Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products 9789811268687

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Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Sasadhar Majhi Kazi Nazrul University, India

Bhubaneswar Mandal Indian Institute of Technology Guwahati, India

World Scientific NEW JERSEY

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LONDON

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SINGAPORE

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BEIJING

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SHANGHAI

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HONG KONG

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TAIPEI

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CHENNAI

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TOKYO

Published by World Scientific Publishing Co. Pte. Ltd. 5 Toh Tuck Link, Singapore 596224 USA office: 27 Warren Street, Suite 401-402, Hackensack, NJ 07601 UK office: 57 Shelton Street, Covent Garden, London WC2H 9HE

Library of Congress Cataloging-in-Publication Data Names: Majhi, Sasadhar, author. | Mandal, Bhubaneswar, author. Title: Modern sustainable techniques in total synthesis of bioactive natural products / Sasadhar Majhi (Kazi Nazrul University, India), Bhubaneswar Mandal (Indian Institute of Technology Guwahati, India). Description: New Jersey : World Scientific, [2023] | Includes bibliographical references and index. Identifiers: LCCN 2022058130 | ISBN 9789811268687 (hardcover) | ISBN 9789811268694 (ebook for institutions) | ISBN 9789811268700 (ebook for individuals) Subjects: LCSH: Bioactive compounds--Synthesis. | Green chemistry. Classification: LCC QD415 .M24 2023 | DDC 572.028/6--dc23/eng20230303 LC record available at https://lccn.loc.gov/2022058130

British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library.

Copyright © 2023 by World Scientific Publishing Co. Pte. Ltd. All rights reserved. This book, or parts thereof, may not be reproduced in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system now known or to be invented, without written permission from the publisher.

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For any available supplementary material, please visit https://www.worldscientific.com/worldscibooks/10.1142/13210#t=suppl Desk Editors: Aanand Jayaraman/Sandhya Devi Typeset by Stallion Press Email: [email protected] Printed in Singapore

This book is dedicated to our teacher, Prof. Goutam Brahmachari, who taught us not only chemistry but also life lessons that would have never been learned from any textbook.

Foreword

Nature provides an abundance of complex elegant molecular structures that accomplish a broad spectrum of activities. These systems are a result of 3.8 billion years of nature performing her own form of research and development. Through evolutionary forces, nature has optimized the efficiency and selectivity of molecular transformations to enable the construction of covalent and non-covalent geometries that have no counterpart in human-designed chemistry. We have much to learn from nature. Not only in the exquisite structure and geometry of natural products but also in how these molecules are made. When one examines the typical industrial synthesis of compounds far less complicated than most natural products, we see the routine use of high temperature and pressure using hazardous reagents and solvents. And yet in nature, these natural products are synthesized within the cells of organisms at ambient temperature and ambient pressure while using water as the reaction media. Ironically, throughout the history of the field of natural products, the process by which the molecules are synthesized in the human-built laboratory is quite “unnatural” and often has negative impacts on human health and the environment. The field of green chemistry emerged in the early 1990s to help articulate a path to change the face of chemistry. The definition of green chemistry is the utilization of a set of principles that reduces or eliminates the use or generation of hazardous substances in the design, manufacture, and application of chemical products. While this sounds straight-forward, the vast majority of chemical transformations are not consistent with these principles. vii

viii  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

In a most general description, when chemical transformations are carried out, one takes a set of reactants and applies a form of energy to increase molecular velocity to facilitate molecular collisions. These collisions are often unoriented and random, thus reactive collisions and non-reactive collisions are equally promoted. An important aspect of green chemistry is to explore reactive conditions that offer an opportunity to not simply increase random molecular collisions but to somehow favor the reactive collision and in so doing use less energy and increase yield in selectivity avoiding the production of waste. This book Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products is an important contribution to the field of green chemistry. In this book, five tools are presented in the context of natural product synthesis. Ultrasonic waves, microwave heating, visible-light photochemistry, organic electrochemistry, and flow chemistry all offer alternative approaches for adding energy into a reactive system to help overcome activation energies. But what excites me the most about these five reactive conditions is the unique mechanisms underlying each of them; there exist approaches to steer the selectivity of collisions to favor the synthesis of desired products vs the random collisions under traditional convection heating. As one reads this excellent book, one might feel that natural product synthesis is a “mature” field. While there has been an enormous amount of work already performed globally over the past several decades, we are still only at the threshold of a revolution in organic synthesis. The five tools described in this book are poised to accomplish the goals of green chemistry while opening new pathways of molecular design. John C. Warner Wilmington, MA January 2023

Preface

More and more bioactive secondary metabolites have been reproduced in the laboratory with the increasing power of synthetic organic chemistry. The total synthesis of natural products and secondary metabolites effectively confirms their hypothetical complex structure since various bioactive secondary metabolites are originated in small quantities from natural sources, particularly those from marine organisms and higher plants. Total synthesis has gained momentum since natural products play a crucial role in drug discovery and development. It is one of the significant challenges for organic synthesis owing to their high chemical diversity, pinnacle biochemical specificity, and stubborn stereochemistry. However, no suitable book is available focusing on the total synthesis of bioactive natural products through emerging sustainable techniques, which is in high demand in academia and industry presently. The book Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products is expected to meet the needs of the organic chemists, pharmacologists, and biological community. Modern green tools such as sonochemistry, microwave irradiation, visible‐light photochemistry, organic electrochemistry, flow chemistry, and or their combinations have a profound role in organic synthesis as well as total synthesis as these modern techniques enhance product yields and purities, improve selectivities, increase reaction rates and reduce unwanted side reactions. The book represented five Parts consisting of five green tools and 72 Chapters for each bioactive natural product. Part 1 demonstrates a greener approach for the total synthesis of bioactive natural products using ultrasound. Part 1 comprises 17 Chapters for each bioactive secondary ix

x  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

metabolite. Part 2 provides the application of microwave irradiation as an unconventional activation technique in the total synthesis of bioactive natural products; Part 2 consists of 17 Chapters for each bioactive molecule of natural origin. Part 3 furnishes visible-light photochemistry in the total synthesis, containing 18 Chapters for bioactive natural products. Parts 4 and 5 demonstrate organic electrochemistry and flow chemistry in the total synthesis as green technologies, and they include 10 Chapters each. Hence, this book may promote the improvement of more environment-friendly synthetic strategies so that the next generations can live on this globe with a minimum energy requirement for chemical transformation with the least pollution. Sasadhar Majhi Bhubaneswar Mandal

About the Authors

Dr. Sasadhar Majhi is currently the coordinator in the PG Department of Chemistry at Triveni Devi Bhalotia College, affiliated with The Kazi Nazrul University, Asansol, Raniganj, West Bengal, India, 713347. He earned his M.Phil in Chemistry in 2009. He also obtained a Ph.D. from Visva-Bharati University. He started his professional career as an Assistant Lecturer at Patha-Bhavana, Visva-Bharati University, Santiniketan, West Bengal. His primary research interests include the isolation and structure determination of natural products, total synthesis, semisynthesis, biological activities, and sustainable chemistry. He has authored seventeen articles, four book chapters, and one book. He has also edited one book. He has been conferred the Outstanding Assistant Professor Award in 2022 for outstanding contributions. Prof. Bhubaneswar Mandal obtained his Ph.D. from EPFL, Lausanne, Switzerland. After his post-doctoral research at the Max-Planck Institute for Molecular Physiology, Dortmund, Germany, as a Marie Curie Fellow, he joined the Department of Chemistry, Indian Institute of Technology Guwahati, as an Assistant Professor. Now he is a Professor there. His research interests include the self-assembly of peptides, disruption of protein aggregation, targeted protein degradation, and recyclable coupling reagent development for a green circular economy in peptide synthesis, and natural product synthesis. He has authored more than eighty articles

xi

xii  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

in internationally reputed journals. More than ten doctoral students have already received Ph.D. from his research group. He also has some patents for his inventions. He has received several awards, including Industrial Green Chemistry World Award (IGCW - 2015) from the Industrial Green Chemistry Foundation.

