hydrazone 37. Trifluoromethylated long-chain ketones have also been synthesized by the SAMP/RAMP methodology as depicted in Scheme 8 [34]. Again, yields of

Pyrrolidines as Chiral Auxiliaries

165 1. TMSCF 3, TBAF, THF, 0 °C 2. DOWEX 50, EtOH

OMe N

1.tBuLi, THF, RX, -100 °C 2. O3, -78 °C

N

O

O

O R O

55-74%

37

O

HO R

52-97%

OH

CF3 OH

39, ee = 92->98% d.r. > 98:2

38, 92-95% ee

Scheme 7 Asymmetric synthesis of 2-trifluoromethyl-1,2,3-triols using the SAMP auxiliary MeO MeO

N N S

R 40 R = C2H5, C4H7, C6H9

O

N N CF3 LDA, Et2O, -100 °C

CF3 S

BF3, Et2O, paraformaldehyde, acetone/H 2O

CF3 S

R

R 41, 79-86% de = 92-94%

42, 79-81% de = 91-93%

Scheme 8 Asymmetric synthesis of long-chained trifluoromethyl ketones using the SAMP auxiliary

α-alkylation to 40 and subsequent cleavage of the auxiliary to ketones 42 were good, and stereoselectivities were excellent. Cleavage of the auxiliary was tested with different procedures, but only treatment of the hydrazone 41 with BF3, followed by paraformaldehyde resulted in racemisation-free SAMP cleavage. The resulting longchained ketones 42 are inhibitors of the pheromone action of two major maize pests Sesamia nonagrioides and Ostrinia nubilalis. The robustness of the SAMP/RAMP α-alkylation chemistry has led to numerous applications in Medicinal Chemistry. Two recent examples for the α-alkylation of cyclic ketones are depicted in Scheme 9 [35]. In a formal synthesis of ramipril, SAMP hydrazone 43 was alkylated with iodoalanine to intermediate 44 (Scheme 9a). Several further steps lead to the synthesis of 2-azabicyclooctane-3-carboxylic acid, an advanced precursor of ramipril. Unfortunately, some experimental details in the paper are missing, and a statement on the diastereoselectivity of alkylation was not made. The same type of α-alkylation was used for the synthesis of oxetanes like 47 (Scheme 9b), which are valuable building blocks in Medicinal Chemistry [36, 37]. Starting from SAMP hydrazone 45, several oxetanes with different substitution patterns were prepared. Simple treatment with BuLi and an electrophile gave monoalkylated hydrazones Z-46, which were converted to the oxetanes 47 by treatment with oxalic acid. The observed optical purities were moderate. Treatment of intermediate Z-46 with an additional equivalent of base and electrophile gave the 2,2-disubstituted hydrazones 48 with good selectivity. The regioselectivity of this second alkylation is dependent on the geometry of the directing hydrazine. The

166

W. Maison

A N N

NHAc

I

OMe

CO2Me

LDA, 0 °C - rt

MeO2C

OMe

H

N N

AcHN

Bn

95%

43

H

EtO2C

N N H

44

CO2H

O

Ramipril

B MeO N

N

O

MeO BuLi, R1X, -78 °C - rt

N O

R1 47, ee = 54-84%

Z-46

BuLi, R2X, -78 °C - rt

O O

45-85%

R1

57-63% 45

(CO2H)2 Et2O, H2O

N

toluene, reflux

33% MeO N

OMe N

N N

O

R2 R1 48, ee = 90%

E-46

O

BuLi, R2X, -78 °C - rt

OMe R2

33%

N N

O R1 49, ee = 86%

R1

Scheme 9 Asymmetric synthesis of ramipril (a) and oxetanes 47, 48 and 49 (b) using the SAMP auxiliary

NO2 F

OMe K2CO3, DMSO

OH

OMe OH

N

N

45% O 50

OMe

O

OMe

51

Scheme 10 α-Arylation of chiral amide 50 via nucleophilic aromatic substitution

activation energy for hydrazone isomerization is relatively high, but heating in toluene allowed the conversion of Z-46 to E-46. Subsequent alkylation of E-46 gave the 2,5-disubstituted hydrazone 49 with good selectivity. Enolates derived from chiral amides 50 may also be used for α-functionalisation. An example using nucleophilic aromatic displacement is shown in Scheme 10 [38]. Chiral amide 50 was converted to α-arylamide 51. However, the yield of the reaction was only moderate, and the product 51 was obtained with low diastereoselectivity (d.r. ¼ 62:38).

Pyrrolidines as Chiral Auxiliaries

167

3 Pyrrolidine Auxiliaries in Aldol Reactions The SAMP and RAMP methodology has found numerous applications in aldol chemistry [11, 12]. A recent modification of the concept has been described by McGlacken and coworkers [39]. The SAMP analogue 56 was synthesized in six steps, starting from Cbz-proline 52 (Scheme 11). The synthetic sequence has some similarity to the SAMP synthesis mentioned earlier and gave the auxiliary 56 in good yield even in large-scale protocols. The auxiliary was applied to different types of stereoselective conversions. Aldol reactions of 57 gave the corresponding adducts 58 with moderate diastereoselectivities. Michael reactions to 59 and α-alkylations to 60

N H DCC

CO2H N Cbz

N Cbz

81%

52

O

1. H2, Pd/C 2. LiAlH4, THF

N

83%

N H

53

N

54

LiAlH4, THF

EtONO, EtOH N NO

91%

N

N N NH2

91%

56

55

N N

N

1. LDA, Et2O, benzaldehyde 2. acetone/H2O, Amberlyst

O OH

39% 57 1. LDA, Et2O, BnBr 2. HCl/H2O

NO2

1. LDA, Et2O 2. HCl/H2O

13%

58, eeanti = 63% anti:syn = 83:17

7% O

O

NO2

60, ee = 89%

59, eesyn = 84% syn:anti = 94:6

Scheme 11 Synthesis of the new hydrazine auxiliary 56 and its applications in aldol reactions, Michael reactions and α-alkylations

168

W. Maison

were more selective, and in many cases the outcome was comparable to that of corresponding conversions with SAMP. However, the yields for the two-step procedures were only moderate to low. Interestingly, it was found that the relative stereochemistry in aldol and Michael products 58 and 59 is opposite to that of the same reactions with SAMP.

4 Pyrrolidine Auxiliaries in Michael Reactions Chiral C2-symmetric pyrrolidine auxiliaries have been used for regio- and stereoselective Michael additions to conjugated amides like 61 (Scheme 12) [40]. Grignard reagents are added to the 6-position of the conjugated double bond system of the 2,6-diphenylpyrrolidine derived amide. The resulting enolate was then alkylated with an appropriate electrophile to give the 3,6-substituted amide 62 with excellent diastereoselectivity. If similar auxiliaries with coordinating sidechains are used, the regioselectivity of alkylation is changed, and substrate 63 was alkylated via Michael addition of MeMgBr to intermediate 65, which upon treatment with methyl iodide gave the 3,4-substituted amide 64, again with excellent diastereoselectivity. Among many applications of the SAMP/RAMP methodology in asymmetric synthesis, conversions of enone-derived hydrazones are relatively less exploited 6

4

O

1. R1MgBr, THF, rt, 1h, then R2X

Ph N

61

1

2

R = alkyl, alkenyl, aryl; R = alkyl

6

4

O

O N

Ph

O

Ph N

R R1

69%

Ph

O 2

Ph

62, d.r. = 95:5

O

O

1. MeMgBr, THF, rt, 1h, then MeI

N

44-87% 63

O

O

O

O O Ph

Ph

64, d.r. = 92:8 - 99:1 MeMgBr Ph

O O

N

Mg Br

O O Ph

O

N

MeI H

O

Ph

O

65

O I Mg Br

O O Ph

Scheme 12 Regioselective Michael additions to chiral conjugated amides 61 and 63

Ph

Pyrrolidines as Chiral Auxiliaries

169

[41–45]. Only recently, Laschat and coworker have developed an efficient strategy for the SAMP-mediated conjugate addition of Gilman cuprates to enones [46]. SAMP hydrazones 66 were treated with Gilman cuprates as depicted in Scheme 13. The resulting products were not the expected substituted hydrazones but the ketones 67 in varying yields and selectivities. It was found that SAMP can be used as a traceless auxiliary in this context, if the workup is performed under slightly acidic conditions leading to Cu-mediated hydrolysis of the intermediate hydrazones. The auxiliary is released as a dimeric copper complex, which was treated with EDTA to recycle SAMP. The diastereoselectivity of the conjugate addition was found to depend on the aryl moiety with electron-rich arenes (e.g. methoxy substituted) giving poor selectivity, whereas electron-withdrawing substituents (e.g. nitro) attached to the arene lead to excellent selectivities. A SAMP-mediated Michael approach was reported by Couture and coworker according to Scheme 14 [47]. SAMP hydrazone 68 was deprotonated with LDA, and the resulting azaenolate was added to various Michael acceptors to give the addition products 69. These were immediately reduced and treated with MOMCl under acidic conditions to effect methylenation and cyclization to 70. At this stage, a diastereomeric ratio of greater than 98:2 was observed as a consequence of the highly selective SAMP-mediated Michael addition in the first step. Cleavage of the

N

OMe

R2CuLi * LiCN, LiBr, Et 2O, -78 °C - 15 °C

N

N

Li N

OMe 66

27-88%

Cu Ar

Ar

R

NH4Cl, CuSO4

X

O

Ar 67, ee = 18-99%

R

Si attack

Scheme 13 SAMP as a traceless auxiliary in the asymmetric 1,4-addition of cuprates to enones CO2Et

R1

N

N

EtO2C

OMe 1. LDA, THF, -78 °C- 0 °C 2. THF, -110 °C

R2

OMe

R1

R1

R2

N

N

AcO OMe 1. LiAlH4, THF 2. MOMCl, AcOH, reflux R2

N N

52-89% 69

68

70, d.r. > 98:2

R1 1. BH3, THF, reflux 2. NaOH

HO

R1 NH

R2

67-98%

DEAD, PPh3, THF, rt

N R2

R1 = H or alkyl; R2 = H, MeO

56-79% 71, ee > 96%

72, ee > 96%

Scheme 14 Asymmetric synthesis of bridged tetrahydro-2-benzazepines 72

170

W. Maison

O F F

N H

N

OMe

CO2Et

OMe

F F

64-75%

n

n

OMe

O

Grubbs II, Ti(OiPr)4, CH2Cl2, 4h

N H

N 4h

n = 1,2

EtO2C 75, dr ~ 50:50

74

73

N N

n

58-62% CO2Et

O

F F

Scheme 15 Tandem cross metathesis/Aza-Michael cyclization to lactams 75

O

O

Ph

Ph N

76

Ph

FVP: 500°C, 0.04 mbar

Ph

N

Ph

Ph

Ph

Ph

O

O

43%

N

O cis-77 7.3

Ph :

O

trans-77 1

Scheme 16 Diastereoselective rearrangement of vinyl epoxide 76 via flash vacuum pyrolysis (FVP)

auxiliary was performed with borane. After saponification of the ester, intermediates 71 were obtained in good yield. A final Mitsunobu conversion gave bridged tetrahydro-2-benzazepines 72. A SAMP-controlled tandem sequence of olefin metathesis and Aza-Michael cyclization has been reported by Fustero and del Pozo [48]. The sequence starts with the SAMP amides 73, which were submitted to olefin metathesis in the presence of ethyl acrylate (Scheme 15). The primary reaction product is olefin 74 derived from cross metathesis. The reaction was performed in refluxing dichloromethane, and under these conditions, the Aza-Michael product 75 is slowly formed after a few hours. The diastereoselectivities of this tandem conversion were low but were improved to moderate, if alkene 74 was isolated and cyclized by alkaline treatment. A palladium-catalysed synthesis of heterocycles via cascade allene insertion/AzaMichael addition has been described by Grigg [49]. Diastereoselectivities of this process were also moderate.

5 Pyrrolidine Auxiliaries in Rearrangements Thermal rearrangements of vinyl epoxides like 76 (Scheme 16) have been reported by the Steel group to give aryl-substituted dihydrofurans 77 [50]. These rearrangements have been shown to proceed with a high degree of cis-selectivity if chiral amides like 76 are used as starting materials. Among other chiral auxiliaries (such as oxazolidinones), C2-symmetric trans-2,5-diphenyl pyrrolidine gave reasonable yields and a good diastereoselectivity upon flash vacuum pyrolysis of 76 to

Pyrrolidines as Chiral Auxiliaries

171

dihydrofuran 77. The resulting products 77 were shown to be valuable synthetic intermediates, particularly for the synthesis of furofuran natural products. γ,δ-Unsaturated amino acids are important natural compounds and versatile building blocks in organic synthesis. The Claisen rearrangement is a well-known strategy for the preparation of this type of amino acid, and a number of valuable variants are available [51–54]. Hruby and coworker have developed an auxiliary protocol using 2,5-dimethyl pyrrolidine amide 78 as a starting material (Scheme 17) [55]. After conversion to the Meerwein salt 79, the rearrangement precursor 80 was obtained by addition of various substituted lithium allylalkoxides. The following rearrangement was initiated by warming the reaction mixture to give amides 81 in good yields and reasonable to good selectivities. Cleavage of the auxiliary was achieved via iodolactonization to iodide 82 and subsequent elimination to the final unsaturated amino acids 83. The reaction was further improved with a Thio-Claisen variant as depicted in Scheme 18 [56]. First step is a conversion of chiral amide 84 to thioamide 85 with Lawesson’s reagent. The following rearrangement is initiated by Lewis acidmediated S-allylation followed by warming up to 45 C. Thio-Claisen product 86 was obtained in good yield and with excellent diastereoselectivity. Different auxiliaries were tested, and the diphenylpyrrolidine depicted gave the best results [57]. The reaction scope is remarkably broad, and a number of substituted allyl bromides were used successfully next to the bromocrotylate depicted in Scheme 18. In addition, the rearrangement might alternatively be triggered under alkaline conditions via a thioenolate intermediate. It should be noted that the selectivity of the Thio-Claisen rearrangement was opposite to the Eschenmoser-Claisen rearrangement depicted in Scheme 17 even if identical auxiliaries were used. Both methods are therefore complementary with respect to stereoselectivity. The authors have attributed this finding to slightly different transition states as a consequence of longer C-S bonds and wider C-S-C bond angles compared to the oxygen analogues. R

R LiO

MeOTf, 2,6-DTBP

O

CH2Cl2

OMe

O N

N

N

N

N

NHCbz

OBn

OBn 78

rt

80 MeO

79 MeO

I2, THF, H 2O

O N R NHCbz 81, d.r. = 75:25 - 97:3

O

I

O R

CbzHN 82

O Zn, AcOH 65-74%, two steps

HO R CbzHN 83

Scheme 17 Diastereoselective Eschenmoser-Claisen rearrangement using a C2-symmetric pyrrolidine auxiliary

172

W. Maison CO2Me

Br

Ph N

S

Ph

O N Ph NHCbz CO2Me

O N

Ph OMe

85

1. mCPBA 2. I2, THF, H2O 3. Zn, AcOH

Ph

NH

S

NHCbz Ph

84

63%

Cbz

N

99%

NHCbz Ph

Ph

Lawesson's reagent

O

1. 20 mol % FeBr3, THF 2. TEA, THF, -78 °C - 45 °C

O HO

79%

NHCbz CO2Me 87

86, d.r. = 99:1

Scheme 18 Thio-Claisen rearrangement using a C2-symmetric pyrrolidine auxiliary CF3 O

DIEA, TiCl 4, THF, CH 2Cl2, -10 °C - 10 °C

N O Ph 88

COCl

OTBS

CF3 N O O

58%

O

O

Ph

Ph 89

OTBS

O

N O

F 90

OH

Scheme 19 Asymmetric acyl-Claisen rearrangement as a key step in the synthesis of NK1-receptor antagonist 90

The choice of a C2-symmertric auxiliary for this sequence was important, because tertiary amides like 84 and thioamides like 85 form slowly equilibrating amide rotamers. The C2-symmetric auxiliary addresses this rotamer issue, which would otherwise compromise the asymmetric induction of less symmetric auxiliaries. The authors have verified this hypothesis with the chiral auxiliary (S)-2-methoxymethyl pyrrolidine, which lead to only low diastereoselectivity compared to the C2-symmetric analogues. An auxiliary-mediated acyl-Claisen rearrangement has been used by Merck scientists to synthesize enantiomerically pure key intermediates of novel NK1receptor antagonist analogues to aprepitant (Emend®) [58]. A methoxy prolinolderived allylamine 88 was acylated with a chiral acid chloride, and the resulting intermediate was transferred by a Lewis acid-catalysed acyl-Claisen rearrangement to amide 89 (Scheme 19). It was found to be essential to use the chiral prolinol

Pyrrolidines as Chiral Auxiliaries

173

auxiliary and the chiral acid chloride to achieve good diastereoselectivity for the rearrangement to amide 89, which is a key intermediate for the construction of the tetrahydropyran ring in 90. Nubbemeyer and coworker have investigated auxiliary-controlled asymmetric acyl-Claisen rearrangements in detail [59]. In this study, acyl fluorides have been used as acylation reagents for chiral allylamines 91 (Scheme 20). Lewis acidmediated rearrangement gave the corresponding amides like 92 in good yield and with excellent diastereoselectivity for the C2-symmetric auxiliary 93. Several different pyrrolidine auxiliaries were tested. C2-symmetric auxiliary 93 and 1,4-disubstituted pyrrolidines 96 with bulky alkoxy groups gave the best results with respect to yield and stereoselectivity. The authors noted that anti/syn diastereoselectivity was almost perfect favouring the anti isomers irrespective of the auxiliary used. However, the relative stereochemistry of the anti configured acyl chain vs the auxiliary was observed to depend on the auxiliary. C2-symmetric auxiliary 93 and 1,4-disubstituted pyrrolidines 96 gave the allS-stereoisomer 92, whereas the other auxiliaries gave the corresponding (R,R,S,S)-diastereoisomer of 92. An interesting auxiliary-controlled Claisen-type rearrangement has been observed by Maulide and coworker while investigating the properties of ketiminium salts [60]. When chiral tertiary amide 97 was treated with Tf2O/collidine, a ketiminium intermediate was formed which triggered a skeletal rearrangement to substituted butyrolactone 98 (Scheme 21). The reaction proceeds most likely via a Claisen-type rearrangement and hydrolytic removal of the chiral auxiliary. The yield was excellent, but the stereoselectivity was only moderate. O F

MeO

OMe

AlMe3, NaCO3, CH2Cl2, -20 °C N

TBSO

Al F O

TBSO

71%

R

MeO 91

MeO

OMe

OR

O

TBSO HN MeO 93

R N

HN RO 94

HN

HN

RO 95

O

S

S

OMe N

S

S

RO

OMe

96 MeO

92, d.r.anti = 92:8 anti/syn > 99:1

Scheme 20 Asymmetric acyl-Claisen rearrangement with acid fluorides and different pyrrolidine auxiliaries

174

W. Maison

OMe Tf2O, CH2Cl2, collidine, 120 °C N

O 97

O O 98, ee = 60%

90%

O

OMe

Tf2O, collidine

H2O

OMe

OMe

N

N

C

Claisenrearrangement

HN

OMe

N O

O

O

Scheme 21 Electrophilic rearrangement of chiral amides 97 to substituted lactones 98 R2 N R1

N H

R2 Cl

tBuOCl, OMe CH2Cl rt 2,

O

R1

99

N

N

OMe

O

100

OMe N

R2 Cl HCl, EtOH R1

N

N OEt O H 101

OMe

R2

loss of Cl, acyl migration rt R1 = F, Cl, Br, Ph R2 = Me, Ph, 4-Cl-Ph

O O

R1

N H 102, 75-95%, d.r. = 66:34 - 92:8

Scheme 22 Oxidative indole rearrangement of 100 with a prolinol-derived auxiliary

Stereoselective functionalisation of indoles is highly attractive due to frequently occurring chiral indole scaffolds in natural products and pharmaceuticals. A particularly interesting variant for the synthesis of 3,3-disubstituted oxindoles is the oxidative rearrangement of indole carboxylic acid derivatives. In this context, Moody and coworkers have used a prolinol-derived auxiliary to synthesize the chiral precursor 99 (Scheme 22) [61]. Treatment of 99 with tBuOCl leads to the formation of chloroindole 100. The addition of ethanol in acidic solution gave the intermediate aminal 101, which was unstable under the reaction conditions and converted slowly to 102. Acyl migration of the prolinol moiety was induced by loss of chloride, and a final hydrolysis gave oxindoles 102 in good yields. The stereoselectivity of the reaction is highly dependent on the substitution of the starting material. Only bulky substituents in 7-position of the indole lead to good asymmetric induction (d.r. up to 94:6 at 0 C and 92:8 at rt), whereas all other derivatives gave relatively pour diastereoselectivities.

Pyrrolidines as Chiral Auxiliaries

175

6 Pyrrolidine Auxiliaries in Nucleophilic Additions to C¼N Bonds Nucleophilic additions of metal organyls to C¼N double bonds of chiral hydrazones have become a standard method for the stereoselective synthesis of amines. These additions are most frequently performed with lithium, magnesium or cerium organyls. A particularly valuable variant is the use of cerium organyls, which was pioneered and nicely reviewed by Denmark [62]. In a recent application, the addition of cerium organyls to SAMP hydrazones was used for the synthesis of cyclic sulphonamides, so-called sultams. These compounds are attractive target compounds due to their frequent use as pharmaceuticals, agrochemicals and chiral auxiliaries. Enders and coworker have reported a versatile stereoselective route via the addition of organocerium compounds to chiral hydrazones 103 (Scheme 23) [63]. The nucleophilic addition of various metal organyls proceeded with high diastereoselectivity and good yields to give hydrazines 104. The SAMP auxiliary was cleaved reductively with borane, and the resulting amine was protected to give Cbz-protected aminosulfonates 105, which were then converted in two steps to sultams 106, retaining the stereochemical purity. Next to cerium organyls, lithium organyls are frequently used for the addition of C-nucleophiles to hydrazones. Recent applications include the addition of heteroaromatic lithium organyls to SAMP hydrazones to give α-heteroarylalkylamines [64]. In addition, SAMP and RAMP hydrazones have recently been used for the separation of enantiomeric cyclophanes as depicted in Scheme 24 [65]. Two diastereomerically pure isomers (RP,S)-107 and (SP,S)-110 have been obtained by chromatographic separation of the diastereomeric mixture. These chiral hydrazones were subsequently alkylated to chiral hydrazines (RP,S)108 and (SP,S)-111. After reductive cleavage of the auxiliary and protection with CbzCl, the α-branched [2.2]paracyclophanylalkylamines (RP,S)-109 and (SP,S)-112 O

O N

O

S

O

O

n

N RM, CeCl3, THF, -100 °C

H

HN O O

75-99%

103

S O

n

N R

104, d.r. = 89:11 - >99:1 R = alkyl, aryl; n = 1,2

1. BH3, THF, reflux, 4h 2. CbzCl, K2CO3, CH2Cl2, reflux 50-99%

NHCbz O O

S O

n

O O S NH

R

105, ee = 78 - 99%

n R 106, ee = 78 - 99%

Scheme 23 Asymmetric synthesis of 3-substituted γ- and δ-sultams using the SAMP auxiliary

176

W. Maison

1. BH3, THF 2. CbzCl, K2CO3

MeLi, THF, -100 °C to rt

86%, 3 steps H

N N

NH N OMe

NHCbz OMe

(Rp,S)-107

(Rp,S)-109 d.r. > 99:1 ee > 99%

(Rp,S,S)-108

1. BH3, THF 2. CbzCl, K2CO3

MeLi, THF, -100 °C to rt

83%, 3 steps N N

H

HN N

MeO

CbzN

MeO (Sp,S)-110

(Sp,S)-112 d.r. = 73:27 ee > 99%

(Sp,S,S)-111

Scheme 24 Matched and mismatched alkylation of SAMP hydrazones (RP,S)-109 and (SP,S)-112

EtO2CN

(EtO)2P(O)TMS, TiCl 4, Et2O, -78 °C - rt

N N

54%

EtO2CN

PO3Et2 NH N

MeO

MeO

113

114, d.r. = 65:35

Scheme 25 Attempt towards stereoselective synthesis of hydrazinophosphonic acid 114 using RAMP hydrazone 113

were obtained in good yield. However, in the mismatched case, (SP,S)-112 was formed with only modest selectivity (de ¼ 45%). A switch in auxiliary to SAMBO/ RAMBO was found to be a solution to this issue providing the mismatched product (SP,S)-112 with perfect diastereoselectivity (de > 99%). Attempts to apply the SAMP/RAMP method to the diastereoselective synthesis of hydrazinophosphonates of type 114 (Scheme 25) were only moderately successful, and the phosphite addition to RAMP hydrazone 113 proceeded with good yield but low selectivity to 114 [66]. Trifluoromethyl groups are important structural elements in drugs and agrochemicals. A method for the catalytic introduction of trifluoromethyl groups into hydrazones like 115 has recently been introduced by Baudoin and coworker (Scheme 26) [67]. Copper-catalysed conversion of SAMP hydrazone 115 gave the trifluoromethylated hydrazone 116, which was subsequently reduced with LiAlH4 to

Pyrrolidines as Chiral Auxiliaries

O

177

O

F 3C I

MeO

MeO

MeO N N

N N

CuCl, 10 mol%, CHCl3, rt 83%

115

CF3

LiAlH4, Et2O, rt 80%

116

O

N H HN CF3

O

O O

O

O

117, d.r. = 78:22

Scheme 26 Synthesis of trifluoromethylated chiral hydrazines 117 Ph R

HN

O

1. Et2O, reflux Ph 2. Ac2O, HBF4

CH2Cl2, -45 °C, then MeOH

O

O

O 40% N

O Ph

CO2Me R

BF4 Ph

118

O

56-90% N R = alkyl, silyloxy

1. L-Selectride 2. HCl, DME, 150 °C

Ph

Ph

R

O

56-90% O 120

119, d.r. > 99:1

Scheme 27 Diels-Alder reactions of cyclic isoimidium salts 118

hydrazine 117 with moderate diastereoselectivity. The sequence is thus an attractive method for the synthesis of α-trifluoromethylated amines.

7 Pyrrolidine Auxiliaries in Cycloadditions Chiral isoimidium salts of type 118 (Scheme 27) can be prepared easily by treatment of maleic anhydride with (S,S)-2,5-bisphenyl pyrrolidine and subsequent cyclization of the intermediate amic acid with HBF4 [68]. Isoimidium salts are highly activated unsymmetrical dienophiles for Diels-Alder reactions. It was demonstrated that these dienophiles react with a number of electron-rich dienes at low temperature without acid catalysis to cyclohexenes 119. The reactions proceed with high regioselectivity and perfect diastereoselectivity. The resulting cyclohexenes 119 were converted to enantiomerically pure bicyclic lactones 120 by reduction of the ester and subsequent alcoholysis of the amide resulting in lactonization accompanied by cleavage of the auxiliary. Aza-Diels-Alder reactions belong to the most versatile methods for the construction of nitrogen heterocycles [69]. An auxiliary-controlled variant with inverse electron demand has recently been reported by Palacios group [70]. The (S)-methoxylmethylpyrrolidine-derived enamine 122 leads to a reasonable

178

W. Maison

diastereoselectivity in the thermal Diels-Alder reaction with electron poor dienophile 121 to tetrahydropyridine 123 (Scheme 28). A photochemical electrocyclization of aromatic enehydrazides 126 (Scheme 29) was reported recently by Couture and coworker as a key step in the synthesis of enantiomerically pure isochinolines [71]. Enehydrazides like 126 are routinely prepared by acid chloride addition to the corresponding hydrazones [72]. However, this approach was unsuccessful for the synthesis of 126, and an alternative route via palladium-catalysed cross coupling reaction of enolphosphate 125 was developed [73]. In this context, it might be of interest that a useful alternative for the preparation of chiral enehydrazides derived from SAMP has recently been reported by Prakash and coworker. The authors established an efficient Cu-catalysed hydroamination of alkynes to indole enehydrazides with SAMP [74]. Photocyclization of enehydrazides 126 was performed in degassed MeOH, and irradiation at 254 nm for 4 h leads to a 6π-electron electrocyclic ring closure followed by a suprafacial [1,5]-H shift to lactams 129. Yields of this reaction were good and NO2

NO2

N

EtO2C

CHCl3, reflux, 24h

N + OMe

121

EtO2C

N

N

75%

OMe

122 123, d.r. = 75:25 NO2

NO2

Scheme 28 Auxiliary-controlled Aza-Diels-Alder reaction with inverse electron demand

OMe Cl

O N

Ar

N

OMe

O P OPh OPh

O

KHMDS 75%

O

N

Ar

N

OMe

O N

Ar

O OPh P OPh 125 O

124

OMe Pd(PPh3)4, NaCO3, THF, ArB(OH)2

N R

126 hν 254 nm, Ar, MeOH

R = H, OMe

O R

N

N

O

H

Ar MeO

61-68% 129, d.r. >99:1

O

N N

R

128

N N H 127

Ar MeO

Scheme 29 Auxiliary-controlled photoinduced electrocyclic ring closure of aromatic enehydrazides 126

Pyrrolidines as Chiral Auxiliaries

179

diastereoselectivity was complete. Lactams 129 were converted by standard cleavage methods to different derivatives of tetrahydroisochinolines and isochinolones. Strigolactones are plant-derived secondary metabolites and have a role as phytohormones. GR-24 (Scheme 30a) is a synthetic strigolactone analogue, which was prepared by an auxiliary-controlled intramolecular [2+2]-cycloaddition of a ketiminium ion derived from chiral amide 130 [75]. The cycloaddition gave tricyclic ketone 131 in good yield and with good diastereoselectivity. Subsequent BaeyerVilliger oxidation and further steps gave (+)-GR-24 in enantiomerically pure form after crystallization. The same approach was used for the synthesis of bicyclic ketone 133 (Scheme 30b), which was obtained in even better stereoselectivity from chiral amide 132 [76]. Intermediates like 133 have been demonstrated to be useful for the preparation of polycyclic lactams like 134. Similar lactams are abundant natural product scaffolds and form the core structure of many peptide mimetics [77]. Allenamides like 135 have also been used for [2+2]-cycloadditions with chiral hydrazones 136 (Scheme 31) [78]. The reaction is catalysed by a carbophilic gold complex and was shown to give substituted cyclobutanes 137 in good yields. The A

1. Tf2O, collidine, CH2Cl2, rt 2. CCl4, H2O, reflux

N

O O

O

O 68%

O 131, ee = 86%

130

O O

(+)-GR-24 B O

1. Tf2O, collidine, CH2Cl2, rt 2. K2CO3

N

N

O

O

H

61%

H

133, ee = 96%

132

134

Scheme 30 Intramolecular [2+2] cycloadditions of ketiminium ions derived from chiral amides 130 and 132

tBu tBu P Au NCMe

O N C 135

O +

R2 R1

OMe N

N DCE, 55 °C

N

63-85%

136 1

2

R , R = alkyl or aryl

O R 2 R1

O N

N

MeO 137, d.r. = 60:40 - 70:30

Scheme 31 Gold-catalysed [2+2] cycloadditions of allenamides 135 with α,β-unsaturated hydrazones 136

180

W. Maison O

138

O

hν, C6H6 Ph

MeO2C

+

* R 2N

CN 139

MeO2C

CN Ph NR2*

(S,R,S)-140

O Ph NR2 MeO2C CN * 71 : 29 (R,S,S)-140

NR2 = (S)-methoxymethyl-1-pyrollidinyl, no product NR2 = (S)-methoxymethyl-1-piperidinyl, 33%

Scheme 32 Paterno-Büchi reaction with chiral auxiliaries

diastereoselectivity is excellent with respect to the cis-arrangement of substituents attached to the cyclobutane. However, stereochemical induction by the SAMP auxiliary was low, and products 137 were formed as mixtures of diastereoisomers (d.r. ¼ 60:40–70:30). Döpp and coworkers have investigated Paterno-Büchi reactions of chiral aminopropene nitriles 139 (Scheme 32) [79]. The authors found that these reactions proceed with moderate yields and diastereoselectivities to oxetanes 140, if proline or pipecolic acid-derived auxiliaries were used. However, the use of (S)-methoxymethyl-1-pyrrolidine as a chiral auxiliary gave an unstable product 140, which was identified in the crude reaction mixture only. With (S)methoxymethyl-1-piperidine in turn, product 140 was obtained as a mixture of two diastereoisomers after chromatographic purification.

8 Pyrrolidine Auxiliaries in Birch Reductions The coordination of the electron-withdrawing Cr(CO)3 moiety to aryl compounds allows the attack of the arene ring by electrophiles from the exo face. The resulting carbanions can be trapped by alkylations and CO-insertion to give substituted 1,3-cyclohexadienes. Kündig et al. have used the chiral RAMP complex 141 to synthesize cyclohexadiene 142 with good yield and excellent diastereoselectivity (Scheme 33) [80]. A following allylation of the ketone and ring-closing metathesis gave the chiral fused-ring system 143 in good yield. Oxidative RAMP cleavage with MMPP gave finally nitrile 144, which is a versatile intermediate for natural product synthesis. Asymmetric Birch reductive alkylations have been reported by Brimble and coworkers to be valuable methods for the construction of bicyclic spirolactams, a structural fragment frequently found in natural products [81]. Chiral amides 145 (Scheme 34) were synthesized from (S)-methoxymethyl pyrrolidine. Birch reduction was done with potassium in liquid ammonia to generate the reactive enolates 146, which were alkylated stereoselectively at low temperature with various bifunctional electrophiles to give cyclohexadienes 147 in good yields and selectivities. Conversion of chlorides 147 (X¼Cl) to amines 148 was achieved via three steps followed by acidic cleavage of the auxiliary and lactam formation by PyBOP coupling to the final spirocyclic lactams 149. Yields of the last two steps were only low due to side

Pyrrolidines as Chiral Auxiliaries 1. Sn(C2H3)4, BuLi, THF, -78 °C 2. MeI, CO, nBu4NBr, -78 °C - rt 3. NaOEt, MeI, -78 °C - rt

O N

181

N

O N

73%

MeO

N

MeO

Cr(CO)3

O 142, d.r. > 98:2

141

O 1. LDA,allylBr, -78 °C - rt 2. Grubbs II, toluene, reflux

N

N

MMPP, MeOH, phosphate buffer, 0 °C

H

68%

CN H

91%

MeO

MeO

O

O

143

144

Scheme 33 Synthesis of fused-ring systems via Cr-mediated dearomatization and following ringclosing metathesis. MMPP magnesium monoperoxyphthalate

X

O

KO

K, tBuOH, NH3, -78 °C

N

OMe

51-87%

O R

R 146

145

1. NaI, acetone, reflux 2. NaN3, DMF, 50 °C 3. PtO2, H2

OMe

N n

I

OMe R

X

n

N

147, d.r. = 80:20-100:0

H2N

OMe

N n

O

1. HCl, H2O, reflux 2. PyBOP, DIEA, DMF, DMAP

n

NH O R

13-31%

60-90%

R = H, Me n = 0,1,CHMe X = Cl, OTBS

R 148

149

Scheme 34 Synthesis of substituted spirolactams via asymmetric Birch reductive alkylation

reactions under the strongly acidic conditions for auxiliary cleavage. Several other conditions for removal of the auxiliary were also tested but were not successful. A very similar synthetic strategy has been used for the synthesis of spirocyclic imine analogues of the neurotoxin gymnodimine [82]. Prolinol amides 150 (Scheme 35) were used for the diastereoselective construction of quaternary stereocentres at highly functionalized cyclohexenones 153 [83, 84]. These compounds have been shown to be valuable precursors for natural product synthesis [85]. The sequence starts with a stereoselective Birch reduction/

182

W. Maison

O

O R

N

1. Li or K, NH3, THF, -78 °C 2. 1,3-pentadiene 3. allylBr

N

57-70%

O

O

O R O

150

151, d.r. = 93:7 - >99:1 R = alkyl, hydroyalkyl, aryl O

O HCl, H2O 64-96%

R

N O 152

O

O Δ, 1,2-DCB 50-100%

R

N O 153

Scheme 35 Sequence of diastereoselective Birch reduction/allylation/Cope rearrangement with a prolinol-derived auxiliary. 1,2-DCB 1,2-dichlorobenzene

allylation of chiral amide 150 to give substituted cyclohexadienes 151 in good yield. The observed diastereoselectivities were good to excellent depending on the alkali metal used for the Birch reduction [86]. If lithium was used, a less reactive enolate was formed, which (after quenching of excess metal) was allylated with higher diastereoselectivity than the corresponding potassium enolate. The resulting enolethers 151 were hydrolysed under acidic conditions to cyclohexenones 152 without epimerisation. A final Cope rearrangement [87] under microwave heating in 1,2-dichlorobenzene gave the target cyclohexenones 153. The reaction has a remarkably broad scope and tolerates various alkyl, hydroxyalkyl and aryl substituents R attached to the starting materials 150. The method has recently been applied to the synthesis of decalin derivatives [88] and tetracyclic terpenoid scaffolds [89, 90].