Contents

Forewordvii Prefaceix About the Authorsxi Part 1 Ultrasound for Total Synthesis of Bioactive Natural Products: A Greener Approach Chapter 1 Aeruginosins 298-A and 98-B Chapter 2 Dihydrostilbenes Chapter 3 Enigmazole A Chapter 4 (–)-Epidihydropinidine

1 3 11 17 23

Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12 Chapter 13

29 35 41 45 51 57 63 69 77

Galanthamine Geigerin, Geigerin Acetate, and 6-Deoxygeigerin Haliclonin A Hemiasterlin (–)-Khayasin Kopsanone Nosiheptide (Also known as RP9617) Psymberin Schilancitrilactone C

xiii

xiv  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Chapter 14 Chapter 15 Chapter 16 Chapter 17

(–)-Stenine Strictinin and Tellimagrandin II Tubulysins U and V WF-1360F

83 89 97 103

Part 2 Application of Microwave in Total Synthesis of Bioactive Natural Products: An Unconventional Activation Technique 109 Chapter 1 α- and β-Amanitin111 Chapter 2 (–)-Ambiguine P 117 Chapter 3 Antibiotic CJ-16,264 123 Chapter 4 Echinoside A (Holothurin A2)129 Chapter 5 (–)-Englerin A 135 Chapter 6 (+)-Erogorgiaene141 Chapter 7 Fidaxomicin (Tiacumicin B or Lipiarmycin A3 or Clostomicin B1) 147 Chapter 8 (−)-Glaucocalyxin A (Leukamenin F) 153 Chapter 9 (–)-Halenaquinone 159 Chapter 10 Harzianic Acid 165 Chapter 11 Hyperforin 169 Chapter 12 Kirkamide 175 Chapter 13 Kopsanone 179 Chapter 14 Luotonin A 185 Chapter 15 (±)-Phyllantidine (Phyllanthidine) 191 Chapter 16 (+)-Rubriflordilactone A 197 Chapter 17 Yaku’amide B 201 Part 3 Visible-Light Photochemistry As a Greener Approach for the Total Synthesis of Bioactive Natural Products Chapter 1 Ambiguine H Chapter 2 Aspergillide A

207 209 213

Contents    xv

Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7

Drimentines A, F, and G and Their Congener Indotertine A (−)-FR901483 and (+)-TAN1251C (+)-Fusarisetin A (+)-Gliocladin C Grandilodine and Lapidilectine Family of Alkaloids

219 225 233 239 245

Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12 Chapter 13 Chapter 14 Chapter 15 Chapter 16 Chapter 17 Chapter 18

(+)-Jungermatrobrunin A Kuwanons Lactacystin Litseaverticillols A, C, D, F, and G Lycoricidine and Narciclasine Specionin Spiroxin A and Spiroxin C Thymarnicol Trehazolin Xiamycins A, C, F, H and Oridamycin A Zaragozic Acid C

251 255 263 271 277 283 287 295 299 305 313

Part 4 Organic Electrochemistry: A Promising Window for the Development of Total Synthesis of Bioactive Natural Products 319 Chapter 1 Alliacol A 321 Chapter 2 Diazonamide A 325 Chapter 3 Dixiamycin B 331 Chapter 4 Furofuran Lignans 335 Chapter 5 (–)-Heptemerone B and (–)-Guanacastepene E 341 Chapter 6 (+)-N-Methylanisomycin347 Chapter 7 Pyrrolophenanthridone Alkaloids 353 Chapter 8 8,9-Seco-ent-kaurane359 Chapter 9 Teleocidins B-1–B-4 365 Chapter 10 Thebaine 371

xvi  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Part 5 Flow Chemistry in Total Synthesis of Bioactive Natural Products: An Efficient and Modern Synthetic Tool Chapter 1 Coronaridine Chapter 2 Dictyodendrin B Chapter 3 Goniofufurone Chapter 4 Grossamide Chapter 5 Hennoxazole A Chapter 6 Massarinolin A Chapter 7 Nazlinine Chapter 8 Neomarchantin A Chapter 9 Spirodienal A Chapter 10 Zephycarinatines

379 381 385 391 397 403 409 415 421 427 435

Index439

Part 1

Ultrasound for Total Synthesis of Bioactive Natural Products: A Greener Approach

Chapter 1

Aeruginosins 298-A and 98-B 1.1.1 Natural Source Microcystis aeruginosa (family: Microcystaceae).1–3

1.1.2 Structure

1.1.3 Systematic Name (2S,3aS,6R,7aS)-N-((S)-5-guanidino-1-hydroxypentan-2-yl)-6-hydroxy1-((R)-2-((R)-2-hydroxy-3-(4-hydroxyphenyl)propanamido)-4-methylpentanoyl)octahydro-1H-indole-2-carboxamide 2,2,2-trifluoroacetate (Aeruginosin 298-A). 3

4  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

1.1.4 Structure

1.1.5 Systematic Name (2S,3aS,6R,7aS)-2-((4-((amino(iminio)methyl)amino)butyl)carbamoyl)1-((2R,3S)-2-((R)-2-hydroxy-3-(4-hydroxyphenyl)propanamido)-3methylpentanoyl)octahydro-1H-indol-6-yl sulfate (Aeruginosin 98-B).

1.1.6 Structural Features Structurally, aeruginosins 298-A (1) and 98-B (2) include four different fragments such as a 2-carboxy-6-hydroxyoctahydroindole (Choi) core, a C-terminus carrying a terminal guanidine, a hydrophobic amino acid, as well as diversely decorated D-hydroxyphenyllactic (Hpla) subunit.1–4 X-ray crystallographic analysis of cocrystal of a tetrapeptide aeruginosin 98-B (2) with trypsin determined the absolute configurations of the seven stereogenic centers.5

1.1.7 Class of Compounds Peptides.1,2



Aeruginosins 298-A and 98-B    5

1.1.8 Pharmaceutical Potential Aeruginosins 298-A (1) and 98-B (2) exhibit potent inhibitory activity against serine proteases.1–3 Aeruginosin 298-A (1) inhibits thrombin and trypsin with a half-maximal inhibitory concentration (IC50) of 0.3 µg/mL and 1.0 µg/mL respectively1 and aeruginosin 98-B (2) inhibits trypsin actively with a half-maximal inhibitory concentration (IC50) of 0.6 µg/mL.2

1.1.9 Conventional Approach In 1994, Murakami et al. isolated a peptidic active-site protease inhibitor aeruginosin 298-A (1) from the blue-green freshwater algae Microcystis aeruginosa for the first time as a colorless amorphous powder bearing molecular formula C30H48O7N6.1 At that time, chiral GC analysis of the acid hydrolysate determined only the leucine stereochemistry. Marfey analysis established the configurations of the hydroxyphenyllactic acid and argininol fragments later.6 In 1998, Tulinsky et al. reported the X-ray crystallographic structure of the ternary complex of aeruginosin 298-A (1) bound to hirugen-thrombin, disclosing various unexpected interactions that may be effective and of consideration for structure-based drug design.7 The interesting molecular structures and impressive biological activities of aeruginosins 298-A (1) and 98-B (2) attracted the attention of the organic synthetic and biological community. As a result, several synthetic groups have reported various successful total syntheses. In 2000, the first total synthesis of aeruginosin 298-A (1) and reassignment of its configuration were disclosed by Bonjoch and co-workers.8 The investigators developed a strategy to assemble the four units of the peptide; key steps of the total synthesis comprise the formation of an appropriately functionalized and stereochemically pure octahydroindole core (Choi core), as well as the coupling with the other fragments, which clarifies the real structure of the natural peptide. In the same year, Wipf et al. achieved the total synthesis and stereochemical revision of (+)-aeruginosin 298-A (1) gracefully; a concise synthesis of the new bicyclic amino acid from L-tyrosine was accomplished that can be adapted easily in synthesizing analogs and peptidomimetic scaffolds also.9 Salient features of this total synthesis comprise the effective formation of other non-proteinogenic building blocks in aeruginosin

6  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

298-A (1) and comprehensive optimization of coupling strategies. In 2001, Bonjoch et al. completed the total syntheses of aeruginosin 298-A (1) as well as aeruginosin 98-B (2) involving the stereocontrolled preparation of (2S,3aS,6R,7aS)-6-hydroxyoctahydroindole-2-carboxylic acid, the synthesis of D-Hpla (R)-benzylglycidol, and a different coupling sequence which was conceptually distinct from Wipf synthesis9 as central steps.10 Shibasaki and co-workers went on to report a versatile synthetic process for aeruginosin 298-A (1) as well as various attractive analogs involving a catalytic asymmetric phase-transfer transformation as a green methodology and epoxidation as leading steps in 2003.11 Takahashi et al. explored a practical synthetic pathway in 2006 for a combinatorial library of aeruginosin analogs on solid phase and evaluated their inhibitory activity against trypsin; it has been observed that derivative D-Hpla-DLeu-L-Choi-Agma is 300 times more potent than the parent natural product aeruginosin 298-A (1) without bearing a sulfate ester.12 In 2015, Baudoin and co-workers demonstrated the divergent synthesis of aeruginosins using an intramolecular C–H alkenylation transformation for the large-scale synthesis of the common (Choi) heterocyclic core of the desired compound and an intermolecular directed C–H arylation for the preparation of fast and divergent access to diversely decorated Hpla fragments.13 The power of this strategy allowed the synthesis of four aeruginosins such as aeruginosins 298-A and 98-B and halogenated aeruginosins 98-A and 98-C for the first time from the chiral pool. In 1995, Murakami and co-workers isolated tetrapeptide aerugi­ nosin 98-B (2) from a blue-green algae Microcystis aeruginosa (Microcystaceae) as a colorless amorphous powder having molecular formula C29H46O9N6S with an unnatural amino acid.2 2D-NMR analysis ascertained the structure of aeruginosins 98-B (2), and the absolute configurations of the seven stereogenic centers were ascertained by X-ray crystallographic analysis of cocrystal of aeruginosins 98-B (2) with trypsin.5 Trost and co-workers achieved the first total synthesis of aeruginosin 98-B (2) in eight steps from the four fragments (Choi, D-allo-Ile, Hpla, and agmatine) involving a fully diastereoselective Pd-catalyzed intramolecular asymmetric allylic alkylation transformation as a central step.5

1.1.10 Demerits of Conventional Approach Various conventional approaches have been reported by Bonjoch,8,10 Wipf,9 and Shibasaki groups11 to build the targeted 2-carboxy-6-



Aeruginosins 298-A and 98-B    7

hydroxyoctahydroindole (Choi) core involving a Michael-type addition as a central step brilliantly. However, conventional approaches were not free from a few demerits as corrosive and hazardous chemicals were employed in the total synthesis of aeruginosins 298-A (1) and 98-B (2). For example, Wipf group constructed a kinetic elimination product from tertiary alcohol using corrosive phosphorous oxychloride, and hazardous hydrogen fluoride (HF) was used to prepare D-Leu-aeruginosin 298-A.9 Besides, Takahashi et al. used corrosive trifluoroacetic acid (TFA) to prepare polymer-supported Choi from the polymer-supported compound.12 Moreover, several groups employed neurotoxin dichloromethane as a solvent in the total synthesis.8–13 Green tools such as ultrasonic irradiation, visible-light photochemistry, microwave, flow chemistry, and organic electrochemistry were not used by conventional protocols as a key step in the total synthesis of bioactive natural products.8–13

1.1.11 Key Features of Total Synthesis Using Ultrasonic Irradiation The key feature for total syntheses of aeruginosins 298-A (1) and 98-B (2) includes the strategic use of two different C(sp3)-H activation reactions; the first protocol furnished the common 2-carboxy-6hydroxyoctahydroindole (Choi) core of the desired compounds on a large scale and the second method delivered fast and divergent access to the several diversely decorated D-hydroxyphenyllactic (Hpla) subunits.4

1.1.12 Type of Reaction C–C bond formation using ultrasonic irradiation.4

1.1.13 Synthetic Strategy Using Ultrasonic Irradiation Cyclopropanation reaction.4

1.1.14 Synthetic Route Baudoin and co-workers developed an effective and scalable total synthesis of bioactive peptides aeruginosins 298-A (1) and 98-B (2)

8  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

involving cyclopropanation reaction using ultrasonic irradiation as a key step in 20154; one of the most important strained rings of natural products cyclopropanes has not only been present in various pharmaceutical molecules and bioactive natural products but has also been widely used in the field of organic synthesis and medicinal chemistry as multipurpose building blocks.14 The investigators began the total syntheses of the aeruginosins 298-A (1) and 98-B (2) from readily available dihomoallylalcohol (3) to furnish ultrasound precursor cyclopentenol (4) in quantitative yield over two steps. Next, the cyclopentenol (4) was treated with bromoform (CHBr3) and sodium hydroxide (NaOH) in the presence of the benzyltriethylammonium chloride (Et3BnNCl) at 20 °C to

Scheme 1.1.1.    Ultrasound-assisted total syntheses of aeruginosin 98-B and 298-A.



Aeruginosins 298-A and 98-B    9

generate dibromobicyclo diphenylsilane (5) using ultrasonic irradiation as a green tool (Scheme 1.1.1). In this key step, dibromo carbene intermediate was obtained first by the reaction of CHBr3 with NaOH and then the addition of this carbene intermediate occurred to the double bond of the cyclopentenol (4) using ultrasonication through cyclopropanation reaction followed by thermal electrocyclic ring-opening at 130 °C to deliver the racemic dibromocyclohexene (6) as an inconsequential 6:1 mixture of diastereoisomers.15 Herein, the role of the ultrasound sonication was crucial to construct the cyclopropane ring, one of the most significant strained rings of natural products. The vital 2-carboxy6-hydroxyoctahydroindole (Choi) core (7) was obtained from dibromocyclohexene (6) over several steps using C(sp3)-H activation reaction as a key step. The 2-carboxy-6-hydroxyoctahydroindole (Choi) core (7) was efficient to deliver secondary metabolites aeruginosins 298-A (1) and 98-B (2) successfully over several steps; this powerful strategy allows the synthesis of other members of this family of marine products comprising the halogenated congeners.4

References   1. Murakami M, Okita Y, Matsuda H et al. (1994) Aeruginosin 298-A, a thrombin and trypsin inhibitor from the blue-green alga Microcystis acruginosa (NIES-298). Tetrahedron Lett 35: 3129–3132.   2. Murakami M, Ishida K, Okino T et al. (1995) Aeruginosins 98-A and B, trypsin inhibitors from the blue-green alga Microcystis aeruginosa (NIES98). Tetrahedron Lett 36: 2785–2788.   3. Ersmark K, Del Valle JR, Hanessian S. (2008) Chemistry and biology of the aeruginosin family of serine protease inhibitors. Angew Chem Int Ed 47: 1202–1223.   4. Dailler D, Danoun G, Baudoin O. (2015) A general and scalable synthesis of aeruginosin marine natural products based on two strategic C(sp3)-H activation reactions. Angew Chem Int Ed 54: 4919–4922.   5. Trost BM, Kaneko T, Andersen NG et al. (2012) Total synthesis of aeruginosin 98B. J Am Chem Soc 134: 18944–18947.   6. Ishida K, Okita Y, Matsuda H et al. (1999) Aeruginosins, protease inhibitors from the cyanobacterium Microcystis aeruginosa. Tetrahedron 55: 10971–10988.   7. Steiner JLR, Murakami M, Tulinsky A. (1998) Structure of thrombin inhibited by aeruginosin 298-A from a blue-green alga. J Am Chem Soc 120: 597–598.