9 Pyrrolidine Auxiliaries in Organometallic Chemistry Pyrrolidine-based amino alcohols like 155 are versatile ligands for dynamic kinetic resolution of lithium organyls (Scheme 36) [91–94]. Proton abstraction of N-Bocpiperidine 154 with sBuLi gives a racemic lithium organyl 156. Since both enantiomeric forms are in equilibrium, a thermodynamic resolution of the lithium organyl with stoichiometric quantities of a chiral ligand is feasible. In a detailed study with a number of different lithium ligands, Coldham and coworker identified chiral amino alcohol 155 as the most efficient ligand for the resolution of piperidinyl lithium 156 [95]. After deprotonation of N-Boc-piperidine 154 with sBuLi, 1.2 equivalents of the chiral ligand 155 were added followed by addition of TMSCl as an electrophilic quencher. TMS-piperidine 157 was obtained in good yield and with reasonable

Pyrrolidines as Chiral Auxiliaries

183

OH N

155

Me2N

sBuLi, Et2O, TMEDA, -78 °C

N Li Boc TMSCl 65%

N Boc

N SiMe3 Boc

154

157, ee = 70% N Li Boc 156

Scheme 36 Dynamic kinetic resolution of piperidinyl lithium 156 with prolinol-based amino alcohol 155 Li Fe

OMe OMe

OMe PCl3, NEt3, THF, 0 °C MeO

N H 158

N P Cl N

1. THF, -78 °C 2. BH3, THF 3. sat. NH4Cl 70%

N MeO

159

1. s-BuLi, TBME, -30 °C 2. ClPPh2, -30 °C 3. NEt3, 50 °C 85%

MeO

O

P N

Fe PPh2

(Sp,S,S)-161

1. HCl, TBME 2. LiAlH4, THF 3. NaOH H 2P

Fe

(S,S)-160

OMe

N

P N

O S O O

LDA, THF FePPh 2

45%

162

P FePPh 2

(Rp,S,S)-163

Scheme 37 Stereoselective synthesis of chiral ferrocenyl diphosphines 163

enantioselectivity. The protocol was also applied to other electrophilic quenchers such as Bu3SnCl, CO2, dithianes and carbonyl compounds. The synthetic potential of the method was demonstrated by synthesis of (+)-β-conhydrine. Chiral pyrrolidines, particularly SAMP/RAMP auxiliaries, have been used frequently for the stereoselective synthesis of chiral metallocene derivatives [12]. In addition, recent applications focussed on the use of (S)-methoxymethylpyrrolidine as a chiral auxiliary. Pfaltz and coworker have developed a straightforward access to chiral ferrocenyl diphosphines 163 as depicted in Scheme 37 [96]. Key intermediate 160 was prepared from (S)-methoxymethylpyrrolidine 158 and PCl3. The resulting chlorophosphite 159 was subsequently converted to the chiral ferrocene (S,S)-160. Diastereoselective lithiation and conversion with ClPPh2 gave 161, which was transferred to Kephos 163 via cleavage of the auxiliary to intermediate phosphane

184

W. Maison

162. The approach is quite general and can be applied to the synthesis of other similar ferrocenylphosphanes such as Taniaphos. Chiral 2-phospha[3]-ferrocenophanes like 167 have been synthesized by Marinetti and coworker using (S)-methoxymethylpyrrolidine as a chiral auxiliary (Scheme 38) [97]. A similar synthetic strategy has been reported earlier by the Enders group with SAMP as an auxiliary [98]. The C2-symmetrical ferrocene 165 was generated from commercial bisaldehyde 164 via reductive amination. The following lithiation and silylation gave ferrocenes 166 in good yields and with perfect diastereoselectivity (d.r. > 95:5). Subsequent cleavage of the auxiliary and conversion with different phosphanes gave the chiral 2-phospha[3]-ferrocenophanes (S,S)-167 termed Si-FerroPHANES for applications in organocatalysis. Chiral Ni-II complexes have been developed by Belokon as efficient platforms for the synthesis of enantiomerically pure amino acids [99]. The necessary auxiliaries contain proline as a source of chiral information. New derivatives thereof with o-fluorobenzyl residues 168 have been recently introduced by Saghyan and coworker (Scheme 39) [100]. These derivatives form chiral glycine complexes with Ni-II 169, which were alkylated according to the Belokon protocol to give allylglycine 170 in excellent enantiomeric excess. Similarly good yields and selectivities were obtained if alanine analogues of 169 are alkylated. MeO HN

MeO

NaBH3CN, CHO MeOH, rt Fe CHO

78%

N Fe

1. s-BuLi, Et2O 2. R3SiCl, -78 °C

MeO N R3Si Fe SiR3

53-73% N

N

MeO

164

1. Ac2O, 90 °C 2. RPH2, AcOH, 60 °C R3Si Fe SiR3 PR 30-34%

MeO

(S,S)-167

(S,S)-166, d.r. > 95:5

(S,S)-165

Scheme 38 Synthesis of chiral Si-FerroPHANEs 167

F O

N

H N O 168

Gly, Ni(NO3)2, NaOMe, MeOH, 50 °C, 1h

O F

O N Ni N

74-92%

N

H H

1. RBr, DMF, NaOH, rt 2. HCl, H2O 74-79%

HO2C

R NH2

170, ee = 92-97% O

R = allyl, Bn

169

Scheme 39 Synthesis of amino acids 170 via Ni-II complexes based on a proline containing chiral auxiliary

Pyrrolidines as Chiral Auxiliaries

10

185

CrossLinkingellaneous Applications of Pyrrolidine Auxiliaries

An auxiliary-controlled approach to pyrrolizidinone 173 has recently been reported by Nicolaou and coworker (Scheme 40) [101]. Chiral amide 171 was treated with I (sym-collidine)2ClO4 to trigger an iodolactonization to iodo pyrrolizidinone 173. This elegant approach did not only provide the target pyrrolizidinone 173 with excellent stereoselectivity but is also traceless with respect to the chiral auxiliary. It is cleaved during aqueous workup of the intermediately formed iminium species 172. Iodo pyrrolizidinone 173 was used as an advanced intermediate of pyrrolizidine-based antibiotics. The authors have tried several different auxiliaries for the iodolactonization described, with commercial C2-symmetric bismethoxymethyl pyrrolidine giving the best results. The SAMP/RAMP strategy has been applied to the synthesis of indolinones like 175 (Scheme 41) [102]. Iodoarenes 174 were used as starting materials, which were cyclized via lithiation to hemiaminals 175. The reaction worked with good yields but showed no diastereoselectivity with respect to the newly formed stereogenic centre. Cleavage of the auxiliary to the free indolinones has been done under oxidative conditions with MMPP as mentioned earlier. An interesting and very short access to chiral allenes 177 has recently been described by a traceless auxiliary method [103]. In a one-pot conversion, the auxiliary 176 was treated with terminal alkynes and aryl aldehydes with ZnBr2 in refluxing toluene (Scheme 42). The resulting allenes 177 were formed with very good enantioselectivity. Presumably, the reaction proceeds via the initial formation of an iminium ion, which is attacked stereoselectively by an intermediately formed zinc acetylide. The resulting chiral propargylamine is then transferred to the

OMe

MeO

OTBS

I(sym-collidine) 2ClO4 MeO

N

H

47% N

O TBSO

N

N

172

173, ee > 98%

Scheme 40 Auxiliary-controlled iodolactonization to iodo pyrrolizidinone 173 OMe OMe I

O N

R

N

O

BuLi, THF, -78 °C

N N

R 77-86%

O

Ar R = H, alkoxy

174

O I

I

171

N O

O MeO

H O

O

O

OTBS

H 2O

HO

Ar

175

Scheme 41 Cyclization of chiral SAMP hydrazone 174 to indolinone 175

186

W. Maison R ZnBr2, toluene, ArCHO, 120 °C, 10 h

Ph Ph OH

N H

H R

35-70%

(S)-176

H

(R)-177, ee = 82-99% R = alkyl, alkenyl, nitriloalkyl, haloalkyl

ArCHO

Ar

N Ph Ph OH

N

ZnBr

Ph Ph OH 178

Br

Ph Ph OH R

N

Ar C

N

ZnBr

Ar

Ph Ph OH

Ar Br2Zn

R

R

Scheme 42 Synthesis of chiral allenes 177 via a traceless chiral auxiliary approach

O

N N

O

KHMDS, ClPO3Ph2, THF, -78 °C

MeO

O

N N

O

MeO

ArB(OH)2, Pd(PPh3)4, NaCO3, H2O

PO3Ph2

65-76%

180

179

N N

Ar

MeO 181

HCO2NH4, Pd/C, MeOH 81-92%

O

O

N N

Ar

MeO 182, d.r. >98:2

MMPP, MeOH, rt 83-90%

O

N H

Ar

183, ee > 96%

Scheme 43 Diastereoselective hydrogenation of arylated cyclic enehydrazides 181. MMPP magnesium monoperoxyphthalate

target allene 177 with efficient chirality transfer via an intramolecular hydride shift. In the last step, the auxiliary is released as imine derivative 178. The reaction has a broad scope, and successful conversions have been demonstrated for a range of functionalized alkynes and several aryl and heteroaryl aldehydes. 6-Arylated piperidinones 183 have been prepared by an auxiliary-controlled diastereoselective hydrogenation of corresponding enehydrazides 181 (Scheme 43) [104]. The key intermediates 181 have been obtained by Pd-catalysed cross coupling of aryl boronates to enol phosphates 180, which were prepared from hydrazide 179. Catalytic hydrogenation of 181 gave the arylated hydrazides 182 in good yield and with excellent diastereoselectivities. Cleavage of the auxiliary was performed with

Pyrrolidines as Chiral Auxiliaries

187

MMPP to give arylated piperidinones 183. The compounds have been shown to be valuable precursors for the synthesis of natural products, as demonstrated with the synthesis of ()-anabasine by the method describe above [105]. An auxiliary-controlled approach to chiral alkoxysilanes has recently been reported starting from trimethoxysilanes 184 (Scheme 44) [106]. Treatment with (S)-lithiummethoxymethyl pyrrolidine 185 gave the chiral aminosilanes 186. Substitution with a lithium organyl gave aminosilanes 187 in very good diastereoselectivity. Final cleavage of the auxiliary was performed with an alcohol or silanol to give chiral siloxane derivatives 188 with complete inversion of configuration upon substitution. The C2-symmetric auxiliary 2,5-diphenyl pyrrolidine has recently been used for the stereoselective C-H amidation of diarylphosphinic amides 189 (Scheme 45) [107]. An iridium-catalysed protocol leads to efficient desymmetrization of diarylphosphinic acids. The products 190 of this conversion were obtained in good yields and with good diastereoselectivity. A broad reaction scope was demonstrated with various substituted starting materials 189 and the introduction of different sulphonamides. Chiral oxaphospholidines 191 with an integrated prolinol-based auxiliary have been prepared as building blocks for the automated synthesis of diastereomerically pure phosphorothioate oligonucleotides 192 (Scheme 46) [108]. A suitable coupling protocol for DNA-synthesis has been established, and the efficient incorporation of oxaphospholidines was shown. The biological properties of these oligonucleotides have been shown previously to depend critically on the stereochemistry at the phosphorothioate linkage [109]. OMe OMe

LiN R1

185

pentane, rt

OMe Si OMe OMe

45%

MeO R1 N Si OMe

184

OMe R2Li, Et2O, -78 °C - 0 °C

R1

36-93%

R2 N Si OMe

R3OH, toluene, reflux 84-92%

187 d.r. = 88:12 - 96:4

(S)-186

R2

R1

OR3 Si OMe 188 ee = 91% - 98%

R1 = aryl; R2 = alkyl, aryl; R3 = aryl, SiAr3

Scheme 44 Diastereoselective synthesis of chiral siloxanes 188

O P R1

R1 Ph

N

189

Ph

[IrCl2(Cp*)]2 2mol% AgNTf2 8.5 mol% PivOH 12 mol%, DCE, rt - 60 °C

O NHSO2R2 PR P R1

R1

83-93%

R1 = Me, OMe, Cl; R2 = aryl, Bn, alkyl

Ph

N

Ph

190, d.r. = 90:10 - 95:5

Scheme 45 Iridium(III)-catalysed C-H amidation of diarylphosphinic amides 190

188

W. Maison

DMTO O

O

B

DMTO O

O

O

P

P

N

O

N

B

O O

B

O

O O P S O O

Ph (SP)-191

O

B

B

O O P O S

O

B

Ph (RP)-191

O

(SP)-192

O

(RP)-192

Scheme 46 Diastereoselective synthesis of phosphorothioate antisense oligonucleotides 192

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Top Heterocycl Chem (2020) 55: 193–252 DOI: 10.1007/7081_2017_12 # Springer International Publishing AG 2018 Published online: 23 March 2018

Synthesis and Utility of Heteroand Non-heterocyclic Chiral Auxiliaries Derived from Terpenes: Camphor and Pinene Robert K. Boeckman, Jr. and Jeremy A. Cody

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Camphor Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Camphor Imine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Camphor Methyl Ketone Enolate Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Camphor Homoallylic Alcohol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Camphor α-Hydroxy Enone 14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Functionalized Camphor Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 A Camphor-Derived δ-Lactol Auxiliary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Hydroxyisoborneol Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Camphor-Derived Auxiliary Cis-3-[N-(Aryl)Benzenesulfonamido]Borneol 34 . . . . 3.4 Camphor Oxazolidinones as Chiral Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Camphor-Based Oxazolidinone O-60 and Oxazolidinethione S-60 Chiral Auxiliaries . . 5 Sultam- and Sulfonamide-Derived Camphor Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 The Aza Camphor Class of Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2 2- and 3-Aza Camphor Lactams and Related Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3 Applications of 2-Aza Camphor Lactam (91) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.4 Applications of 1,7,7-Trimethyl-3-Azabicyclo[2.2.1]-Heptan-2-one (94) . . . . . . . . . . 6.5 Applications of (105) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.6 Applications of 6,6-Dimethyl-3-Aza Camphor Lactam (108) . . . . . . . . . . . . . . . . . . . . . . . 6.7 Applications of 8-Phenyl-3-Azabicyclo[2.2.1]Heptan-3-One (97) . . . . . . . . . . . . . . . . . . 6.8 Auxiliary Removal and Recovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Auxiliaries Derived from Pinene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1 A Chiral Auxiliary Derived from α-Pinene (2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2 Chiral Alcohol Auxiliaries Derived from β-Pinene (3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R.K. Boeckman, Jr. (*) Department of Chemistry, University of Rochester, Rochester, NY, USA e-mail: [email protected] J.A. Cody (*) School of Chemistry and Materials Science, RIT College of Science, Rochester, NY, USA e-mail: [email protected]

194 195 195 195 196 197 200 200 200 202 204 207 208 212 212 213 216 224 234 236 239 242 242 243 243

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7.3 Pinene-Derived Lactam Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 8 Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248

Abstract This chapter reviews the literature through the end of 2016 directed to the preparation and use of heterocyclic chiral auxiliaries derived for terpenes, principally camphor, borneol (via ent-camphor), and pinene. Since they are closely aligned in their utility, the scope of this chapter was expanded somewhat to include non-heterocyclic chiral auxiliaries derived from these terpenes where relevant and appropriate. The chapter is organized by auxiliary, and within the section on a given auxiliary are subsections on preparation and the various applications of that auxiliary to asymmetric synthesis organized generally by reaction type. A wide variety of applications are reviewed including cycloadditions, condensations, sigmatropic rearrangements, alkylations, and acylations to name a few. While the chapter is not intended to be comprehensive, it is intended to give the reader the scope and breadth of the structural types of auxiliaries derived from camphor, borneol, and pinene and their applications to asymmetric synthesis. Keywords Asymmetric synthesis · Aza camphor · Camphor · Camphor-derived lactam · Pinene · Stereoselective · Terpenes

1 Introduction Terpenes have great structural variety, often possessing rigid three-dimensional frameworks, undergo well-known chemical transformations, and are readily available, allowing them to play an essential role as naturally occurring sources of chirality in asymmetric synthesis [1, 2]. Camphor (1) and pinene (2 and 3) have been used successfully as building blocks for creation of innovative and effective chiral auxiliaries (Fig. 1) [3]. This chapter will cover use of camphor- and pinene-derived chiral auxiliaries including, but not limited to, heterocyclic derivatives prepared from 1 to 3. This chapter does not aim to be comprehensive in its coverage, as such a review already exists covering the literature through 2011 [3]. Rather, this chapter will cover the highlights appearing in the literature prior to 2017. Fig. 1 Camphor and pinene terpenes O camphor (1)

alpha-pinene (2)

beta-pinene (3)

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2 Camphor Auxiliaries Utilizing camphor itself as a chiral auxiliary has been effective in a number of stereoselective reactions. The following section covers some successful examples.

2.1

Camphor Imine

McIntosh et al. published a series of papers from 1986 to 1988 describing the successful use of camphor as an auxiliary to provide diastereoselective additions of benzyl and allylic electrophiles to glycine imines (4a–c, Scheme 1) [4–7]. Camphor imine glycinates (4a–c) could not be prepared directly from camphor but required the more reactive thione 5. In practice 4c was synthesized smoothly and provided the greater stereoselectivity relative to 4a and 4b. Although many electrophiles were explored, the most diastereoselective and highest-yielding alkylation electrophile was BnBr (89% yield, >98% de). The proposed transition state of the (R)-camphor auxiliary is consistent with experimental observations and results in Re face selectivity. Cleavage of the robust imine may be accomplished with hydroxylamine acetate.

2.2

Camphor Methyl Ketone Enolate Derivatives

Obtaining high stereoselectivities of acetate aldol reactions to prepare β-hydroxy ketones has been difficult to control using chiral auxiliaries. In the late 1990s, Palomo and co-workers used (R)-camphor as a chiral auxiliary to obtain high stereoselectivities of acetate aldol reactions [8, 9]. Palomo employed a successful

+ O 1X=O 5X=S

toluene H2N

COOR

reflux

X

Li O

R1 N

Proposed transition state

X = Br, I

R1-X

Ot-Bu O

OR

N

H H

N M

OR

O 4a R = CH3 b R = CH2CH3 c R = C (CH3)3

6a R = CH3 b R = CH2CH3 c R = C(CH3)3

H

LDA N

R1

+ Ot-Bu

N

Ot-Bu

O O 7b minor 7a major R1 = allyl, Bn, i-Pr, Bu 20-89% yield, 75:25-99:1 d.r.

Scheme 1 Preparation and alkylation of camphor imines of tert-butyl glycinate. All reactions run at
78 C for 1–2 h with 1 equiv. of HMPA

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Fig. 2 Proposed transition state for the acetate aldol reactions Table 1 Stereoselective acetate aldol reactions

R¼ H TMS

Selectivity ratio 10:11 (yield %) R’ ¼ C6H5 R’ ¼ C6H5CH2CH2 72:28 (86) 75:25 (ND) 88:12 (67)a 88:12 (75)a 96:4 (80) 95:5 (85)

R’ ¼ (CH3)2CHCH2 89:11 (ND) 93:7 (75)a 96:4 (75)

ND not determined a Addition of sixfold excess of LiCl and yield of isolated 10

strategy to increase stereoselectivity by creating a system that moves the prochiral center closer to the camphor’s densely packed chiral scaffold. The resulting stereoselectivity is explained using a three point chelation with Li and a Zimmerman-Traxler six-membered transition state (Fig. 2). The approach of the aldehyde is from the rear side of the camphor system as depicted in Fig. 2. A study of the acetate aldol reactions reveals good to excellent stereoselectivity and yields (Table 1). Improvements to the selectivity were achieved by adding LiCl (6 equiv) or silylating the tertiary alcohol with TMS. Recovery of the camphor auxiliary and formation of β-hydroxy carboxylic acids are accomplished with oxidative cleavage.

2.3

Camphor Homoallylic Alcohol

In 2004, Loh reported a novel method to prepare cis-homoallylic alcohols with control of both the olefin geometry (up to 99% cis) and enantioselectivity (up to 99% ee) using camphor as a chiral auxiliary [10]. Treatment of camphor (1) with 1,2-addition of crotyl magnesium bromide provides substrate 12 (Scheme 2). Camphor homoallylic alcohol 12 is used in excess (3 mol equivalents relative to aldehyde) and converted to cis-homoallylic alcohols 13 and recovered camphor by treatment with catalytic CSA (10 mol%). The authors proposed a mechanism that explains the observed results (Scheme 3). Upon reaction workup and isolation the syn/anti ratio of recovered 12 changed from 70:30 to 40:60.

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Scheme 2 General reaction for formation of cis-homoallylic alcohols

Scheme 3 Proposed source of selectivity

The anti-camphor homoallylic alcohol is unproductive due to the sterics encountered in the conformation required for the oxonia [3,3]-sigmatropic rearrangement. The syn-diastereomer is converted preferentially as no such steric encumbrance occurs in the pathway to Z-13.

2.4

Camphor α-Hydroxy Enone 14

Palomo and co-workers developed α’-hydroxy enone 14 as an important structural motif that imparted excellent stereoselectivity in both Diels-Alder reactions and 1,4-additions [11–14]. Enone 14 may be prepared from camphor in a one-pot two-step process (Scheme 4). The true ingenuity of the system results from the internal hydrogen bonding that both rigidifies the prochiral functionality around the camphor chirality and activates the enone. After the diastereoselective reaction is complete camphor is readily recovered through an oxidative cleavage.

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Scheme 4 Formation of α’-hydroxy enone 14 Table 2 Diels-Alder reactions of enone 14 and dienes

Entry 1 2 3 4 5

Diene

Catalyst (equiv) None TfOH (0.1)

t (h) 24 2–3

Temp. ( C) 25
78

None Cu(OTf)2 (0.1) TfOH (0.1)

72 1

20 20

1.5


78

Major diastereomer 16 X c OH O

X c OH O

Endo: exoa 16:1 49:1

drb 98:2 98:2

– 98:2

– 98:2

c

>150:1

98:2

95

Yield (%) 95 98

d

a

Determined by HPLC or 13C NMR b Determined for major product by 13C NMR c 99% conversion

In 2002, Palomo and co-workers published their initial work using prochiral enone 14 that takes advantage of the camphor chiral environment (Table 2) [11]. The group utilizes α’-hydroxy enone 14 as the chiral dienophile in the Diels-Alder reaction. Later that decade the group publishes a detailed discussion in a full article [12]. The more reactive dienophile, cyclopentadiene, undergoes a facile Diels-Alder reaction in good yield and selectivity without any added catalyst (Table 2, Entry 1). When the less reactive diene, cyclohexa-1,3-diene, is reacted with enone 14, the Diels-Alder reaction does not proceed (Table 2, Entry 3). Less reactive dienes do proceed if a catalyst is used (Table 2, Entries 4 and 5). In summary, Palomo and co-workers developed conditions for the Diels-Alder reaction that can be tuned based on the reactivity of the diene to provide excellent yields and selectivity. The selectivity and reactivity observed can be explained using the proposed internal hydrogen bonding model without any catalyst and the hydrogen bonding networks under acidic conditions (Fig. 3). The reaction and selectivity are promoted by a bridging hydrogen bond between the hydroxyl group and the carbonyl oxygen. Additional activation and conformational organization are strengthened by the presence of a strong Brønsted acid.

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Fig. 3 Arguments for the stereoselectivity and reactivity of the metal-free Diels-Alder reactions

Scheme 5 Methyl ether enone 17 reactivity

Scheme 6 1,4-Additions of β-ketoesters to α’-hydroxy enone 14

Additional supporting evidence for the internal hydrogen bonding model was observed in reacting ether enone 17 with cyclopentadiene (Scheme 5). Ether enone 17 did not react with cyclopentadiene. In contrast hydroxyl enone 14 reacted to completion under the same conditions. Generation of all-carbon quaternary centers is difficult to prepare and especially challenging to accomplish with high enantioenrichment. Palomo and co-workers developed a method to prepare all-carbon quaternary carbons with good stereoselectivity by a 1,4-addition of substituted β-ketoesters 18 and 19 to camphor-based α’-hydroxy enone 14 (Scheme 6) [13]. As can be seen in Scheme 9, the 1,4-adducts were obtained in good yields and diastereomeric ratio. The greater steric bulk of the t-butyl ester functionality provides better selectivity compared to the Me, Et, or i-Pr esters (not shown). Given the above successful stereochemical transformations, the Palomo group further employed α’-hydroxy enone 14 in stereoselective 1,4-additions of nitroalkane 22, which is challenging due to the remote γ-position (Scheme 7) [14]. Optimization of the reaction conditions showed that three reagents were required for good yields and stereoselectivity. For the conjugate addition to proceed at all, a tertiary amine base was required, but no stereoselectivity was observed. It was reasoned that it was necessary to restrict the conformations of the enone relative to the auxiliary with a Lewis acid. Further development provided the optimized Lewis acid/Brønsted base system, copper triflate, and N-methylpiperidine (NMP) with the additive, molecular

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Scheme 7 Nitroalkane 1,4-additions to α’-hydroxy enone 14

sieves, as seen in Scheme 7. An ester and ketone functional groups were compatible with the reaction. Alcohols resulted in poor yields (50%) due mainly to alkoxide addition to the enone. Upon oxidative cleavage of the camphor auxiliary, an important class of building blocks, γ-amino acids, is obtained. Additional cleavage procedures were developed that afforded aldehydes and ketones.

3 Functionalized Camphor Auxiliaries Functionalizing the camphor skeleton has resulted in many highly effective chiral auxiliaries that utilize camphor’s dense chiral framework in diastereoselective reactions.

3.1

A Camphor-Derived δ-Lactol Auxiliary

Dixon and co-workers developed a camphor-derived lactol auxiliary that desymmetrized glycinamide residues. The chiral auxiliary linked glycinamide residues 24 were employed to prepare chiral α-amino carbonyl compounds 25 and 26 by alkylation (Scheme 8) and Michael reactions (Scheme 9) in good yield and with high diastereoselectivity [15, 16]. The resulting stereochemistry observed in the products was through a Re-face addition to the Z-enolate. The stereochemical model proposed was a seven-membered ring transition state that incorporates chelation to the lactol oxygen and subsequent blocking of the Si-face by the steric bulk of the camphor skeleton. Removal of the camphor THP auxiliary is easily accomplished by acid catalyzed hydrolysis.

3.2

Hydroxyisoborneol Auxiliaries

Early in the development of chiral auxiliaries, the use of a “molecular wall” was employed to block one face of the prochiral centers. One of the early systems studied was the isoborneol derivatives 27 (Fig. 4) wherein different “molecular walls” were positioned to control the approach of reagents to the reaction substrates attached via the hydroxyl group [17–19]. A classic example, neopentyl ether derivative 28, will be showcased to demonstrate the system.

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Scheme 8 Diastereoselective α-alkylation of CamTHP glycinamide 24

Scheme 9 Diastereoselective Michael addition to α,β-unsaturated esters and lactone with CamTHP glycinamide 24

Fig. 4 3-Hydroxyisoborneol systems

Scheme 10 Diels-Alder of acrylate 30 with 1,3-butadiene

Oppolzer’s neopentyl ether chiral auxiliary 28 provided a bench mark in the field for facial selectivity in the Diels-Alder reactions providing adduct 29 in excellent yield with high diastereoselectivity (Scheme 10) [20]. Although, the results in Scheme 10 were impressive, the additions were limited to acrylates. Crotonates resulted in low conversion, as polymerization byproducts predominated. Further utilization of neopentyl ether 28 auxiliary in the 1,4-addition to enolates 31 afforded high diastereoselectivity and good yields (Scheme 11) [21, 22]. Conjugate addition products 32 are readily hydrolyzed to provide enantioenriched carboxylic acids (92–99% ee) and recovery of the chiral auxiliary.

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Scheme 11 1,4-Additions of alkylcopper and alkenylcopper reagents to chiral enolates 31

3.3

Camphor-Derived Auxiliary Cis-3-[N-(Aryl) Benzenesulfonamido]Borneol 34

Helmchen and co-workers developed stereoselective reactions using their novel exo- and endo-cis-benzenesulfonamidoborneol 34 as a camphor-derived auxiliary from 1981 to 1996. The auxiliaries have been employed for diastereoselective alkylations, anti-aldol reactions, and 1,4-additions of organocopper reagents. Camphor is transformed to exo-34 in four steps and to endo-34 in five steps as described in Scheme 12 [23]. Employment of exo- or endo-cis-benzenesulfonamidoborneol 34 proceeds in alkylation reactions good to excellent diastereoselectivity and good yields (Scheme 13) [23, 24]. The alkylation reaction proceeded through a lithium enolate. Helmchen and co-workers discovered that the enolate geometry could be controlled by adjusting the solvent(s). It was observed that using THF as the only solvent provided E-enolate 37, but when HMPT was present as a cosolvent during the deprotonation, the Z-enolate was prepared. Interestingly, the Re-face of endo-enolate 37 was exposed and reacted with the alkylating reagent and the Si-face of exo-enolate 37.

3.3.1

Aldol Reactions Using Borneol Auxiliaries 34

Helmchem and co-workers explored the use of endo-cis-benzenesulfonamidoborneol 34 in acetate and propionate aldol reactions [25]. The lithium enolates gave poor selectivity, but good diastereoselectivity was achieved via use of titanium tetrachloride-mediated additions of O-silyl ketene acetals generated from the lithium enolates. Addition of propionate endo-39 to isobutyraldehyde provided access to antialdol product 40 (Scheme 14). The syn/anti ratio was 93.5:5.5 and facial selectivity for the anti-aldol was 92:1.5. The stereoselectivity of the major diastereomer, endo40, agrees with the Zimmerman-Traxler model. In 1985 conjugate addition of cuprates to enolates bearing borneol auxiliary 34 was reported by Helmchen and co-workers [26]. The conjugate additions of organocuprates generally provided excellent diastereoselectivity (98:2 to >99:1 dr) and good yields (>80%), as seen in Scheme 15. Removal of the chiral auxiliary with potassium hydroxide in methanol readily gives carboxylic acids 41 (R ¼ Et, i-Pr, H2C ¼ CH, Ph).

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Scheme 12 Preparation of exo- and endo-cis-3-[N-(3,5-dimethylphenyl)benzenesulfonamido] borneol (34)

Scheme 13 Ester enolate alkylations

Scheme 14 Diastereoselective propionate aldol reaction

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Scheme 15 Conjugate addition of cuprates to endo-enolate 42

3.4

Camphor Oxazolidinones as Chiral Auxiliaries

In the early 1990s, a series of three oxazolidinone chiral auxiliaries (44, 45, and 46, Fig. 5) were prepared and developed for alkylation, aldol, and Diels-Alder reactions [27]. Acylation of the auxiliaries proceeds smoothly and in high yield. In 1992, Banks and co-workers developed 44 as a chiral auxiliary for alkylation, aldol, and Diels-Alder reactions (Scheme 16) [27]. The high selectivity (>99:1 dr) of the alkylation of endo-N-propionyloxazolidinone 47 was general for all alkyl halides tried, but the yields varied from 6 to 70%. Use of endo-oxazolidinone 44 as the chiral auxiliary in a series of aldol reactions proved very effective. For example, syn-aldol product 48 (R ¼ Ph or iPr) was prepared with high de and moderate to good yield (52% when R ¼ Ph and 86% when R ¼ iPr). In addition to the alkylations and aldol reactions, Banks also reported their result on the Diels-Alder reaction using endo-oxazolidinone 44 as a chiral auxiliary and discovered π-facial selectivity was poor and the endo/exo ratio not controlled well [27, 28]. The lack of selectivity was reasoned to be a result of poor differentiation s-cis/s-trans conformations in dienophile 49. Preparation of exo-oxazolidinone 45 can be accomplished in four steps starting from camphorquinone in 60% overall yield [29]. In 1991 Thornton and co-workers employed exo-oxazolidinone 45 in the aldol reaction (Scheme 17) [29]. Acylation of exo-oxazolidinone 45 by deprotonation with n-BuLi to form Npropionyloxazolidinone 52 proceeded in 93% yield. The aldol reactions were run with either lithium or titanium (IV) enolates of 52, which were then treated with two equivalence of aldehyde. The syn-adducts were the major products, and generally simple acyclic aldehydes gave the greatest selectivity. For example, when trimethylacetaldehyde was added to the lithium enolate of 52, the aldol products were observed to have a 98:2 dr. Whereas, treatment of cyclohexane carboxaldehyde under the same reaction conditions provided a syn/anti ratio of (2:1) and a 94:6 dr for the syn products (R ¼ cyclohexyl, Scheme 17). In 1993, Tanaka employed exo-oxazolidinone 45 in a series of Diels-Alder reactions in direct comparison to endo-oxazolidinone 44 chiral auxiliary [28, 29]. Interestingly, the opposite facial selectivity is observed in reactions of 44 relative to 45, as a result of the difference in orientation of the oxazolidinone ring (exo versus endo). Unfortunately, exo-auxiliary 45 suffers from poor facial selectivity as did the endo-oxazolidinone 44 owing to poor control over the s-cis/strans rotamers.

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Fig. 5 Oxazolidinone chiral auxiliaries

Scheme 16 Employment of endo-oxazolidinone 44 auxiliary

In 1994, exo-oxazolidinone 46 was first prepared by the Palomo group, and the route was refined by Cadogen and co-workers in 1996 [30, 31]. In their initial report, the Palomo group described the use of oxazolidinone 46 as a chiral auxiliary for stereoselective alkylations, 1,4-additions, and Diels-Alder reactions. As with endo-oxazolidinone 44 and exo-oxazolidinone 45, exo-oxazolidinone 46 provided excellent stereocontrol in the reported alkylation reactions (99:1 dr) with yields ranging from 40 to 83% (Scheme 18). In Palomo’s study of the Diels-Alder reactions, using exo-oxazolidinone 46 as a chiral auxiliary, the stereochemical control was poor. Unfortunately, the reaction was conducted in THF, a coordinating solvent, with Et2AlCl as the initiator [30]. In 1996, Cadogen and co-workers repeated Palomo’s experiment, but instead of using THF as solvent, they used dichloromethane, and the solvent change resulted in excellent stereocontrol (Scheme 18) [31]. When comparing the three chiral auxiliaries (44, 45, and 46) in the Diels-Alder reaction, exo-oxazolidinone 46 exerts greater stereocontrol. Specifically, the π-facial selectivity is superior and likely is a result of the preference of the reacting dienophiles

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Scheme 17 Employment of exo-oxazolidinone 45 auxiliary

Scheme 18 Employment of exo-oxazolidinone 46 auxiliary

56 to adopt the s-cis conformation. The preference for the s-cis rotomer can be envisioned to result from proximity of the enone moiety to the sterically more encumbered methyl-substituted bridgehead carbon, which provides a steric bias for the s-cis conformation [30–32].

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4 Camphor-Based Oxazolidinone O-60 and Oxazolidinethione S-60 Chiral Auxiliaries Yan and co-workers introduced camphor-based oxazolidinone O-60 and oxazolidinethione S-60 auxiliaries in 1991, which were prepared in two steps and three steps, respectively, from ketopinic acid (Fig. 6) [33]. Yan and co-workers explored the utility of their auxiliaries in alkylation and aldol reactions. Alkylation of oxazolidinone 61 proceeded through enolate Z-62 with a range of different reactive alkyl halides in excellent stereoselectivities (>97:3 dr) as seen in Scheme 19 [33]. Yan and co-workers published a series of papers describing their development of different reaction conditions for the aldol reaction using auxiliary oxazolidinone O-60 and oxazolidinethione S-60 to prepare all but one of the four possible stereoisomers in high diastereoselectivity (Scheme 20) [34–36]. Re-syn-64b is the major product when Ti-S-65 is reacted with the selected aldehydes. The opposite π-selectivity for the syn product is observed with multiple conditions, as seen in Scheme 20. A highly selective aldol reaction was also developed to give Re-anti-64c by forming boron enolates O-65 and adding sub-stoichiometric equivalents of Lewis acids (TiCl4 or SnCl4) [37]. Conditions were not developed that would give rise to the opposite π-facial selectivity for the anti-aldol product.

Fig. 6 Camphor-based oxazolidinone O-60 and oxazolidinethione S-60 chiral auxiliaries

Scheme 19 Alkylation of propionyloxazolidinone 61 with a series of alkyl halides

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Scheme 20 Aldol reactions using oxazolidinone O-60 and oxazolidinethione S-60

In addition to the aldol reactions described in Scheme 20, Yan and co-workers successfully employed oxazolidinone in acetate aldol reactions with moderate to excellent stereoselectivity [38–40]. Removal the auxiliary by hydrolysis of adducts with basic hydrogen peroxide gave the expected carboxylic acids and recovered auxiliary.

5 Sultam- and Sulfonamide-Derived Camphor Auxiliaries Oppolzer and co-workers developed a series of camphor-derived chiral auxiliaries with the most enduring auxiliary being sultam 66 (Fig. 7). Hydroxyisoborneol auxiliary 28 was discussed above. In the following section, an overview of sultam 66 and sulfonamides 67 and 68 will be presented. For a more detailed discussion on these auxiliaries, Oppolzer has authored two reviews in 1987 and 1990 that are worth noting [2, 41]. These reviews have been recently updated [42]. In developing chiral auxiliaries, Oppolzer understood the importance of using chiral auxiliaries that were highly crystalline and imparted crystallinity to the derived reagents and products. Sulfonamides 67 and 68 and sultam 66 are crystalline in nature and

Synthesis and Utility of Hetero- and Non-heterocyclic Chiral. . .