10  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

  8. Valls N, Lýpez-Canet M, Vallribera M et al. (2000) Total synthesis and reassignment of configuration of aeruginosin 298-A. J Am Chem Soc 122: 11248–11249.   9. Wipf P, Methot J-L. (2000) Total synthesis and stereochemical revision of (+)-aeruginosin 298-A. Org Lett 2: 4213–4216. 10. Valls N, Lýpez-Canet M, Vallribera M et al. (2001) First total syntheses of aeruginosin 298-A and aeruginosin 298-B, based on a stereocontrolled route to the new amino acid 6-hydroxyoctahydroindole-2-carboxylic acid. Chem Eur J 7: 3446–3460. 11. Ohshima T, Gnanadesikan V, Shibuguchi T et al. (2003) Enantioselective syntheses of aeruginosin 298-A and its analogues using a catalytic asym­ metric phase-transfer reaction and epoxidation. J Am Chem Soc 125: 11206–11207. 12. Doi T, Hoshina Y, Mogi H et al. (2006) Solid-phase combinatorial synthesis of aeruginosin derivatives and their biological evaluation. J Comb Chem 8: 571–582. 13. Dailler D, Danoun G, Ourri B et al. (2015) Divergent synthesis of aeruginosins based on a C(sp3)-H activation strategy. Chem Eur J 21: 9370–9379. 14. Qian D, Zhang J. (2015) Gold-catalyzed cyclopropanation reactions using a carbenoid precursor toolbox. Chem Soc Rev 44: 677–698. 15. Halton B, Harvey J. (2006) Electrocyclic ring-opening reactions of gemdibromocyclopropanes in the synthesis of natural products and related compounds. Synlett 13: 1975–2000.

Chapter 2

Dihydrostilbenes 1.2.1 Natural Source Bulbophyllum odoratissimum Lindl. (family: Orchidaceae).1

1.2.2 Structure

1.2.3 Systematic Name 3-(2-(7-methoxybenzo[d][1,3]dioxol-5-yl)ethyl)phenol (1). 6-(3-hydroxyphenethyl)benzo[d][1,3]dioxol-4-ol (2).

1.2.4 Structural Features Two aromatic rings are connected by an aliphatic two-carbon chain in dihydrostilbenes of its bibenzyl (1,2-diarylethane) structure; the relatively simple structure of dihydrostilbenes includes 1,3-benzodioxole and one phenolic hydroxyl group.2 11

12  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

1.2.5 Class of Compounds Phenolic compounds.2,3

1.2.6 Pharmaceutical Potential Two natural stilbenoids 3-(2-(7-methoxybenzo[d][1,3]dioxol-5-yl)-ethyl) phenol (1) and 6-(3-hydroxyphenethyl)benzo[d][1,3]-dioxol-4-ol (2) exhibit anti-proliferative activity against three human cancer cell lines such as SGC-7901 gastric carcinoma [IC50 (µM) = 8.30, 9.20; for compounds 1 and 2, respectively], KB nasopharyngeal carcinoma [IC50 (µM) = 5.50, 8.70; for compounds 1 and 2, respectively], and HT-1080 fibrosarcoma [IC50 (µM) = 25.5, 40.0; for compounds 1 and 2, respectively], by colorimetric 3-(4,5-dimethylthiazolyl-2)-2,5diphenyltetrazolium bromide (MTT) assay employing cisplatin as positive control.2

1.2.7 Conventional Approach A significant class of natural products stilbenoids (dihydrostilbenes, stilbenes, phenanthrenes, as well as their oligomers) comprise a 1,2-diphenylethane scaffold which is closely linked to the flavonoids biosynthetically and attract increasing interest toward synthetic along with biological community because of their various pharmacological effects.4–7 Hence, several conventional approaches have been developed to describe the total synthesis of natural products stilbenoids including dihydrostilbenes. Braun et al. reported a straightforward methodology for the synthesis of dihydrostilbenes bearing multiple phenolic substitutions involving Murai’s ruthenium-catalyzed hydroarylation of olefins with O-protected 2,5-dihydroxyacetophenones in a fully regioselective manner and made accessible the aglycon of scorzodihydrostilbenes B and D also in 2019.8 In 2016, Jun et al. accomplished an efficient synthesis of dihydrostilbenes from readily available starting materials such as 2,4,5-trimethoxy benzaldehyde and boron trichloride using Wittig–Horner reaction and hydrogenation as vital steps, as well as the investigators evaluated  in vitro anti-inflammatory activity of dihydrostilbenes.9 Yao  et al. achieved total syntheses of two novel dihydrostilbenes 5-(2-benzo[1,3]dioxole-5-ylethyl)-6-methoxy benzo[1,3]dioxole-4-ol and 5-(2-benzo[1,3]dioxole-5-ylethyl)benzo[1,3]dioxole-4,7-diol with

Dihydrostilbenes    13

significant cytotoxicity toward human cancer cell lines involving the Baeyer–Villiger oxidation, a Vilsmeier reaction, and Horner reaction as key steps.10

1.2.8 Demerits of Conventional Approach Conventional approaches face a few demerits such as a synthetic approach developed by the Braun group needs a long time of 7–10 days to prepare dihydrostilbenes; moreover, the yield of the tetramethoxy-substituted derivative was comparatively lower (40%).8 A corrosive chemical phosphorus tribromide was used to construct Wittig–Horner reagents by the Jun group.9 Yao et al. used high shock-sensitive meta-chloroperbenzoic acid (m-CPBA) to prepare phenol through the Baeyer–Villiger oxidation.10

1.2.9 Key Features of Total Synthesis Using Ultrasonic Irradiation The key features of the two natural dihydrostilbenes 3-(2-(7methoxybenzo[d][1,3]dioxol-5-yl)-ethyl)phenol (1) and 6-(3hydroxyphenethyl)benzo[d][1,3]-dioxol-4-ol (2) include a safe and inexpensive reduction of the ester by NaBH4/I2, highly selective oxidation of the benzylic alcohol, Michaelis–Arbuzov reaction of the benzylic chloride, and Wittig–Horner reaction as key steps.2

1.2.10 Type of Reaction C–O bond formation using ultrasonic irradiation.2

1.2.11 Synthetic Strategy Using Ultrasonic Irradiation Oxidation reaction.2

1.2.12 Synthetic Route The first total syntheses of two bioactive natural dihydro­ stilbenes 3-(2-(7-methoxybenzo[d][1,3]dioxol-5-yl)-ethyl)phenol (1)

14  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Scheme 1.2.1.    Ultrasound-assisted total syntheses of (–)-dihydrostilbenes.

and 6-(3-hydroxyphenethyl)benzo[d][1,3]-dioxol-4-ol (2) were completed by Yao and co-workers in 28% and 20% overall yield, respectively, using an oxidation reaction under ultrasound irradiation as a key step; the investigators also conducted significant anti-proliferative activity against human cancer cell lines.2 The synthesis was commenced from 3-hydroxy benzoic acid (3) to produce important primary alcohol (4) in 88.9% yield over three steps. Next, the primary alcohol (4) underwent the oxidation reaction in the presence of the KMnO4 and the zirconyl chloride (ZrOCl2·8H2O) in THF at room temperature to afford the aromatic aldehyde (5) in 98.5% yield for 10 h using ultrasound sonication as a greener technology (Scheme 1.2.1). Herein, the role of ultrasound irradiation was significant to provide a new C–O bond through the oxidation reaction. The key aromatic aldehyde (5) was efficient to generate the targeted two natural dihydrostilbenes (1 and 2) through Wittig–Horner reaction as another crucial step; natural dihydrostilbenes (1 and 2) and nine analogs of (1) and (2) were evaluated for their antiproliferative property against SGC-7901, KB, and HT-1080 cell lines employing colorimetric MTT assay.2

References   1. Cao Z-H-B. (1999) State Administration of Traditional Chinese Medicine, vol. 8, p. 681. Shanghai Science and Technology Press, Shanghai.   2. Zhang WG, Zhao R, Ren J et al. (2007) Synthesis and anti-proliferative invitro activity of two natural dihydrostilbenes and their analogues. Arch Pharm Chem Life Sci 340: 244–250.   3. Gakh AA, Anisimova NY, Kiselevsky MV et al. (2010) Dihydro-resveratrol — A potent dietary polyphenol. Bioorganic Med Chem Lett 20: 6149–6151.