209

Fig. 7 Oppolzer’s 3-hydroxyisoborneol, sulfonamides, and sultam chiral auxiliaries

Scheme 21 Diels-Alder reactions using chiral auxiliary sulfonamides 67 and 68

Scheme 22 Aldol reactions of propionate 73

readily prepared from the commercially available camphor-10-sulfonyl chloride [43, 44]. In 1984, Oppolzer and co-workers utilized sulfonamides 67 and 68 as auxiliaries for dienophiles in Diels-Alder reactions. Excellent yields and good stereochemical control in the Diels-Alder reactions were observed. As an example, when cyclopentadiene was used as the diene and acrylate sulfonamide 70 as the dienophile, adduct 72 was obtained in excellent yield (97%) and with good diastereoselectivity (96% endo, 96:4 dr, Scheme 21) [43]. Stereoselective aldol reactions employing propionate sulfonamide 73 were reported in 1986 (Scheme 22) [45]. The major product is the result of an antialdol reaction with approach of the aldehyde from the Si-face of E-ketene acetal 74. Besides the aldol reaction, other electrophiles have been reacted with the enolate derived from 73. The Oppolzer group obtained high diastereoselectivity in electrophilic additions at the alpha carbon in the following: α-alkylation [46], α-halogenation [47], α-acetoxylation [45], and α-amination [48]. After sultam 66 was introduced in 1984 by Oppolzer and co-workers, it was widely adopted and even became commercially available in kg quantities [41–43, 49]. Due to the wide use of sultam 66 as a chiral auxiliary, studies on the source of

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the stereochemistry in detail by Oppolzer [43] and Curran were carried out [49, 50]. Acylation of chiral auxiliary sultam 66 to afford N-enoylsultam and Nacyl derivatives has been established using a variety of methods [51–53]. Once prepared dienophiles 76 are reactive in the Diels-Alder reaction and provide excellent stereoselectivity in the presence of bis-coordinate Lewis acids (Scheme 23) [44, 54]. The transition state is highly organized due to the bis-coordinate Lewis acid that chelates a sulfone oxygen and the carbonyl oxygen. The s-cis-conformation of the enone is prevalent due to the steric interactions of the β-vinyl hydrogen and the exo-methylene hydrogen on C-3 in the s-trans conformation. As can be seen from the examples in Scheme 23, the Diels-Alder reaction proceeds with good yields (88–98%) and diastereoselectivities (96:4 to 97:5 dr.). Additionally, auxiliary 66 has been effective in both intramolecular Diels-Alder reactions [53, 55] and [2 + 3] cycloadditions [51, 56]. In 1987 Oppolzer reported that Grignard reagents can undergo 1,4-conjugate additions to N-enoyl sultam 76 (R ¼ CH3, Scheme 24) [57]. Taking advantage of the formed enolate 81, an in situ trapping of an electrophile was explored. Conjugate hydride addition with L-Selectride proceeds with very good diastereoselectivity on the β-face of the enoyl group of N-enoyl sultams 76

Scheme 23 Diastereoselective Lewis acid mediated Diels-Alder reactions

Scheme 24 1,4-Additions/enolate trapping

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211

(Scheme 25) [58]. Once enolate 83 is formed, an in situ trapping with methyl iodide can take place with high diastereoselectivity. Stereoselective reductions of N-enoyl sultam 76 may be completed with heterogenous catalyst (Pd/C, 100 psi hydrogen gas) with excellent stereocontrol and yields (Scheme 25) [59]. Oppolzer and co-workers developed three different reaction conditions for the aldol reaction in which each reaction condition provided a different aldol adduct stereoisomer as the major product (Scheme 26) [41, 42, 53, 60]. Both syn-aldol

Scheme 25 1,4-Hydride addition/enolate trapping

Scheme 26 Aldol reactions with derivatives of Oppolzer’s camphor-derived sultam 66

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R.K. Boeckman and J.A. Cody

products could be obtained by either going through the boron enolate or tin (IV) enolate, 97:3 to 99:1 dr of 87 and 89:11 to 92:8 of 88, respectively [53]. The boron enolate is envisioned to go through a dipole-controlled transition state giving syn-aldol product 87, whereas the tin enolate reacts through a chelation-controlled transition state giving syn-aldol product 88. Preparation of anti-aldol product 89 is brought about in good yields and excellent selectivity (99:1 dr) by treating the Esilyl ketene acetals from 90 with aldehydes and TiCl4 [60, 61]. The anti-aldol product is envisioned to proceed through an “open” transition state. In addition to the aldol reaction, enolates derived from acylated sultam 88 also react with several other electrophiles. Reactions that were carried out included alkylations [62], halogenations [57], nitrations [63, 64], and alkylation of glycine analogues [65].

6 The Aza Camphor Class of Auxiliaries 6.1

Introduction

All of the terpene-derived auxiliaries discussed thus far exhibit the common feature that the reactive subunits are attached outside the camphor framework itself, primarily but not exclusively at C2, for example, consider the camphorsultam class of auxiliaries. However, the rich and unique chemistry of the camphor nucleus allows for ready functionalization of the C2, C3, C6, C7, C8, C9, and C10 positions of camphor. Money and co-workers have examined in detail the remote functionalizations mediated by the facile and reversible Wagner-Meerwein rearrangements realized upon exposure to acids and other strong electrophiles [66]. 9

5

4

8 3

6

2 7

1 10

O

(1R, 3R)-(+)-Camphor (1)

Relatively few examples of modification of the camphor framework itself have been described. Camphanic acid [67], a well-described derivative of camphor, is such an example resulting from insertion of oxygen into the camphor framework. Replacement of the C2 or C3 carbons with oxygen has also been described affording the corresponding lactones [68]. Since the presence of oxygen within the framework does not provide a functional handle for attachment of a reactive group, only camphanic acid [67], a nitrogen analogue [69, 70], and a ring expanded lactol [71– 73], where attachment of the reactive group is outside the camphor framework, have seen use as chiral controller molecules. Since nitrogen being trivalent can permit attachment of reactive groups at C2 and C3 positions of camphor nucleus, the corresponding nitrogen derivatives have been explored. Both the 2- and 3-aza camphor lactams, the latter first prepared by Woodward for use in his Vitamin

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213

B12 synthesis [74], have been described and have seen significant development for use as chiral auxiliaries as described in the following sections, principally by our group at the University of Rochester.

6.2

2- and 3-Aza Camphor Lactams and Related Derivatives

6.2.1

Preparation of 2-Aza Camphor Lactam (91) and 3-Aza Camphor Lactam (94)

The starting point for all the aza camphor and related derivatives is the appropriate antipode of camphoric acid or a functionalized derivative. Both antipodes of camphoric acid are commercially available. However, the nonnatural antipode, 1S,3R-camphoric acid, is considerably more costly but is readily prepared from inexpensive 1S-(endo)-borneol by oxidation with nitric acid [75, 76]. The reaction sequence for preparation of either antipode of 2-aza camphor lactams 91 and 94 employs a Curtius rearrangement of an acyl azide derived from the appropriate antipode of camphoric acid monoester 93, followed by trapping of the intermediate isocyanate with methanol to afford carbamate 92 and base-induced ring closure to lactams 91 and 94 (Scheme 27) except that the appropriate antipode of the alternate regioisomeric camphoric acid 95 is required for lactam 94 (Scheme 1) [77–79].

6.2.2

8-Phenyl-3-Aza and 10-Phenyl-3-Aza Camphor Lactams 97 and 103

As shown in Scheme 28, one example of a substituted derivative, the 8-phenyl analogue 97, is, in turn, made from 8-bromocamphor 98 which is readily available from camphor using the procedure developed by Money [80]. 8-Bromocamphor 98 is converted to the dioxolane 99 followed by nickel-catalyzed coupling with PhMgBr affording after acidic hydrolysis of the ketal, 8-phenyl camphor 100 in

CO2H CO2H

H2SO4 CH3OH 68%

CO2CH3 CO2H 93

1. H2SO4 CH3OH 2. KOH CH3OH H2O 87%

CO2H CO2CH3 95

1. (COCl)2, PhCH3 2. NaN3, H2O 3. toluene, reflux 4. CH3OH, TEA 78% 1. EtO2CCl, TEA 2. NaN3, H2O 3. toluene, D 4. CH3OH, TEA 90%

Scheme 27 Preparation of camphor lactams 91 and 94

CO2CH3 N CO2CH3 H 92

N CO2CH3 H CO2CH3 96

O

NaH THF reflux 82%

NaH THF reflux 80%

NH 91

NH 94 O

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R.K. Boeckman and J.A. Cody

Br

Br TMSCl 98

O

1.

2.

OH HO 79% NaOCl THF / H2O CH3I K2CO3 DMF 70%

O 99 O

1. PhMgBr (Ph3P)2NiCl2 Et2O 2. 10% HCl THF 68%

SeO2

O

100

102

CH3OH reflux

O 101

O

1. EtO2CCl, TEA acetone 2. NaN3, H2O

KOH CO2CH3 CO2CH3

xylenes reflux 24 h 92%

CO2H 3. toluene, reflux CO2CH3 4. CH OH, TEA 3

NaOCH3 N CO2CH3 H CO2CH3

NH CH3OH / THF rt 70% overall

O 97

Scheme 28 Preparation of 8-phenyl camphor lactam 97

68% yield (Scheme 28) [81]. Ketone 100 is then oxidized with SeO2 to afford the 8-phenyl camphorquinone 101 which upon further oxidation with NaOCl and esterification affords the 8-phenyl camphoric acid dimethyl ester 102. From this point, the route parallels that used for preparation of 3-aza camphor lactam 94, providing the 8-phenyl-3-aza -camphor lactam 97 in 70% overall yield from 102. Preparation of the related 10-phenyl-3-aza camphor lactam 103 proceeds via treatment of the potassium salt of 10-camphorsulfonic acid [82] with PBr5 and the subsequent radical-mediated desulfonylation of the 10-camphor sulfonyl bromide affording the known 10-bromocamphor 104 [83] as shown in Scheme 29. The route then follows the general sequence used to obtain the 8-phenyl isomer affording 103 as depicted in Scheme 29 [83]. The routes to these derivatives are quite flexible permitting coupling with a variety of different aromatic, vinyl, and alkyl Grignard reagents, the only requirement being the absence of a β-hydrogen in the Grignard reagent so as to avoid competing rapid β elimination from the competing intermediate RR’Ni(0) intermediate.

6.2.3

Unsaturated or Rearranged Camphor Lactams 105 and 108

Introduction of unsaturation as well as nitrogen into the camphor nucleus is also possible as well as preparation of rearranged derivative wherein the C-5 methyl groups are now found at C-7. Both derivatives are available from a common intermediate olefinic ester 106 obtained by oxidative decarboxylation of camphoric acid mono methyl ester 95 [68, 84]. The sequence to unsaturated lactam 105 (Scheme 30) proceeds via 106 which is converted to primary amide under standard conditions. Regioselectivity (N vs O) in the subsequent ring closure was then controlled by carbamoylation with ethyl carbamate. Ring closure is then effected by bromination at low temperature and immediate base treatment also at low temperature. Final elimination and

Synthesis and Utility of Hetero- and Non-heterocyclic Chiral. . .

TMSCl OH

1. PBr5 / Et2O

HO

O 2. BrCCl3 (as solvent) AIBN reflux 71%

KO3S

O Br

1. PhMgBr (Ph3P)2NiCl2 Et2O

O

HC(OCH3) 90%

O

O

Br

104 1. SeO2 xylenes reflux 24 h

2. 10% HCl THF 83%

CO2CH3 CO2CH3

2. Na2CO3-H2O2 acetone / H2O CH3I K2CO3 DMF 60%

3.

KOH CO2H CO2CH3

CH3OH reflux 16h

215

1. EtO2CCl, TEA acetone 2. NaN3, H2O 3. toluene, reflux 4. CH3OH, TEA

NaH

CO2CH3 N H CO2CH3

NH

THF reflux 70% overall

O 103

Scheme 29 Preparation of 10-phenyl-3-aza camphor lactam 103

CO2H CO2CH3 105

Ag2SO4 CuSO4•5H2O

1. KOH CH3OH / H2O

(NH4)2S2O8 pyridine CH3CN / H2O 77%

CO2CH3 2. SOCl2 (neat) 3. NH4OH (xs) 106 0°C 61%

1. Br2 / CH2Cl2 -78°C CONHCO2Et

107

2. NaHMDS -78 → rt 69% 1. NaH /THF rt 2. NBS -78°C 94%

1. (COCl)2 CONH2 2. EtOH 89%

KOtBu NCO2Et Br

O

Br

NH THF reflux 87%

NCO2Et O

1. H2 (3.5 atm) Pd-C EtOH 2.

NaOH EtOH 70%

O 105

NH O 108

Scheme 30 Preparation of Δ5,6 3-aza camphor lactam 105 and 6,6-dimethyl-3-aza camphor lactam 108

decarbamylation are accomplished by treatment with KOtBu at reflux providing 6,7-dehydro-3-aza camphor lactam 105. The regiochemistry of the ring closure to reform the bicyclic lactam system was readily modified by conducting the ring closure halolactamization under kinetic control by preformation of the anion of the carbamate followed by treatment with NBS providing ready access to lactam 108 possessing a rearranged fenchane skeleton (Scheme 30) [85].

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6.3

Applications of 2-Aza Camphor Lactam (91)

6.3.1

Attachment of Reactive Subunits

Reactive subunits are readily attached to the nitrogen of 2-aza lactam 91 by conversion of 91 anion with n-BuLi, LHMDS, or NaH in THF or DMF and treatment with acid chlorides or mixed anhydrides (Scheme 31). Yields generally range from 75 to 90% for a variety of saturated and unsaturated acyl halides and mixed anydrides [83–87]. For example, in an application to Diels-Alder reactions, treatment of 91 with NaH in THF with 2-methyl-2-propenoyl chloride and crotonoyl chloride affords the imide dienophiles 109 and 110 both in 93% yield [77–79]. For alkylation and aldol reactions, attachment of a variety of alkyl residues via the precursor acid chlorides or mixed anhydrides has been reported with yields ranging between 70 and 95% [88–91]. Lactam 91 also undergoes facile exclusive N-alkylation in high yields with both aliphatic and allylic bromides, iodides, tosylates, and mesylates [92, 93].

6.3.2

Applications to Diels-Alder Reactions

Only limited studies of cycloaddition reactions with 2-aza lactam 1 have been conducted since this auxiliary proved to be less useful for this application (Scheme 32) [77, 79]. Treatment of dienophiles 109 and 110 with excess isoprene in the presence of 1.5 equivalents of CH3AlCl2 at
78 C afforded an approximately 1:1 mixture of diastereomeric (π-facial selectivity) Diels-Alder adducts in 75 and 65% yields. The low selectivity was not unexpected owing to the anticipated poor control over the rotamer population of the critical Naux-CO bond [77, 79].

6.3.3

Aldol Reactions

Aldol reactions of acylated derivatives of 91 were also examined briefly, and again the reactivity and selectivity were found to be poor [86]. Direct enolization O O

Cl

N

77% O

O O O

Cl

NH 91

N

O R1

X

NaH THF reflux

NH

90%

R2 X = Cl, OC(O)R3 R1 = Alkyl, Aryl, OAllkyl R2 = H, Alkyl R3 = Alkyl, OAlkyl 70-95%

110

O

Br

109 O NaH THF reflux

91

O

O N

R2

O

R1

Scheme 31 Acylation and alkylation of 2-aza camphor lactam 91

N

96% R2O

N3 R1

O

80-82%% R1 = H, Ph R2 = Ts, Ms

N

N3 R1

Synthesis and Utility of Hetero- and Non-heterocyclic Chiral. . .

O

217

O

N

CH3AlCl2 (1,5 equiv) CH2Cl2 -78°C 75%

109 O

N O (~1:1 π-facial selectivity)

O

O

N

CH3AlCl2 (1,5 equiv) CH2Cl2 -78°C

110 O

N O

65%

H

(~1:1 π-facial selectivity)

Scheme 32 Diels-Alder reactions of camphor lactam dienophiles 109–110

O NH 91

O Cl nBuLi THF 0° C 88%

O

Et2BOTf

O

N

DIPEA CH2Cl2 0°C

N

111 O

112 CHO

O

0°C 4.5h

N

35%

O

HO

O BEt2

HO

N

+

113 O

114 O 2.2

:

1

Scheme 33 Aldol reactions of 2-aza camphor imide 111

of N-propionyl imide 111 with LHMDS afforded both poor yields and diastereoselectivity owing to the high basicity of the resulting Li enolate. When 111 was converted to the corresponding Z-enolborinate 112 by treatment with Et2BOTf and Hünig’s base [86], reaction of 22 with isobutyraldehyde afforded only a 2.2:1 mixture of syn diastereomers (2S,3R)-113 and (2R,3S)-114 in 35% yield (Scheme 33). The sense of asymmetric induction was established by X-ray crystallographic structure determination of the crystalline minor diastereomer 114 [86]. In view of the inferior selectivity observed, the studies of application of 91 to aldol reactions were discontinued.

6.3.4

Alkylation Reactions

It is in the application to diastereoselective alkylation reactions that lactam 91 is truly superior. Enolization of N-acyl derivatives like 115 at low temperatures with a variety of bases including LDA, LHMDS, sodium diisopropyl amide (NDA), and NaHMDS affords a chelated Z-enolate 116, exclusively. Reaction of 116 from the β

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face with a variety of alkyl, allyl, and benzyl halides at temperatures between
78 and 0 C affords exclusively monoalkylation products 117 in 50–99% yields and 98:2–99:1 dr (Scheme 34) [88, 90, 91]. A second alkylation of 117 can be effected to create quaternary carbon centers by the use of NDA and sufficiently reactive halides (1 alkyl, allyl, benzyl bromides, and iodides) affording 119 in 60–67% yields and 95:5–99:1 dr (Scheme 8) [88]. Again, alkylation proceeds via highly selective enolization of the anti-rotamer 117 this time followed by reaction from the β face apparently through a nonchelated enolate 118. The absolute configuration of the products (and thus the sense of asymmetric induction) was established by X-ray crystallography [88]. A single exception to the high selectivities observed in alkylation of enolates derived from acylated derivatives of 91 was encountered during the alkylation α-heteroatom enolates derived from 91. Deprotonation of 120 using either LiHMDS or NaHMDS and then treatment with allyl bromide gave the monoalkylation products in 62–74% yield and significantly lower diastereoselectivities (1.4–3.6:1) than those observed with simple acyl derivatives such as 111 (Scheme 35) [88]. The major diastereomer was again R, as previously observed, indicating alkylation again proceeded principally via a chelated enolate with electrophile approach from the β face. The origin of these anomalous results was ultimately traced to the

O

R1 115

R2 X

O

THF -78°0°C

N

O

LDA, -78oC

N

N

THF

O

116

Li O

R2

117

50-99% 98:2-99:1 dr

R1

β

R1 O

R1 = 1° alkyl (linear & branched), allyl benzyl aryl, heteroaryl R2 = 1° alkyl (linear & branched), allyl, benzyl X = Br, I O

O

I

NDA

N

R1

THF -78°0°C 119 60-67% β 95:5-99:1 dr R1 = 1° alkyl (linear & branched), allyl benzyl aryl, heteroaryl

THF -78oC

118 O Na

N

R1 O

Scheme 34 Alkylation of 2-aza camphor imides 115

O

Li or NaHMDS

N 120

o

OBn THF -78 C O

O

O N 121 H

Li O OBn

R 2X

O

THF -78°0°C

N

R2

NLi +

H

O

Scheme 35 Alkylation of α-alkoxy camphor imide 120

OBn

62-74% 1.4-3.6:1 dr

122

OBn O

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219

slower alkylation with α-halo ethers resulting in competing reversible elimination of the lactam anion to a ketene intermediate serving to scramble the geometry of the kinetic Z-enolate. This asymmetric alkylation method has seen application to complex molecule synthesis (Scheme 36). Preparation of a key intermediate 123 toward tetronolide 124 proceeds via diastereoselective alkylation of ent-111 with PMB-protected allylic iodide 125 affording 126 in 70% yield and >98:2 dr [90].

6.3.5

Acylation Reactions

Acyl derivatives of 91, such as imides 115, using either propionyl or benzoyl chloride, also occur through the chelated lithiated Z-imide enolate to afford the acylated product 127 in 68% and 82% yield, respectively, with 20–50:1 diastereomeric ratios (Scheme 37). In the case of propionyl chloride, the major C-acylated product was accompanied by 28% yield of the O-acylation product limiting the yield [79, 94].

O

O i) LDA, 0oC

N O ent-111

OPMB

N

OPMB

ii) I

O

125

126

70%, >98:2 dr OHC O

TBDPSO

O OH H

H BnO

OH O

HO OMOM 123 HO

124

Scheme 36 Application to the total synthesis of tetronolide (124)

O N

1. LDA, -78oC 2

R1

2. R COCl

O

R1

N

68-82% 127 O O O 20-50:1 dr R1 = 1° alkyl (linear & branched), allyl benzyl aryl, heteroaryl R2 = Et, Ph

115

Scheme 37 Acylation of camphor imides 115

R2

220

6.3.6

R.K. Boeckman and J.A. Cody

Sequential Homologation-Alkylation

Somewhat unexpectedly, reaction of 91 with (triphenylphosphoranylidene)ketene (the Bestmann ylide) occurs thermally in the absence of base providing simple access to the chiral stabilized ylide 128 in a 90% yield (Scheme 38) [95]. Lactam 91 (and the other aza camphor lactam derivatives) represents one of the very few examples of the reaction of 2 amides with the Bestmann ylide, which usually is reactive only with compounds bearing acidic hydrogens. Chiral stabilized ylide 128 reacts with simple aldehydes affording exclusively E-α,β-unsaturated imide 129 in high yields (Scheme 38). Chiral stabilized ylide 128 can also be employed in a highly flexible iterative construction of polypropionate derivatives that has been applied to the total synthesis of (
)-rasfonin (Scheme 39) [91]. Beginning with propionyl imide 130 (ent111), alkylation of the Li enolate with tiglic iodide affords 131 (87%). Cleavage of the auxiliary by reduction with LiBH4 followed by Swern oxidation provides aldehyde 132 (76%). Homologation of 132 by condensation with ylide 128 to O O

Ph3P C C O

NH

toluene, reflux 90%

O

O

ClCH2CH2Cl PPh3 reflux, 19h

N 128

91

H

O

N 129

O

98%

Scheme 38 Tandem acylation-Wittig reaction of 2-aza camphor lactam with Bestmann ylide O O

Ph3P C C O

NH

toluene, reflux 90%

H

O

ClCH2CH2Cl PPh3 reflux, 19h

N 128

91

O

O

1.

N O

130

O

LDA THF -78°C

N

2. I THF -78°0°C 87%

131

2. (COCl)2 DMSO Et3N -78°0°C

O

1.

PPh3

O

133

OHC 132

Et3SiH Pd/CaCO3/PbO acetone 50oC

O N

N ClCH2CH2Cl reflux, 18h 80%

LiBH4 CH3OH-Et2O 0°Crt

76%

O N 128 O

O

98%

1. O

N 129

2.

O

LiHMDS THF-78oC then CH3I 84%

134

Scheme 39 Application to the synthesis of a key intermediate for rasfonin

O

Synthesis and Utility of Hetero- and Non-heterocyclic Chiral. . .

221

afford (E,E) imide 133 (80%), followed by Pd-catalyzed reduction of the conjugated imide with Et3SiH and alkylation of the Li enolate of the resulting imide with CH3I, affords the enantiomerically pure syn polypropionate derivative 134 in 84% yield and >95:5 dr. By judicious choice of the enantiomer of the auxiliary, any of the four diastereomers of the side chain acyl group are accessible by this sequence, since the chirality of the auxiliary and the order of introduction of the alkyl groups dictate the absolute and relative stereochemistry at the newly introduced chiral centers. Additional iterative cycles are conceivable affording higher homologs of 134.

6.3.7

Oxidative Acetal Formation

Methacryloyl imide 109 can be treated with CH3OH, PdCl2, and CuCl to afford the acetal 135 in 52% yield and 2:1 dr favoring 2S configuration in the side chain (Scheme 40) [96].

6.3.8

Preparation and Reactions of Chiral Ynamides Derived from 91

Thermally sensitive chiral ynamides derived from 91 can be synthesized using a protocol developed by Hsung and co-workers. Catalytic Cu(II) and 1,10phenanthroline catalyzed the N-alkynylation of 91 by various alkynyl bromides affording ynamides 136 in 70–98% yields (Scheme 41) [97]. Catalytic reduction of ynamide 137, derived from 91, has been successful using quinoline-poisoned Pd-BaSO4 as catalyst affording Z-enamide 138 in 70% yield and >95:5 Z/E selectivity. The minor amount of the E-isomer is attributed to isomerization during the reaction and/or purification (Scheme 42) [98].

O

CH3OH, PdCl2,

N

CuCl, DME

109

52%

O

O N 135

OCH3 O

OCH3

Scheme 40 Diastereoselective Wacker-type oxidative acetal formation of 109

Br

O +

NH 91

R

O

CuSO4-5H2O (5-10 mol%) 1,10-phenanthroline K3PO4 toluene, 60-65oC 70-98%

Scheme 41 Preparation of ynamides from camphor lactam 91

N 136 R

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R.K. Boeckman and J.A. Cody

Pd-BaSO4 1 mol % quinoline

O N

O N

EtOAc 70%

137

OTBS

138

OTBS

Scheme 42 Semi-reduction of ynamides derived from camphor lactam 91

O

O

N

O

25 mol% lewis acid

H

CH2Cl2, rt

N

42-56%

139

O

140

Scheme 43 Hetero ring-closing metathesis of ynamide 139

OH O

O

toluene, PNBSA

R

o

N

60-80 C

136

N 141

R

H R

O

Scheme 44 The Ficini-Claisen rearrangement of ynamides derived from camphor lactam 91

Although no chirality was induced during the process, a hetero ring-closing metathesis of ynamide 139 catalyzed by a variety of Lewis acids (BF3OEt2, Mg (OTf)2, Sn(OTf)2, Zn(OTf)2) has been reported. The resulting unsaturated imide 140 was obtained in moderate yields (42–56%) depending upon the choice of Lewis acid (Scheme 43) [99]. The transformation of ynamides 136 to chiral allenes 141 (the Saucy-Marbet rearrangement) was explored using enantiomerically pure 2-propyn-1-ol in toluene and in the presence of p-nitrobenzenesulfonic acid (PNBSA) (Scheme 44). Yields were dependent on temperature and ranged from 40 to 80%. The auxiliary did not exert high levels of stereocontrol affording 1–3.3:1 dr depending on the R group [100, 101]. Chiral ynamides, employing 91 as the chiral control element, have been used in the Ficini-Claisen rearrangement. For example, the ynamide 142 was reacted with an allylic alcohol to generate the Claisen rearrangement precursor 143 which then undergoes [4] sigmatropic rearrangement to afford imide 144 in 80% yield and 87:13 dr [102]. The sense of asymmetric induction is the same as that observed for alkylation with the dienyl ether reacting via a conformation wherein the ether unit approaches the ketenaminol double bond from the front or β face (Scheme 45). When a more functionalized E-allylic alcohol was employed, the 2S,3R-syn diastereomer 145 was obtained in 63% yield and 95:5 dr with the minor component comprised of a mixture of the other three possible diastereomers (Scheme 45) [102].

Synthesis and Utility of Hetero- and Non-heterocyclic Chiral. . .

HO PNBSA, toluene

O N

144 iPr

OH

BnO

iPr

N

O

143

N 142

O i-Pr

25-50oC 80% 87:13 dr

O

223

PNBSA, toluene 80oC 63% 95: 5 dr

O i-Pr

+

N 145

O

O

miture of the 3 other diastereomers

OBn

Scheme 45 Ficini-Claisen rearrangements of chiral ynamides derived from camphor lactam 91

O

4.0 equiv RhCl(PPh3)3 (15 mol%)

N

16.5 mol % AgSbF6 0.0014 M in DCE 84% 1:1 dr

146

O OMe

N 147

MeO

Scheme 46 Rh(I)-catalyzed [2 + 2 + 2] cycloaddition reactions of aryl ynamides derived from 91

148

O

1. 1.05 equiv. Co2(CO)8 CH2Cl2, rt, 30 min

O

N

2. CH2Cl2, -10oC 6.0 equiv Me3NO

N

n-hex

n-hex H

149 O

H

36% very low dr

Scheme 47 Pauson-Khand cycloadditions of ynamides derived from camphor lactam 91

Aryl ynamide 146, derived from 91, has been employed in attempts to effect enantioselective Rh(I)-catalyzed [2 + 2 + 2] cycloaddition. The [2 + 2 + 2] cycloaddition occurred smoothly to afford biaryl 147; however the P/M selectivity is low (1:1 dr) in accord with the modest selectivities seen in efforts to effect such enantioselective cycloadditions with other chiral auxiliaries (Scheme 46) [103]. Chiral ynamides such as 148, derived from 1, have also been employed in Pauson-Khand cycloadditions (Scheme 47). However, as is often observed, the cycloaddition proceeded in modest yield and was essentially non-stereoselective affording all four possible diastereomers of the condensation product with norbornadiene 149 [104]. Additional steric bulk in the auxiliary appears necessary to obtain high stereoselectivity in such Pauson-Khand cycloadditions.

224

6.3.9

R.K. Boeckman and J.A. Cody

[2,3]-Meisenheimer Rearrangements

Diastereoselective [2,3]-Meisenheimer rearrangements of the amines 150 derived from N-allylation of 91 and reduction of the resulting N-allyl lactams 151 with LAH have been reported [105, 106]. The oxidation-[2,3]-rearrangement sequence rapidly affords chiral allylic hydroxyl amines 152 via the intermediate N-oxide in moderate yields (19–48%) and diastereoselectivities (1.5–2:1 dr), the highest diastereoselectivity thus far observed for this rearrangement (Scheme 48). The hydroxylamines 152 can be converted to the chiral allylic alcohols by reduction with Zn in HOAc with no loss of enantioselectivity [105, 106].

6.4 6.4.1

Applications of 1,7,7-Trimethyl-3-Azabicyclo[2.2.1]Heptan-2-one (94) Attachment of Reactive Subunits

As was the case for 2-aza camphor 91, lithiated 3-aza camphor 94 readily adds to a variety of acid chlorides and mixed anhydrides in high yields to afford N-acyl imides such as 153 and 154 (Scheme 49) [77, 79, 83–91]. The use of NaH with the

O

151

THF

R2

N

R2

N 150

R1

O N SO2Ph

Ph

O

LiAlH4

R1

O R2

Et2O, rt

N

19-48% 1.5-2:1 dr

O

R1

152

Scheme 48 Diastereoselective [2,3] Meisenheimer rearrangements of N-allyl camphor lactams

OMe NH

nBuLi, THF, -20oC

N

O

O Cl

O

94

OCH3 80%

153 O O

O

CO2-Li+

PhSO2Cl (1.5 eq), TMEDA(4.8 eq),

O

N

then NLi 77%

NH 94

Cl

O R2 R1

nBuLi, THF, -20oC

O O

154

O N

R1 R2

77-90%

Scheme 49 Acylation of 3-aza camphor lactam 94

155

O

O

Synthesis and Utility of Hetero- and Non-heterocyclic Chiral. . .

225

appropriate acid chloride also affords acylation products 155 in 77–90% yield [77, 79, 88]. A limited number of examples of N-alkylation for the 3-azabicyclo lactam have been reported. In all cases, N-alkylation is obtained exclusively. For example, deprotonation of lactam 94 with NAH followed by addition of methyl iodide affords the N-methylated lactam 156 in 81% yield (Scheme 50) [79, 107].

6.4.2

Applications of 94 to Diels-Alder Reactions

The most prominent use of 3-aza camphor lactam 94 has been in Lewis acidpromoted Diels-Alder cycloaddition reactions. In this application, derivatives of 94 have provided substantially superior diastereoselectivity relative to the comparable derivatives of 91. The methacrylate carboximide dienophile 157, prepared by acylation of the sodium anion of 94 with methacrolyl chloride, is treated with cyclopentadiene in the presence of 1.5 equiv. of CH3AlCl2 at
90 C to afford the adducts 158 and 159 (9:1 endo/exo) in 98% yield with the major endo adduct exhibiting 91:9 dr (Scheme 51) [77, 79]. Both the methacryloyl carboximide 157 (Scheme 51 and Table 3) and crotonoyl carboximide dienophile 160 (Table 4) were examined using a selection of dienes affording cycloaddition products in 61–98% yield with selectivities in the range of 90–96% dr. Interestingly, these observed selectivities are complementary to the selectivities observed for dienophiles derived from the Evans oxazolidinone class of auxiliaries providing higher dr for simple internally substituted dienes relative to simple terminally substituted dienes [77–79, 87]. Initial cycloaddition studies of chiral dienophile 157 with simple oxygensubstituted dienes promoted by Et2AlCl afforded high regioselectivities and yields

NH

NaH DME

N

CH3

then 94

O

CH3I 81%

156 O

Scheme 50 N-alkylation of camphor lactam 94

CH3AlCl2 N 157 O

O

+

N

CH2Cl2, -90oC 98%

158

O

O

N +

91:9 dr 9:1 endo:exo

159 O

Scheme 51 The Diels-Alder reaction of 3-aza methacryloyl camphor imide 157

O

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R.K. Boeckman and J.A. Cody

Table 3 Diastereoselectivity of Diels-Alder reactions of methacryloyl carboximide 157a–c Dienophile 157

Diene

dr 91:9d

Endo/exo 90:10

Yield (%) 93

157 157

85:15e 90:10

– –

61 79

157

95:5

–

82

157 157

OTIPS

90:10 57:43f

67:33 –

63 89

157

OTIPS

50:50f

87:13

91

157

OTIPS

88:12g,h

>98:2

95

OTIPS a

All reactions employed diene (xs) [alkyl (5–10 equiv), oxygenated (1,2 equiv)]; CH3AlCl2/ CH2CI2 (1.5 equiv) CH3AICI2/CH2CI2 at ~0.25M at
78 C b Diastereomer ratios determined by capillary glc c Isolated yields of chromatographically pure material d T ( C) ¼
90 C e T ( C) ¼
30 C f L.A. ¼ (CH3)2AlCl g Slow addition of L.A. to a mixture of diene and dienophile h T ( C) ¼
20 C

Table 4 Diastereoselectivity of Diels-Alder reactions of crotonoyl carboximide 160a–c CH2)n

N

O

N

O

CH2)n

+

N

O

O O

Dienophile 160

dr 95:5

Endo/exo –

Yield (%) 82

160

~95:5

92:8

97

160

96:4

–

83

a

Diene

O

All reactions employed diene (xs) [alkyl (5–10 equiv), oxygenated (1,2 equiv)]; CH3AlCl2/ CH2CI2 (1.5 equiv) CH3AICI2/CH2CI2 at ~0.25 M at –78 C b Diastereomer ratios determined by capillary glc c Isolated yields of chromatographically pure material

Synthesis and Utility of Hetero- and Non-heterocyclic Chiral. . .

227

(89–95%) of the expected cycloadducts but low dr (1.2:1) as seen in Table 1 [77, 79]. It was later discovered that the use of a TiCl4-SbPh3 complex leads to successful cycloaddition with oxygen-substituted dienes, for example, reaction of 161 (ent-157) with oxygenated triene 162 affords 163 in 89% yield (11:1 endo/exo) with the major isomer having >99:1 dr (Scheme 52 and last entry Table 1) [78]. The TiCl4-SbPh3 complex minimizes free TiCl4 in solution and is thus well-suited for reactions involving acid-sensitive substrates. Addition of an equivalent of (CH3)3Al serves as a proton scavenger to avoid decomposition of the acid-sensitive dienes. An inverse demand hetero [4 + 2] cycloaddition of allenimide 164 has also been reported [108]. Thermal reaction of 164 with the N-phenylsulfonyl imine of methacrolein afforded a 29% yield of the expected cycloadduct 165 having 3:1 dr (Scheme 53). Although the observed dr is similar to several other oxazolidinone and camphorsultam auxiliaries examined, 164 proved more thermally labile resulting in a lower yield [108].

6.4.3

Applications of 94 to Aldol Reactions

Asymmetric aldol reactions of acylated 3-aza camphor lactam 166 have been investigated. Lithium diisopropyl amide (LDA) can be utilized to effect stereoselective formation of chelated Z-lithium enolates. These lithium enolates proved to be highly basic thus unsuitable for use in aldol reactions affording low diastereoselectivity and low yields with aliphatic aldehydes owing to competing enolization. The Z-enolborinates obtained by soft enolization using diethylboron triflate and Hünig’s base proved to be suitable [75, 84–87, 89, 94, 109].

OTIPS o

i) TiCl4, CH2Cl2, -20 C

O N

O

TIPSO

161

Xc =

ii) -78oC, SbPh3, Me3Al OTIPS TIPSO

O

162 89%

163

Xc

O N

OTIPS OTIPS

Scheme 52 Application to preparation of a key intermediate for the total synthesis of cassioside

PhO2S

N

O

+ N

H 164

CH3CN 90oC, 12h sealed tube 29% 3:1 dr

O N H PhO2S N 165

Scheme 53 Hetero [4 + 2] cycloaddition of N-allenyl camphor lactam 164

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R.K. Boeckman and J.A. Cody

Aldol reactions performed using acylated 3-azabicyclo lactam 166 afforded high yields and very good diastereomeric ratios favoring the syn diastereomer 167 over the anti-diastereomer 168. The Z-diethylboron enolate can be treated with a variety of aldehydes to afford the syn product in 43–92% yields with 6.1–24:1 ratios favoring the (2S) diastereomer (Scheme 54). The stereoselectivity can be rationalized based upon the model shown in Scheme 55 wherein the A1,3 interactions in the Z,Z chair transition state are balanced against the larger non-bonded interactions between the alkyl groups on boron and the auxiliary two carbon bridge in the E,Z transition state. Examination of both transition states led to the conclusion that the limitations in selectivity might be alleviated by redesigning the auxiliary. That redesign led to examination of the isomeric chiral lactam 4,5,5-trimethyl-2azabicyclo[2.2.1]heptan-3-one (169) [75].

6.4.4

Applications of 94 to Alkylation Reactions

For applications to diastereoselective alkylation reactions, enolization of lactams such as 170 and 171, acylated derivatives of 94, have been effected with a number of bases including LDA and LiHMDS. In accord with the clean formation of Zenolates from 1, alkylation of the Z-lithium enolates derived from 170 and 171 by deprotonation with LDA or LiHMDS affords monoalkylation products 172 and 173 in high yield and very good dr (10–11.5:1) as shown in Scheme 56 [79, 91]. As expected, the major diastereomers have the 2R (172) and 2S (173) configuration, respectively, at the newly created stereogenic carbons. This result is in accord with the expectation that the electrophile will approach the Si-face of the enolate. Soft enolization using TiCl4 and DIPEA has also provided a Z-titanium enolate for alkylation when acylated 3-aza camphor lactam 174, derived from ent-94, was employed [76, 91]. This Z-titanium enolate undergoes highly diastereoselective O

Et2BOTf iPrNEt/CH2Cl2

N

O

O

R+

N

then RCHO

O

OH

R

O 168 syn-(2R)

O 167 syn-(2S)

166

N

OH

Scheme 54 Boron-mediated aldol reactions of N-propionyl camphor carboximide 166

167 syn-(2S)

Major Pathway

H H R

H

H

N Et O

O CH3

Et

B

Z,Z-Chair

N

Minor H

O H

B Et

Et

O

Pathway

168 syn-(2R)

O NH 169

R CH3

E,Z-Chair

Scheme 55 Rational for the diastereoselectivity of boron-mediated aldol reactions of 166

Synthesis and Utility of Hetero- and Non-heterocyclic Chiral. . .

229

O LDA (2 equiv)

N O 170 O

N

CH3I THF -78oC

N

97% 8-11:1 dr

O O

172 O

Li

I

O i) LiHMDS

N

N

THF, 0oC 171 O

O O

O

THF, -78°C

N

86% 11.5:1 dr

Li

173 O

Scheme 56 Origin of the diastereoselectivity in alkylation reactions of N-acyl derivatives of 94

TiCl4, DIPEA

O

O

CH2Cl2, 0oC BOMCl 81% >95:5 dr

N 174 O

OBn

N 175 O

Scheme 57 Diastereoselective α-benzyloxymethylation of camphor carboximide 174

R OBn N O 176 O

NaHMDS RX

OBn N O

THF -78oC 86-99% 4.4-6.4:1 dr

177 O

RX = CH3I, PhCH2Br

Scheme 58 Diastereoselective α-alkylation of O-benzylglycol camphor carboximide 176

exclusive C-alkylation with α-halo ethers such as benzyl chloromethyl ether affording 175 with extraordinarily high dr (>95:5) again with electrophile approach anti to the gem dimethyl bridge (this time from the Re face) as shown in Scheme 57. The corresponding lithium enolate derived from 174 affords mainly recovered starting material which is thought to arise by hydrolysis of the O-alkylated ketene aminal upon workup. As with derivatives of 91, alkylation of α-heteroatom enolates is significantly more complex, and reduced diastereoselectivity is observed. Deprotonation of the 3-aza lactam 176 using sodium hexamethyldisilazide and then treatment with benzyl bromide or methyl iodide gave the monoalkylation products 177 in 86–99% yield and 4.4–6.4:1 dr (Scheme 58) [79, 88]. The sense of asymmetric induction favors the 2’R diastereomer. This stereochemical outcome does not follow the model (bottom face approach of the electrophile to a chelated imide enolate) used to rationalize the prior alkylation

230

R.K. Boeckman and J.A. Cody

results from simple acyl derivatives of both 91 and 94. These results are best rationalized by invoking chelation to the α-heteroatom substituent rather than the auxiliary lactam carbonyl group (Scheme 59). The lower diastereoselectivity is a result of poorer control over the Naux-C rotamer population by dipole forces as shown in Scheme 59. The observed change in diastereoselectivity with time likely results from reversible elimination to a ketene intermediate and lactam anion. This interpretation is supported by the fact that the R diastereomer 91 is favored over the S in the alkylation of α-alkoxy derivatives of both 91 and 94 [88].

6.4.5

Applications of 94 to Enolate C-Acylation Reactions

Very limited studies were conducted of C-acylation of α-alkoxy-acyl derivatives 179 of 3-aza lactam 94 using either acid chlorides or mixed anhydrides (Scheme 60) [79, 94]. Acylation was found to occur through the chelated lithiated Z-imide enolate to afford 180 in 77–94% yields and exhibiting 2.4–4:1 diastereomeric ratios. Use of a low polarity solvent medium is important when conducting such acylations in order to suppress formation of O-acylation products.

Si M

O

N

OBn

N

OBn base

O

Re

R RX

N

R R

OBn +

N

O

O

O

177 O

176 O

178 O

O C

Na N + H

OBn

O

Scheme 59 Mechanistic rationale for the low diastereoselectivity of alkylations of 176

LDA 1:6 THF:toluene -78oC O

O N

179

O

O

Cl OCH3

94% 4:1 dr

O

N OCH3

LDA toluene, -45oC

O

180

S

O

O

F3C

O 77% 3.3:1 dr

Scheme 60 Diastereoselective C-acylation of O-methylglycol camphor carboximide 179

OBn

Synthesis and Utility of Hetero- and Non-heterocyclic Chiral. . .

6.4.6

231

Olefination of Aldehydes

Acylation of the 3-aza lactam 94 with (triphenylphosphoranylidene)ketene (Bestmann ylide) provides the imide ylide 181 in an 88% yield without the use of an additional base (Scheme 61) [95]. The ylides 181 can undergo modification at the α carbon by alkylation and acylation by primary alkyl, allyl and benzyl bromides, and iodides and acid chlorides [95]. The ylides 181, as characteristic of stabilized ylides, react smoothly with aldehydes including those bearing α chiral centers to afford E di and trisubstituted α,β-unsaturated imides such as 182 in 86–99% yields and no loss in chirality where applicable (Scheme 61). Chiral α,β-unsaturated imides, such as 182, could serve as substrates for diastereoselective conjugate addition as well as conjugate reduction and alkylation or acylation [91].

6.4.7

Application to Diastereoselective Anchimerically Assisted Substitution

An example of a diastereoselective anchimerically assisted substitution using an acylated derivative of 3-aza lactam 94 has been reported [87, 90]. Sequential treatment vinyl enolpyruvyl lactam 183 with bromine followed by immediate exposure to dienol ester 184 in the presence of AgOTf afforded the mixed bromo acetal 185 in 64% yield and 96:4 dr (Scheme 62). The stability of 184 to the reaction conditions was critical to success. The sense of asymmetric induction could be rationalized by assuming Ag+assisted ionization of bromide 186 with anchimeric assistance affording dioxolenium ion 187 preferentially over the diastereomeric dioxolenium ion 188 owing to steric interactions between the bridge and the bromomethyl group (Scheme 63) O

O NH 94

O

Ph3P C C O toluene, reflux 88%

N 181 O

PPh3

O

H N CH2Cl2 Δ 4h 98%

182 O

Scheme 61 Tandem acylation-Wittig reaction of 94 using Bestmann ylide

O N 183 O

O

O

1. Br2, Na2CO3 CH2Cl2, -78oC

N 2. AgOTf, 2,6-lutidine HO CO2tBu

184 64% overall 96:4 dr

185 O

O

H

O

CO2tBu

Br

Scheme 62 Highly diastereoselective anchimerically assisted mixed acetal formation using 183

232

R.K. Boeckman and J.A. Cody

H O AgOTf

H O + O

CO2tBu O

N Br

O

Br

185 O O

Br

186 O

O

N

+ 184 AgOtf

O N 188

CO2tBu

Br

O

189

H O + O

Br

(S) O

H

CO2tBu

HO

CO2tBu

H

187 O

Br

O

N

(R) O

O

N

CO2tBu

H

O

Scheme 63 Mechanistic rationale for the sense of asymmetric induction during formation of 185

O

N

O

H

Ti(OiPr)4 Br

Δ 155°C (batth)

H O Br 191

+ CO2iPr

O

H

O

O

CO2iPr

Br

1:5

Br

190 OHC

CO2tBu

H

65%

O

95% CO2tBu

O

iPrO2C

toluene rt

185 O K2CO3 BHT xylenes

CO2tBu

CO2tBu

O

OTBPS MOMO H O

O

O H

O HH

OH O

HO

iPrO2C 193

HO

194

192

Scheme 64 Application to the total synthesis of (+)-tetronolide (194)

[87, 90]. Attack of 184 on 187 and 188 then proceeds with inversion with the former pathway leading to the major diastereomer mixed acetal 185 and the latter pathway leading to the minor diastereomer 189. The chiral mixed acetal 185, via ester 190 and cycloadduct 192 (obtained along with 191 in a dr of 5:1), served as a key intermediate in the preparation of chiral cyclohexene ester 193, which served as a principal synthon in the synthesis of (+)tetronolide 194 (Scheme 64) [90].

6.4.8

Oxidative Acetal Formation

As was done with 91, lactam 157, the methacryloyl derivative of lactam 94, can be treated with MeOH, PdCl2, and CuCl to afford the acetal 195 in 78% yield and a 2.38:1 dr favoring 2’R (Scheme 65) [96]. Although the diastereoselectivity is very

Synthesis and Utility of Hetero- and Non-heterocyclic Chiral. . .

233

O

O N

OMe R

MeOH, PdCl2,

N

OMe

CuCl, DME 78% 2.38:1 dr

157 O

195 O

Scheme 65 Diastereoselective Wacker-type oxidative acetal formation of 157

Br NH 94

+

O

R CuSO4-5H2O (5-10 mol%)

N

1,10-phenanthroline K3PO4 toluene, 60-65oC 95-97%

R

196 O

Scheme 66 Preparation of ynamide derivatives of 94

N H Tf2NH (10mol%)

O N

O N

CH2Cl2 -35oC

197 nHex

nHex

89%

198

N H

Scheme 67 Cis-hydroarylation of ynamide 197 with indole

modest, it is significant that the comparable 2-aza lactam derivative affords the opposite diastereoselection (20 S).

6.4.9

Preparation and Reactions of Chiral Ynamides Derived from 94

As for 91, thermally sensitive chiral ynamides can be synthesized using a protocol developed by Hsung and co-workers. Catalytic CuSO4H2O and 1,10-phenantrholine are required for amidations of various alkynyl bromides affording the ynamides 196 in 95–97% yield (Scheme 66) [97, 110]. Cis-hydroarylation of ynamides such as 197 derived from the ent-94 with indole catalyzed by 10 mol% Tf2NH affords the enamine 198 in 89% yield with >25:1 Z/E selectivity (Scheme 67) [111, 112].

234

6.5 6.5.1

R.K. Boeckman and J.A. Cody

Applications of (105) Attachment of Reactive Subunits

The required chiral dienophiles to test this model were obtained from 105 by acylation of the N-lithiated lactam obtained by deprotonation of 105 with n-BuLi with methacrolyl and crotonoyl chlorides affording the imides 199 and 200 in 95% and 92% yields, respectively (Scheme 68) [84].

6.5.2

Diels-Alder Reactions of Dienophiles Derived from 105

The unsaturated analogue of 94 was examined on the supposition that decreasing the steric repulsion of the 2 carbon bridge thereby increasing the differential steric size of the 1 carbon versus the 2 carbon bridge ought to improve the diastereoselectivity in Diels-Alder cycloadditions (Scheme 69) [84, 113]. O N 199 O

nBuLi THF

NH

95% -78°C then ClCOR

105 O

O N

200 92%

O

Scheme 68 N-acylation of Δ5,6 3-aza camphor lactam 105

O N 199

O

O

O

diene (10 equiv)

N

Lewis acid, AlMe3, CH2Cl2, -78°C

L.A. = CH3AlCl2 or TiCl4

N

O 201 major diastereomer 1,8-2.7:1 endo/exo 3.4:1 dr

202

O

major diastereomer 1.7-3.5:1 dr

O

O diene (10 equiv)

N

200

O

Lewis acid, AlMe3, CH2Cl2, -78°C

L.A. = CH3AlCl2 or TiCl4

N O 203 major diastereomer 19:1 endo/exo 1.5-1.7:1 dr

Scheme 69 Diastereoselective Diels-Alder reactions of carboximides 199 and 200

R

Synthesis and Utility of Hetero- and Non-heterocyclic Chiral. . .

235

Surprisingly, when methacryloyl 199 was treated with cyclopentadiene in the presence of CH3AlCl2 or TiCl4, the expected major product 201 was obtained; however much poorer diastereoselectivities were obtained (3.4:1). Even the endo/exo selectivity was low (1.8–2.7:1). Reaction of 201 with isoprene and 2,3-dimethylbutadiene exhibited the same trend providing the expected major product 202 but with very poor observed diastereoselectivities (1.7–3.5:1) as shown in Scheme 69 [84, 113]. When crotonoyl dienophile 200 was reacted with cyclopentadiene, the observed endo/exo selectivity was much improved (19:1) as shown in Scheme 69. Unfortunately, the observed diastereoselectivity was even poorer (1.5–1.7:1). The same general trends in the diastereoselectivity were observed when more reactive oxygenated dienes were employed with 199 (~3:1 dr) and 200 (~3:1 dr) [84, 113]. A rationale for the surprisingly poor observed diastereoselectivities, supported by calculations, suggests that subtle changes in the internal angles around the C1 bridgehead as a result of the introduction of the C5–C6 double bond cause increased steric interference of the bridgehead hydrogen with the preferred s-trans conformation of the dienophile side chain resulting in loss of control over the rotamer population around the Naux-C(O) bond of the reactive side chain [84].

6.5.3

Aldol Reactions of Acylated Derivatives of 105

A brief study of aldol reactions of acylated derivatives of 105 was also conducted (Scheme 70). Exposure of propionyl lactam 204 to benzaldehyde in the presence of Et2BOTf afforded the two syn adducts 205 and 206 in yields up to 85% depending on reaction conditions. However, remarkably low diastereoselectivities (1–1.5:1 dr) favoring the expected 2R diastereomer 205 were observed. It was noted that when a very bulky boron triflate such as dicyclopentylboron triflate was employed, the diastereoselectivity increased significantly (5:1 dr) but remained too low to be preparatively useful [84, 113].

O N 204

O

1) L2BOTf, Hunig's base, CH2Cl2, 0°C 2) PhCHO 3) MeOH/H2O2

O N 205

O

OH

O

Ph +

N 206

O

Scheme 70 Aldol reaction of N-propanoyl carboximide 204 with benzaldehyde

OH Ph

236

6.6 6.6.1

R.K. Boeckman and J.A. Cody

Applications of 6,6-Dimethyl-3-Aza Camphor Lactam (108) Acylation of Lactam 108

Acylation of lactam 108 proceeds smoothly with both aliphatic and α,β-olefinic acid chlorides under standard conditions. Treatment of 108 with n-BuLi in THF followed by inverse addition of the lithium anion of 108 to a THF solution of either methacryloyl chloride or propionyl chloride in THF provides the desired crystalline imides 207 and 208 in 89% and 90% yields, respectively (Scheme 71) [75, 85].

6.6.2

Application of Acylated Derivatives of 108 to the Diels-Alder Reaction

A brief study of the reaction of imide 207 with 2,3-dimethylbutadiene was conducted (Scheme 72) [75, 76]. Both CH3AlCl2 and TiCl4 were found to promote the cycloaddition at
40 C in reasonable yield; however the observed diastereoselectivities were very low to nonexistent (1–2:1 dr of 209:210) [75]. The major stereoisomeric Diels-Alder adduct was demonstrated to have the R configuration as was observed for Diels-Alder reactions of acylated derivatives of 94 [75].

nBuLi THF

O

O N

-78°C then O Cl

O

207

89%

NH 108

nBuLi THF

O

-78°C then O Cl 90%

N O

208

Scheme 71 N-acylation of 6,6-dimethyl-3-aza camphor lactam 108

O N 207

1) CH3AlCl2 or TiCl4 2)

O

O

-40°C 209

70-80% 1-2 : 1 dr

O

+

N O

N 210

O

Scheme 72 Diels-Alder reaction of carboximide 207 with 2,3-dimethylbutadiene

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237

Application of Acylated Derivatives of 108 to Aldol Reactions

The primary impetus to prepare lactam 108 was to improve the selectivity in aldol reactions of acylated derivatives of 108 over the corresponding derivatives of 91 and 94 based on the model shown in Scheme 55 above (Table 3) [81]. That goal was realized as enolization of propionyl lactam 208 with Et2BOTf and Hünig’s base at
78 C followed by addition of the aldehydes, and standard oxidative workup afforded the expected syn-2’R diastereomer 211 with dramatically improved diastereoselectivities (Table 5) [85]. The improved stereocontrol was interpreted as arising from a combination of favorable dipole alignment and minimized unfavorable steric interactions between the alkyl groups on boron in the transition state leading to the syn-2’R diastereomer 211 (Scheme 73) [81]. Aldol reactions employing 108 (or its enantiomer) as a chiral controller have seen applications in complex molecule synthesis (Scheme 74) [89, 94, 109]. Benzyloxyacetyl lactam 212, derived from ent-108 by acylation of the lithium salt of ent-108 with benzyloxoacetyl chloride (89%), is converted to the boron enolate by reaction with Et2BOTf and Hünig’s base as described above and condensed with enal 213 affording the expected syn-2S,3S-2-benzyloxy-3-hydroximide 214 in >24:1 dr. Immediate protection of 124 as the TBS ether afforded differential protected imide 215 in 80% overall yield from 212. Imide 215 was subsequently elaborated to three natural bengamides B (216), Z (217), and E (218) [89, 109]. Table 5 Highly diastereoselective boron-mediated aldol reactions of carboximide 208a

O

a) Et2BOTf, iPr2NEt, 0°C b) RCHO c) H2O2/CH3OH

N 208 O Aldehyde R

a

O N R

211 syn-(2R)

O

OH

Diastereoselectivity syn-(2R):syn-(2S) >98:2

Yielda % 75(90)

>98:2

80(95)

>98:2

95(100)

>98:2

80(80)

>98:2

90(40)

>98:2

74(90)

Isolated yields of aldol products after flash chromatography corrected for conversion which is given in parentheses

238

R.K. Boeckman and J.A. Cody ‡ H H

B O O

O

O

N H

N 211 O 2'R

R

R OH

Scheme 73 Rationale for the high syn-2’R diastereoselectivity of aldol reactions of 208 Bn H 213

O N BnO

O

TBSCl imidazole

212

O O B O

O

O

BnO H

Et2BOTf i-Pr2NEt CH2Cl2 -78°C

O

N

O

CH2Cl2

214

OH

OH

O BnO

N

OCH3

N OH

O 215 TBSO

OH

H N

O N

R1

O

216 R1 = CH3, R2 = O2C(CH2)12CH3 R2 217 R1 = CH3, R2 = OH 218 R1 = H, R2 = H

Scheme 74 Application to the synthesis of the bengamides B, Z, and E O Ph3P C C O NH

N

toluene, Δ 82%

O

O ent-108

PPh3

219

Scheme 75 Preparation of chiral ylide 219 using Bestmann ylide

6.6.4

Acylation of Lactam ent-108 with the Bestmann Ylide

Acylation of lactam ent-108 with (triphenylphosphoranylidene)ketene (Bestmann ylide) provides the imide ylide 219 in an 82% yield without the use of an additional base (Scheme 75) [95]. No chemistry has yet been reported using ylide 219. Presumably it can undergo modification at the α carbon by alkylation and acylation by primary alkyl, allyl and benzyl bromides, and iodides and acid chlorides and will participate in Wittig olefination reactions with aldehydes by analogy to ylides 128 (Schemes 38 and 39) and 181 (Scheme 61) [95]. Such chiral α,β-unsaturated imides could serve as substrates for diastereoselective conjugate addition as well as conjugate reduction followed by alkylation or acylation [95].

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239

Applications of 8-Phenyl-3-Azabicyclo[2.2.1]Heptan-3One (97)

The 8-phenyl-substituted camphor nucleus, from which lactam 97 is derived, was specifically designed to enhance the selectivity for cycloaddition reactions by increasing the steric demand of the substituents on the 1-C bridge of lactam 97. The supposition was that increased steric differentiation between the top and bottom faces of the dienophile (syn and anti to the 1-C bridge, respectively) should result in increased diastereoselectivity in Lewis acid-promoted Diels-Alder reactions of 97, by enhancing the selectivity for bottom face approach of the dienes already seen for imide derivatives of 94.

6.7.1

Attachment of Reactive Subunits

Acylation of lactam 97 proceeds uneventfully α,β-unsaturated imides chlorides under standard conditions. Treatment of 97 with n-BuLi in THF followed by addition of either methacryloyl chloride or crotonoyl chloride in THF provides the desired imides 220 and 221 in 88% and 81% yields, respectively (Scheme 76) [81].

6.7.2

Application of Imide Derivatives of 97 to Diels-Alder Reactions

Preliminary experiments were conducted using methacryloyl imide 220 and cyclopentadiene with CH3AlCl2 as the Lewis acid promoter. Yields were erratic (max 61%), and diastereoselectivities (~4:1 dr) were not improved relative to derivatives of imide derivatives of 94. At least part of the problem was believed to be the result of the presence of Brønsted acids in the medium. Protic acids are known to cause diene polymerization, and their presence may also have changed the nature of the promoter (i.e., by conversion of CH3AlCl2 to AlCl3). Since it had been previously observed that scavenging protons by the addition of compatible Lewis bases was beneficial [78], the reaction was conducted in the presence of 1.5 equivalents of CH3AlCl2 and >1 equivalents of (CH3)3Al (two Scheme 76 N-acylation of 8-phenyl-3-aza camphor lactam 97

n-BuLi

O

O Cl O

O

N 220

88%

NH 97

n-BuLi O

O O

N

Cl 81%

221

240

R.K. Boeckman and J.A. Cody

equivalents were optimal). Under these modified conditions, reaction of 220 with cyclopentadiene afforded the desired adduct 222 in dramatically higher yield (75%), endo/exo selectivity (96:4), and diastereoselectivity (95:5 dr) as shown in Scheme 77 [81]. These reaction conditions proved to be general. When these reaction conditions were applied to a selection of aliphatic dienes, including butadiene, isoprene, piperylene, and 2,3-dimethylbutadiene, uniformly high yields endo/exo selectivities (where applicable) and diastereoselectivities were observed as shown in Table 6. The absolute configuration of the adducts was assigned based upon comparison of the optical rotations of the derived cyclohexenylmethanols obtained upon LAH reduction of the adducts 222 and 223. Remarkably, this comparison indicated that,

CH3AlCl2 (1.5 equiv) (CH3)Al (2.0 equiv)

O N O 220

O N

CH2Cl2, -78°→ 55°C 24 h 95:5 dr 94:4 endo/exo

O 222

Scheme 77 Diels-Alder reaction of methacryloyl carboximide 220 with cyclopentadiene Table 6 Diastereoselectivity of Diels-Alder reactions of carboximide 220a

Diene

a

Major adduct

π-facial selectivity 95:5

Endo:Exo –

Yield (%) 73

93:7

–

78

99:1

99:1

>99(50)a

95:5

–

70

50% conversion, conversion unoptimized

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241

quite unexpectedly, the configuration at the newly created quaternary center was S rather than R as had been observed for the comparable Diels-Alder reactions of acylated derivatives of 91 and 94 [81]. Although no firm conclusion could be drawn as to the origin of either the enhanced diastereoselectivity upon addition of (CH3)3Al or the reversal of the sense of asymmetric induction observed in Diels-Alder reactions of 220, it was surmised that the increased steric congestion owing to the presence of the phenyl substituent resulted directly or indirectly in reaction proceeding through the more commonly observed s-cis rotamer about the Naux-C(O) bond rather than the s-trans rotamer as was observed for acylated derivatives of 91 and 94 as illustrated for reaction with butadiene in Scheme 78 [81]. Following the protocol developed for cycloaddition reactions employing methacryloyl imide 220, crotonoyl imide 221 was complexed with (CH3)3Al (2.0 equiv) and CH3AlCl2 (1.5 equiv) at
78 C in CH2Cl2 followed by addition of cyclopentadiene (~20 equiv). After stirring at
78 C for 24 h, a mixture of diastereomers was obtained in quantitative yield from which the major diastereomer 224 was obtained with 4:1 endo/exo selectivity and 6:1 dr (Scheme 79) [81]. Adduct 224 was demonstrated to have the 2S by comparison with known materials. Thus, imide 134 also preferentially reacts via the s-cis conformer about the Naux-C(O) bond. Reactions of imide 221 were not investigated further in view of the unexpectedly low endo/exo and diastereoselectivities. Scheme 78 Rationale for the sense of asymmetric induction during DielsAlder reactions of 220

(CH3)2AlC l2

(CH3)2AlC l2

CH3

+ Al O

CH3 CH3

N

O

+ Al O

CH3

H2C

H3C minor

major

O

O

N

N

O

O (R)-223

Scheme 79 Diels-Alder reaction of crotonoyl carboximide 221 with cyclopentadiene

(S)-223

O O

N

O

N

221

CH3AlCl2 (1.5 eq) (CH3)3Al (2.0 eq) CH2Cl2, -78°C 24 h

O H

N O

224

242

R.K. Boeckman and J.A. Cody

6.8

Auxiliary Removal and Recovery

A set of methods common to all imide-type auxiliaries (including aza camphor, camphorsultam, and oxazolidinone auxiliaries) have been developed for auxiliary removal. Specific conditions employed differ depending upon the auxiliary class employed. Generally, it has been observed that attack at the exocyclic carbonyl in true imide-type auxiliaries occurs upon exposure to nucleophilic cleavage reagents, whereas electrophilic cleavage methods tend to result in mixtures or preferential attack at the endocyclic carbonyl. Specifically with reference to the aza camphor auxiliaries under consideration in this review, a wide variety of reductive and hydrolytic methods have been employed to remove 2- and 3-aza camphor auxiliaries. In each of the following transformations, the lactam auxiliary is recovered in high yield (Scheme 80) [77– 79, 86, 87, 89, 90, 109]. It is important to note that although these methods have been used to transform both regioisomers of the auxiliary, it has been observed that removal of the 2-azabicylco lactam is slightly more difficult due to the increased steric hindrance owing to the proximity of the reacting center to the bridgehead methyl group. In all cases, yields of recovered chromatographically pure cleavage products are generally 80–99%, and the recovered auxiliary is obtained in 85–90% [77–79, 86, 87, 89, 90, 109].

7 Auxiliaries Derived from Pinene The pinene isomers (2–3) are important components found in pine resin (Fig. 8). Pinene is a reasonable chiral auxiliary source as all of the isomers are available at reasonable price and the double bond allows for ready functionalization. One drawback is that the pinene isomers are liquids, whereas camphor is a solid. O R

HO

1

O H

R

R

HO 2

O

6 N

O

3 RO

R O 4

5

O

O EtS

R

MeO N

R

Reagents: 1. tBuOOH / LiOH or LiOH / H2O2 2. LiBH4/ THF or LAH / Et2O 3. LiOBn or TiCl2(OEt)2 or Ti(OiPr)4 4. Et2AlCl / HN(OCH3)CH3 / DiBAl-H 5. LiSEt 6. Two step processes: a. LAH / E2O then (COCl)2 / DMSO/ Et3N b. LAH / Et2O then TPAP / NMO/ 4Å MS c. EtAlClN(OCH3)CH3 then DiBAl-H d. LiSEt then DiBAl-H

R

Scheme 80 Transformations of N-acylated camphor carboximides resulting in auxiliary cleavage

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243

Fig. 8 Pinene isomers

7.1

(+)-α-pinene ((+)-1R, 5R)-2)

(-)-α-pinene ((-)-1S, 5S)-2)

(+)-β-pinene ((+)-1R, 5R)-3)

(-)-β-pinene ((-)-1S, 5S)-3)

A Chiral Auxiliary Derived from α-Pinene (2)

The first pinene-derived auxiliary, ketol 225 [114], was reported in 1976 by Yamada and co-workers in their preparation of chiral amino acid derivatives (Scheme 81) [115]. The stereoselective alkylation of Schiff’s base 226 afforded 227. The target amino acid derivative 228 and recovery of ketol chiral auxiliary 225 were afforded by hydrolysis of Schiff’s base 227 by treatment with aqueous citric acid or H2NOH.HOAc. Additional example of employing ketol 225 as a chiral auxiliary is the synthesis of (S)-dolaphenine [116] and D-erythro-sphingosine [117]. In 1996, Roth and co-workers reported an enolate lactam system derived from α-pinene that generates chiral quaternary carbon centers in high diastereoselectivity [118, 119]. To highlight the chemistry, 3-benzoylpropionic acid (229) is provided as an example in Scheme 82. Lactam 230 was prepared by acid-catalyzed condensation of amino alcohol 231 with keto acid 229 (Scheme 82). To prepare the required quaternary chiral centers, sequential enolate formation and subsequent alkylations were conducted. Although, the first alkylation generally gave modest to excellent diastereoselectivity (33 to >99:1 dr), the second enolate destroys the chirality by forming a prochiral planer center. In all cases the second alkylation provided excellent diastereoselectivity (98:2 to >99:1 dr). The source of the diastereoselectivity is not fully understood, but in all cases, the electrophile approaches from the exo face. The auxiliary may be removed by esterification of the dialkylated lactam.

7.2

Chiral Alcohol Auxiliaries Derived from β-Pinene (3)

The alcohol functionality was employed to bring the dense chirality of the pinene carbon framework close to prochiral centers via an ester linker. A series of chiral alcohols derived from β-pinene have been synthesized (Fig. 9). Chiral alcohol auxiliaries 235a,d–h were prepared from (
)-β-pinene (3) in four steps using standard transformations [120]. The six different analogues were generated by varying the aromatic group added via a 1,2-addition of the organolithium reagent to nopinone in the second step in the sequence. The last two steps of the sequence were dehydration to the double bond and hydroboration/oxidation. The remaining alcohol chiral auxiliaries anti-236 and syn-237 were prepared starting with

244

R.K. Boeckman and J.A. Cody

Scheme 81 Stereoselective alkylation using pinenederived chiral auxiliary ketol 225

Scheme 82 Double alkylation using pinenederived auxiliary 231

Fig. 9 Alcohol chiral auxiliaries derived from β-pinene (3)

nopinone condensation with a series of aromatic aldehydes to give α,β-unsaturated ketones [121]. Reduction of the double bond followed by reduction of the ketones provides either the anti- or syn-alcohols 236 and 237 by varying the carbonyl reduction conditions.

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Reduction of β-ketoesters 238a,d–h, derived from 235a,d–h, with zinc borohydride provides β-hydroxyesters 239a,d–h with poor to moderate stereoselectivity (~1:1 to 85:15 dr) but good yields (Scheme 83) [120]. The clear trend emerges from the study. The larger the aromatic group in 238, the greater the selectivity of the reduction. A comparison of the diastereomeric excess obtained for β-hydroxyester 239f–g (all 85:15 dr) and 239a,d (both ~1:1 dr) demonstrates this trend. Recovery of chiral auxiliary 235a,d–h and generation of the desired enantiomerically enriched diol 240 are brought about by reduction of 239a,d–h with lithium aluminum hydride. Generation of highly congested carbon centers stereoselectively is always a challenge. An asymmetric Friedel-Crafts reaction was employed with β-pinenederived chiral auxiliaries 236 and 237 to prepare a highly congested ether functionality (as an example, 237 is shown in Scheme 84) [122]. Both SnCl4 and BF3. OEt2 were used to induce the reaction with use of SnCl4 affording higher selectivity. Removal of the chiral auxiliary by a saponification reaction efficiently reveals enantiomerically enriched carboxylic acid 241.

7.3 7.3.1

Pinene-Derived Lactam Auxiliaries Preparation of Pinene-Derived Lactam 244

Sabater, working with the Boeckman group, prepared a pinene-derived lactam 244 [123]. Beginning with nopinone 245, conversion to the oxime 246 under standard

Scheme 83 Diastereoselective reduction of ketoester 238 and removal of auxiliary 235

Scheme 84 Generation of congested stereocenter and removal of auxiliary 237

246

R.K. Boeckman and J.A. Cody

conditions followed by a Beckmann rearrangement conducted under classical conditions afforded pinene-derived lactam 244 in 70% yield (Scheme 85).

7.3.2

Diels-Alder Reactions of Imide Dienophiles Derived from 244

Acylation of the N-lithiolactam, obtained by treatment of 244 with n-BuLi, with methacryloyl chloride or crotonoyl chloride afforded the dienophiles 247 and 248 in 97% and 91% yield, respectively (Scheme 86) [123].

7.3.3

Diels-Alder Reactions of Dienophiles 247 and 248 Derived from Pinene

A brief study of the Diels-Alder reactions of 247 and 248 was conducted. A variety of Lewis acid promoters were screened including Et2AlCl and EtAlCl2, TiCl4, and SnCl4. In the case of the reaction of 247 with cyclopentadiene (Scheme 87), the NH2OH-HCl

H2SO4

EtOH O

245

246

N OH

N H

H2O-EtOH 70% overall from 245

O

244

Scheme 85 Preparation of pinene-derived lactam auxiliary 244

nBuLi THF N H

O

N

O

340

O

O 341

Cl nBuLi THF N H

340

O

N

O

O

O 342

Cl

Scheme 86 Preparation of dienophiles 247 and 248

N

O

(CH3)2AlCl, TiCl4 SnCl4 CH2Cl2 -78°C

O 247

60-74%% 1.5:3:1 exo/endo 97-79:3-21-%dr

N

O +

N

O

O

249

250

O

Scheme 87 Diastereoselective Diels-Alder reaction of carboximide 247 with cyclopentadiene

Synthesis and Utility of Hetero- and Non-heterocyclic Chiral. . .

247

cycloaddition afforded the expected adducts 249 and 250 in modest endo/exo selectivity (1.5–3:1), good to excellent diastereoselectivity, and good to very good chemical yields (60–74%). The optimal Lewis acid based on this screening was found to be SnCl4 affording 97:3 dr. Remarkably, when the cycloaddition was promoted by Et2AlCl, the exo diastereomer 344 was slightly preferred (2–3:1), but the diastereoselectivity was diminished to ~2:1. Reaction of dienophile 247 with acyclic dienes isoprene and 2,3-dimethylbutadiene was also examined (Scheme 88). The expected adducts 251 and 252 were obtained 22 with 47–77% yield with diastereoselectivities ranging from ~1:1 for isoprene promoted by TiCl4 to 7:1 for 2,3-dimethylbutadiene and isoprene [the latter accompanied by the regioisomeric adduct(s)]. The relative and absolute configuration of the adducts was established by removal of the auxiliary and comparison of the derived esters to known materials. A brief examination of the reactions of crotonate dienophile 248 was also conducted. Reaction of 248 with triisopropylsiloxy butadienes depicted in Scheme 89 afforded the adducts 253 (major) and 254 (minor). In these reactions, as had been noted previsously [103, 105], conducting the cycloaddition in the presence of Lewis bases such as Me3Al was beneficial in improving both yields and diastereoselectivity. Indeed, conducting the cycloaddition in the presence of 0.5

N

Et2AlCl, TiCl4 SnCl4 CH2Cl2

O

N

O +

O

O R 56-87% 67-82%dr

247

N

R

251

O

O

R 92% 95%dr

R

252

O

N

247

R= H, CH3

O

SnCl4 Al(CH3)3 CH2Cl2

O

O

N

R= CH3 R

251

Scheme 88 Diastereoselectivity of Diels-Alder reactions of 247 with substituted butadienes

N

O

SnCl4 Al(CH3)3 CH2Cl2

N

OTIPS

+

O

O 248

O R

N

O R

R = CH3, CH2OTIPS

O

or

OTIPS

OTIPS

253

OTIPS

254

OTIPS

72-80% 3-10%dr

Scheme 89 Diastereoselectivity of Diels-Alder reactions of 248 with oxygenated butadienes

248

R.K. Boeckman and J.A. Cody

equivalents of Me3Al afforded a substantial increase of both yield and diastereoselectivity affording modest to very good dr (3–10:1) favoring 253 (Scheme 89) [123].

8 Concluding Remarks While the use of covalently bound chiral auxiliaries is well established, the rapid development of inherently more efficient catalytic methods for the preparation of enantiomerically enriched compounds has certainly provided effective alternatives to some methods employing chiral auxiliaries. However, not all catalytic methods can achieve the same levels of diastereoselectivity as stoichiometric covalently bound auxiliary methods nor are all reactions amenable to the application of asymmetric catalysis. Thus, there will be a continued need for the development of even more effective and general chiral auxiliaries. Use of covalently bound chiral auxiliaries will remain one of the core methods to practically and efficiently prepare enantiomerically enriched organic compounds for the foreseeable future.