Dihydrostilbenes    15

  4. Lin LG, Yang XZ, Tang CP et al. (2008) Antibacterial stilbenoids from the roots of Stemona tuberosa. Phytochemistry 69: 457–463.   5. Biondi DM, Rocco C, Ruberto G. (2003) New dihydrostilbene derivatives from the leaves of Glycyrrhiza glabra and evaluation of their antioxidant activity. J Nat Prod 66: 477–480.   6. Likhitwitayawuid K, Sawasdee K, Kirtikara K. (2002) Flavonoids and stilbenoids with COX-1 and COX-2 inhibitory activity from Dracaena loureiri. Planta Med 68: 841–843.   7. Cushman M, Nagarathnam D, Gopal D et al. (1991) Synthesis and evaluation of stilbene and dihydrostilbene derivatives as potential anticancer agents that inhibit tubulin polymerization. J Med Chem 34: 2579–2588.   8. Weimann K, Braun M. (2019) Synthesis of the aglycon of scorzodihydrostilbenes B and D. Beilstein J Org Chem 15: 610–616.   9. Jang HY, Park HJ, Damodar K et al. (2016) Dihydrostilbenes and diaryl­ propanes: Synthesis and in vitro pharmacological evaluation as potent nitric oxide production inhibition agents. Bioorganic Med Chem Lett 26: 5438–5443. 10. Zhang WG, Lin JG, Niu ZY et al. (2007) Total synthesis of two new dihydrostilbenes from Bulbophyllum odoratissimum. J Asian Nat Prod Res 9: 23–28.

Chapter 3

Enigmazole A 1.3.1 Natural Source Cinachyrella enigmatica (family: Tetillidae).1

1.3.2 Structure

17

18  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

1.3.3 Systematic Name (1R,3S,4S,6S,9S,11S,15R)-11-hydroxy-9-(2-((R,Z)-3-methoxy-2methylbut-1-en-1-yl)oxazol-4-yl)-4,6-dimethyl-17-methylene-7-oxo8,19-dioxabicyclo[13.3.1]nonadecan-3-yl dihydrogen phosphate.

1.3.4 Structural Features The architecturally complex marine metabolite enigmazole A (1) is structurally characterized by an 18-membered macrolactone embedded with a densely functionalized 2,4-disubstituted oxazole at C17 position, attached with an exomethylene-substituted tetrahydropyran ring, fully decorated with a phosphate ester at C5 position, as well as consisting of eight chiral centers within its structure.1 The existence of a phosphate group in the cytotoxic marine macrolide enigmazole A (1) was ascertained by the single resonance at δ 2.17 ppm in a 31P NMR spectrum.2

1.3.5 Class of Compounds Phosphate-containing macrolide.1

1.3.6 Pharmaceutical Potential The marine metabolite enigmazole A (1) displays potent cytotoxicity against the NCI-60 cell panel, with a mean growth inhibitory 50% (GI50) of 1.7 μΜ.1

1.3.7 Conventional Approach Enigmazole A (1) (molecular formula of C29H46NO10P) and its congeners, (−)-15-O-methylenigmazole A (molecular formula of C30H47NO10P) and (−)-13-hydroxy-15-O-methylenigmazole A (molecular formula of C30H47NO11P), were isolated from Papua New Guinean marine sponge Cinachyrella enigmatica (Tetillidae) as pale yellow solids by Gustafson and co-workers in 2010.1 The planar structure of enigmazole A (1) was established by detailed 2D NMR studies; the absolute stereochemistry of the eight stereogenic centers within this phosphorylated marine macrolide



Enigmazole A    19

was determined through degradation/derivatization experiments including a modified Mosher analysis. The entire stereostructure of enigmazole A (1) was finally established by total first synthesis by Molinski Gustafson and co-workers in 2010 using the construction of the highly functionalized 2,4-disubstituted oxazole fragment by an effective Negishi-type coupling, the formation of the central embedded pyran ring by a hetero-Diels–Alder, and a Wittig transformation to combine Eastern and Western hemispheres through the longest linear sequence in 22 steps and 0.41% overall yield from the known aldehyde.3 A highly convergent, stereocontrolled total synthesis of the phosphorylated marine macrolide enigmazole A (1) was explored by the Smith group in 4.4% overall yield from readily available (R)-3-butyn-2-ol with a longest linear sequence of 22 steps using a versatile protocol late-stage large-fragment three-stage Petasis−Ferrier union/rearrangement as a leading step in 2015.4 The same group also disclosed the total synthesis of the (−)-enigmazole A (1) together with the mono- and di-sodium phosphate salts involving a multicomponent Type I Anion Relay Chemistry (ARC) as a crucial step in 2018.5 Fuwa et al. accomplished the total synthesis of (−)-enigmazole A (1) by applying the stereoselective formation of the tetrahydropyran moiety by a domino olefin cross-metathesis/intramolecular oxa-Michael addition along with a gold-catalyzed rearrangement of a propargylic benzoate as central steps in 2018.6 The same investigators also described the unified total synthesis of cytotoxic (−)-enigmazole A and its congener (−)-15-Omethylenigmazole A using the stereoselective formation of the 2,6-cissubstituted tetrahydropyran ring by the tandem olefin cross-metathesis/ intramolecular oxa-Michael addition and macrocyclic ring-closing metathesis sequence as key steps in 2020.7

1.3.8 Demerits of Conventional Approach The phosphorylated marine macrolide enigmazole A (1) has been a fascinating synthetic target among the synthetic community because of its architecturally complex structure and significant biological activity. Conventional approaches for synthesizing (−)-enigmazole A (1) were not free from a few demerits. Fuwa and co-workers in 2020 used a hazardous liquid oxalyl chloride to construct the desired aldehyde from known alcohol through the oxidation reaction.7,8 Molinski et al. used toxic boron tribromide during the synthesis of eastern hemisphere phosphonium salt.3

20  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Smith et al. employed Grignard reagent to prepare dithiane which is not safe for green chemistry as Grignard reaction comprises a heat-generating metal (volatile metal magnesium) as well as a flammable solvent, namely, ether.4

1.3.9 Key Features of Total Synthesis Using Ultrasonic Irradiation A robust, concise, and convergent total synthesis of enigmazole A (1) consisted of a gold-catalyzed cascade involving a [3,3]-sigmatropic rearrangement of a propargyl acetate as a key step. The unique features of the total synthesis also included the transannular hydroalkoxylation of the transient allenyl acetate, the construction of the oxazole building block through C–H activation by a palladium catalyst along a rapid ring-closing alkyne metathesis (RCAM) of a substrate diyne carrying a propargylic leaving group.9

1.3.10 Type of Reaction O–H bond formation under ultrasonic irradiation.9

1.3.11 Synthetic Strategy Using Ultrasonic Irradiation Deprotection reaction.9

1.3.12 Synthetic Route An efficient total synthesis of the phosphorylated cytotoxic marine macrolide enigmazole A (1) was conducted by Furstner and co-workers in 2016 through an ultrasound-accelerated trichloroethyloxycarbonyl (Troc) cleavage as a leading step.9 The concise total synthesis was commenced from commercial propargyl alcohol (2) to furnish the targeted ultrasound precursor cycloalkyne (3) on a gram scale (single largest batch) over several steps, including a palladium-catalyzed C–H activation, an asymmetric Keck allylation, and a ring-closing alkyne metathesis as central steps. Then, an effective ultrasound-accelerated Troc cleavage



Enigmazole A    21

Scheme 1.3.1.    Ultrasound-assisted total synthesis of enigmazole A.

occurred as a green protocol in the presence of the zinc dust in acetic acid to provide crucial alcohol (4) in excellent yield (93%) as an adequate substrate for the critical π-acid-catalyzed transformation cascade (Scheme 1.3.1). Herein, the role of the ultrasound irradiation was vital to construct a new O–H bond efficiently through the deprotection reaction. The targeted bioactive natural product enigmazole A (1) was obtained from important alcohol (4) over several steps consisting of gold-catalyzed [3,3]-sigmatropic rearrangements as a central step10; the total synthesis efforts subscribe to an extensive mechanistic understanding of noble metal catalysis as a whole.9

References   1. Oku N, Takada K, Fuller RW et al. (2010) Isolation, structural elucidation, and absolute stereochemistry of enigmazole A, a cytotoxic phosphomacrolide from the Papua New Guinea marine sponge Cinachyrella enigmatica. J Am Chem Soc 132: 10278–10285.