References 1. Money T (1985) Nat Prod Rep 2:253–289 2. Oppolzer W (1987) Tetrahedron 43:1969–2004 3. Cody JA, Boeckman RK Jr (2012) Synthetic methods II: chiral auxiliaries. In: Carreira EM, Boeckman RK Jr, Yamamoto H (eds) Comprehensive chirality, vol 3. Elsevier, Amsterdam, pp 42–105. Chap. 3, Sect 3.3 4. McIntosh JM, Mishra P (1986) Can J Chem 64:726–731 5. McIntosh JM, Leavitt RK, Mishra P, Cassidy KC, Drake JE, Chadha R (1988) J Org Chem 53:1947–1952 6. McIntosh JM, Leavitt RK (1986) Tetrahedron Lett 27:3839–3842 7. Mcintosh JM, Cassidy KC (1988) Can J Chem 66:3116–3119 8. Palomo C, Gonza´lez A, Garcı´a JM, Landa C, Oiarbide M, Rodrı´guez S, Linden A (1998) Angew Chem Int Ed 37:180–182 9. Palomo C, Oiarbide M, Aizpurua JM, Gonzalez A, Garcia JM, Landa C, Odriozola I, Lindens A (1999) J Org Chem 64:8193–8200 10. Lee CLK, Lee CHA, Tan KT, Loh TP (2004) Org Lett 6:1281–1283 11. Palomo C, Oiarbide M, Garcia JM, Gonzalez A, Lecumberri A, Linden A (2002) J Am Chem Soc 124:10288–10289 12. Ba~ nuelos P, Garcı´a JM, Go´mez-Bengoa E, Herrero A, Odriozola JM, Oiarbide M, Palomo C, Razkin J (2010) J Org Chem 75:1458–1473 13. Palomo C, Oiarbide M, Garcı´a JM, Ba~nuelos P, Odriozola JM, Razkin J, Linden A (2008) Org Lett 10:2637–2640 14. Garcı´a JM, Maestro MA, Oiarbide M, Odriozola JM, Razkin J, Palomo C (2009) Org Lett 11:3826–3829 15. Dixon DJ, Horan RAJ, Monck NJT (2004) Org Lett 6:4423–4426 16. Dixon DJ, Horan RAJ, Monck NJT, Berg P (2004) Org Lett 6:4427–4429

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Top Heterocycl Chem (2020) 55: 253–310 DOI: 10.1007/7081_2018_26 # Springer Nature Switzerland AG 2018 Published online: 1 November 2018

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products Akriti Srivastava, Kirana D. Veeranna, and Sundarababu Baskaran

Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Oxazolidinone-Based Chiral Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 (+)-Brefeldin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2 Baulamycin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3 Calcaripeptides A–C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4 Glucolipsin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5 Apoptolidinone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6 Bleomycin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.7 Brasilinolide A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.8 FD-891 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.9 (
)-FR182877 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Pyrrolidine-Based Chiral Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 (+)-Streptenol A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 (
)-α-Elemene . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 (
)-Neonepetalactone, Dehydroiridodial, and Dehydroiridodiol . . . . . . . . . . . . . . . . . . . . 3.4 (+)-Sordidin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 (
)-Callystatin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Sulfur-Based Chiral Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 (
)-Manzacidin B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 (+)-Bakuchiol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Phosphorous-Based Chiral Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Methyl Jasmonate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 (
)-Anthoplalone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3 (
)-Berkelic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4 (+)-Ambruticin S . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5 Estrone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.6 Nudiflosides A and D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Imidazolidinone-Based Chiral Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1 (
)-Lavandulol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Pyrimidinone-Based Chiral Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1 Oxyneolignan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

A. Srivastava, K. D. Veeranna, and S. Baskaran (*) Department of Chemistry, Indian Institute of Technology Madras, Chennai, India e-mail: [email protected]; [email protected]; [email protected]

254 265 265 266 269 271 272 274 276 277 280 283 284 285 286 287 288 292 292 293 294 294 296 297 298 300 301 303 303 303 303

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8 Oxazolinyl Ketone as Chiral Auxiliaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 8.1 (
)-Rhazinilam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 307

Abstract Heterocyclic chiral auxiliary is widely considered to be an efficient choice to bring about asymmetric induction in the stereoselective synthesis of natural products. Various heterocyclic chiral auxiliaries are frequently used in asymmetric alkylation, Diels-Alder, Michael addition, and aldol reaction to synthesize complex chiral intermediates in enantiomerically pure form that are further employed in the synthesis of natural targets of biological and pharmaceutical importance. Amongst the various auxiliaries, Evans’ oxazolidinones and their sulfur analogues are the most sought after chiral auxiliaries in asymmetric synthesis owing to their ability to induce good to excellent selectivities. The versatility of oxazolidinones is brought forth by their utilization in the total synthesis of complex natural targets like brefeldin A, calcaripeptides A, B, and C, and apoptolidinone. In addition to Evans’ oxazolidinones, this chapter will also focus on application of Enders’ SAMP/RAMP hydrazone, camphorsultam, phosphonamide, pyrimidinone, and oxazolinyl ketone as chiral auxiliaries in the total synthesis of natural products and bioactive molecules. Keywords Asymmetric synthesis · Camphorsultam · Enantioselective total synthesis · Heterocyclic chiral auxiliaries · Imidazolidinone · Natural products · Oxazolidinone · Oxazolinyl ketone · Phosphonamide · Pyrimidinone · SAMP/ RAMP hydrazine

1 Introduction Most biologically active molecules as well as pharmaceutical targets exist as a single enantiomer; henceforth, chemical syntheses of such natural products and pharmaceutically active molecules are designed to obtain the natural products in enantiomerically pure form [1]. The development of asymmetric synthesis is one of the most challenging aspects in organic synthesis, and various protocols have been demonstrated by the chemists worldwide to arrive at enantiomerically pure compounds. Other than using chiral reagent or chiral solvent/media, the most frequently employed strategies for stereoinduction in a chemical reaction include the use of chiral ligands wherein various transition metal catalysts coordinate to facilitate intermolecular asymmetric induction or the use of chiral auxiliaries which facilitate intramolecular asymmetric induction [1, 2]. A chiral auxiliary is a stereogenic group or unit that is temporarily attached to an organic molecule in order to bias the stereochemical outcome of an organic reaction

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by providing a chiral spatial environment to bring about chiral induction in organic synthesis [1, 2]. To meet this purpose, synthetic chemists resort to chiral auxiliaries to selectively produce the desired stereoisomer of the given compound by employing them into the synthetic routes, allowing the required diastereoselective transformations and, finally, removing the auxiliary under such conditions that would avoid racemization of the desired product. Also, the products of such auxiliary-directed transformations are diastereomers which enable facile separation by column chromatography or crystallization [3, 4]. Most chiral auxiliaries have been derived from natural sources such as carbohydrates, terpenes, amino acids, etc. However, owing to limitations like that of stoichiometric requirements of the auxiliary, difficulty to access the materials in large quantities in optically pure form, availability of both isomers, structural limitations, and several unnatural chiral molecules have been designed and utilized to bring about stereoregulation in asymmetric synthesis [5]. For example, 1,2-amino alcohols are widely used as chiral auxiliaries or ligands to generate new stereogenic centers [5]. Thus, characteristics of versatile chiral auxiliary are ready availability, excellent asymmetric induction, selective removal under mild conditions without racemization [6], and tolerance to a wide range of reagents and reactions conditions [1, 3]. In addition, the recovery and recyclability of chiral auxiliary are important requirements while designing large scale synthesis. The groundwork for auxiliary-based asymmetric synthesis dates back to 1956 when Prelog explained the utility of (
)-menthol as an optical activating agent in the asymmetric synthesis of atrolactic acid. The synthesis was described originally by Boyd and McKervey ([7] and references cited therein) and submitted to conformational analysis by Prelog [8]. Other examples wherein Prelog’s rule has been employed for the determination of configuration of C-atoms bearing the hydroxyl group, for instance, in a series of triterpenes and steroids are also available in literature [8]. The use of chiral auxiliaries in the synthesis of enantiomerically pure compounds was pioneered and introduced by Corey, in 1975, with chiral 8-phenylmenthol 1 to generate key prostaglandin intermediate [9]. Corey’s phenylmenthol auxiliary was followed by Enders’ RAMP/SAMP chiral hydrazones. Another early milestone in the use of chiral auxiliary for asymmetric alkylation was set forth by Meyers’ oxazolines [10]. Till date, a plethora of chiral auxiliaries are available that are widely used for asymmetric transformations, and many of them have been reviewed (vide infra). Hitherto, the most notable chiral auxiliaries that are extensively used in asymmetric synthesis include Evans’ oxazolidinone 2, their sulphur variants: thiazolidinethione 3 and oxazolidinethione 4, Enders’ SAMP/RAMP hydrazone, camphor derivatives like camphorsultam 5, chiral 2-imidazolidinone 7, chiral sulfoxide, carbohydrate-based auxiliaries 6, and chiral phosphonamide 8 (Fig. 1). The design and development of aforementioned chiral auxiliaries have already been covered in the previous chapters, and their synthetic usefulness in total synthesis of natural products is illustrated in this chapter. Evans’ chiral auxiliary, belonging to the class of chiral oxazolidinones, has been one of the most versatile auxiliaries. Introduced by David Evans and coworkers in 1981, a number of structural modifications of the so-called Evans’ chiral

256 Fig. 1 Chiral auxiliaries employed in total synthesis of natural products

A. Srivastava et al. O H3C CH3 Ph

O

S

O R

N

OH

Bn H3C 8-phenylmenthol, 1 Oxazolidinone, 2 H3C

CH3 OR NH

S O2 Camphorsultam, 5

RO

R

N

NH2

OR Sugar-based auxiliary, 6

O

O N

R

Bn R' Thiazolidinethione, 3 Oxazolidinethione, 4

O

OR O

S

S

O

R N

NH

R1

R2

R2 N O P R1 N R2

2-Imidazolidinone, 7 Phosphonamide, 8

auxiliary have been accomplished and reported [11–14]. Asymmetric aldol reactions, alkylations, and Diels-Alder reaction are most well-known applications of the oxazolidinone chiral auxiliaries in asymmetric synthesis, which are thoroughly covered by Czekelius under Chapter “Oxazolidinones and Related Heterocycles as Chiral Auxiliaries/Evans and Post-Evans Auxiliaries” of this book. Boron- or titanium-mediated asymmetric aldol reactions result in syn-aldol adducts with high diastereoselectivity; however later, Evans group demonstrated an extension of the aldol process to obtain the anti-aldol products, in the presence of catalytic amount of magnesium salts [14]. Useful reviews that reveal different aspects and issues of the aldol reaction are available in literature [15–18]. Chiral auxiliary-based aldol reaction, in which enolate chemistry plays the key role, is one of the most sought-after strategies for accessing single isomers of β-hydroxy acid derivatives as chiral building blocks for bioactive compounds, thus making Evans oxazolidinones as one of the most soughtafter chiral auxiliaries for stereoselective synthesis of natural products. Cytovaricin, produced by Streptomyces diastatochromogenes, is a spiroketal macrolide and was shown to have significant inhibitory activity against Yoshida sarcoma cells in vitro [19]. The first total synthesis of cytovaricin [20], accomplished by Evans et al. in 1990, is one of the most notable examples of auxiliary-controlled synthesis of natural products. It utilizes oxazolidinone chiral auxiliaries for asymmetric alkylation and aldol reactions. Nine-membered cyclic ethers are present in metabolites like obtusenyne, neolaurallene, and isolaurallene [21]. In 2001, Crimmins et al. accomplished the first total synthesis of isolaurallene 15 using alcohol 11 as a key intermediate ([22] and references cited therein). Diastereoselective alkylation of glycolate oxazolidinone 9 provided compound 10 which on subsequent removal of chiral auxiliary using NaBH4 furnished alcohol 11 (Scheme 1). Following a series of transformations, alcohol 11 was further transformed into a highly functionalized glycolate oxazolidinone 12 and subsequent alkylation to furnish the product 13 with excellent stereoselectivity (dr 98:2). The oxazolidinone auxiliary in 13 was removed using NaBH4 to provide the advanced intermediate 14 which was then transformed into (
)-isolaurallene 15 in few synthetic steps (Scheme 1) [22, 23]. Facile removal of the oxazolidinone auxiliary can be effected using different conditions and reagents depending upon the functional group required in the product (Scheme 2) [5, 24].

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

NaN(SiMe3)2 -40 oC THF , toluene

Bn BnO

N O 9

O

I

O

N O

Bn

H3C

O

N

O

O

12 O

OBn

Bn BnO

NaBH4 THF-H2O

O O

NaN(SiMe3)2 -45 oC THF , toluene

10

OBn

OH 11

OBn Bn

H3C

N

O

I

BnO

257

NaBH4 THF-H2O

O

13 O

OBn

O

OBn O

Br

H3C

O

H3C O OBn

14

C H (-)-Isolaurallene (15) Br

OH

Scheme 1 Synthesis of (
)-isolaurallene (15) [22] O OH NH(OMe)Me.HCl O OH OTBS 1. TBSCl, Imidazole O 2. NaSEt AlMe3 H3CO R N O R N R EtS CH3 CH3 CH3 CH3 Bn 17 Weinreb amide, 18 Thioester, 16 O

LAH

LiOBn

OH HO CH3 Alcohol, 19

R

O BnO

LiOOH, H2O Na2SO3 O

OH R

CH3 Benzyl ester, 20

OH

R CH3 Carboxylic acid, 21 HO

Scheme 2 Different synthetic methods for the removal of oxazolidinone auxiliary [24]

The structural variants of Evans’ oxazolidinones such as oxazolidinethione and thiazolidinethione have proven to be an efficient class of chiral auxiliaries in asymmetric synthesis [25]. The oxazolidinethiones are readily prepared in high yield from chiral amino alcohols using carbon disulfide and triethylamine. Unlike oxazolidinone, N-acyloxazolidinethione auxiliaries are readily removed under mild conditions [26–28]. Oxazolidinethione-based chiral auxiliaries have been utilized in a variety of synthetic transformations such as aldol condensation, alkylation, etc. Excellent diastereoselectivities are achieved in the acetate aldol reaction of titanium enolate derived from the N-acylated thiazolidinethione auxiliary (Scheme 3). Interestingly, under the reaction conditions, the use of PhBCl2 instead of TiCl4 could change the stereochemical outcome of the product [29]. Starting with the same chiral auxiliary, Crimmins has shown in detail that by choosing the appropriate reaction condition, it is possible to selectively synthesize aldol condensation products bearing either “Evans-syn” or “non-Evans-syn” stereochemistry. Both N-propionyloxazolidinethiones and N-propionylthiazolidinethiones

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Scheme 3 Diastereoselective acetate aldol reaction of titanium enolate [29]

Scheme 4 Transition state model for aldol reaction [26]

28, 1 eq TiCl 4 2.5 eq (-)-sparteine

S O

S O

O N

28

Bn

O CH3 H

CH3 CH3 29

O

steps H

N

OTBDMS CH3 CH3 CH3 30

O

Bn 28, 2 eq TiCl 4 1 eq (-)-sparteine

S O

O N Bn

OH OTBDMS CH3 CH3 CH3 CH3 31 83%, dr 98:2 OH OTBDMS CH3 CH3 CH3 CH3 32 77%, dr 98:2

Scheme 5 Iterative aldol sequence [32]

have been used to this effect. The change in facial selectivity in aldol addition can be explained by non-chelated TS 25a and chelated TS 25b in Scheme 4 [26]. In 2006, Crimmins and DeBaillie successfully explored the synthetic usefulness of thiazolidinethione auxiliary in a convergent enantioselective total synthesis of bistramide A [30, 31]. The sulfur variants of oxazolidinone auxiliaries have also been employed to accomplish iterative aldol sequences with high diastereoselectivity (Scheme 5) [32]. Crimmins demonstrated the utility of this strategy to access either the synsyn-syn adduct 31 or syn-anti-syn adduct 32 depending on the reaction conditions.

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products OCH3 O

OCH3 H 3C

OCH3 33

CH3

41, TiCl 4, i-Pr2NEt

S

34

OCH3 O S

N

H3C

CH2Cl2, 64%, dr 98:2

259

CH3 CH3 H3C

DIBAL-H CH2Cl2, 88%

H

H3C CH3 CH3

35 CH3

S

OCH3 OR1 O 1. 42, TiCl 4, i-Pr2NEt

N

H3C

OCH3 OR1 O DIBAL-H

S

CH3 CH3H3C

88%, dr 95:5 2. TESOTf, 2,6-lutidine

CH2Cl2, 91%

36 R1=OTES

H

H3C CH3 CH3 37 R1=OTES

CH3

H3C 1. 43, TiCl 4,sparteine 65%, dr 20:1 2. TESOTf, 2,6-lutidine

OCH3 OR1 OR2 O

S

OCH3 OR1 OR2 O

DIBAL-H N

H3C CH3 CH3

38 R1,R2=OTES

S

Bn

O OCH3 OH

Steps

Et CH3 CH3 39 R1,R2=OTES CH3 H 3C

H3C

Bn

CH3

O

H3C

N

S CH3 CH3

H

H 3C

CH2Cl2 98%

Et

CH3

Et

(-)-Pironetin (40)

S

O

thione A, 41

CH3 CH3 S

N

S S

O

thione B, 42

N S

CH3 O

thione C, 43

Scheme 6 Synthetic route to (
)-pironetin (40) [33]

Shortly thereafter, Crimmins reported an enantioselective synthesis of (
)-pironetin (40) by utilizing their titanium-mediated iterative aldol sequence for the introduction of contiguous stereocenters in the natural product (Scheme 6) [33]. Several synthetic routes, many of which apply chiral auxiliary method to install the stereocenters, have been developed for the accomplishment of this structural moiety. In 2009, Enders et al. reported a convergent synthesis of (
)-pironetin (40) using SAMP/RAMP hydrazone alkylation [34]. Notably, (
)-pironetin has been identified for its antiproliferative activity against various tumor cell lines and immunosuppressant activity [35]. The applications of oxazolidinones, thiazolidinones, and oxazolidinethiones in asymmetric synthesis are summarized in Chap. 3 of this book. In this chapter, a few choicest examples of asymmetric total synthesis of natural products using the chiral auxiliaries in one or more decisive steps will be discussed. The versatility of the camphor scaffold due to conformational rigidity and sterical demand and its usefulness in the enantioselective synthesis of natural products has been well reviewed [36]. Moreover, the synthetic utility of terpene derivatives like aza-camphor and camphorsultam as chiral auxiliaries is well documented by Cody and Boeckman in Chapter “Terpene-Derived Heterocycles as Chiral-Auxiliaries/ Azacamphor and Camphorsultam as Chiral Auxiliaries” of this book. Also, derivatives of both (+)- and (
)-camphor have been used in the construction of a wide range of chiral auxiliaries which have been utilized in the enantioselective synthesis of natural products [37–40]. For example, an oxazoline-based chiral auxiliary derived from camphor afforded good diastereoselectivity in the synthesis of egenine (44), bicuculline (45), corytensine (46), and corlumine (47) (Fig. 2) [41, 42].

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A. Srivastava et al.

NMe

O

NMe

O

O

O

OH

O

OH (+)-Egenine (44)

O

O

O

O

O

O

O

O

NMe

MeO

NMe

O

O

O

MeO

O

O

O

(+)-Corytensine (46)

(+)-Bicuculline (45)

O

(+)-Corlumine (47)

Fig. 2 Biologically active natural products [41, 42]

H3C

CH3

H3C NH

S O2

CH3 N

HN S O2

O

CH3

N

1R-(+)-2,10-camphorsultam, 48 1S-(-)-2,10-camphorsultam, 49 Camphor-based oxazoline auxiliary, 50

Fig. 3 Camphor-based auxiliaries

Camphorsultam, derived from camphor, exhibits excellent chirality transfer in various synthetic transformations [37, 38]. These include the Diels-Alder, alkylation, acylation, and aldol reactions. The chiral auxiliary (1R)- camphorsultam 48 and its antipode 49, respectively (Fig. 3), were readily prepared from the corresponding camphorsulfonyl chloride [39]. In their pioneering work, Oppolzer and co-workers utilized camphorsultam in the total synthesis of β-necrodol, a defensive pheromone of carrion beetle. Herein, the key step was the conjugate addition of methyl cuprate to a chiral N-enoyl sultam [43]. Since then, the quest for the synthesis of structurally related auxiliaries has continued. Other valuable transformations including alkylations, aldol reactions, and Diels-Alder reactions as well as their applications in asymmetric synthesis involving this sultam have also been reported by Oppolzer and other research groups. The various representative transformations of the sultam auxiliary and their applications in the total synthesis of natural products have been summarized by Heravi and Zadsirjan [44]. The high levels of selectivity observed in these reactions are attributed to the attacking species approaching from the least hindered reface of the enolate or dienophile, i.e., away from the bornane ring. This selective approach is well exemplified in the total synthesis of pulo’upone by Oppolzer et al. [45]. As a notable example, Boeckman et al. exemplified the utility of camphor-based auxiliaries in the total synthesis of (
)-rasfonin 63 which exhibits significant potential for a novel class of therapeutics for the treatment of tumors (Schemes 7 and 8) [45, 46]. The required stereochemistry present in the side chain was achieved using auxiliary-controlled asymmetric alkylation and eventually leading to the synthesis of key intermediates, pyran fragment 59, and diene acid derivative 62 (Scheme 8). The key fragments were assembled via Yamaguchi coupling reaction to arrive at the target structure of (
)-rasfonin (63) (Scheme 8).

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products CH3 O R N

H3C

H 3C CH3 1. LiHMDS, THF, 0 oC 2. I

CH3 O

H 3C 55

N H

CH3 CH3 O 53, R=CH3

CH3

O 51, R=CH3 H 3C

CH3 O R N

CH3 52

H 3C Ph3P C C O

CH3

toluene, reflux

N

1. LiBH4, MeOH, Et2O H 0 oC-RT CH3 2. Swern oxidation

1. 54, DCE, 70 oC 2. Et3SiH, Pd/CaCO3/PbO H3C acetone, 50 oC

O

H 3C

261

3. LiHMDS, THF, -78 oC then MeI, -78 to -40 oC

PPh3

56 O

2. NMO, TPAP, 4Å MS, RT

CH3 CH3 CH3 54

CH3 O CH3 CH3 CH3

H 3C

N

CH3 O

57

CH3 CH3 CH3

O 1. LAH, Et2O, RT

O

O

O

Steps

H

CH3

CH3 CH3 CH3 CH3 58

OH pyran fragment 59

Scheme 7 Synthesis of pyran fragment 59 [46] H3C

CH3 R

H3C O

o

CH3 R

TiCl 4, DIPEA, CH2Cl2, 0 C

N

O OBn

Steps

N

then BOMCl, 0 oC O 60, R=CH3

O 61, R=CH3 CH3 CH3 CH3

OH OTBS

O CH3

OTBS

O

O

CH3

pyran fragment 59 O

Steps

diene acid fragment 62

OH

O CH3 (-)-Rasfonin (63)

OH

Scheme 8 Stereoselective synthesis of (
)-rasfonin (63) [46]

In addition to significant natural abundance and cheap availability, stereogenic centers present in carbohydrates qualify them as efficient chiral auxiliaries in the regio- and stereoselective transformations [47]. The earliest investigation of carbohydrate enolates both in chiral pool syntheses and also in auxiliary-supported stereoselective transformations was reported by Heathcock et al. [48]. The sugarbased chiral templates used in asymmetric synthesis are mainly classified as fivemembered glycofuranosidic frameworks and six-membered glycopyranosidic frameworks. Various hexafuranose- and hexapyranose-derived templates have been used as chiral auxiliaries and also as chiral ligands. Among glycofuranosidic templates, 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose and the so-called diacetone-D-glucose have been extensively investigated [47, 48]. Kunz and coworkers have extensively explored the usefulness of pyranose-derived chiral auxiliary in asymmetric carbon-carbon bond-forming reactions [47, 49]. Moreover, synthesis and application of carbohydrate-derived auxiliaries in asymmetric transformation have been already covered by Kunz and co-workers in the previous chapter of this book. The use of pseudoephedrine as chiral auxiliary is also well documented in the literature and is widely used to effect asymmetric alkylation reactions. Both

262

A. Srivastava et al.

enantiomers of pseudoephedrine are commercially available and can be used as chiral auxiliary [50–52]. For the first time, Myers et al. reported asymmetric alkylation of carboxamides employing pseudoephedrine as a chiral auxiliary [50]. Treatment of either enantiomers of pseudoephedrine with carboxylic acids, acid anhydrides, or acid chlorides leads to the corresponding N-acylated tertiary amides 64. Pseudoephedrine 64 is deprotonated to generate the corresponding enolate which on alkylation furnishes the compound 65 with high degree of selectivity (Scheme 9). Owing to their ability to act as synthetic equivalents to aldehydes and ketones, N,N-dialkylhydrazones are known for their diverse reactivity. Chiral N, N-dialkylhydrazones reported by Corey exemplify the usage of enantiopure pyrrolidine as chiral auxiliary in asymmetric synthesis [53–55]. Enders developed a successful approach for the synthesis of enantiomerically pure compounds based on the reactions of chiral N,N-dialkylhydrazones and prolinol-derived chiral hydrazines known as SAMP 66 and its enantiomer RAMP 67 (Fig. 4). Other chiral hydrazines 68–71 shown in Fig. 4 were developed later for specific purposes. Proline-based asymmetric α-alkylation provides a ready access to optically active intermediates used in the synthesis of pharmaceutically important natural products [55]. These natural products include (
)-C10-desmethyl arteannuin B [56]; the polypropionate metabolite (
)-denticulatins A and B [56]; zaragozic acid A, an inhibitor of sterol synthase [57]; and epothilones A and B [58]. Synthesis of heterocycles like piperidine- and pyrrolidine-containing alkaloids has been a subject of much interest among synthetic chemists. Recently, Denniau et al. reported the synthetic utility of SMP chiral auxiliary in total synthesis of (
)-anabasine [58]. Cleavage of the N,N-dialkylhydrazones can be effected by various methods. General cleavage methods include oxidative, hydrolytic, and reductive protocols. Owing to the mild conditions, ozonolysis is the most broadly adopted oxidative protocol. Methods for removal and recovery of carbonyl compounds from N,N-dimethyl SAMP/RAMP hydrazones have been reviewed in literature [59]. Chiral 2-imidazolidinone 7, a functionalized heterocycle, was reported by Close (Fig. 1). Since then, different variants of chiral 2-imidazolidinones in asymmetric Scheme 9 Stereoselective alkylation

CH 3 O OH 64

Fig. 4 Proline-based chiral auxiliaries [55]

N CH 3

1. LDA, LiCl R

SAMP, 66

OCH3 N Et Et NH2 SAEP, 69

N OH CH 3 R' 65

2. R'X

OCH3 N NH2

CH 3 O

OCH3 N NH2 RAMP, 67

OCH3 N Ph Ph NH2 SAPP, 70

R

OCH3 N CH3 CH 3 NH2 SADP, 68

OCH3 N NH2 RAMBO, 71

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

263

transformations have been reported. Owing to its ready availability in either enantiomeric forms and ease of preparation and that it can be attached and removed under mild conditions, chiral 2-imidazolidinone is a popular choice as chiral auxiliary [60]. Their versatility has been demonstrated by high degree of stereocontrol induced in asymmetric alkylation, Michael addition, aldol, Diels-Alder, and nucleophilic substitution reaction [60]. The ability of phosphonamide reagents to render excellent stereocontrol in organic transformations has been utilized in asymmetric synthesis [61, 62]. Various phosphonamide-based reagents are represented in Fig. 5. Among them, diazaphospholidine 73, introduced by Hanessian and co-workers, represents the most commonly used phosphonamide in organic synthesis (Fig. 5) [61]. Diazaphosphorinane 74 and oxazaphosphorinanes 77 and 78 have been explored by Denmark et al. [62–64]. Oxazaphospholidine 75 was developed by Hua et al. [65, 66] and Sting and Steglich [67], whereas camphor oxazaphospholidine 76 was reported by Giovenzana et al. [68] and Cravotto et al. [69]. Phosphonamides are prepared by four major methods, including Arbuzov reaction, condensation of phosphonic acid dichlorides, nucleophilic displacement, and alkylation of 2-oxo-1,3,2-diazaphospholidine. These methods have been used extensively for the synthesis of enantiomerically pure C2-symmetrical phosphonamides. Asymmetric Michael reaction involving chiral phosphonamide is an important transformation to generate contiguous stereocenters in a single step with high degree of stereocontrol [66]. Cyclopropanation, aziridination, and olefination are among other applications. Hanessian and Focken have summarized the utility of phosphonamide reagents in stereoselective carbon-carbon bond-forming reactions and their application in the total synthesis of natural products and biologically active molecules (79–81) (Fig. 6) [70]. R2 N O P R1 N R2 72 R2 N O H3C P R1 H3C O CH3 76

R2 CH3 Ph Ph O O N O N O P R1 P R P R1 N N N H 3C 74 R2 75 R2 73 Ph CH3 R4 H3C R3 O O O S P P R1 R1 N N R2 77 R2 78

Fig. 5 Representative phosphonamide reagents used in asymmetric synthesis [70] OCH3

N

O

CH3 CH3 H

H3CO

O S O O

CH3

HO NHOH

MMP inhibitor, 79

H

O O Jerangolid A (80)

Fig. 6 Biologically active natural products

CH3

HO H H H3C

H OCH3 N

O

CO2Na

trinem antibiotic, 81

264

A. Srivastava et al.

The presence of C2-symmetric axis within the chiral auxiliary reduces the possible number of competing diastereomeric transition states and allows absolute stereocontrol, thus providing higher levels of stereoselectivity [71]. DIOP, introduced by Kagan as the first C2-symmetric chiral auxiliary, afforded excellent asymmetric induction [72]. Tanner and Katsuki reported the synthetic utility of C2-symmetric aziridines and C2-symmetric pyrrolidine derivatives, respectively [73, 74]. For example, pyrrolidine-based asymmetric transformation is depicted in Scheme 10. Moreover, Whitesell reviewed the C2-symmetric chiral auxiliaries and their application in asymmetric synthesis [71]. In 1992, Salvadori et al. published a comprehensive review on the synthesis and enantioselective reactions of C2-symmetric 2,20 ,1,10 -binaphthylic compounds [75]. Giese et al. demonstrated the application of fumaramide bearing the C2-symmetric pyrrolidine moiety as chiral auxiliary with high diastereoselectivities in asymmetric radical reaction [76]. Modified guanidines have also been reported to induce asymmetric induction [77]. Moreover, synthesis of a highly potent chitinase inhibitor, allosamizoline (89), was accomplished using asymmetric desymmetrization of the meso-cyclopentitol derivative 85 with C2-symmetrical 1,5-benzodithiepan-3-one 1,5-dioxide, 90 as the key step (Scheme 11) [78]. So far we briefly discussed about different types of chiral auxiliaries in asymmetric transformations. Furthermore, the application of each of this class of auxiliaries in the stereoselective syntheses of some biologically active and pharmaceutically important natural products will be discussed. OCH2OCH3

OCH2OCH3 Et

LDA, EtCl N

H3C O

N

H3C

OCH2OCH3

OCH2OCH3 O dr 97.5:2.5, 83

82

Scheme 10 Stereoselective alkylation of C2-symmetric auxiliary [74]

OBn

OBn OBn OBn

BnO HO

OH 84

OBn

BnO

OBn

BnO 1. TMSCl, Et3N, THF

KHMDS, 18-crown-6

2. 90, TMSOTf, CHCl3 O

O

O

10% HCl, acetone BnO

THF, -78 oC, BnBr O

S

S

S 85

OBn

BnO BnO

OH 87

86

OAc AcO

OH HO

O

AcO 88

N H

S O

O

OBn

O

O

O S

O

N HO (-)-Allosamizoline (89)

Scheme 11 Total synthesis of (
)-allosamizoline (89) [78]

O

NMe2

S O

(R,R), 90

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

265

2 Oxazolidinone-Based Chiral Auxiliaries Evans’ oxazolidinones are some of the most established and extensively used chiral auxiliaries in stereoselective formation of carbon-carbon and carbon-heteroatom bonds. Several review articles are available that offer valuable information about these chiral auxiliaries as well as their applications in total synthesis of natural products [24, 25]. In addition to this, subsequent to initial reports regarding oxazolidinones, several structural variants of oxazolidinones have also been reported and well explored in asymmetric synthesis. Moreover, synthesis and importance of Evans and post-Evans auxiliaries in organic synthesis are well documented by Czekelius and co-workers in the previous chapter of this book. To illustrate further the importance of oxazolidinones and related auxiliaries like oxazolidinethione and thiazolidinethione in the stereoselective synthesis of natural targets, some selective examples of total synthesis of natural products which were accomplished using Evans chiral auxiliary or related heterocycle in one or more key steps will be discussed.

2.1

(+)-Brefeldin A

Brefeldin A, isolated from Penicillium brefeldianum [79], has been one of the most attractive targets for synthesis due to its broad spectrum of biological activities that include antifungal, antimitotic, antiviral, and antitumor activities [80, 81]. Owing to its widespread biological significance, more than 30 formal/total synthesis routes to brefeldin have been reported in literature ([82–85] and references cited therein). The derivatives and analogues of brefeldin A have also evoked much interest among the synthetic and medicinal chemists [85, 86]. Wu et al. developed an aldol approach for the total synthesis of (+)-brefeldin A 91 and 7-epi-brefeldin A 92 [86]. The retrosynthesis of (+)-brefeldin A 91 is represented in Scheme 12. The synthetic strategy exploits thiazolidinethione auxiliary-controlled

Y

6

H

OH 4

2 O

7

X

8

15

10

H

OR''

O CH3

12

I

OR' R

O

CH3 93

95

Brefeldin A (91) X = H, Y = OH 7-epi-Brefeldin A (92) X = OH, Y = H OR

O H3 C 94

R"'

R O

CHO 96

Z O

+ Z R

H 97

Scheme 12 Retrosynthesis of (+)-brefeldin A (91) [86]

O CH3

N O Bn

masked 98, Z = O, S

266

A. Srivastava et al. S S

S

O TiCl4, TMEDA

N

S

CH3 (E)-BnOCH2CH=CHCHO

Bn

S

O

OH OBn

N Bn

S

S

S

O

100 OH OTBS

OTBS

OCH3OTBS OBn 1.SO3.Py, 96%

OBn

N Bn

DMF, 96%

S

99

S

TBSCl, 2,6-lutidine

CH3

LiBH4

CH3 S

S

CH3

Et2O-MeOH, 96%

S

S 102

101

O

1. PPTS/benzene/ethyleneglycol, reflux, 97%

OTBS

O CH3

2. I2/NaHCO3/acetone-H2O, 89%

CH3

2. CH(MeO)3, TsOH MeOH (traces), 98%

1. LDA/TMSCl/-78 oC OBn 2. TiCl /CH Cl , -78 oC 4 2 2 3. DBU/MeOH, 97%

OBn

H3CO S

S 103

H

OTBS

O

OBn 105

O 104 H

OH O

Steps HO

O

CH3

H (+)-Brefeldin A (91)

Scheme 13 Total synthesis of (+)-brefeldin A (91) [86]

aldol reaction to establish C-4/C-5 stereocenters. Stereogenic center at C-15 was established using Jacobsen HKR (hydrolytic kinetic resolution) protocol. The synthesis of key intermediate 105 required for the synthesis of (+)-brefeldin A is represented in Scheme 13. Reaction of thiazolidinethione auxiliary 99 with aldehyde in the presence of TiCl4 and TMEDA furnished syn-aldol 100 with high degree of selectivity. Protection of free hydroxyl group in compound 100 as TBS ether and further removal of the chiral auxiliary resulted in alcohol derivative 102 in excellent yield. Oxidation of compound 102 and subsequent protection of corresponding aldehyde as dimethyl acetal afforded compound 103 which on reaction with PPTS/ethylene glycol/benzene, followed by treatment with I2/NaHCO3/ acetone-H2O, resulted in compound 104. Finally, aldol reaction of keto-acetal 104 under Mukaiyama conditions afforded cyclopentenone intermediate 105 with desired stereochemistry in excellent yield. Intermediate 105 was transformed into (+)-brefeldin A (91) through a series of synthetic transformations (Scheme 13).

2.2

Baulamycin A

The natural products baulamycins A and B, isolated from a marine source, are known to exhibit in vitro activity against nonribosomal peptide synthetaseindependent siderophore (NIS), SbnE and AsbA [87]. Goswami et al. reported a flexible route for the stereoselective synthesis of baulamycin A (106) and its congeners [88]. The synthetic highlights of his approach are depicted in Fig. 7. These include auxiliary-controlled aldol reaction, HWE olefination, and Evans methylation to introduce the required stereochemistry.

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products HWE Olefination 9 10

R

OH

CH3 S

R

15

HO

R

S 13

CH3

R

OH

3

CH3

O

CH3

OH

Evans Methylation

CH3

R 12

OH

267

CH3 Crimmins Acetate Aldol

Crimmins Aldol Baulamycin A (106)

Fig. 7 Structure of baulamycin A (106) [88]

O

O TBSO

OH

CHO N

+ H3C OTBS 107

O

CH2Cl2, 0 oC, 2.5 h 95%

108

H3C OTBS

OTBS O TBSO

Bn 109

OTBS OH

O

S

CH3

OTBS

S

O N

CH2Cl2, -40 to -78 oC, 1.5 h dr 5:1

1. 2,6-lutidine, TBSOTf 0 oC-rt, 1 h (96%) 2. LiBH4, THF, 0 oC 1 h, 89% 3. (COCl)2, DMSO, Et3N, CH2Cl2, -78 oC, 1.5 h

112, TiCl4, DIPEA

CH3 110

CH3

TBSO

H

OTBS

O

N

TiCl4, DIPEA, NMP

Bn CH3

O

O

TBSO

S

H3C

CH3 Bn CH3 111

N

S

Bn 112

Scheme 14 Synthesis of fragment 111 [88] H OTBDPS

HO CH3 CH3 113 O O

Swern oxd. quant. yield

O CH3 CH3

O

O N

OTBDPS CH3 CH3

Bn

OTBDPS 114

NaHMDS, MeI

O

HO

1. NaH, BnBr, TBAI, THF 6 h, 0 oC-rt, 88% 2. TBAF, THF, 0 oC, 4 h 82%

CH3 CH3 CH3 117 O

LiBH4. THF

OTBDPS CH3 CH3 CH3 116

BnO

0 oC-rt, 6 h, 87%

Swern oxd.

OH

quant. yield

CH3 CH3 CH3 118 O

H

BnO

O

Bn

OTBDPS

2. H2, 10% Pd/C, EtOAc overnight, 93%

N

THF, -78 oC, 4 h, 68%

115

1. 120, LiCl, DIPEA CH3CN, rt, 24 h 79%

O

O N

CH3 CH3 CH3 119, dr 9.4:1

Bn

O P OEt OEt 120

Scheme 15 Synthesis of fragment 119 [88]

The synthesis of key fragments 111 and 119 is depicted in Schemes 14 and 15, respectively. The aldol reaction of the aldehyde 107 with the oxazolidinone chiral auxiliary 108 in the presence of TiCl4, DIPEA, and NMP afforded adduct

268

A. Srivastava et al.

109 as a single isomer. Protection of the free hydroxyl group in 109, subsequent removal of auxiliary followed by oxidation furnished aldehyde 110. Further, asymmetric aldol reaction of aldehyde 110 with titanium enolate derived from N-acetylthiazolidinethione auxiliary 112 afforded compound 111 as the major isomer (dr 5:1). Another chiral coupling partner 119 was synthesized from phosphonate oxazolidinone 120 (Scheme 15). Aldehyde 114 was subjected to HornerWadsworth-Emmons olefination with phosphonate-oxazolidinone 120 to furnish the coupled product which was further hydrogenated to give compound 115. Treatment of compound 115 with NaHMDS and MeI furnished compound 116 as a single isomer in good yield followed by removal of auxiliary afforded alcohol 117. Subsequent benzylation of the free hydroxyl group of 117 followed by desilylation procedure using TBAF gave compound 118 which was converted to corresponding aldehyde 119 by Swern oxidation (Scheme 15). Completion of the total synthesis of baulamycin A (106) as reported by Goswami et al. is outlined in Scheme 16. Compound 111 on esterification followed by silylation gave TES ether 121 which was readily converted to phosphonate 122 using (MeO)2P(O)Me/nBuLi. HWE olefination of phosphonate 122 with chiral aldehyde 119 (Scheme 16) afforded the coupled product which was debenzylated to furnish compound 123. Selective deprotection of TES ether and subsequent OTBSOTES

111

TBSO

1. imidazole, MeOH 0 oC-rt, overnight, 88%

OTBSOTESO CO2CH3 (MeO)2P(O)Me, nBuLi, -78 oC,

CH3

2. 2,6-lutidine, TESOTf, 0 oC-rt, 30 min, 94%

OTBS 121

CH3

O P OCH3 OCH3

TBSO CH3 CH3 122

OTBS

83%

OTBSOTESO TBSO

CH3

1. 119, Ba(OH)2.8H2O, THF:H2O (40:1), 0 oC-rt, 1.5 h, 84% 2. H2 10% Pd/C, EtOAc overnight, 98%

o CH3 2. DIBAL-H, THF, -78 C 15 min (77%, dr 3:1)

CH3 123

OTBS

OH OTBSOH

OH CH3

2,2-DMP, CSA CH3 CH2Cl2:MeOH (8:1), 1 h

CH3

OH

H3C

O CH3 CH3

CH3 CH3

OTBS

125

CH3 OH

CH3

OTBSO

2. EtMgBr, THF, 0 oC, 15 min (79%, dr 6:1) 3. DMP, CH2Cl2, 0 oC-rt 1 h, 78%

CH3

TBSO

89%

CH3

CH3 124

1. DMP, NaHCO3, CH2Cl2, 0 oC-rt 1 h, quant. yield

H3C

OTBSO

TBSO

OTBS

1. CSA, CH2Cl2:MeOH (8:1), 0 oC-rt, 2 h (79%)

CH3

CH3

O

TBSO

CH3 CH3 OTBS

CH3

70% HF-Py, THF, 0 oC-rt, 12 h

CH3

CH3 126

O CH3

Scheme 16 Completion of synthesis of baulamycin A (106) [88]

90%

Baulamycin A (106)

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

269

reduction of α,β-unsaturated carbonyl group in compound 123 provided 1,3-diol 124 (dr 3:1). Treatment of diol 124 with 2,2-DMP/CSA produced 1,3-acetonide 125 which also confirmed the relative stereochemistry of the hydroxyl center produced as a result of DIBAL-H reduction. The advanced intermediate 125 with required stereochemistry was further transformed to baulamycin A (106) in few synthetic steps (Scheme 16).