22  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

  2. Kato Y, Fusetani N, Matsunaga S et al. (1986) Bioactive marine metabolites. Part 16. Calyculin A. A novel antitumor metabolite from the marine sponge Discodermia calyx. J Am Chem Soc 108: 2780–2781.   3. Skepper CK, Quach T, Molinski TF. (2010) Total synthesis of enigmazole A from Cinachyrella enigmatica. Bidirectional bond constructions with an  ambident 2,4-disubstituted oxazole synthon. J Am Chem Soc 132: 10286–10292.   4. Ai Y, Kozytska MV, Zou Y et al. (2015) Total synthesis of (−)-enigmazole A. J Am Chem Soc 137: 15426–15429.   5. Ai Y, Kozytska MV, Zou Y et al. (2018) Total synthesis of the marine phosphomacrolide, (−)-enigmazole A, exploiting multicomponent type I anion relay chemistry (ARC) in conjunction with a late-stage Petasis−Ferrier union/rearrangement. J Org Chem 83: 6110–6126.   6. Sakurai K, Sasaki M, Fuwa H. (2018) Total synthesis of (−)-enigmazole A. Angew Chem Int Ed 57: 5143–5146.   7. Sakurai K, Sakamoto K, Sasaki M et al. (2020) Unified total synthesis of (–)-enigmazole A and (–)-15-O-methylenigmazole A. Chem Asian J 15: 3494–3502.  8. Barbee SJ, Stone JJ, Hilaski RJ. (1995) Acute inhalation toxicology of oxalyl chloride. Am Ind Hyg Assoc J 56: 74–76.   9. Ahlers A, de Haro T, Gabor B et al. (2016) Concise total synthesis of enigmazole A. Angew Chem Int Ed 55: 1406–1411. 10. Mauleýn P, Krinsky JL, Toste FD. (2009) Mechanistic studies on Au(I)catalyzed [3,3]-sigmatropic rearrangements using cyclopropane probes. J Am Chem Soc 131: 4513–4520.

Chapter 4

(–)-Epidihydropinidine 1.4.1 Natural Source Picea engelmannii (family: Pinaceae).1

1.4.2 Structure

1.4.3 Systematic Name (2S,6S)-2-methyl-6-propylpiperidine hydrochloride.

1.4.4 Structural Features The trans stereochemistry of epidihydropinidine (1) is of particular interest to organic synthetic chemists since another important alkaloid pinidinol comprises cis ring substitution in alkaloids of Picea; the key structural feature of this alkaloid includes trans-2-methyl which is directly linked to the six-membered piperidine ring. The relatively very simple structure of epidihydropinidine (1) possesses two stereocenters and n-propyl at the side chain.1,2 23

24  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

1.4.5 Class of Compounds Alkaloid.1,2

1.4.6 Pharmaceutical Potential Epidihydropinidine (1) shows antibacterial and antifungal effects with a minimum inhibitory concentration (MIC) value of 5.37 mg/mL against  Pseudomonas aeruginosa, Candida glabrata, C. albicans, and Enterococcus faecalis and with a MIC value of 10.75 mg/mL against Bacillus cereus and Staphylococcus aureus (MIC 10.75 mg/mL) as well as against Salmonella enterica (MIC and MBC (minimum bactericidal concentration) 43 mg/mL).2

1.4.7 Conventional Approach Many Picea (spruce) and/or Pinus (pinus) species and different insects are valuable sources of the 2,6-disubstituted piperidine alkaloids1 including (–)-epidihydropinidine (1) (as HCl salts), (+)-dihydropinidine (2), and (–)-pinidinone (3). Only two syntheses of (–)-epidihydropinidine (1) have been reported to date by the Yamauchi group and Passarella group3,4; although various synthetic pathways to (+)-epidihydropinidine have been disclosed successfully.5–10 Yamauchi et al. accomplished the syntheses of (+)- and (–)-epidihydropinidine involving yeast reduction of methyl (2-oxocyclohexyl)acetate as a key step.3 Passarella and co-workers developed the syntheses of (+)- and (–)-epidihydropinidine based on the introduction of a methyl group at the piperidine alcohol by the formation of the carbanion, the construction of an aldehyde from the primary alcohol through a Dess–Martin oxidation, the formation of the 2-allyl-6-methylpiperidine via Wittig reaction as central steps.4

1.4.8 Demerits of Conventional Approach Conventional approaches for syntheses of (+)- and (–)-epidihydropinidine were not free from a few demerits. Passarella et al. used hazardous flammable liquid tert-butyldimethylsilyl chloride (TBDMSCl) in dichloromethane (DCM) to construct the TBDMS (tert-butyldimethylsilyl group) protected derivative from the primary alcohol. Besides, an

(–)-Epidihydropinidine    25

organolithium reagent toxic n-BuLi (n-butyllithium) in ether at –78 °C was employed to introduce the methyl group at the piperidine ring in comparatively low yield (39%). Moreover, a corrosive reagent trifluoroacetic acid (TFA) was applied to obtain epidihydropinidine.4 To prepare crucial alcohol, Yamauchi and co-workers used hazardous p-toluenesulfonyl chloride (which causes gastrointestinal tract burns and contact with water releases toxic gas).3

1.4.9 Key Features of Total Synthesis using Ultrasonic Irradiation The protecting group free total synthesis of (–)-epidihydropinidine (1) represents the shortest routes with the highest overall yields (in 32% overall yield over seven steps); the pathways include regioselective Wacker–Tsuji oxidation of alkenylazides and highly diastereoselective reduction of cyclic imine as key steps.11 The proposed absolute configuration of the (–)-epidihydropinidine hydrochloride is to be (2S,6S) which was confirmed by the first single-crystal X-ray analysis of it, corresponding to that of the isolated molecule of the natural origin.

1.4.10 Type of Reaction C–N bond formation using ultrasonic irradiation.11

1.4.11 Synthetic Strategy Using Ultrasonic Irradiation Substitution reaction.11

1.4.12 Synthetic Route Szolcsanyi and co-workers planned the total syntheses of three naturally occurring defense chemicals such as (–)-epidihydropinidine (1) (as HCl salts), (+)-dihydropinidine (2), and (–)- pinidinone (3) in 2011 involving C–N bond constructions as key steps under ultrasonic irradiation.11 The shortest routes for the total syntheses of the 2,6-disubstituted piperidine alkaloids were initiated from (S)-epichlorohydrin (4) as a common

26  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

substrate with the highest overall yields (32–54%). The ultrasound precursor the mesylate (5) was obtained from the common starting material (S)-epichlorohydrin (4) over four steps efficiently. Next, mesylate (5) was treated with sodium azide (NaN3) in dimethylformamide (DMF) at 50 °C to afford alkenylazide (6) in a 95% yield through the substitution reaction using ultrasonic irradiation as an unconventional activation technique (Scheme 1.4.1). Herein, the role of the ultrasonic irradiation was significant to deliver a key intermediate alkenylazide (6) through the C–N bond formation. Then, alkenylazide (6) underwent Wacker–Tsuji oxidation to produce the targeted ketone (7) in 85% yield in the presence of the pure oxygen in dimethylacetamide using PdCl2 in a solvent mixture of N-methyl-2-pyrrolidone (NMP)/water (8/1 w/w) at room temperature for 24 h using copper-free conditions. Finally, a bioactive alkaloid (–)-epidihydropinidine (1) (as HCl salts) was prepared from the azidoketone (7) involving Staudinger-aza-Wittig condensation as a leading step. The common key substrate the azidoketone (7) was effective to deliver another alkaloid (+)-dihydropinidine (2) successfully; another natural alkaloid

Scheme 1.4.1.    Ultrasound-assisted total (–)-epidihydropinidine, and (–)-pinidinone.