2.3

Calcaripeptides A–C

Recently, Goswami et al. reported a stereoselective total synthesis of calcaripeptides A, B, and C [89, 90]. They have strategically employed chiral auxiliary-controlled Evans alkylation and asymmetric aldol reaction for the construction of stereocenters with required configuration. The synthesis was further completed by Wittig olefination followed by Shiina macrolactonization [90]. The disconnection strategy followed for the synthesis of calcaripeptides is shown in Fig. 8. The hydroxy acid derivative 130, derived from L-malic acid, was coupled with oxazolidinone 131, and subsequent reaction with NaHMDS and methyl iodide afforded compound 132 as the major isomer (dr 10:1) (Scheme 17). Removal of chiral auxiliary and subsequent oxidation produced corresponding aldehyde 133. Treatment of aldehyde 133 with titanium enolate derived from thiazolidinethione 134 furnished syn-aldol adduct 135 as a single diastereomer. The hydroxyl group in compound 135 was protected as TIPS ether followed by removal of the chiral auxiliary to furnish the required acid 136. The acid 136 with appropriately installed stereocenters was then converted to the target molecule calcaripeptide C (129) in few steps (Scheme 17). Moreover, the aldehyde 133 on Wittig olefination with the ylide Ph3P¼CH(Me) CO2Et followed by DIBAL-H reduction and subsequent oxidation furnished the α,β-unsaturated aldehyde 137. Reaction of titanium enolate derived from thiazolidinethione 134 afforded syn-aldol 138 with the required configuration as a major isomer. Silylation of 138 and subsequent cleavage of chiral auxiliary resulted

O

N O

Macrolactonization CH3 Evans alkylation CH3 O 9 H3C Wittig O N H

Ph

2

O CH3 Crimmins Aldol Peptide coupling

Calcaripeptide A (127)

CH3

O

N O

N H

2

O N

O

Ph Calcaripeptide B (128)

Fig. 8 Structure of calcaripeptides A, B, and C [90]

CH3

O CH3

O 9 H3C O

O

N H Ph

7

CH3

O 2

O

CH3

Calcaripeptide C (129)

270

A. Srivastava et al.

OTBS

1. 131, Et3N, PivCl, LiCl THF, -20 to 0 oC, 89%

O

H3 C

OTBS

2. NaHMDS, MeI, THF, -78 oC, 76%

OH 130

O

O N

H3C

O

OTBS

1. LiBH4, THF O 2. IBX, EtOAc H C 3

H

CH3 132

133 CH3 Ph

OTBS 134, TiCl4, DIPEA, CH2Cl2 o

0 to -78 C, 74%

S

OH O N

H3 C

S

1. TIPSOTf, 2,6-lutidine, CH2Cl2 0 oC to rt, 96%

OTBS

2. LiOH, H2O2, THF:H2O (3:1) 0 oC, 81%

CH3 CH3 135, single isomer

OTIPS CO2H

H3C

136 CH3 CH3

Ph O Steps (macrolactonization)

HN

S

O N

O

Calcaripeptide C (129)

CH3

131 Ph

S

134 Ph

Scheme 17 Synthesis of calcaripeptide C (129) [90]

-40 to -78 C, 1h, 73%, dr 8:1 OTBS

134, TiCl 4, DIPEA, CH2Cl2 H

H3C

o

N

OTBS Ph

OTBS

OTIPS COOH

1. Silylation 2. Hydrolysis OTIPS COOH

OTBS S N

141CH3 CH3

S

O S

H3C

N

H3C S

CH3 CH3 CH3 139

CH3 134 Ph Calcaripeptide B (128)

Ph

133 CH3

O

S

CH3 CH3 CH3 138

H

H3C

1. Silylation 2. Hydrolysis

H3C

N

H3C

O

S

OH O

OTBS S

CH3 CH3 140

0 to -78 oC, 1h, 81%, dr 18:1

CH3 CH3 137

S

OH O

H3C

O

OTBS

142, TiCl 4, DIPEA, CH2Cl2

142 Ph Calcaripeptide A (127)

Scheme 18 Syntheses of calcaripeptide A (127) and calcaripeptide B (128) [90]

in the polyketide fragment 139, which was readily converted to the natural product calcaripeptide A (127) in few steps (Scheme 18). Similarly, treatment of aldehyde 137 with titanium enolate derived from N-acetylthiazolidinethione 142 provided adduct 140 as a major isomer (dr 8:1). TIPS protection of 140 followed by cleavage of chiral auxiliary produced acid derivative 141, which was subsequently converted to the natural molecule calcaripeptide B (128) (Scheme 18).

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

2.4

271

Glucolipsin A

Glucolipsin A, produced by Streptomyces Purpurogeniscleroticus and Nocardia vaccinii, is known to possess glucokinase-activating properties [91]. In 2003, Fürstner and co-workers reported the stereostructure of glucolipsin A as (2R,20 R,3S,30 S) [92]. They envisaged that the macrodiolide can be prepared by auxiliary-controlled aldol reaction followed by glycosidation and hydrolytic cleavage of the auxiliary. The retrosynthesis of glucolipsin A (143) as proposed by Fürstner et al. is outlined in Scheme 19 [92]. The synthetic route to glucolipsin A (143) began with aldehyde 149 which was prepared from 12-bromo-1-dodecanol. Reaction of aldehyde 149 with auxiliary 148 and n-Bu2BOTf furnished (2R,3S)-configured syn-aldol derivative 150 (dr 99.5:0.5) (Scheme 20). H3C H3C

CH3

OH

HO

OH

O

O

O O

O

HO

O Cyclodimerization

RO O

O

OH M O

11

OH

H3C Glucolipsin A (143)

CH3

R'O HO

CH3

OR OR

CH3

Glycosidation O

O

RO

OR OR 144

OH 142 HO

+

OH

CH3

OH

Xc

O OR

H3C

O

O

OR

RO

11

11

H3C

OAc

CH3

CH3

Asymmetric aldol

11

H3C 145

O H3C

147

CH3 O CH3 O 11

CH3

149

5

O

+ O

N

Ph

CH3 148

CH3

Scheme 19 Retrosynthesis of glucolipsin A (143) [92] O

AcO O N

O

CH3

O

Ph

CH3

O 11

CH3 149

O

148 R1O O

AcO BnO

OBn

9

CH3

HO

CH3 CH3 aq. THF, 79%

OBn

BnO CH3 11

O LiOH, H2O2

O

OH

CH3 CH3 150

n-Bu2BOTf, Et3N, DCM Ph 63%

CH3

O N

O

CH3

152, R1 = auxiliary

HO

O

BnO

O

OBn

O

9

1. 154, KH, DMAP, CH2Cl2

CH3

2. H2, Pd(OH)2, MeOH

153 Cl

Glucolipsin A (143)

Scheme 20 Total synthesis of glucolipsin A (143) [92]

NH

CCl OBn 3 OBn 151

TMSOTf, MeCN 45%

CH3 CH3

OBn

O

H3C N

+

Cl N CH3 154

–

272

A. Srivastava et al.

Glycosidation reaction of compound 150 with trichloroacetimidate 151 resulted in compound 152 (β:α ¼ 5.2:1) which on removal of auxiliary and acetate hydrolysis provided hydroxy acid 153. Finally, glucolipsin A (143) was obtained on sequential macrodilactonization and debenzylation of compound 153 (Scheme 20).

2.5

Apoptolidinone

Apoptolidin A, a secondary metabolite, induces selective cell apoptosis and thus gains considerable interest in cancer treatment [93]. Apoptolidinone, an aglycon of antitumor agent apoptolidin A, possesses 12 stereogenic centers, and several syntheses have been reported in the literature. Crimmins and co-workers reported the asymmetric synthesis of apoptolidinone by exploiting the iterative propionate aldol reaction using thiazolidinethione as chiral auxiliary [94]. The retrosynthesis of apoptolidinone (155) is outlined in Scheme 21. The desired target was envisaged from two fragments 156 and 157 via cross metathesis. The densely functionalized fragment 158 in turn was obtained by employing the combination of iterative asymmetric aldol and glycolate alkylation reactions (Scheme 21). The synthesis of C20–C28 fragment 158 was realized, starting from thiazolidinethione 161 (Scheme 22). Thus, treatment of enolate, derived from thiazolidinethione 161, with aldehyde 160 afforded Evans syn-aldol adduct 162 in good yield. The alcohol 162 was protected as TES ether and subsequent reductive removal of chiral auxiliary afforded the aldehyde 163. The chiral aldehyde was then subjected to non-Evans syn-aldol reaction to furnish the desired product 164 aldol

CH3 CH3 HO cross metathesis

9

11

H3C

5 7

H3C

CH3 CH3

macrolactonization

HO

O

HO H3C H H3CO HO

H3C 11

O OH H O

17

21

H3C

5

7

3

27

OCH3

25

OH CH3

23

OH Apoptolidinone (155)

156 H3C

H3C

19

H H3CO HO H3C

OH OH H O

aldol

AcO

13

OCH3

OH CH3 OH 157

alkylation OTBS

O 1

OEt

+

OH

3

CH3 CH3

alkylation

OCH3 19 21 H CO P CHO + 3 27 OCH3 17 OCH3 O O OR2 OR1 OBn 159 158, R1=TES; R2=TMS

Scheme 21 Retrosynthetic analysis of apoptolidinone (155) [94]

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

273

Bn H

OCH 3 O

N

S

NMP, CH2Cl2, 90%

OBn 160

1. Et3SiOTf, 2,6-lutidine CH2Cl2, 97%

CH3

161, TiCl4, (-)-sparteine

OCH 3 O

S

162

OH

2. i-Bu2AlH, heptane CH2Cl2, 86%

OBn

Bn CH3

161, TiCl4, i-Pr2NEt

H

OCH 3 O

CH2Cl2, 62%

OR1 OBn 163, R1=TES

H3CO

CH3 CH3

S

N S

OCH 3 O

OH OR1 OBn 164, R1=TES

H 3C

2. (MeO) 2P(O)Me n-BuLi, THF, -78 oC 96%

S

O

CH3 CH3 OCH 3 P OCH 3 O O OR2 OR1 OBn 158, R1= TES; R2= TMS

1. Me3SiCl, Et3N, DMAP CH2Cl2, 0 oC, 79%

N

S 161

Bn

Scheme 22 Synthesis of C20–C28 fragment 158 [94] O

O H3CO

N

O

Bn 165

OTBS

1. LiN(i-Pr)2, THF, -78 oC then Me2C=CHCH 2I, THF, 70% 2. LiBH4, MeOH, Et2O, 0 oC, 80% 3. (COCl) 2, Me2SO, CH2Cl2, then Et3N, 99%

CH3 CH3

OCH3 167

O

CH3

H OCH3 166

1. catecholborane, ClRh(PPh 3)3, THF then H2O2, NaOH 2. Ac2O, Et3N, DMAP, CH2Cl2 77%, 2 steps 3. O3, CH2Cl2, -78 oC, then Me2S, 80%

1.TiCl4, H2C=CHCH 2SiMe3 CH2Cl2, -78 oC, 79%

CH3 2. t-BuSiMe OTf, 2,6-lutidine 2 CH2Cl2, -78 oC, 97%

OTBS AcO 159

CHO + 158 OCH3

Steps Apoptolidinone (155)

Scheme 23 Total synthesis of apoptolidinone (155) [94]

with excellent selectivity. The hydroxyl group in 164 was protected as TMS ether, and the chiral auxiliary was cleaved to provide the ketophosphonate 158 in very good yield (Scheme 22). Similarly, the synthesis of C13–C19 fragment 159 achieved starting from the glycolyl imide 165 (Scheme 23). The asymmetric alkylation of glycolyl imide 165, reductive removal of auxiliary, and subsequent Swern oxidation afforded the aldehyde 166 in good yield with high degree of stereoselectivity (Scheme 23). The TiCl4 mediated allylation of aldehyde 166 furnished the alcohol with excellent diastereoselectivity (dr 98:2). The desired aldehyde 159 was obtained in good yield by following a series of steps as delineated in Scheme 23 [94]. After achieving the synthesis of key fragments 158 and 159 with the required stereochemistry, Crimmins and co-workers accomplished the total syntheses of apoptolidinone [94] and apoptolidin A [95] by following a series of steps.

274

A. Srivastava et al.

2.6

Bleomycin A

Bleomycin A2 (Fig. 9), a glycopeptide, is an antitumor antibiotic and a major constituent of the clinical anticancer drug Blenoxane prescribed for the treatment of Hodgkin’s lymphoma, melanomas, head and neck carcinomas, and testicular cancer. The detailed SAR studies on bleomycin and its structural analogues have been well documented in the literature [96–98]. Bleomycin A2 can be described as an assembly of tetrapeptide S 169, pyrimidoblamic acid A 171, imidazole fragment 170, and the glycone fragment. Retrosynthesis and synthetic fragments of bleomycin A2 are shown in Fig. 9. In 1994, Boger et al. reported diastereoselective syntheses of bleomycin A2 (168) subunits using oxazolidinone auxiliary 174 [99]. Reaction of the (Z)-enolate of oxazolidinone 174 with aldehyde 175 provided syn-aldol adduct 176 which was readily converted to imidazole fragment 170 (Scheme 24). This compound 170 serves as a linker between tetrapeptide S 169 and pyrimidoblamic acid subunit 171. Similarly, stereoselective syn-aldol addition reaction of 177 with N-(tert-butoxycarbonyl)-D-alaninal 178 resulted in adduct 179 H 2N

O

N

CH3 Cl S H 3C

NH2

H H N

CH3 O

CH3 HN H O OH O

HO

H H N

HO O

O CH3 HO

N H N

N

O

S NH

N S

CH3

Bleomycin A2 (168)

H NH

O

OH

OH OH

O O

OH

NH2

O

CH3 H 2N

O

NH2

H N N

NH2 O

N R'

H 2N R

OH

O

N

+

H 3C +

NH2

CH3

HO

170

O CH3 HO

H 2N

O

H H N

Pyrimidoblamic acid A

OH

H N

S

O

OH O

HO

OCH3

N Tr

O

CONH 2

N

H 2N

H N

N

O

S NH

CH3

BocHN

H H N

O CH3 HO

glycone fragment

O CH3

OH + CH3

172

Fig. 9 Retrosynthesis of bleomycin A2 (168) [99]

S

O O

S

169

HO

OH OH

O OH

N

CH3

Tetrapeptide S

171

O

OH

+

N

N

H N

S O 173

S

NH2

NH2

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products CHO

N N Tr

O

O

O

N

N N Tr

174 CH3 CH3

Me

H3 C CH3

BocHN

Br H3C 176

N

O

NCS Ph

CH3 CH3

H H N S

Sn(OTf)2, CH3CHO, 77%

180

O

N

1. LiOH 2. 6N HCl 3. Boc2O 78% overall

O

O

R H 182, R=CH3 Ph

181

OH

BocHN

THF-H2O, 88%

O

O

LiOOH, 0 oC

O

N OH O 179

N-ethyl piperidine

OCH3 NH2 170

N

CH3

BocHN

O

O

N

Tr

H3 C CH3 CH3

CHO

OH O

1. NaN3, 94% 2. NaOMe, 60% 3. H2S, 84%

CH3

Bu2BOTf, iPr2NEt, 73%

O 177 O

O

N

178

O

N

O

OH O

175

Bu2BOTf Et3N, 65%

Br H3 C

275

CH2N2, 91% HCl, 95%

RHN HO

H

OH O

O OR1 CH3 183a, R = Boc, R1 =H 183b. R = H.HCl, R1 = Me

Scheme 24 Syntheses of fragments 183a and 183b [99]

CH3 CH3

CH3 CH3 183b +

OH 1. EDCl, HOBt, 72%

BocHN OH 180

O

BocHN

2. LiOH, 91%

H H N COOH 1. 173, EDCl, HOBt, 84% 2. MeI, MeoH, 97% OH O HO CH3 3. HCl-EtOAc, 99% H 172

O CH3 HO HCl.HN

H H N

O CH3 HO

O N H CH3

N

N S

S

N H

CH3 S CH3

Tetrapeptide S 169

Scheme 25 Completion of synthesis of tetrapeptide S 169 [99]

which on hydrolytic removal of auxiliary provided acid 180 for carboxylate coupling (Scheme 24). Further, syn-aldol addition of Z-enolate of 181 to acetaldehyde provided compound 182 which on hydrolysis and subsequent reaction with HCl followed by treatment with Boc2O provided N-(tert-butoxycarbony1)-L-threonine 183a. Subsequent esterification and N-Boc deprotection of 183a provided L-threonine methyl ester 183b which was utilized for coupling at the amine terminal. Finally, EDC-mediated coupling of 180 with 183b provided amide 172 which was further transformed to tetrapeptide S 169 by coupling with bithiazole unit 173 and subsequent S-methylation and acid-catalyzed N-Boc deprotection sequence (Scheme 25) [99].

276

2.7

A. Srivastava et al.

Brasilinolide A

Macrolide brasilinolide A (184), isolated from pathogenic actinomycete Nocardia brasiliensis IFM-0406, exhibits potent immunosuppressant activity [100]. Paterson et al. reported the convergent synthesis of polyol subunit of macrolide brasilinolide A using asymmetric Myers alkylation and Evans Michael addition protocols [101]. The retrosynthetic analysis of 32-membered macrolide 184 reveals that glycosylation at C37 and subsequent macrolactonization are the most crucial steps in the total synthesis (Scheme 26). The advanced intermediate C1–C38 seco-acid could in turn be synthesized from the densely functionalized intermediates 185 and 186 by employing aldol reaction. Similarly, C1–C19 segment 185 and C20–C38 segment 186, respectively, could be assembled through iterative asymmetric aldol reactions. Using Myers asymmetric alkylation protocol, the synthesis of C9–C13 segment 188 was achieved starting from chiral pseudoephedrine 191 (Scheme 27). The propionamide 191 on asymmetric alkylation followed by reductive removal of chiral auxiliary resulted in the alcohol derivative, which on Swern oxidation provided the desired aldehyde 188 in good yield. On the other hand, asymmetric Michael reaction of titanium enolate derived from 193 with acrylonitrile afforded the adduct 194 with good stereoselectivity (dr 96:4). The chiral auxiliary was then removed, and the corresponding alcohol was protected using TBSCl. Finally, DIBAL-H reduction of nitrile afforded the desired fragment 189 in good yield with high enantioselectivity (92% ee) (Scheme 27). Similarly, synthesis of C1–C19 fragment 185 was achieved

O

HO HO

31

OR1

20

OH O

19

HO HO

15

O

CH3 CH3 CH3 CH3

23

37

O

OH OH

OR2

O

CH3 O

OR3

1

CH3

CH3

13

7

OH OH OH OH Brasilinolide A (184), R1= COCH2CO2H, R2= COBu, R3= H PMBO

19

OTBS

17

O

PMBO

20

CH3 9

13

OTBS

TBSO

19

17

7

1

5

O O OPMB Si t-Bu t-Bu 185

OPMB 14 CH3 +

OP O 187

O

H C OCH3 + 3 O

O

9

188

CH3

OP

CH3

13

O

38

OP

OP

OP

OP

186

CH3 H

OP

CH3 CH3 CH3 CH3

or TBSO

13

8 9

189

Scheme 26 Retrosynthesis of brasilinolide A (185) [101]

O

H

+

H3C

1

O

OPMB 190

O

OMe

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products 1. LDA, LiCl, THF, -78 oC 2. I

CH3 O Ph

N OH CH3 CH3 191

O O

O

98%

OH

O

1. TiCl3(Oi-Pr). i-Pr2NEt 2. acrylonitrile

N

CH3 Bn 193

CH3 O Ph

O

83%

277

1. LDA, NH3.BH3 2. Swern oxidation H 88%, 2 steps

N CH3 CH3 192

1. NaBH4, H2O, THF 2. TBSCl, imidazole CN 3. DIBAL-H, CH2Cl2

O N

9

O 188, 97% ee

CH3 TBSO

13

9

H

O 189, 92% ee

58%, 3 steps

CH3 Bn 194

CH3 13

Scheme 27 Syntheses of aldehyde 188 and 189 [101]

PMBO

1. Bu2BOTf, i-Pr2NEt, -78 oC, Et2O 2. 188, -98 oC to -78 oC

187

OTBS 17

O

PMBO

3. TBSOTf, lutidine

CH3

13

195

OTBS O3, NaHCO3 95% Sudan red, -78 oC MeOH, CH2Cl2

PMBO

OTBS 17

c-Hex2BCl, Et3N 0 oC, Et2O

OCH3 + PMBO L 2B

O

OPMB 196

O

O

CH3

13

197

9

OTBS

H

O

-78 oC, 81%

185

1. Me4NBH(OAc)3, -30 oC PMBO MeCN, AcOH 2. t-Bu2Si(OTf)2, lutidine PMBO 54%, 2 steps

19

OTBS

17

O

CH3

13

OTBS

5

9

OH

O 198

OPMB

1

OCH3

O

Scheme 28 Synthesis of C1–C19 segment 185 [101]

by following a series of aldol reactions as mentioned in Scheme 28. Notably, Paterson et al. reported the synthesis of key fragment 186 by employing iterative aldol reactions [101]. Having the key intermediates 185 and 186 in hand, Paterson et al. accomplished the synthesis of brasilinolide A (184) framework [101].

2.8

FD-891

The antitumor agent FD-891 was isolated from Streptomyces graminofaciens A-8890 [102]. Crimmins and co-workers accomplished the first total synthesis of 16-membered macrolide FD-891 [103]. They envisaged accomplishing the desired

278

A. Srivastava et al.

target 199 from fragments 200, 201, and 202. The macrolide could be derived using cross metathesis of fragments 200 and 201 and followed by lactonization protocol. The required fragments 201 and 202 will be synthesized from a common chiral intermediate 204, whereas the fragment 200 will be realized from the chiral intermediate 203 using asymmetric aldol reactions as key steps (Scheme 29). The synthesis of epoxide 200 is represented in Scheme 30. The asymmetric aldol reaction of titanium enolate, derived from thioimide 161, with aldehyde 205 afforded CH3 CH3 CH3 7

HO

H

O

O

1

6

10

15

H

21

16

22

23

CH3 CH3 7

OAc

H

O

+ 10

S

15

ArO2S

O

OTBS

16

21

+

N

7

22

23

OCH3 24 25

CH3

OH

S

O

OTBS N

CH3 Bn

CH3 O

CH3 CH3 202

OTBS 6

CH3

O

201 CH3

H 200 TBSO

S

25

H 3C

OPiv

6

24

CH3 FD-891 (199) CH3 CH3

HO

TBSO

OCH3

OH

OH

O

S

CH3 Bn 204

203

Scheme 29 Retrosynthetic analysis of FD-891 (199) [103]

S S

1. TiCl4, (-)-sparteine, NMP, 78% OHC

O

205

CH3

N

OTBS

2. TBSOTf, 2,6-lutidine CH2Cl2, 92%

Bn 161

CH3 CH3 TBSO

OPiv

1. NH4F, MeOH, 85% 2. (+)-DET, (i-PrO) 4Ti t-BuOOH, MS, 72%

CH3 CH3

O

OPiv

6

OTBS 6

N Bn

OTBS

7

CH3

CH3 CH3 TBSO

OPiv H 208

O

H 10

H TBSO 200

Scheme 30 Synthesis of epoxide 200 [103]

1. i-Bu2AlH, CH2Cl2, 74% 2. Ph3P=C(CH 3)CO2Et, 92% 3. i-Bu2AlH, THF, 98% 4. pyridine, PivCl, 99%

206

OH

OTBS

7

S

O

H

207

TBSO

S

1. DMP, NaHCO 3, CH2Cl2, 97% 2. MgBr 2(Et2O), CH2=CHCH 2SiMe 3 CH2Cl2, 70% (dr 20:1) 3. TBSCl, imidazole, DMAP, 99%

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products S

TiCl4, (-)-sparteine CH3 3-butenal, CH2Cl2

O N

S

N

0 oC, 73%

1. TESOTf, 2,6-lutidine CH2Cl2, -78 oC, 96%

OTES

2. LiBH4, Et2O, MeOH 98%

210 CH3

OH

1. i-Bu2AlH, toluene, -78 oC, 88% 2. NaBH4, CH2Cl2, MeOH, 84%

OTES CN

90%

S

CH3 Bn 209

Bn 161

acetone cyanohydrin DEAD, PPh3, toluene

S

OH O

279

211 CH3

OAc OTBS

3. TBSCl, imidazole, CH2Cl2, 92% 4. Ac2O, DMAP, Et3N, CH2Cl2, 98%

CH3 201

Scheme 31 Synthesis of C13–C18 fragment 201 [103]

S

OR1 O N

S

CH3 Bn 212, R1=TES

1. i-Bu2AlH, CH2Cl2, -78 oC, 84% 2. 212, TiCl 4, (-)-sparteine, NMP CH2Cl2, then aldehyde, 87%

CH3 CH3 CH3 214, R1=TES, R2=MOM

CH3 OCH3 O CH3 CH3 CH3 216

NaBH4, CeCl3.7H2O MeOH, 0 oC, 75%

S

O

N CH3 CH3 213 Bn

1. CH3N(OCH3)H.HCl imidazole, CH2Cl2, 78% 2. MOMCl, i-Pr2NEt, DMF, o S 50 C, 87% 3. MeMgCl, Et2O 0 oC, 97%

1. NaH, MeI, THF, 81% 2. Con. HCl, MeOH, 78%

OR1 OR2 OH

OR1 OR2 O

H3C O

OR1 OH

CH3 3. 2,2-dimethoxypropane, PTSA 88% CH3 CH3 215, R1=TES, R2=MOM H3C O

1. O3, CH2Cl2, MeOH, -78 oC then NaBH4, 81% 2. DIAD, 2-mercaptobenzothiazole PPh3, CH2Cl2, 93% 3. H2O2, (NH4)6Mo7O24.4H2O EtOH, 89%

CH3 OCH3 O CH3

ArO2S CH3 CH3 202

Scheme 32 Synthesis of sulfone 202 [103]

the Evans-syn aldol adduct with excellent selectivity. The TBS ether protection of alcohol and subsequent reductive removal of the chiral auxiliary of compound 206 provided the desired aldehyde. Following a series of reactions as shown in Scheme 30, the required epoxide 200 was obtained in good yield [103]. The synthesis of fragment 201 is outlined in Scheme 31. Addition of 3-butenal to titanium enolate of thiazolidinethione 161 afforded the non-Evans-syn product 209 with excellent diastereoselectivity (dr 15:1). Following the sequence of reaction as given in Scheme 31, the desired fragment 201 was synthesized with good selectivity [103]. Then synthesis of sulfone 202 was achieved by following a series of steps as outlined in Scheme 32. Finally, the total synthesis of natural product FD-891 (199) was realized by employing cross metathesis between fragments 200 and 201 followed by lactonization as shown in the Scheme 33.

280

A. Srivastava et al. CH3 CH3 7

TBSO

CH3 CH3

OPiv

6

TBSO

AcO

H

O

+

15

10

H TBSO 200

OTBS Cl2(Cy3P)(IMes)Ru=CHPh CH2Cl2, 40 oC, 68% CH3 201

16

CH3 CH3 CH3 1. i-Bu2AlH, CH2Cl2, -78 oC, 85% TBSO 2. MnO 2, CH2Cl2, 40 oC then O n-BuLi, Ph3P(O)C(CH 3)CO2Me

7

H 10

15

H TBSO

66%, 2 steps

218

H

O

15

H TBSO

TBSO

O

10

15

16

219

OTBS

16

OTBS

CH3 217, Z-isomer

61%, 2 steps

CH3 CH3 CH3 O

1

6

AcO

10

H TBSO

CH3

CH3 CH3 CH3 7

TBSO

H

O

OTBS

16

OPiv

6

1. TMSOK, THF 2. Cl2C6H3COCl, Et3N, THF then DMAP, toluene

1

CO2CH3 AcO

6

7

1. PPTS, MeOH, 90% 2. DMP, NaHCO 3, 82%

7

1

6

H

O

O

10

H TBSO

CH3

O

15

220

16

202, KHMDS, THF -78 oC then 220, 80% CHO

CH3

CH3 CH3 CH3 TBSO

7

1

6

H

O 10

H TBSO

O

O 15

H 3C O 21

16

CH3

221

CH3 OCH 3 O 22

23

24

25

CH3

H2SiF6 20% in H2O, CH3CN

FD-891 (199)

90%

CH3 CH3

Scheme 33 Total synthesis of FD-891(197) [103]

2.9

(
)-FR182877

FR182877, a cytotoxic natural product, was isolated from Streptomyces sp. #9885 by Sato et al. [104]. Owing to its potent antitumor activity, several strategies toward the construction of this polycyclic framework have been reported in literature [105–109]. Notably, (
)-FR182877 (222) is a fused polycyclic ring system, with 12 stereogenic centers, bearing bridged vinylogous carbonate. Hexacyclinic acid (224), isolated from Streptomyces, also possesses same carbon connectivity as (
)-FR182877 (222) (Scheme 34) [110]. Owing to this structural relationship between FR182877 (222) and hexacyclinic acid (224), Evans and Starr elegantly envisioned their synthetic strategy based on a macrocyclic intermediate 223 that could be derived from Suzuki cross-coupling of C3–C10 (boronic acid fragment 225) with C11–C20 (dibromide fragment 226) followed by homologation [111]. The retrosynthetic analysis of this intermediate 223 is shown in Scheme 35. In the retrosynthetic analysis, the fragments 225 and 226 were envisaged from auxiliarycontrolled syn-aldol reactions (Scheme 35) [111].

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products HO H CH3 A H3C B OH H H C O H DO H3C EO F

281 AcO H

1

RO

CO2R

6

RO

CH3 O

8

19

18

HO2C H

CH3 OR

DO F

EO

OH

H CH3 Hexacyclinic Acid (224)

19-Carbon macrocyclic intermediate, 223

(-)-FR182877 (222)

OH H O

H

H H3C

CH3

H CH3

B C

11

Br

CH3

A

Scheme 34 Application of 19-membered macrocyclic intermediate, 223 [110, 111]

O

OR OR 19-Carbon macrocyclic intermediate, 223

Suzuki coupling

OTBDPS

(HO)2B

H3CO +

homologation

CH3

Boronic acid fragment, 225

O

OH

O Dibromide fragment, 226

OTBDPS 6

228

Stereoselective aldol

O

O

OH CH3

N

O

H

227

CH3

Bn

Br

O OTBDPS

N

O

CH3

N 20 18 CH3 CH3

Dibromide fragment, 226 Br

Boronic acid fragment, 225 O

OR

CH3

Bn

H OTBS

229

CH3

18

230

OTBS

Scheme 35 Retrosynthetic analysis of macrocyclic intermediate 223 [111]

O O

O

O Bu2BOTf, Et3N

N

193 Bn

CH3

O

O

OH CH3

CH3 Bn 86% 231, syn-Aldol

CH3

H

O N

230

MeNHOMe.HCl, Me3Al THF, 96%

OTBS

OTBS O H3CO

OH

N CH3 CH3 232

O OTBS H3CO CH3 1. TBSCl, DMF, imid. 96% n N 2. TsOH: Bu4NHSO4(1:4), MeOH, 89% CH3 CH3 3. DMP, NaHCO3, 94% 233

CH3 CHO

OTBS CBr4, PPh3

O OTBS CH2Cl2, NaHCO3 H3CO N 74% CH3 CH3

CH3

226

Br Br

Scheme 36 Synthesis of dibromide fragment, 226 [111]

The syntheses of the fragments 225 and 226 and assembling of these fragments leading to natural product (
)-FR182877 (222) are shown in Schemes 36, 37, and 38.

282

A. Srivastava et al. O O

O

Bu2BOTf, Et3N O

N

O

CH3

OTBDPS

H

O

N

O

OH

8

6

CH3 Bn

MeNHOMe.HCl, Me3Al OTBDPS

OH

O

OH

DIBAL, -78 oC

MgBr

N CH3 CH3 235

OH

THF, 98%, dr 20:1

77%

OTBDPS

CH3 236

OTBDPS

OTBS OTBS

OH TBSCl, imidazole

8

THF, 97%

234

228

193 Bn

H3CO

O

6

DMF, 98%

CH3 237

OTBDPS

8

Catechol-BH, Cy2BH (0.1 eq)

6

CH3 238

OTBDPS

then 1N NaOH; 97%

OTBS OTBS (HO)2B

8

6

CH3

225 OTBDPS

Scheme 37 Synthesis of boronic acid fragment, 225 [111]

Aldehyde fragments 228 and 230 were readily synthesized from 3-buten-1-ol to cis-2-buten-1,4-diol, respectively. Aldol addition of oxazolidinone 193 to aldehyde 230 in presence of Bu2BOTf furnished syn-aldol adduct 231, thus establishing C18 and C19 stereocenter. Removal of auxiliary from adduct 231 furnished corresponding Weinreb amide 232. Further, silylation of the secondary hydroxyl group and desilylation of primary alcohol followed by Dess-Martin periodinane oxidation provided the required aldehyde 233. Corey-Fuchs olefination of aldehyde 233 afforded the C11–C20 “dibromide fragment” 226 (Scheme 36). For the synthesis of C3–C10 “boronic acid fragment” 225, aldol addition of aldehyde 228 to oxazolidinone 193 was carried out to obtain the syn-aldol adduct 234. Removal of auxiliary converted the aldol adduct 234 to Weinreb amide 235 which was then treated with ethynyl magnesium bromide to obtain ynone 236. DIBAL-H reduction of this ynone resulted in syn-diol 237 (4:1-syn selective) which was then subjected to double silylation followed by alkyne hydroboration followed by saponification to afford C3–C10 boronic acid fragment 225 (Scheme 37). The dibromide fragment 226 and boronic acid fragment 225 were subjected to Suzuki coupling reaction using Pd(PPh3)4 to obtain bromodiene 239 (Scheme 38). Partial reduction afforded the corresponding aldehyde, which was subjected to carbon homologation to give β-keto ester 240. Selective removal of TBDPS group followed by iodination resulted in allyl iodide which was subjected to macrocyclization to afford macrocycle 241 (Scheme 38). Oxidation of macrocycle 241 followed by subsequent heating initiated a sequence of transannular cycloadditions, a normal electron-demand Diels-Alder with complete endo-selectivity to give 243 which underwent an inverse electron-demand hetero-Diels-Alder resulting in the formation of pentacyclic ring system, 244 as a single diastereomer. To complete

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products O H3CO

225

+

OTBS CH3

N CH3 CH3

Pd(PPh3)4 (5 mol%), Tl2CO3

226

Br

H2O-THF (1:3), 23 oC, 84% TBDPSO

OTBS 239

O

1. DIBAL, CH2Cl2, -78 oC 2. ethyldiazoacetate, SnCl2 70% (2 steps)

OTBS

O

283

CH3

OTBS CH3

EtO

CO2Et

TBSO

CH3

1. TBAF, AcOH, DMF, 92% 2. I2, PPh3, CH2Cl2

Br

TBSO

3. Cs2CO3, THF, 23 oC

OTBS

77% (2 steps)

OTBS

241 Br

TBDPSO

CH3

OTBS 240

CH3

CH3 O

CH3 2 CO2Et

TBSO 6 TBSO 8

Ph2Se2O3, SO3-Pyr, Et3N

CH3 O

THF, 23 oC then hexane, 50 oC

8

CH3

6

Br H

OTBS Br

OTBS CH3

H

H O

H3C

242 CH3

2 CO Et 2

CH3 OTBS

TBSO H 8 63%

HO H 8

CH3 6

Br H

H

OTBS

2 CO2Et

H3C

RO O

1. HF-MeCN, 89%;

H3C H

2. Me3B3O3, Pd(dppf)Cl (0.1 eq.) Cs2CO3, DMF-H2O (2:1), 100 oC, 71%

H

H H3C

H CH3 244, R=TBS

OTBS

243

CH3 6

H

OH

2 CO2Et

HO O

H

245 H CH3

1. TMSOK, THF 2. Mukaiyama's reagent, NaHCO3, CH2Cl2, 62%, (2 steps)

(-)-FR182877 (222)

Scheme 38 Completion of synthesis of (
)-FR182877 (222) [111]

the synthesis of (
)-FR182877, the triol obtained on complete desilylation of macrocycle 244 was subjected to Suzuki methylation to give 245. Finally, saponification of ethyl ester 245 followed by lactonization afforded the natural product (
)-FR182877 (222) (Scheme 38).

3 Pyrrolidine-Based Chiral Auxiliaries Popularly known as Enders’ chiral auxiliary, SAMP and RAMP auxiliaries derived from (S)-proline and (R)-glutamic acid, respectively, have also been extensively exploited in asymmetric synthesis. More sterically demanding analogues of RAMP and SAMP auxiliaries like RAMBO, SADP, SAEP, and SAPP are also known

284

A. Srivastava et al.

(Fig. 4) [55]. Extensive information concerning the synthesis, cleavage, and efficiency of RAMP/SAMP auxiliaries in several asymmetric transformations are well summarized by Maison and co-workers in Chapter “Pyrrolidines as Chiral Auxiliaries” of this book. Besides α-alkylation, the hydrazone auxiliaries have also been put to good use in the introduction of required chirality during the synthesis of the desired enantiomer of natural products of biological importance [53–55].

3.1

(+)-Streptenol A

Streptenols are secondary metabolites isolated from several Streptomyces species and known as inhibitors of cholesterol biosynthesis [112, 113]. Very recently, Cañedo and co-workers reported the isolation of four new natural products belonging to this class of metabolites, namely, streptenols F, G, H, and I from Streptomyces misionensis [114]. Moreover, (+)-streptenol is utilized as a versatile chiral building block in the synthesis of several members of the important class of δ-lactones [115]. Several syntheses of ()-streptenols B, C, and D have been reported in the literature, and the most general approach to ()-streptenols B, C, and D relies on the 2-(20 ,20 -dimethyl-1,3-dioxan-4-yl)-acetaldehyde 248 as a key precursor [116, 117]. In 1999, Enders and co-workers reported the first asymmetric synthesis of natural (+)-streptenol A (249) [118, 119]. They envisaged that the α-alkylation/deoxygenation protocol would allow an efficient access to either (S)- or (R)-2-(2,2-dimethyl1,3-dioxan-4-yl)acetaldehyde 248 depending on the chiral auxiliary used, and hence, this method allowed the asymmetric syntheses of both (+)- and (
)-streptenol A (Scheme 39) [119]. The enantioselective synthesis of (+)-streptenol A (249) is outlined in Scheme 40. Treatment of lithium aza-enolate of RAMP-hydrazone (R)-246 with 2-bromo-1-tertbutyldimethylsilyloxyethane at
105 C furnished the corresponding α-alkylated hydrazone with excellent diastereoselectivity. The auxiliary was removed under mild conditions using oxalic acid, and the corresponding (R)-keto-derivative 252 was isolated in 95% yield with dr 98:2. Reduction of the carbonyl group in (R)-252 with NaBH4 and subsequent reaction of the hydroxy group with sodium hydride, CS2, and iodomethane afforded (R,S/R)-xanthate 253. Further, Barton-McCombie deoxygenation of (R,S/R)-253 was carried out in presence of nBu3SnH to give (S)-dioxane derivative which on silylether deprotection with TBAF and subsequent

N

N OCH3

O H3 C

O

CH3 246 RAMP-hydrazone

O H3C

O

CH3

O

CH3 248

Scheme 39 Strategic plan for the synthesis of streptenol A [119]

OH

OH

O

249 (+)-Streptenol A

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

N

N

O

N OCH3

O

285

H3CO

t-BuLi, BrCH2CH2OTBS

O

O

THF, quant. yield

H 3C CH3 246

OTBS

OTBS aq. oxalic acid

O

H 3C

H 3C

Et2O, 95%

CH3

O

O CH3

(R)-252, dr 98:2

(R,R)-251, dr 98:2 S O

SMe OTBS 1. (nBu3)SnH, AIBN, toluene, 82% 2. TBAF, THF, 93%

1. NaBH4, MeOH, 85 % O

2. NaH, MeI, CS2, THF, 94%

H 3C

O

3. TPAP, NMO, MS Å4, CH2Cl2, 88%

CH3 253

CH3

Mg, (E)-5-bromopent-2-ene O

THF, 81%

H 3C

O

O

O

O

H 3C CH3 (S)-248, dr 98:2

OH

1. PCC, celite, MS Å4 CH2Cl2, 72%

CH3

2. TFA, THF/H2O (4:1) OH OH O (+)-Streptenol A (249) 78% (dr 98:2)

CH3 (S/R, S)-254

Scheme 40 Asymmetric synthesis of (+)-streptenol A (249) [119]

N

N OCH3

O H3C

O CH3

(S)-247

O H3C

O

O

CH3

(-)-Streptenol A (250) (dr 98:2)

(R)-248, dr 98:2

Scheme 41 Asymmetric synthesis of (
)-streptenol A (250) [119]

TPAP oxidation furnished the key building block (S)-2-(2,2-dimethyl-1,3-dioxan-4yl)acetaldehyde 248, in 51% overall yield with dr 98:2. Reaction of (S)-aldehyde 248 with (E)-3-penten-1-ylmagnesium bromide furnished a diastereomeric mixture of (S/R,S)-alcohol 254 which on subsequent oxidation with PCC followed by the deprotection of acetonide gave the natural product (+)-streptenol A (249) in 23% overall yield (Scheme 40). Following a similar sequence of reactions, SAMP-hydrazone 247 was converted to enantiomerically pure (R)-aldehyde 248 in good yield, which was later utilized in the synthesis of (
)-streptenol A (250) (Scheme 41). Thus, the required stereogenic center was efficiently obtained using SAMP or RAMP as chiral auxiliary. Moreover, the chiral auxiliary can be recovered and recycled.

3.2

(
)-α-Elemene

The total synthesis of (
)-α-elemene, a naturally occurring terpene, was accomplished by Rawal et al. using chiral 1-amino-3-siloxy-1,3-butadiene bearing a

286

A. Srivastava et al. O

CH3

TBSO

O H N

Ph

Ph

H3CO

256

CH3 CH3

Ph

255

Ph KHMDS; TBSCl

CH3 Ph

1. Ph3PCH3Br n-BuLi, THF, 99%

260 1. i-PrLi, CeCl 3 Et2O, -78 oC 2. PCC, CH2Cl2 74%

N

Ph

CHO 259 toluene, 20 oC

258

TBSO

CHO N

Ph

-78 to 20 oC 94-100 %

257

TBSO

Ph

N

aq. HCl Ph

N

CH3 Ph

O

THF, 82% CH3 262

261 CH3

CH3

1. i-PrLi, CeCl 3 Et2O, -78 oC

H 3C O 263

CH3

2. HClO 4, AcOH 81%

H 3C CH3 H 3C CH3 (-)-α-Elemene (264)

Scheme 42 Total synthesis of (
)-α-elemene (264) [120]

C2-symmetric 2,5-diphenyl pyrrolidine auxiliary as a diene component in the DielsAlder reaction [120]. The chiral aminosiloxydiene was prepared from the enantiomerically pure 2,5-substituted pyrrolidine. The synthetic route to (
)-α-elemene (264) is represented in Scheme 42. The required chiral diene 258 was prepared by the reaction of trans-2,5-diphenyl pyrrolidine 255 with 4-methoxy-3-buten-2-one 256, followed by silylation to afford 1-amino-3-siloxy-1,3-butadiene 258. The chiral diene was then reacted with methacrolein (259) at 20 C in toluene to give adduct 260 as the major product. The Diels-Alder adduct 260 was then subjected to Wittig olefination to give vinyl derivative 261 followed by hydrolysis with aqueous acid afforded 4-methyl-4-vinyl cyclohexenone 262 in 82% yield. At this stage, an iterative alkylation strategy was followed for installing the isopropyl groups. Thus, cyclohexenone derivate 262 was allowed to react with iPrLi and CeCl3, and subsequent oxidation with PCC yielded enone 263. The CeCl3 promoted second alkylation of 263 with iPrLi followed by acid-catalyzed dehydration which afforded the natural product (
)-α-elemene (264) in good yield (Scheme 42). Moreover, Rawal and co-workers have elegantly demonstrated the synthetic utility of aminosiloxydiene in the total synthesis of the Aspidosperma alkaloid, tabersonine [121, 122].

3.3

(
)-Neonepetalactone, Dehydroiridodial, and Dehydroiridodiol

Monoterpenes, namely, neonepetalactone, dehydroiridodiol, and dehydroiridodial were isolated from Actinidia polygama plant [123, 124]. Owing to their biological

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

OCH3 N

O

O

+

N

OCH3

CH3

H

O

1. LDA, THF, 0 oC 2. TMEDA, -78 oC 3. Michael acceptor THF, -78 oC

O OCH3 CH3

N N

95% 266

287

t-BuCOCl, Et3N DMPU

H

(S)-265 267

OCH3

O (H3C)3C

O

O OCH3 CH3

N N

(CH3)2CuLi, Et2O -78 oC to -25 oC then 6N HCl, rt

CH3 O OCH3 CH3

89%

O

65% H

CHO

H

269, dr 98:2

OCH3

O

H 3C

L-selectride THF, -78 oC

CH3

(-)-Neonepetalactone (270) dr 98:2

268

Scheme 43 Four-step synthesis of (
)-neonepetalactone (270) [125]

CH3 O OCH3 CHO CH3 269, dr 98:2

LiAlH4 Et2O, 0 oC

CH3 OH

1. (COCl)2, DMSO CH2Cl2, -78 oC

o OH 2. (iPr)2NH, 0 C

65% CH3

Dehydroiridodiol (271) dr 98:2

CH3 CHO CHO CH3

Dehydroiridodial (272) dr 98:2

Scheme 44 Syntheses of dehydroiridodiol (271) and dehydroiridodial (272) [126]

importance, several syntheses of neonepetalactone have been reported starting from (S)-limonene and (R)-carvone as common precursors [125]. Enders et al. reported an efficient synthesis of (
)-neonepetalactone (270) by employing asymmetric Michael addition of propanal-derived SAMP-hydrazone 265 to 2-cyclopentenecarboxylate 266 as a key step (Scheme 43) [125]. Enol-pivaloate 268, derived from the Michael adduct 267 (dr 98:2) and pivaloyl chloride, was treated with lithium dimethylcuprate followed by the removal of chiral auxiliary which afforded the 5-substituted 2-methylcyclopentene carboxylate 269 in good yield with excellent stereoselectivity (dr 98:2). L-selectride-mediated reduction of ester-aldehyde 269 afforded the desired (
)-neonepetalactone (270) in good yield (Scheme 43). As expected, LiAlH4 reduction of compound 269 afforded dehydroiridodiol (271) in excellent yield (Scheme 44) [126]. Further, Swern oxidation of dehydroiridodiol provided the desired natural product dehydroiridodial (272) [126].

3.4

(+)-Sordidin

(+)-Sordidin and (
)-7-epi-sordidin are pheromone of banana weevil Cosmopolites sordidus [127]. Owing to their biological importance, several syntheses have

288

A. Srivastava et al.

H3C O

Et Et O

5

CH3 O 1 3 H3C H3C 7 (+)-Sordidin (273)

H3C

CH3

TBSO

O

CH3

OHHO CH3 CH3 274

OCH3

CH3

275

+

N

N

H3C

CH3 276

OCH3 N

CH3

H3C

N

O O

O

H3C CH3 246

O

H3C

OTs

CH3 277

Scheme 45 Retrosynthesis of (+)-sordidin (273) [128]

been reported based on the concept of ex-chiral pool. Asymmetric synthesis of (+)sordidin (273), reported by Enders et al., involved iterative asymmetric alkylation of RAMP hydrazone as a key strategy [128]. The synthesis of (+)-sordidin (273) was envisaged from the key intermediate epoxide 275, which in turn could be obtained from RAMP hydrazone 246 via tosylate derivative 277 (Scheme 45). The total syntheses of (+)-sordidin (273) and (
)-7-epi-sordidin (286) are presented in Scheme 46. The iterative alkylation of RAMP hydrazone 246 provided the trialkylated hydrazone 279 in good yield (dr 98:2). The chiral auxiliary was removed by ozonolysis followed by radical deoxygenation via xanthate using Barton-McCombie procedure [129]. The deprotection of benzyl ether group provided alcohol 282, which on tosylation followed by the cleavage of acetonide afforded the diol-tosylate 283 in good yield. The chemoselective protection of the secondary alcohol followed by the treatment of sodium hydride afforded the desired enantiomerically pure epoxide 275 with excellent stereoselectivity. Treatment of aza-enolate, derived from 3-pentanone SAEP-hydrazone 276, with epoxide 275 provided a mixture of hydrazones 285, which on subsequent hydrolysis furnished a diastereomeric mixture of acetals (1.5:1), (+)-sordidin (273) and (
)-7-episordidin (286), respectively, with high degree of selectivity (Scheme 46).

3.5

(
)-Callystatin A

Belonging to the leptomycin family of antibiotics, callystatin A is a potent cytotoxic polyketide and was isolated by Kobayashi et al. from the marine sponge Callyspongia truncata [130]. The leptomycin family of antibiotics includes several well-known antitumor antibiotics such as leptomycins A and B, anguinomycins A and B, kazusamycin, and leptofuranins A–D ([131, 132] and references cited therein). Owing to the very limited natural abundance of callystatin A and promising biological activities, several groups have been involved in the total synthesis of this attractive target [133–137].

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products OCH3

OCH3 N

N

N

1. t-BuLi, MeI 2. t-BuLi, MeI

OCH3

O

CH3 O

O

NaBH4 MeOH

CH3 OBn O

O

O

CH3 OH O

H 3C

O

O

H3C

CH3 280, dr 98:2

1. NaH, THF, 0 oC then CS2, MeI 2. nBu3SnH, AIBN, toluene, reflux

CH3 OBn

H3C

H 3C

O

CH3 279, dr 98:2 OH

O H3C

79%

H3C

O H3C

CH3 278, dr 98:2

246

CH3 OBn

92%

O

N

H3C

H 3C

CH3

O3, CH2Cl2 -78 oC

N

1. t-BuLi, THF, -78 oC 2. BOMCl, -100 oC to rt

N

H3C

79%, 2 steps H 3C

289

3. Ca/NH3, 93%, 3 steps

CH3

281

1. Et3N, DMAP, CH2Cl2 TsCl, rt 2. 3N HCl, H2O/MeOH, rt

H3C OH

CH3

2,6-lutidine, CH 2Cl2 TBSOTf, 0 oC

CH3 OTs OH

H 3C

283

282

CH3 OTs OR OH 284, R= TBS Et

Et NaH, THF, 0 oC

TBSO

99%

O

OCH3

OCH3

CH3 CH3

+

275, dr 98:2

N

LiCl, LDA, THF -78 oC

CH3

1 OH R CH3 CH3

274, R1=OH

R1

CH3 CH3

285, R= TBS, R1=OH H 3C O

CH3

CH3 OR

O H 3C

N

H3C

N

H3C

N

276 3N HCl H2O/n-pentane rt, 6 d

Et

Et

H 3C

O

CH3 + H3C

H3C O

H 3C

O

CH3

CH3

(+)-Sordidin (273) dr 99.5:0.5

7-epi-Sordidin (286) dr 98.5:1.5

(dr 1.5:1)

Scheme 46 Total syntheses of (+)-sordidin (273) and (
)-7-epi-sordidin (286) [128]

Enders et al. reported the total synthesis of (
)-callystatin A (287) by applying their RAMP/SAMP asymmetric hydrazone alkylation methodology, enantioselective biocatalytic reduction, and syn-selective aldol protocol [132]. Retrosynthesis of callystatin A (287) is shown in Scheme 47. C6–C7 and C12–C13 disconnections led to fragments 288 and 289, respectively, and that could be synthesized by E-selective Wittig olefinations between tributyl phosphorus ylides derived from the corresponding allylic bromides, 294 and 289, respectively. The aldehyde precursor 296 was transformed to allyl bromide derivative 294 by employing asymmetric alkylation using RAMP/SAMP method. The allyl bromide derivative 289 was prepared by syn-selective aldol reaction between enolates of 291 and aldehyde 292. Enders et al. synthesized the key intermediate 293 starting from tert-butyl 6-chloro-3,5-dioxohexanoate 297 in 94% ee following biocatalytic enantioselective reduction to furnish hydroxy-keto-ester 295. Compound 295 was transformed to α,β-unsaturated δ-lactone 293 in a few synthetic steps (Scheme 48).

290

A. Srivastava et al. O

1

OiPr Wittig olefination

O

CH3 CH3 CH3 CH3

O

6 7

CH3

12

10

H3C 24

16

O (-)-Callystatin A (287)

H3C

22

OH OTBS

CHO

OH

289

288

ig n itt tio W fina e l o

CH3 CH3 CH3

OiPr O

CH3

CH3

CH3

20

15

9

+ Br

CH3 CH3 CH3 CH3

HO

Br

CH3

CH3 OPG OH OTBS 290

+ H3C

CHO 293

294

Aldol O

CO2tBu OH

CH3 CH3

CH3 OPG

CH3 CH3

+ OHC

OHC OBn O 291

296 Cl 295

292

Scheme 47 Retrosynthesis of (
)-callystatin A (287) [132]

O

CO2tBu dried baker's yeast, RT O XAD-7/H2O, 50%

O

CO2tBu OH

OiPr Steps

O CHO 293

Cl 295

Cl 297

Scheme 48 Synthesis of chiral aldehyde 293 from 3,5-dioxohexanoate 297 [132]

N

1. LDA, THF, 0 oC, 5 h 2. MeI, -100 oC N

H3CO 298

N

85%, dr 97.5:2.5 2

300, NaH, THF, 0 oC, 85%

299

R1

OHC

86% OTBDPS

H3CO

OTBDPS

CH3

O3, CH2Cl2, -78 0C N

OTBDPS 296

CH3 Br

CH3

1. DIBAL-H, CH2Cl2, -78 oC OTBDPS 2. CBr , PPh CH CN, RT, 95% 4 3 3, CH3 301, R1= CO2Et

CH3 OTBDPS

CH3

294

OiPr steps

O H3C CH3 H 3C

CHO

O P(OR') 2

O EtO 300, R' = O-(MeO)C 6H4

288

Scheme 49 Synthesis of aldehyde 288 [132]

To synthesize the required allyl bromide fragment 294 for the synthesis of chiral aldehyde 288, α-methylation of SAMP hydrazone of O-protected 4-hydroxy-butanal 298 was carried out to furnish 299 with the required configuration (R) at the newly created stereogenic center (Scheme 49). Oxidative removal of the auxiliary resulted

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products CH3 N

N

OCH3

1. LDA, THF, 0 oC 2. MeI, -100 oC, 72% 3. O3, CH2Cl2, -78 oC

291

CH3 CH3

OHC 292

302 H 3C

CH3 N

N OCH3

1. LDA, Et2O, 0 oC 2. BOMCl, -100 oC, 72% 3. O3, CH2Cl2, -78 oC

CH3 CH3 BnO 291 O

303

CH3

OHC

CH3 CH3 CH3

1. Sn(OTf)2, Et3N, CH2Cl2, -78 oC

CH3

BnO

2. 291, -78 oC, 87% (dr 98.5:1.5)

O

292

CH3 CH3 CH3

o

1. TiCl4, EtN(iPr)2, CH2Cl2, -78 C

CH3 OHC

CH3

BnO

CH3

2. 291, -78 oC, 96% (dr 97:3) O

305

OH 306

CH3 CH3 CH3 CH3

CH3 CH3 CH3 CH3 304 or 306

CH3 OH 304

CH3 or Br

Br OH OTBS 289

CH3 OH OTBS 307

Scheme 50 Synthesis of key intermediates 289, 291, and 292 [132]

in the formation of enantiopure aldehyde 296. The aldehyde 296 was then subjected to Z-selective HWE olefination followed by DIBAL-H reduction, and subsequent treatment with CBr4/PPh3 afforded the allyl bromide fragment 294. This allyl bromide fragment 294 was converted to aldehyde 288 in a few synthetic steps. The construction of polypropionate fragments required for the synthesis of callystatin A is depicted in Scheme 50. Asymmetric alkylation of compound 303, with BOMCl and subsequent removal of auxiliary, resulted in the formation of chiral carbonyl precursor 291 in dr 98:2. Similarly, treatment of butanal-RAMP and butanal-SAMP hydrazones (302/ent-302) with iodomethane and subsequent cleavage of auxiliary led to the formation of (S) and (R)-2-methyl butanal 292 and 305, respectively, in good yields (Scheme 50). Further, Sn(OTf)2- and Ti(IV)-mediated aldol reaction of substrate 291 with aldehydes 292 and 305 furnished the adducts 304 and its epimer 306, respectively. The aldol adducts 304 and 306 were subjected to a series of synthetic transformations to arrive at the required allyl bromide fragment 289 and 307, respectively (Scheme 50). The allyl bromide fragment 289 and the chiral intermediate 288 were then assembled by Wittig olefination, followed by PCC oxidation and finally, deprotection of TBS ether to arrive at the target (
)-callystatin A (287) (Scheme 51). They also synthesized its analogue, (
)-20-epi-callystatin A by making use of the key intermediate 307.

292

A. Srivastava et al. O

OiPr CH3 CH3 CH3 CH3 Br

CH3 OH

289

OTBS

Steps

O

O

+ CH3

CH3 H3C

CHO

288

CH3 CH3 CH3 CH3

H3C

CH3 (-)-Callystatin A (287) O

OH

Scheme 51 Synthesis of (
)-callystatin A (287) [132]

4 Sulfur-Based Chiral Auxiliaries Among the sulfur-based auxiliaries, the extensive applicability and efficiency of Oppolzer’s camphorsultam are well exemplified in a variety of asymmetric transformations including allylation, 1,3-dipolar cycloaddition, Diels-Alder, aldol, and ene reactions. Moreover, scope and significance of camphorsultam as chiral auxiliaries in organic synthesis are well documented. These auxiliary-controlled reactions have been widely employed for the construction of synthetic intermediates with desired stereocenters that are employed in the total synthesis of natural targets. Notably, sulfur variant of oxazolidinone like thiazolidinethione is found to be an ideal auxiliary in aldol reactions and is illustrated under oxazolidinone-based chiral auxiliaries of this chapter.

4.1

(
)-Manzacidin B

Marine natural products manzacidins A, B, and C were isolated from Okinawan sponge Hymeniacidon [138]. Ohfune et al. reported the total synthesis of (
)manzacidin B (308) by Cu-catalyzed asymmetric aldol reaction using Oppolzer’s camphorsultam 310 [139]. Retrosynthetic analysis of marine natural product reveals that trans-oxazoline (4R,5R) 309 is the key intermediate which could be derived from the aldol reaction of (1R)-camphorsultam derivative 310 with aldehyde 311 (Scheme 52). The aldol reaction of chiral aldehyde 311, derived from α-methylserine, with (1R)-camphorsultam 310 resulted in a double asymmetric induction leading to a mixture of diastereomeric adducts (dr 13:1), 309a and 309b, respectively (Scheme 53). Intriguingly, the same aldol reaction using (S)-oxazolidinone as chiral auxiliary resulted in an equimolar mixture of trans-oxazolines [139]. In the case of camphorsultam, formation of Z-enolate is more favored due to the steric hindrance exerted by isocyanide and sulfone group, and hence, the enolate readily undergoes reface attack with aldehyde. Removal of camphorsultam group followed by acid hydrolysis provided the desired amino acid derivative 313 in good yield. Following the synthetic sequence reported by Ohfune and co-workers, the synthesis

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

293 H 3C

H3C

CH3

CH3

Br

O HN

N

H 3C

H OH

O

N H O

H 3C RO

CO2H

CN

NHBoc O N O

SO2

N

H 3C RO

309

(-)-Manzacidin B (308)

N SO2 + 310 NHBoc CHO

311

Scheme 52 Retrosynthetic analysis of (
)-manzacidin B (308) [139]

H3C NHBoc RO

+ CHO CN CH3

O

H3C

CH3 Cu(t-butSal)2 (5 mol%) Et3N (5 mol%), DCE, rt

NHBoc O RO

N

SO2 311, R= TBS/ MOM 310, (1R)-sultam

H3C

+ N

N

O

H3C

CH3

NHBoc O RO

SO2

H3C

309a

N N

O

R= TBS, 13:1, 59% R= MOM, 13:1, 84% AcOH, THF, H2O OHCHN (3:1:1) 309a rt, 84%

309b

O Br

HO NHBoc H3C 311

NH2 NH2 HO H3C

SO2

309b

O

N H

6N HCl

1. 1N LiOH 2. 6N HCl

CH3

3

ste

ps

HN

N

H3C

H OH

O O

CO2H

(-)-Manzacidin B (308)

CO2H OH 313

Scheme 53 Total synthesis of (
)-manzacidin B (308) [139]

of (
)-manzacidin B (308) was achieved in few steps from the key intermediate 313 [140].

4.2

(+)-Bakuchiol

Bakuchiol is a meroterpene isolated from the herb plant Psoralea corylifolia [141]. Tadano and co-workers reported the asymmetric synthesis of (+)-bakuchiol using chiral auxiliary-controlled asymmetric Claisen rearrangement (Scheme 54) [142]. The Michael reaction of geraniol with N-propioloyl camphorsultam 314 afforded the adduct 315, which on heating with butylated hydroxytoluene (BHT) at 140 C afforded the Claisen rearranged products 316a and 316b, respectively, as a mixture of diastereomers (dr 9:1) in good yield. The chiral auxiliary of the major isomer 316a was removed by hydrolysis under basic conditions with simultaneous

294

H3 C

A. Srivastava et al.

H3C

CH3

CH3

N S O2

N

CH2Cl2, 77% O

S O2

O O H3C

S O2 O H3C

H3C H3C

CH3

p-MeOC6H4MgBr

317

Et2O 55% for 2 steps

CHO N

3 CH3 +

2

S O2 O H3C

3 CH3

H3C 316b, 8% (2S,3R)

H3CO

H3CO CH3

KOH

2

H3C 316a, 72% (2R,3S)

CH3 315

OHC THF/H2O (1:1)

H3 C

N

BHT toluene 140 oC

H3C

314

316a

CH3

H3C

CHO

n-Bu3P geraniol

OH H3C

CH3

H3C 318

POCl3 pyridine reflux, 90%

CH3 H3C H3C 319

HO

MeMgI 180 oC, 91%

CH3 H3C H3C (+)-Bakuchiol (320)

Scheme 54 Total synthesis of (+)-bakuchiol (320) [142]

decarboxylation which provided the desired enantiomerically pure aldehyde 317 in good yield. The aldehyde 317 was reacted with Grignard reagent, and the resultant alcohol 318 was dehydrated with POCl3 and pyridine. Finally, methyl ether cleavage of anisole derivative 319 was achieved using MeMgI at high temperature to give the desired (+)-bakuchiol (320) in good yield.

5 Phosphorous-Based Chiral Auxiliaries Applications of cyclic phosphonamide-based ligands as chiral auxiliaries in the asymmetric synthesis of some selected natural products are discussed in this part.

5.1

Methyl Jasmonate

Hailes and co-workers reported the synthesis of methyl dihydrojasmonates (321 and 322) and methyl jasmonates (323 and 324) (Fig. 10) using 2propenylphosphonamide as chiral auxiliary in asymmetric Michael addition reaction [143]. The Michael addition reaction of chiral phosphonamide 325 with 2-pentyl-2cyclopenten-1-one 326 resulted in the formation of desired β-substituted adduct 327a in good yield (dr 19:1) (Scheme 55). Oxidative cleavage of phosphonamide 327a afforded the (
)-methyl dihydrojasmonate 321 with good enantioselectivity (Scheme 55).

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products O

O

O

O

CH3

CH3

CH3

CH3

CO2CH3

CO2CH3

CO2CH3

295

(-) and (+) methyl dihydrojasmonates (321 and 322)

CO2CH3

(-) and (+) methyl jasmonates (323 and 324)

Fig. 10 Structure of methyl dihydrojasmonates and methyl jasmonates [143]

Ph H 3C

O O N P CH3 325

1. n-BuLi, THF, -78 oC 2. O CH3 326

H 3C

H 3C O

Ph H 3C

O O P N CH3 327a, major

O Ph

O O P N CH3 327b, minor

H 3C

O3, CH2Cl2 2.5 M NaOH/ MeOH O CH3 CO2CH3 (-)-methyl dihydrojasmonate (321) ee= 91%

Scheme 55 Stereoselective synthesis of (
)-methyl dihydrojasmonate (321) [143]

H3C

H3C

1. n-BuLi, THF, -78 oC 2. O Ph H3C

O O N P CH3 325

328

CH3

O Ph H3C

O Ph

O

O P N CH3 329a, major

H3C

O

O P N CH3 329b, minor

1. O3, CH2Cl2 2.5 M NaOH/ MeOH 2. H2, Lindlar Catalyst

O CH3 CO2CH3 (-)-methyl jasmonate (323) ee= 90%

Scheme 56 Asymmetric synthesis of (
)-methyl jasmonate (323) [143]

Similarly, 1,4-addition of chiral phosphonamide 325 with compound 328 furnished adduct 329a with good selectivity (Scheme 56). The cleavage of phosphonamide template of 329a followed by reduction using Lindlar’s catalyst provided the desired (
)-methyl jasmonate 323 in good yield (Scheme 56).

296

A. Srivastava et al.

5.2

(
)-Anthoplalone

Cytotoxic agent, (
)-anthoplalone, was isolated from Okinawan actinian Anthopleura pacifica [144]. Owing to its antitumor activity, several syntheses have been reported. Cantin and co-workers developed a novel synthetic route using bicyclic chloroallyl phosphonamide 335 as a chiral auxiliary [145]. They envisioned that the synthesis of (
)-anthoplalone (330) could be accomplished using Julia coupling reaction of sulfone 331 with ketone 332 (Scheme 57). The cyclopropane derivative 334 could be prepared using asymmetric 1,4-addition of chloroallyl derivative 335 to t-butyl 3,3-dimethyl acrylate (336). Addition of tert-butyl 3,3-dimethyl acrylate 336 to anion of chloroallyl phosphonamide 335 furnished substituted cyclopropane 334 in good yield with good diastereoselectivity (Scheme 58). Removal of chiral auxiliary followed by NaBH4 reduction led to alcohol 333. Further coupling reaction of substituted CH3 H3C CH3

O H3C

SO2Ar +

H3C

O

CO2t-Bu

H3C

332

331

(-)-Anthoplalone (330)

CH3 H3C CH3 N O P CO2t-Bu N 334 CH3

H3C CH3 CO2t-Bu

HO

H3C CH3

O

RO OR

333

CH3 N O P N 335 CH3

t-BuO2C Cl + H3C CH3 336

Scheme 57 Retrosynthetic analysis of (
)-anthoplalone (330) [145]

Me N O P N Me 335

CO2t-Bu

Cl + H 3C

336

CH3

Me H3C CH3 N O O3, NaBH4 P CO2t-Bu 83% N Me 334

O

H3C CH3

O CO2t-Bu + H 3C

H 3C

SmI2, THF 84%

O

CO2t-Bu

HO 333

46%

1. DMSO, (COCl) 2, Et3N CH2Cl2, Ph3P=CHC(O)Me 2. H2, Pd(OH) 2/C 82%, 2 steps

O

HO CH3

H3C CH3 CO2t-Bu

SO2Im 339

LiAlH4, THF 87%

CH3 H3C CH3

H 3C

Ot-Bu Cl 337

N

H 3C 340, 2:1 E/Z not separable mixture

O

H3C CH3O

CH3 O nBuLi, THF, -78 0C N H 3C 98%

CH3 H3C CH3 CO2t-Bu

O

E-isomer Amberlite (IR-120, H+) 79%

H3C CH3

O O S

O 338

332

Me N O P N Me

n-BuLi, Et2O, -78 oC

O H 3C

OH

75%

Scheme 58 Total synthesis of (
)-anthoplalone (330) [145]

CH3 H3C CH3 OH 341

O

TPAP, NMO

342

O

CH3 H3C CH3

H 3C

O (-)-Anthoplalone (330)

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

297

cyclopropyl ketone 332 derived from alcohol 333 and sulfone 338 provided the desired adduct 339 in excellent yield. The reaction of sulfone 339 with SmI2 furnished an inseparable mixture of E/Z-alkenes 340, which was further reduced to alcohol 341. The E-isomer was separated, and subsequent deprotection of ketal afforded the hydroxyl-ketone 342. Finally, the TPAP oxidation of terminal alcohol furnished the desired (
)-Anthoplalone (330) in good yield (Scheme 58).

5.3

(
)-Berkelic Acid

Snider et al. reported the total synthesis of (
)-berkelic acid employing the phosphorous-based chiral auxiliaries to control the stereoselectivity at C18 and C19 positions [146]. The retrosynthetic analysis of berkelic acid (343), leading to ketal aldehyde 344 and benzoic acid derivative 345, is presented in Scheme 59. Synthesis of key intermediate ketal aldehyde 351 is outlined in Scheme 60 [147]. Conjugate addition of anion of chiral phosphonamide 347 to 2-butenolide followed by trapping of the enolate with methyl iodide afforded an adduct 348 in good yield with good selectivity. Deprotection of chiral auxiliary and subsequent NaBH4 reduction led to the alcohol, which was protected as TBDPS ether to give silylether derivative 349. Treatment of 349 with lithium enolate of tert-butyl acetate afforded the ketal-ester 350, which on DIBAL-H reduction afforded the desired ketal O H3CO2C H3 C

O

19

22

18

C2 H5

H3 C

O

CO2H OH

O

OCH3 CHO

17 15

H

R

HO

CO2H O

HO

+

CH3

O

CO2H OH

O

HO

344

C5H11 Pulvilloric acid (346)

C5H11

C5H11 (-)-Berkelic acid (343)

345

Scheme 59 Retrosynthesis of (
)-berkelic acid (343) [146]

CH3 N O P N CH3 347

n-BuLi, -100 oC 2-butenolide, MeI 73%

1. t-BuOAc, LiHMDS, -78 oC 2. Dowex 50WX8-400-H+, MeOH 78%

CH3 N O P N CH3

O

CH3

O

CH3

OCH3 CO2t-Bu

O

TBDPSO CH3

349

348

O TBDPSO 350

1. O3, MeOH/CH2Cl2 then NaBH4 O 2. TBDPSCl, imidazole 52%

O DIBAL-H, Et2O -78 oC, 43%

OCH3

TBDPSO

CHO CH3 351, Ketal aldehyde Steps Berkelic acid (343)

Scheme 60 Synthesis of ketal aldehyde 351 via asymmetric Michael addition [147]

298

A. Srivastava et al.

aldehyde 351. The key intermediate 351 was further converted to the desired berkelic acid (343) in few steps [146].

5.4

(+)-Ambruticin S

An antifungal agent, ambruticin S, was isolated from myxobacterium Polyangium cellulosum and [148]. Hanessian et al. reported the enantioselective synthesis of (+)-ambruticin S, having ten stereogenic centers, by employing asymmetric cyclopropanation using chiral phosphonamide as a key strategy [149]. The reported retrosynthesis of (+)-ambruticin S is represented in Scheme 61. The synthesis of (+)-ambruticin S (352) was envisioned from three subunits 353, 354, and 355. Fragment 354 in turn could be realized by the stereoselective cyclopropanation of phosphonamide 335 with (R)-Roche ester 356, whereas the fragment 355 could be synthesized from (R)-glycidol benzyl ether 357 (Scheme 61). The enantioselective synthesis of cyclopropane subunit 358 was accomplished by the deprotonation of trans-chloro-allylphosphonamide 335 with n-BuLi, followed by the treatment with tert-butyl crotonate which afforded the cyclopropane adduct with high degree of stereoselectivity (Scheme 62). Removal of phosphonamide CH3 H HO2C

O

H

CH3 CH3 H

O

OH

CH3

C

B

A

H

CH3

(+)-Ambruticin S (352)

OH

O

HO

H3C CH3 N O P

CH3

OCH3 +

HO

OH OH 353

354

N

CH3 Cl + HO

OCH3 356 O

CH3 335

CH3 CH3

CH3

TIPS

CH3 N O P N

OH

BnO +

OH 355

O OBn 357

Scheme 61 Retrosynthetic analysis of (+)-ambruticin S (352) [149]

CH3 N O P N CH3 335

CO2t-Bu H 3C n-BuLi, THF, -78 oC 89%, dr 99:1 Cl

CH3 N O P N CH3 358

H

O3, CH2Cl2, -78 oC

CH3

then DMS, 70% CO2t-Bu

Scheme 62 Synthesis of cyclopropane fragment 359 [149]

CH3

O 359

CO2t-Bu

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

299

auxiliary via ozonolysis provided the desired cyclopropyl aldehyde 359 in good yield. The complete synthesis of antifungal natural product (+)-ambruticin (352) is depicted in Scheme 63. The reaction of 3-tert-butyldimethylsilyloxy-2-methylpropyl iodide 360 with 1,3-dimethyl-2-oxo-1,3,2-diazaphospholidine 361 afforded the phosphonamide 362 in excellent yield. The reaction of ketone 363 with the anion of phosphonamide 362 provided the desired adduct as a 6:1 mixture of E/Z isomers, and conventional removal of TBS protection led to alcohol 364 in good yield. Next, the alcohol was converted to iodide, and subsequent displacement of iodide with phosphorus acid diamide 361 furnished the phosphonamide 365. Olefination of cyclopropanealdehyde 359 with anion of phosphonamide 365 afforded the key intermediate 366 with excellent selectivity (E/Z > 25:1). Following a sequence of reactions, Hanessian and co-workers accomplished the synthesis of (+)-ambruticin (352) from the key intermediate 366 with high degree of stereoselectivity (Scheme 63) [149].