syntheses

of

(+)-dihydropinidine,

(–)-Epidihydropinidine    27

(–)-pinidinone (3) was also prepared from the same starting material (S)-epichlorohydrin (4) using ultrasonic irradiation as a central step to construct a new C–N bond.11

References   1. Schneider MJ, Montali JA, Hazen D et al. (1991) Alkaloids of Picea. J Nat Prod 54: 905–909.  2. Fyhrquist P, Virjamo V, Hiltunen E et al. (2019) Epidihydropinidine, the main piperidine alkaloid compound of Norway spruce (Picea abies) shows antibacterial and anti-Candida activity. Fitoterapia 134: 503–511.   3. Yamauchi S, Mori S, Hirai Y et al. (2004) Syntheses of (+)- and (−)-dihydropinidine and (+)- and (−)-epidihydropinidine by using yeast reduction of methyl (2-oxocyclohexyl)acetate. Biosci Biotechnol Biochem 68: 676–684.   4. Passarella D, Riva S, Grieco G et al. (2009) Enantiopure N-Boc piperidine2-ethanol for the synthesis of (+)- and (−)-dumetorine, and (+)- and (−)-­epidihydropinidine. Tetrahedron Asymmetry 20: 192–197.   5. Takahata H, Kubota M, Takahashi S et al. (1996) A new asymmetric entry to 2-substituted piperidines. A concise synthesis of (+)-coniine, (−)-pelletierine, (+)-d-coniceine, and (+)-epidihydropinidine. Tetrahedron Asymmetry 7: 3047–3054.  6. Takahata H, Yotsui Y, Momose T. (1998) A general asymmetric route to trans- or cis-2,6-disubstituted piperidine. First total synthesis of (+)-9-epi6-epipinidinol and (−)-pinidinol. Tetrahedron 54: 13505–13516.   7. Dobbs AP, Guesne SJJ. (2005) Rapid access to trans-2,6-disubstituted piperidines: Expedient total syntheses of (−)-solenopsin A and (+)-epi-dihydropinidine. Synlett 13: 2101–2103.   8. Takahata H, Inose K, Araya N et al. (1994) A new procedure for construction of 2,6-trans-disubstituted piperidines using osmium-catalyzed asymmetric dihydroxylation: Application to the synthesis of (+)-epidihydropinidine and (+)-solenopsin A1. Heterocycle 38: 1961–1964.   9. Takahata H, Saito Y, Ichinose M. (2006) A new route to trans-2,6-disubstituted piperidine-related alkaloids using a novel C2-symmetric 2,6-diallylpiperidine carboxylic acid methyl ester. Org Biomol Chem 48: 1587–1595. 10. Adamo MFA, Aggarwal VK, Sage MA. (1999) An improved resolution of 2-methyl piperidine and its use in the synthesis of homochiral trans-2,6-dialkyl piperidines. Synth Commun 29: 1747–1756. 11. Kavala M, Mathia F, Kozisek J et al. (2011) Efficient total synthesis of (+)-dihydropinidine, (−)-epidihydropinidine, and (−)-pinidinone. J Nat Prod 74: 803–808.

Chapter 5

Galanthamine 1.5.1 Natural Source Galanthus woronowii and Lycoris radia (family: Amaryllidaceae).1–3

1.5.2 Structure

1.5.3 Structural Features The tetracyclic Amaryllidaceae alkaloid galanthamine (1) includes a unique tricyclic benzofuran skeleton bearing a chiral arylated-quaternary carbon center; the seven-membered D-ring with tertiary nitrogen, hydroxyl, and methoxy groups is situated at C-ring and aromatic A-ring, respectively.2

1.5.4 Class of Compounds Alkaloid.1,2 29

30  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

1.5.5 Pharmaceutical Potential (–)-Galanthamine (1) is a selective, reversible, and competitive acetylcholinesterase (AChE) inhibitor,2,4 and it is one of the FDAapproved drugs for symptomatic treatment of Alzheimer’s disease5; it includes the capability to cross the blood–brain barrier (BBB) as well as it is also found to behave as a nicotinic acetylcholine receptor.6

1.5.6 Conventional Approach Amaryllidaceae alkaloid galanthamine (1) has attracted much attention from the organic synthetic community due to its interesting and challeng­ ing scaffold as well as remarkable biological activities.7 However, no commercially viable synthesis of this bioactive natural alkaloid has been established.8 Besides, several synthetic strategies have been developed for the syntheses of tetracyclic galanthamine and its analogs due to the limited supplies of these alkaloids from Mother Nature as a valuable natural source.9 Hence, Barton and Kirby in 1962 reported the total synthesis of galanthamine (1) using the construction of the common precursor norbelladine through a biomimetic but low-yielding intra­ molecular oxidative phenol coupling reaction that established the full ABCD-ring framework.10 Next, various researchers have taken up the challenge of manifesting synthetic pathways as compiled in a review by Garcia and co-workers in 20062 and Hudlicky et al. in 2016.11 However, most of the reported synthetic strategies covered total syntheses of the alkaloids in racemic form.2 After two reviews, total syntheses of alkaloid galanthamine comprise the efforts of Hudlicky and co-workers12 and the Nagase group.13 The unique features of the reported total syntheses include oxidative cyclization, rare metal-catalyzed C–C bond construction, important chiron approach, key ring-closing metathesis, and so on. More recently, Chandrasekhar and co-workers explored the total synthesis of (±)-galanthamine involving crucial regioselective aryne introduction transformation into γ-amino butyric acid (GABA) derivative within ~5% overall yield in 2019.14

1.5.7 Demerits of Conventional Approach The enantioselective formation of the sterically congested quaternary carbon center is the main challenge in the total syntheses of these

Galanthamine    31

galanthamine-type alkaloids including galanthamine (1) as these alkaloids include a unique tricyclic benzofuran core structure having a chiral arylated-quaternary carbon center. Hence, conventional approaches were not free from a few demerits. Zhou et al. constructed the optically pure α-aryloxy cyclohexanone (S)-compound using a hazardous liquid molecule oxalyl chloride9 [LC50 (lethal concentration 50) of oxalyl chloride is 1840 ppm having the 95% confidence interval between 1531 ppm and 2210 ppm].15 A harmful substance trifluoroacetic acid (TFA) was employed to produce the important tetracyclic intermediate (S,R) by the same investigators. Chandrasekhar and co-workers used a corrosive chemical thionyl chloride to build the important ester from the protected γ-amino butyric acid (GABA).14 Besides, the tricyclic [6,5,7]-membered core of galanthamine was constructed by using harmful trifluoroacetic acid (TFA).

1.5.8 Key Features of Total Synthesis Using Ultrasonic Irradiation The key feature of the tetracyclic alkaloid galanthamine (1) includes the formation of the aromatic ring from non-aromatic precursors involving a Diels–Alder cycloaddition reaction. The other unique features of the total synthesis comprise a modified Bischler–Napieralski reaction to construct the seven-membered D-ring, the formation of the keyring substructure, and related quaternary carbon center by employing a palladium-catalyzed intramolecular Alder-ene reaction.16

1.5.9 Type of Reaction N–H bond formation using ultrasonic irradiation.16

1.5.10 Synthetic Strategy Using Ultrasonic Irradiation Substitution reaction (deprotection of tosyl group).16

1.5.11 Synthetic Route Total synthesis of the Amaryllidaceae alkaloid (–)-galanthamine (1) was reported by Banwell and co-workers in 2015 including the formation of

32  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

the seven-membered D-ring through ultrasonic irradiation as a leading step.16 The total synthesis of the naturally occurring tertiary amine galanthamine (1) was commenced from the readily available monoethylene ketal (2) of cyclohexane-1,4-dione to deliver ultrasound precursor methoxyarene (3) that embodies the aromatic ring of galanthamine over several steps involving a Pd0-catalyzed cross-coupling reaction, a saponification reaction, and an intramolecular Alder-ene (IMAE) reaction as key steps. Then, the methoxyarene (3) was treated with Mg in methanol to give the secondary amine (4) in 83% yield through a deprotection reaction using ultrasonication for 16 h as an unconventional activation technique (Scheme 1.5.1). Herein, the role of the ultrasonic irradiation was significant to break the tosyl bond for the construction of the seven-membered D-ring of the natural alkaloid (–)-galanthamine (1). Finally, the tricyclic secondary amine (4) was able to yield the targeted bioactive tetracyclic alkaloid (–)-galanthamine (1) over four steps; the total synthesis using de novo formation of the aromatic ring provided an established precursor (narwedine) to both (+)and (–)-galanthamine.16

Scheme 1.5.1.    Ultrasound-assisted total synthesis of (–)-galanthamine.