CH3 I

OTBS

H3C N P N CH3 H O 361 NaH, DMF THF, 0 oC 95%

360

1. I2, PPh3, imidazole CH2Cl2, 0 oC, 97%

N 2. LiHMDS, THF, 361 H C 3

N H3C

CH3 N CH3 O P OTBS

CH3

DIBAL-H THF, 0 oC 96%

CH3 R

H

HO

O

CH3

OBn 2. BF3.OEt2, Et3SiH CH3CN, CH2Cl2, -40 oC

HO

O

OH OH

O

CH3 R

372, R=CH3,

359

CH3 R

O

H

O

CH3 CH3

CH3

364, R=CH3,

CH3

CH3 R

H

O

CH3

H CH3

CH3 R

H

O

H CH3 CH3

369, R=CH3, 82%, 2 steps

CH3 1. LiDBB, THF, -78 oC, 89% 2. Red-Al, Et2O, 0 oC, 80% E/Z> 10:1

1. N-(CHO)Bt, i-Pr2NEt, DMAP, CH2Cl2, 85% 2. Pt, O2, H2O, i-PrOH, Me2CO 50 oC, 91%

Scheme 63 Synthesis of (+)-ambruticin (352) [149]

H

H

371, R=CH3, 98% borsm

H

O

CH3 366, R=CH3, 64%, E/Z> 25:1

CO2t-Bu

CH3

H

H

t-BuO2C

H

H

OBn

H

CH3 R HO

CH3 2. K CO , MeOH 2 3 O O CH3 OCH3 P H3C OCH3 N2 368

OBn

CH3 H

O

CH3

363 CH3 n-BuLi, THF, -78 oC

CH3

CH3

OBn BnO

H

1. DMSO, (COCl)2, NEt3 CH2Cl2, -78 oC

1. n-BuLi, THF, -78 oC BnO O O

370

O

CH3

H

367, R=CH3,

H

H

n-BuLi, THF

CH3

365, R=CH3, 76%

O

2. TBAF, THF, 58% 2 steps, E/Z= 6:1

362

CH3 N CH3 R O H H P O

1. H3C

(+)- Ambruticin (352)

300

A. Srivastava et al.

5.5

Estrone

Estrone, a major mammalian estrogen, is biosynthesized from cholesterol [150]. Owing to the wide-ranging biological functions, several syntheses of estrone have been reported. Linclau and co-workers reported the divergent strategy for the synthesis of D-ring template using phosphonamide as chiral auxiliary [151]. They envisioned that estrone (373) could be assembled by ring-closing metathesis (RCM) and followed by Heck coupling reaction of the chiral intermediate 374 (Scheme 64). Hence, the key intermediate 374 could be obtained from chiral phosphonamide 376, 2-methyl-2-cyclopentenone 375, and allyl bromide. The stereoselective synthesis of estrone (373) is shown in Scheme 65. Treatment of dibromo derivative 378 with allenyl magnesium bromide and subsequent CH3 O

C H H

A HO

D H

RCM

N

Heck

H 3C

CH3 O

CH3 N O P

13 14 8

Br

Br N

+

H

+

CH3 N O P

H 3C

O

OCH 3 Br

H 3C

B Estrone (373)

CH3

374

MeO

377

MeO

376

375

Scheme 64 Retrosynthetic route for estrone (373) [151]

Br 1. CH2=C=CHMgBr Et2O/THF, 94%

NBS H3CO

CH3

70%

2. LDA, THF Br then CH2O, 83%

H3CO

378

377

CH3 N P OEt N

Cl

381 CH3

Br

N

NaI, toluene reflux, 85%

H3CO

CH3 N O P

2. Cl3C(C=O)CCl3 PPh3, CH2Cl2, 94%

H3CO

379

BuLi, THF, -78 oC

Br

H3C

Br

OH 1. Zn, EtOH BrCH2CH2Br reflux, 98%

N

O

then

H3C

CH3 O

CH3 N O P

H

Br

H3C

380

H3CO

375

376

Br

then

H3CO

374, 52-59%

CH3 O 13 14

Hoveyda-Grubbs II (35 mol%) toluene, 58%

Br

8

H

CH3 O 9

H

H H3CO

H

2

CH3 O +

H

9

H

H H3CO

385a

H

384 2 mol%

98%

H

(oTol)2 P PdOAc 383 H3CO

382

H3CO

Pd/C cyclohexadiene EtOH

CH3 O

Bu4NOAc, CH3CN/DMF/H2O (1:1:0.2), 115 oC

(3:7)

Scheme 65 Total synthesis of estrone (373) [151]

385b

CH3 O H

AlCl3, NaI H

compound 385b 92%

H

H

HO Estrone (373)

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

301

one-carbon homologation afforded the propargyl alcohol derivative 379. The propargyl alcohol derivative 379 was then transformed to allyl chloride derivative 380, and subsequent reaction with phospholane 381 led to the formation of phosphonamide 376 in excellent yield. Diastereoselective Michael addition of phosphonamide 376 with 2-methyl-2-cyclopentenone 375 followed by the treatment with allyl bromide furnished the desired adduct 374. The resultant Michael adduct 374 on RCM with Hoveyda-Grubbs II catalyst provided the desired transhydrindene derivative 382 in good yield. The subsequent Heck B-ring closure was achieved using Tietze protocol [152] with isomerization of double bond. Finally, hydrogenation followed by deprotection of O-methyl ether led to the formation of desired estrone (373) in very good yield.

5.6

Nudiflosides A and D

Cyclopentanoid-based monoterpene secoiridoid glucosides have been isolated from the plant Jasminum nudiflorum by Tanahashi et al. [153]. Asymmetric Michael addition of phosphonamide anion to cyclopentenone has been considered a ready access for the stereoselective synthesis of natural products containing cyclopentane subunit [147, 154]. Hanessian et al. reported the stereoselective synthesis of natural product nudiflosides A (386) and D (387) by using chiral phosphoramide-mediated asymmetric Michael addition as a key step [155]. The retrosynthetic route for the total synthesis is represented in the Scheme 66. The complete synthesis of nudiflosides A (386) and D (387) was started from the O-protected 2-(hydroxymethyl) cyclopentenone 391 (Scheme 67). The ketal 391 on the treatment with n-BuLi and benzyloxymethyl chloride (BOMCl) in THF afforded the benzyl ether 390 in good yield. Highly selective 1,4-addition of lithium anion of crotyl phosphonamide 392 to cyclopentenone 390 provided the desired adduct 393 in 72% yield. Ozonolysis of Michael adduct 393, reduction of corresponding aldehyde to alcohol, and finally TBDPS protection of alcohol afforded the compound 394. The resultant compound was oxidized by PCC to ketone 395 in good CO2CH3 O

O GlcO

O

O H R= H3C

CO2CH3

HO

CO2H

(AcO)4GlcO

CH3 H

OR

CH3 R= H, Nudifloside D (387)

BnO

CO2CH3

O

CH3

CH3

+ HO

CH3

H OR CH3 389

388

O BnO

O

OGlc Nudifloside A (386) 390

Scheme 66 Retrosynthetic analysis of nudiflosides A (386) and D (387) [155]

302

A. Srivastava et al.

1. n-BuLi, THF, -78 oC O 2. BnOCH Cl 2

O Br

CH3 N O P N 392 CH3

OBn O

94%, 2 steps

3. TBDPSCl, DMAP, Et3N CH2Cl2, 86%

OBn O

PCC, CH2Cl2 94%

R 1O

R 1O

H

OBn O

H2O2, MeOH aq KOH

CH3 396, R1=TBDPS

74%

H

CH3 397, R1=TBDPS OH

OBn

CH3

1. BCl3, CH2Cl2, 73% R 1O

H

OH

CH3 399, R1=TBDPS

O

2. [Ir(COD)Py(PCy3)] H2, CH2Cl2, 76%

O

CH3

CH3 HO

H OH CH3 400, R1= TBDPS

N O P

393

H CH3

or LiHMDS, THF, PhSeBr -78 oC, then H2O2 71% borsm

R 1O

Nysted's reagent THF, TiCl4 74%

H OH CH3 398, R1=TBDPS CO2CH3 O CO2H (AcO)4GlcO 388 CH3

1. 2,4,6-trichlorobenzoyl chloride, Et3N CH2Cl2 then DMAP, 65 to 95% 2. Bu4NF, THF, 74 to 85% 3. Et2NH, MeOH, 54 to 56%

O CO2CH3 H

CO2CH3 O

GlcO

R1 O

OBn O

LDA, THF, TMSCl, Pd(OAc)2 75% borsm

OBn O

Na[PhSeB(OEt)3] EtOH O

R 1O

H

H

CH3 395, R1=TBDPS

CH3 394, R1=TBDPS

80%, 9:1

R 1O

N H 3C

OBn O

OBn OH

1. O3, CH2Cl2, -78 oC 2. NaBH4, 0 oC (96%, 2 steps)

CH3

n-BuLi, THF, -78 oC 72%

390

391

CH3

H CH3

OR

R= H 3C

O

OGlc Nudifloside A (386) R= H, Nudifloside D (387)

Scheme 67 Total synthesis of nudiflosides A (386) and D (387) [155]

yield. The enone 396 was achieved by either treatment of ketone 395 with LDA/TMSCl followed by addition of Pd(OAc)2 or formation of α-phenylseleno ketone followed by H2O2-mediated oxidative elimination. The resultant enone 396 was transformed into epoxide 397 using H2O2/aq. KOH in 80% yield. The regioselective reductive ring opening of epoxide 397 followed by transformation of keto to exomethylene unit has been performed with Nysted reagent to give the compound 399 in good yield. Subsequent debenzylation using BCl3 in CH2Cl2 followed by Crabtree catalystmediated reduction provided the compound 400. On conventional removal of TBDPS, protection afforded the triol, which on esterification with oleoside monomethyl ester peracetate according to Yamaguchi procedure to give the ester in good yield. Moreover, the sequential removal of TBDPS and acetate resulted in the natural products nudiflosides A (386) and D (387) (Scheme 67).

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

R1

N CH3 O N H

n-BuLi Me2C=CHCOCl

R1

N CH3 O N

O

LDA, -78 oC Me2C=CHCH2Br

CH3

CH3 LiAlH4, 0 oC

HO

CH3

H3C (-)-Lavandulol (404)

R1

N CH3 O N

R2

H3C 402, R1= CH3

401, imidazolidine-2-one 4R,5S, R1= CH3

303

H H

O

H H3C 403, R1= CH3, R2= CH2HC=CMe2

E+ favored

R1 N

N CH3 O O Li

402a R

Scheme 68 Asymmetric synthesis of (
)-lavandulol (404) [156]

6 Imidazolidinone-Based Chiral Auxiliaries 6.1

(
)-Lavandulol

(
)-Lavandulol, a natural monoterpene alcohol, is present in several essential oils. Cardillo et al. developed a novel route for the synthesis of (
)- and (+)lavandulol via asymmetric alkylation using imidazolidine-2-one derivative as chiral auxiliary [156]. Reaction of lithium amide of 4R,5S-imidazolidine-2-one 401 with 3-methyl-2-butenoyl chloride afforded the acylated product 402. Stereoselective alkylation of enolate derived from 402 provided the compound 403 with high degree of selectivity, which on subsequent reductive cleavage of the chiral auxiliary with LAH afforded (
)-lavandulol (404) in good yield with 92% ee (Scheme 68). Moreover, synthesis of (+)-lavandulol was accomplished by following a similar sequence of reactions using 4S,5R-imidazolidine-2-one as chiral auxiliary. The diastereofacial selectivity of this alkylation reaction can be rationalized by invoking the transition state model 402a (Scheme 68). In this model, the α–face of the (Z )-enolate is completely blocked by the phenyl group which in turn controls the stereochemistry of the new stereogenic center.

7 Pyrimidinone-Based Chiral Auxiliaries 7.1

Oxyneolignan

Nair and co-workers reported the synthesis of novel pyrimidinone-based chiral auxiliary, (S)-4-isopropyl-1-phenyltetrahydropyrimidin-2(1H)-one, and its application in asymmetric aldol and alkylation reactions [157]. The synthetic usefulness of this chiral auxiliary was exemplified in the stereoselective

304

A. Srivastava et al. Xc

HO HO

HO

(S)

OCH3

(S)

O

H3CO

HO Oxyneolignan (405) H +

PO

OP

H3CO

O 406, Xc= chiral auxiliary

O

O N

N

OCH3

Ph

HO

(S)

R OCH3

O

H3CO

R

OP

OP

407

CO2H

OCH3 O

H3CO

OCH3 O

H3CO

H3CO

O

O

(R) (S)

CO2H

Syringic acid (409)

408, R=CH3

Scheme 69 Retrosynthesis of oxyneolignan (405) [157] O OH H3CO

1. SOCl2, MeOH 0 oC to reflux

OCH3

O

2. Br

OBn

O H3CO

OCH3

O

OH

O

Pd/C, H2, MeOH

H3CO

OCH3

98%

410

CO2H OBn Syringic acid (409) K2CO3, acetone, reflux

CO2CH3

412 CO2CH3

411, 84%, 2 steps

OH O 1. oxalyl chloride cat. DMF, DCM, 0 oC

OCH3 O

O

2. HN H3C

(S)

N

O N

R OCH3

Ph H3CO2C

H3CO

O N

Ph

(S)

H3CO

R 408, R=CH3, 75%, 2 steps

413

TiCl4, DIPEA, DCM 0 oC to -78 oC

BnO

CHO

O N

N

Ph

(S)

O R OCH3

407

H3CO2C 406, R=CH3, 68% OH OH

OH OH

80%

(R)

R

BnO H3CO

CH3 n-BuLi, THF, -78 oC NaBH4 THF:H2O (9:1)

(S)

H3CO BnO

(S)

(S)

OCH3

O

1. Pd/C, H2, MeOH 2. LiOH, THF:H2O (3:1) 74%, 2 steps

H3CO

414

CO2CH3

H3CO HO

(S)

(S)

OCH3

O H3CO CO2H Oxyneolignan (405)

Scheme 70 Total synthesis of oxyneolignan (405) [157]

synthesis of oxyneolignan, (+)-(7S,8S)-4-hydroxy-3,30 ,50 -trimethoxy-80 ,90 -dinor8,40 -oxyneoligna-7,9-diol-70 -oic acid (405) [157]. The retrosynthetic analysis for the synthesis of natural product oxyneolignan (405) is outlined in Scheme 69. The key intermediate 406 was envisaged by the asymmetric aldol reaction of 4-(benzyloxy)-3-methoxybenzaldehyde (407) with acylated derivative of (S)-4isopropyl-1-phenyltetrahydropyrimidin-2(1H)-one 408. The required acyl derivative 408 could be synthesized from syringic acid (409) (Scheme 69). The asymmetric synthesis of oxyneolignan (405) is represented in Scheme 70. Esterification of syringic acid (409) and subsequent reaction with K2CO3 and benzyl bromoacetate 410 provided the adduct 411, which on catalytic hydrogenation furnished the acid 412. The acid chloride derived from 412 was coupled with (S)-4-isopropyl-1-phenyltetrahydropyrimidin-2(1H)-one 413 to furnish acylated

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

305

derivative 408 in good yield. Treatment of 408 with TiCl4 and DIPEA resulted in the generation of Ti-(Z)-enolate which on subsequent reaction with 4-(benzyloxy)-3methoxybenzaldehyde (407) afforded the Evans-syn-aldol product 406 in good yield with high degree of diastereoselectivity (dr 9:1). The reductive cleavage of chiral auxiliary with NaBH4, deprotection of benzyl ether under catalytic hydrogenation conditions, and subsequent hydrolysis of methyl ester furnished the desired natural product oxyneolignan (405) in good yield (Scheme 70).

8 Oxazolinyl Ketone as Chiral Auxiliaries 8.1

(
)-Rhazinilam

The alkaloid rhazinilam, isolated from Rhazya stricta and, is known to exhibit antitumor activity [158]. Sames and co-workers reported the total synthesis of (
)-rhazinilam (415) using asymmetric C-H activation as a key step [159] (Scheme 71). The reaction of in situ generated imine 419 and o-nitrocinnamyl bromide 418 afforded an iminium ion adduct 420, which on subsequent reaction with silver carbonate furnished the bicyclic pyrrole intermediate 421 in good yield (Scheme 72). The reactive ortho-position of pyrrole was protected by installing the methyl carboxylate group on the pyrrole derivative 421 followed by reduction of nitro group which afforded the aniline derivative 417 in good yield. The Schiff base 423, derived from chiral ligand 422 and aniline derivative 417, on reaction with [Me2Pt (μ-SMe)2]2 afforded the platinum complex 424. Exposure of oxazoline-Schiff base complex 424 to TfOH resulted in a mixture of diastereomers 425 and 426. The major diastereomeric complex 425 was separated and subjected to thermolysis to furnish the desired complex 427 through an intramolecular C-H activation mediated by the Pt-chiral Schiff base complex. Decomplexation and subsequent removal of Schiff base were achieved by the reaction of aq. KCN and hydroxyl amine, respectively.

N

H3CO

CH3

O N

Carbonylation N O H (-)-Rhazinilam (415)

H3CO CH3 Asymmetric C-H bond activation

NH2 416 Br N

Pyrrole annulation + NO2

CH3 CH3 418

419

Scheme 71 Retrosynthetic analysis of (
)-rhazinilam (415) [159]

O N

NH2

CH3 417

CH3

306

A. Srivastava et al. Br N

NO2 +

Br

CH3 CH3

NO2 CH3 CH3

418

toluene, reflux 70%

H 3C H 3C

420

H3CO

1. CCl3COCl 2. NaOMe, MeOH 3. H2, Pd/C

H2 N

H3CO

Ph

N

O

Ph

H3CO

CH3

N

O

O 425, R=cyclohexyl

H3CO

CH3

1. KCN

CF3CH2OH, 70 C

Ph CH3

N

CH3

2. NH2OH

427, R=cyclohexyl

1. Pd/C, dppb, HCO2H DME, CO, 150 oC, 58% 2. NaOH (aq), MeOH then HCl (aq), 50 oC, 90%

416

N Pt H TfO N R O

426, R=cyclohexyl

O

CH3

o

N

NH2

O N

O

H3CO

CH N Pt CH3 3 TfO N R

Ph

TfO O

CH3

TfOH CH3

R CH2

O N

R

Pt

R

423, R=cyclohexyl

424, R=cyclohexyl

N

N

Ph O

N

O

CH3

N

417

H3CO

N H3 C Pt N H3 C

CH3

N

TsOH, toluene, 65%

45%

O

R

O 422, R=cyclohexyl

N

88%, 3 steps

[Me2Pt(µ-SMe2)]2

421

O

O

H3C H 3C

N

Ag2CO3

90%

419

Ph

O 2N

N

DMF, 100 oC

N

CH3

N O H (-)-Rhazinilam (415)

Scheme 72 Completion of the synthesis of (
)-rhazinilam (415) [159]

Intramolecular macrolactam formation in 416 was achieved in the presence of Pd/C using 1,4-bis(diphenylphosphino)butane (dppb), CO, and formic acid. Further deprotection of methyl ester provided the desired optically pure (
)-rhazinilam (415) in very good yield. In conclusion, in this chapter, we have tried to bring forth the importance of various chiral auxiliaries in a wide range of asymmetric reactions and particularly, for the synthesis of valuable intermediates that are used in the total synthesis of complex natural targets. This has been illustrated above by stereoselective routes to several natural products of biological or pharmaceutical importance. It is worth mentioning here that all of these routes to complex natural targets involve one or more type of chiral auxiliary in one or more of the steps of synthesis to induce

Heterocyclic Chiral Auxiliaries in Total Synthesis of Natural Products

307

desired chirality in the key intermediates that would subsequently lead to the required enantiomer of the target. When contemplating the versatility of chiral auxiliaries in stereoselective syntheses, Evans’ oxazolidinones and related sulfur analogues are most desirable owing to their ability to induce chirality with good to excellent selectivity during various asymmetric reactions, especially for aldol addition and alkylation of enolate among others. Amino acid-derived Enders’ SAMP/ RAMP and its sterically demanding analogues have also been much exploited in the stereoselective syntheses of various targets like (
)-neonepetalactone, dehydroiridodial, streptenol, callystatin as discussed above, and likewise many others (ramulosin, maritimol, etc.) [54]. The widespread usage of enantiomers of camphorsultams in stereoselective synthesis of natural targets like manzacidin and bakuchiol is credited to their easy availability. Also, the usefulness of chiral phosphonamides in the total synthesis of various bioactive compounds such as methyl jasmonate, estrone, and nudiflosides A and D has been illustrated.

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Top Heterocycl Chem (2020) 55: 311–312 https://doi.org/10.1007/7081_2020_37 # Springer Nature Switzerland AG 2020 Published online: 12 August 2020

Correction to: Carbohydrates as Stereodifferentiating Auxiliaries Horst Kunz and Alexander Stoye

Correction to: Chapter “Carbohydrates as Stereodifferentiating Auxiliaries” in: Horst Kunz and Alexander Stoye, Top Heterocycl Chem, DOI: 10.1007/7081_2020_7 The original version of this chapter unfortunately contained errors. The presentation of Scheme 13 was incorrect. The corrected Scheme 13 is given below.

O

O O O O

t BuOCl

NOH

O

O

O O O N O Cl

34

35

1.

O + N H2

–70 oC 2. H2O

O

36 -

Cl

ee > 96%

O O O O

O

Scheme 13 Glycosyl nitroso dienophiles in stereoselective hetero-Diels-Alder reactions [31]

The online version of the chapter can be found at DOI: 10.1007/7081_2017_7

312

H. Kunz and A. Stoye

The presentation of Scheme 44 was incorrect. The corrected Scheme 44 is given below. O PivO

R

OPiv O

SnCl4

NH2

PivO

PivO

HO P(OEt) 2 H

OPiv O

H

PivO

THF, 0 °C

O P OEt OEt

N PivO

PivO

(S)-112

101

R

for example: R = 4-Me-C6H4: yield 78% b S 91% b R 6.2% a S 2.0% a R 0.8% O PivO

Ph

OPiv O

PivO OPiv

HO P(OEt) 2 H

OPiv NH2

SnCl 4

O

OPiv

H N

PO(OEt)2

THF, –15 to 15 °C Ph (R)-112

110

94 %, a R 68% a S 13% b R 16% b S 3%

Scheme 44 Diastereoselective synthesis of α-aminophosphonic acid derivatives [91]

The presentation of Scheme 45 was incorrect. The corrected Scheme 45 is given below.

PivO OPiv O N R PivO PivO H 103

R1

OSiMe3

H

OSiMe3

113 ZnCl2 / THF

PivO OPiv R1 O H N PivO COOH PivO R 114

114a R = 3-Cl-Ph, R1 = Me, temp. –30 oC, time 48 h, yield 94%, d.r. > 95 : 5 : 0 : 0 114b R = n-pentyl, R1 = Ph, temp. –30 oC, time 96 h, yield 72%. d.r. = 94 : 6 : 0 : 0

Scheme 45 β-Amino acids with two new chiral centers through Mannich reaction of N-galactosyl imines 103 with bis-silyl ketene acetals 113 [93]

Top Heterocycl Chem (2020) 55: 313–314 https://doi.org/10.1007/7081_2020_38 # Springer Nature Switzerland AG 2020 Published online: 12 August 2020

Correction to: Oxazolidinones and Related Heterocycles as Chiral Auxiliaries/Evans and Post-Evans Auxiliaries Asmaa Kamal Mourad and Constantin Czekelius

Correction to: Chapter “Oxazolidinones and Related Heterocycles as Chiral Auxiliaries/Evans and Post-Evans Auxiliaries” in: Asmaa Kamal Mourad and Constantin Czekelius, Top Heterocycl Chem, DOI: 10.1007/7081_2020_36 The original version of this chapter unfortunately contained an error. A part of the presentation of Scheme 56 was missing. The corrected Scheme 56 is given below.

Scheme 56 Diastereoselective addition of cuprates to crotonyl-oxazolidinones

The online version of the chapter can be found at DOI: 10.1007/7081_2020_36

Top Heterocycl Chem (2020) 55: 315–316 https://doi.org/10.1007/7081_2020_39 # Springer Nature Switzerland AG 2020 Published online: 28 July 2020

Correction to: Pyrrolidines as Chiral Auxiliaries Wolfgang Maison

Correction to: Chapter “Pyrrolidines as Chiral Auxiliaries” in: Wolfgang Maison, Top Heterocycl Chem, DOI: 10.1007/7081_2019_34 The original version of this chapter unfortunately contained few mistakes. In page 162, first paragraph, in line 42, the cross-referred chapter titles were incorrect. The corrected chapter titles are given below. Next to other chiral auxiliaries highlighted in this book, such as amino acid auxiliaries [2] and carbohydrate auxiliaries (Chapter “Carbohydrates as Stereodifferentiating Auxiliaries”), terpene derived auxiliaries (Chapter “Synthesis and Utility of Hetero- and Non-heterocyclic Chiral Auxiliaries Derived from Terpenes: Camphor and Pinene”), oxazolidinones (Chapter “Oxazolidinones and Related Heterocycles as Chiral Auxiliaries/Evans and Post-Evans Auxiliaries”), and boron containing auxiliaries, they belong to the most powerful tools in diastereoselective synthesis.

The online version of the chapter can be found at DOI: 10.1007/7081_2019_34

Index

A Acivicin, 13 Actinidia polygama, 292 N-Acyloxazolidinethione, 263 Acyloxazolidinones, α,β-unsaturated, 140 Aldol reactions, 60, 76, 81, 97, 117, 128, 152, 171, 201–244, 260, 262 additions, 1, 144, 264 asymmetric, 261, 275 condensation, 49, 263 diastereoselective, 134 pyrrolidines, 171 Aldopyranoses, 2 Alkaloids, 2, 38, 41, 47, 56, 137, 144, 150, 268, 292, 311 α-Alkylation, pyrrolidine, 165 Alkynyl-oxazolidinones, 152 Allenamides, 183 Allenes, chiral, 189, 228 lithiated, 15 Allosamizoline, 270 Allyl addition, 73, 76–79, 88, 92, 98–101 Allyl carbamates, 124, 126 Allyl glycopyranosides, 22 Allyl glucosides, Simmons-Smith cyclopropanation, 23 Ambruticin, 304 Amino acids, 2, 24, 130, 145, 175, 188, 261 esters, 3, 61 3-Aminoalkyl-indole, 34 Aminomethyl-pyrrolidines, 162 α-Amino nitriles, 2 Aminophosphonic acids, 28 Aminosiloxydiene, 292 Anabasine, 38, 191, 268

Anguinomycins, 294 Anhydrosorbitol acrylate, 6 Anthoplalone, 302 Anthopleura pacifica, 302 Anthracene, 8 Apoptolidin A, 278 Apoptolidinone, 278 Arabinopyranosylamine, 27 Arabinosamine, 10 N-Arabinosyl dehydro-piperidinone, 38 cis-3-[N-(Aryl)benzenesulfonamido]borneol, 208 3-Aryl-oxazolidinones, 121 Asymmetric synthesis, 3, 68, 73, 148, 162, 200, 260 Awajanomycin, 103 Aza camphor, 200 lactams, 219 Azetidinones, 20 Aziridines, 34, 123, 270

B Bakuchiol, 299 Baulamycins, 272 Benzenesulfonamidoborneol, 208 Benzoazepines, 168 Benzomorphans, 46, 47, 59, 60 Benzyl-tetrahydroisoquinolines, 62 Berkelic acid, 303 Bestmann ylide [(triphenylphosphoranylidene) ketene], 244 Bicuculline, 265 Birch reductions, pyrrolidines, 184 Bis-silylketene acetals, 29

317

318 Bistramide A, 264 Bleomycin, 280 Boracycles, 76 Boron, 73 Boron-cyclopropanes, 82 Brasilinolide A, 282 Brefeldin A, 271 Bursehemin, 132 tert-Butyl-glycinol, 138

C Calcaripeptides, 275 Callyspongia truncata, 294 Callystatin, 294 Camphor, 99, 100, 138, 200, 248, 266 Camphor α-hydroxy enone, 203 Camphor-derived lactams, 200 Camphor homoallylic alcohol, 202 Camphor imine, 201 Camphor lactams, 219 Camphor methyl ketone enolates, 201 Camphor oxazaphospholidine, 269 Camphor oxazolidinones, 210 Camphorsultams, 260, 262, 266, 298, 313 CamTHP glycinamide, 207 Carbohydrates, auxiliaries, 2 organocatalysts, 2 Carbonyl allylation, 77, 80, 90 Castoreum, 51 Conhydrine, 187 Coniine, 36 Conjugate additions, 40, 64, 118, 128, 152, 173, 205, 210, 237, 244, 303 Convolutamydines, 137 Corlumine, 265 Coronamic acid, 22 Corytensine, 265 Cosmopolites sordidus, 293 N-Crotonoyl-oxazinone, 9 Cycloadditions, 2, 5, 79, 82, 85, 147, 181, 200, 216, 238, 253, 288, 298 [2+1], 22 [2+2], 19, 20, 183 [2+2+2], 229 [2+3], 216 [3+2], 79 [4+2], 84, 147, 233 Diels-Alder, 240 Pauson-Khand, 229 pyrrolidine, 181 Cyclobutanones, 21, 150 Cyclohexene-3-carboxylate, 7 Cyclohexenones, 133, 185, 186, 292 Cyclopentadiene, 6

Index Cyclopropanations, 22, 77–84, 133, 149, 152, 269, 304 Cytovaricin, 262

D Danishefsky’s diene, 13, 35 Decahydroquinoline alkaloids, 48 Decahydro-quinolines, 2 Dehydroiridodiol, 292 Dehydropiperidinones, 39 Dendrobates histrionicus, 2, 48 Dendrobates pumilio, 2, 41, 48 Denticulatins, 268 Deoxygalactopyranosyl hydroperoxide, 23 Diacetone-D-glucose, 267 Diastereoselectivity, 2, 73, 79, 161 Diazaborolidine, 76 Diazaphosphorinane, 269 Diels-Alder reaction, 6 Dienophiles, 5–14, 24, 65, 84, 146, 181, 204, 240, 266 carbohydrate-linked, 5 Diethylaluminum chloride, 66 Dihydro-1,2-oxazines, 13 Dihydro-pinidine, 40 Diisobutylaluminum chloride, 66 Diisopropylidene-glucofuranose, 13, 64 Dimethyl-3-aza camphor lactam, 242 Dioxaboracycles, 76 Diphenylvalinol, 138 Dolaphenine, 249 Domino Mannich-Michael cascades, 35

E Egenine, 265 Elemene, 291 Enantioselective total synthesis, 260 Enders’ chiral auxiliary, 162, 165, 179, 289 Enehydrazides, 182 Enolates, 117 Epothilones, 268 Epoxidation, 23, 79, 82, 83, 122, 149 sharpless, 122 Ester enolates, 64, 88, 97, 209 Estrone, 306 Evans auxiliaries, 117

F FD-891, 283 Ferrocenyl diphosphines, 187 FR182877, 286

Index G Galactopyranosyl-(R)-amino acid amides, 26 Galactosamine, 9, 10, 66 N-Galactosyl imines, hetero-Diels-Alder, 11 N-Galactosyl piperidinone, 37 Galactosylamines, 24, 25, 35, 39, 42, 44, 48, 63 Gephyrotoxine 167B, 41 GlucoBox ligands, 23 Glucokinase, activation, 277 Glucolipsin A, 277 Glucosyl juglone, 9 Glutamic acid, 163, 289 Glutarimides, 140 Glycosyl allenyl ethers, 15 Glycosylamines, 2, 24, 35, 47, 53, 56, 63, 68 N-Glycosyl dehydropiperidinones, 39 Glycosyl hydroperoxides, 23 Glycosyl imines, 2, 11, 20, 24, 35, 39, 56 Goniothalamin, 93 Gulonic acid, 9

H Haloalkanes, 100 Hodgkin’s lymphoma, 280 Homoallylamines, 30, 31 Hydrazinophosphonic acid, 180 Hydroboration, 75–83, 93, 249, 288 Hydroxyisoborneol, 206, 215

I 2-Imidazolidinone, 260, 262, 268 Indolizidines, 51, 52, 56 Indolizidinones, 41, 51 Indolizines, 2 Iodo pyrrolizidinone, 189 Isoborneol, 206 Isochinolines, 182 Isoimidium salts, 181 Isolaurallene, 262 Isopropylidene-3-acryloyl-glucofuranose, 6 (S)-4-Isopropyl-1-phenyltetrahydropyrimidin-2 (1H )-one, 309 Isoxazilines, 14 Isoxazines, bicyclic, 11 Isoxazolidines, 4, 13 Isoxazolines, 16, 17, 85, 86

J Jasminum nudiflorum, 307 Jerangolid A, 269

319 K Kazusamycin, 294 Keto boronates, 96 Ketohexoses, 2 Kinugasa reactions, 18

L β-Lactam antibiotics, 18 Lactol, 206, 218 Lasubin, 41 Lavandulol, 309 Leptofuranins, 294 Leptomycins, 294 Lithium organyls, 186

M Mannich reactions, 2, 24, 53, 63, 139, 153 Mannofuranosyl nitrone, 4 Mannono-hydroximino-lactone, 11 Manzacidin, 298 Massoia lactone, 93 Matteson homologation, 76, 80, 86 Meisenheimer rearrangements, 230 Methyl crotonoate, 17 Methyl dihydrojasmonate, 300 Methyl jasmonate, 300 6-Methyl-norbornen-5-yl-carboxylic acid, 9 Michael reactions, 64, 163, 172, 206, 269, 282, 299 pyrrolidines, 172 MMP inhibitor, 269 Monoterpenes, 292, 307, 309

N Neolaurallene, 262 Neonepetalactone, 292 9-Borabicyclo(3.3.1)nonane (9-BBN), 99 Nojirimycin, 13 Norborn-2-ene-5-carboxylates, 10 Nudiflosides, 307

O Obtusenyne, 262 Oligonucleotides, antisense, 192 Organoboron, 73 Oxaphospholidines, 191 Oxazaborolidine, 76 Oxazaphosphorinanes, 269 Oxazinones, 9, 65

320 Oxazolidinethiones, 138, 213, 262 Oxazolidinones, 9, 65, 117, 210, 260 Oxazolidinonyl-1,4-pentadien-3-ones, 151 Oxazolinyl ketone, 260 Oxetanes, 169, 184 bicyclic, 22 Oxiranylboranes, 82 Oxyneolignan, 309

P Parasorbic acid, 93 Paterno-Büchi reaction, 22, 184 Pauson-Khand-type reactions, 150, 229 Penicillium brefeldianum, 271 Penta-O-acetyl-galactopyranose, 24 Perhydro-219A, 50 Perloruside, 103 Peroxyselenous acid, 167 Phenyl-alaninol, 119 8-Phenyl-3-azabicyclo[2.2.1]heptan-3-one, 245 8-Phenyl camphor lactam, 220 Phosphonamides, 260, 262, 269, 300–307, 313 Pictet-Spengler cyclization, 61, 62 Pinene, 200, 248 Piperazine carboxylic acid, 13 Piperidines, 268 substituted, 2, 36, 40, 51, 56 Piperidinones, 2, 36 Piperidinyl lithium, 186 Pironetin, 265 Pivaloyl-galactopyranosyl imine, 34 O-Pivaloyl protection, 24, 63 Polyangium cellulosum, 304 Post-Evans auxiliaries, 117 Proline, 161 esters, 162 Prolinol, 161, 162 ethers, 162 N-Propionyloxazolidinethiones, 263 Propionyloxazolidinone, 214 Pseudoephedrine, 267 Psoralea corylifolia, 299 Pumiliotoxin, 49 Pyrimidinone, 260, 309 Pyrrilidinones, 15 Pyrrolidine auxiliaries, 32, 52, 147, 161–191, 268, 289, 292

Q Quinazolines, 2

Index R RAMBO, 167, 268, 289 Ramipril, 169 RAMP, 162–189, 261–297, 313 hydrazine, 260 Rasfonin, 266 Rhazinilam, 311 Rhazya stricta, 311 Ribofuranosyl cloronitroso compounds, 11 Rugulactone, 93

S SADP, 167, 268, 289 SAEP, 167, 268, 289 SAMP, 162–189, 268, 289, 313 hydrazines/hydrazones, 260, 265, 291–297 SAPP, 167, 268, 289 Si-FerroPHANEs, 188 [3,3]-Sigmatropic rearrangement 93 Siloxanes, 191 Silyl dienol ethers, 35 Silylketene acetals, 29 2-Silyloxy-butadienes, 2 Simmons-Smith cyclopropanation, 23 Sintokamide B, 131 SN2 reactions, 68, 77, 89, 133 Solandolactones, 95 Sordidin, 293 Sphingosine, 249 Stereoselectivity, 200 Stilbene diamine, 99 Strecker reactions, 2, 24, 28, 39, 68, 119 Streptenols, 290 Streptomyces graminofaciens, 283 Streptomyces misionensis, 290 Strigolactones, 183 N-Sulfonyloxycarbamates, 126 Sulphonamides, 179, 191, 214 Sultams, 98, 147, 179, 214, 218, 261 Syringic acid, 310

T Tabersonine, 292 Taniaphos, 188 Terpenes, 2, 100, 200, 218, 261, 291 Tetra-O-pivaloyl-β-galactopyranosyl acrylate, 8 amine, 24 Tetrafibricin, 103 Tetrahydro-2-benzazepines, 173 Tetrahydroisoquinolines, 62 Tetrahydroxydiborane, 92

Index

321

Tetraponera punctulata, 52 Tetraponerines, 52 Thiazolidinethiones, 138, 262 Thienamycins, 18 Thiocarbonyl dienophiles, 10 Threonine, 99, 100, 281 Traceless auxiliaries, 161 1,7,7-Trimethyl-3-azabicyclo[2.2.1]-heptan-2one, 230 Trinem antibiotic, 269

V Valinol, 119 Vinylboronic esters, 94 Voacangalactone, 150

U Ugi reactions, 2, 24

Z Zaragozic acid A, 268

X Xylo-oxazolidinone, 20 Xylosyl N-allyloxy-(Aloc)-glycinate, 3