Galanthamine    33

References   1. Proskurnina NF, Yakovleva AP. (1952) Alkaloids of Galanthus woronowi. II. Isolation of a new alkaloid [Russian]. Zh Obschchei Khim (J Gen Chem) 22: 1899–1902.   2. Marco-Contelles J, Carreiras MC, Rodriguez C et al. (2006) Synthesis and pharmacology of galantamine. Chem Rev 106: 116–133.   3. Heinrich M, Teoh HL. (2004) Galanthamine from snowdrop — The development of a modern drug against Alzheimer’s disease from local Caucasian knowledge. J Ethnopharmacol 92: 147–162.   4. Sramek JJ, Frackiewicz JE, Cutler NR. (2000) Review of the acetylcholinesterase inhibitor galanthamine. Expert Opin Investig Drugs 9: 2393–2402.   5. Yiannopoulou KG, Papageorgiou SG. (2013) Current and future treatments for Alzheimer’s disease. Ther Adv Neurol Disord 6: 19–33.   6. Hamouda AK, Kimm T, Cohen JB. (2013) Physostigmine and galanthamine bind in the presence of agonist at the canonical and noncanonical subunit interfaces of a nicotinic acetylcholine receptor. J Neurosci 33: 485–494.   7. Cordell GA. (2010) The Alkaloids: Chemistry and Biology, vol. 68. Elsevier, Amsterdam.   8. Appendino G. (2014) Omnia praeclara rara. The quest for ingenol heats up. Angew Chem Int Ed 53: 927–929.   9. Chen JQ, Xie JH, Bao DH et al. (2012) Total synthesis of (−)-galanthamine and (−)-lycoramine via catalytic asymmetric hydrogenation and intramolecular reductive Heck cyclization. Org Lett 14: 2714–2717. 10. Barton DHR, Kirby GW. (1962) 153. Phenol oxidation and biosynthesis. Part V. The synthesis of galanthamine. J Chem Soc 806–817. 11. Rinner U, Dank C, Hudlicky T. (2016) Galanthamine. In Targets in Heterocyclic Systems: Chemistry and Properties, vol. 20. Attanasi OA, Merino P, Spinelli D (Eds.). Societa Chimica Italiana, 283–315. 12. Endoma-Arias MAA, Hudlicky T. (2016) Chemoenzymatic total synthesis of (+)-galanthamine and (+)-narwedine from phenethyl acetate. Chem Eur J 22: 14540–14543. 13. Yamamoto N, Okada T, Harada Y et al. (2017) The application of a specific morphinan template to the synthesis of galanthamine. Tetrahedron 73: 5751–5758. 14. Venkatesh T, Mainkar PS, Chandrasekhar S. (2019) Total synthesis of (±)-galanthamine from GABA through regioselective aryne insertion. Org Biomol Chem 17: 2192–2198. 15. Barbee SJ, Stone JJ, Hilaski RJ. (1995) Acute inhalation toxicology of oxalyl chloride. Am Ind Hyg Assoc J 56: 74–76. 16. Nugent J, Matoušová E, Banwell MG. (2015) A total synthesis of galanthamine involving de novo construction of the aromatic C-ring. Eur J Org Chem 2015: 3771–3778.

Chapter 6

Geigerin, Geigerin Acetate, and 6-Deoxygeigerin 1.6.1 Natural Source Geigeria aspera Harv. (family: Asteraceae).1,2

1.6.2 Structure

1.6.3 Systematic Name (3R,3aS,4S,7aR,8S)-4-hydroxy-3,5,8-trimethyl-3a,4,7a,8,9,9a-hexahydro­ azuleno[6,5-b]furan-2,6(3H,7H)-dione (Geigerin). (3R,3aR,4S,7aR,8S)-3,5,8-trimethyl-2,6-dioxo-2,3,3a,4,6,7,7a,8,9,9adecahydroazuleno[6,5-b]furan-4-yl acetate (Geigerin acetate).

35

36  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

(3R,3aR,7aR,8S)-3,5,8-trimethyl-3a,4,7a,8,9,9a-hexahydro­azuleno[6,5-b] furan-2,6(3H,7H)-dione (6-Deoxygeigerin).

1.6.4 Structural Features Geigerin (1) is a member of the guaian-8,12-olide class which includes six stereogenic centers and was first proposed by Barton and Levisalles based on an elegant series of degradation studies3; the absolute stereochemistry of the natural geigerin (1) was recently reported as 3R,3aS,4S,7aR,8S,9aR.2 The structural feature of the sesquiterpene lactone geigerin (1) comprises one hydroxyl group at C4 position with a bicyclo[5.3.0]decane skeleton, two carbonyl groups, such as α,βunsaturated carbonyl group, and a carbonyl group of the lactone ring as well as three methyl groups.4

1.6.5 Class of Compounds Sesquiterpenes.2

1.6.6 Pharmaceutical Potential Geigerin (1) shows cytotoxicity with the median effective concentrations (EC50s) value of 0.0029 by the methyl-thiazolyl-tetrazolium (MTT) assay2; cytotoxicity of geigerin (1) was ascertained by exposing a murine skeletal myoblast (C2C12) cell line employing the MTT assay. Apoptosis was the major mechanism through which natural sesquiterpene lactone geigerin (1) induced the observed cell death.5

1.6.7 Conventional Approach Sesquiterpene lactones are relatively stable molecules, colorless, and have a bitter taste6; the genus, Geigeria, is a valuable source of sesquiterpene lactones.7 Geigerin (1), a sesquiterpene lactone, was initially isolated in 1936 as colorless needles carrying molecular formula C15H20O4 from Geigeria aspera Harv., a woody, semi-perennial shrub bearing bright yellow flowers, and a South African species of Geigeria, called colloquially as the vermeerbos (“vomiting bush”).8 In 1958, the structure of natural



Geigerin, Geigerin Acetate, and 6-Deoxygeigerin    37

geigerin (1) was first proposed based on an elegant series of degradation studies by Barton and Levisalles3 and its structure was confirmed by X-ray analysis of the 1-bromo derivative of geigerin acetate (2) in 1960.9 Barton and co-workers achieved the partial syntheses of deoxygeigerin and anhydrogeigerin from artemisin in 1964 with full stereochemical control at every step using the critical photochemical rearrangement of the eudesmanolide to the guaianolide skeleton in 0.1–0.3% yield.10 Jacobi  et al. reported a synthetic approach to geigerin (1) involving a chemoselective oxy-Cope transformation and a Diels–Alder/retro-Diels– Alder reaction of an acetylenic oxazole as key steps in 1992.11 In 2003, Depres et al. accomplished a concise total synthesis of 6-deoxygeigerin and a guaian-8,12-olide through a conceptually novel and highly multitalented approach to bicyclo[5.3.0]decanes involving dichloroketene cycloaddition−diazoalkane ring expansion as a crucial step.12 However, in 2019, Maimone and co-workers explored a double-allylation strategy for synthesizing five complex guaianolide natural products from both the Apiaceae and Asteraceae plant families in 9−14 synthetic steps.13

1.6.8 Demerits of Conventional Approach No conventional approach is available for the total synthesis of geigerin (1).4

1.6.9 Key Features of Total Synthesis using Ultrasonic Irradiation The total syntheses of geigerin (1), as well as geigerin acetate (2) and 6-deoxygeigerin (3), feature a versatile, regio- and stereo-selective synthetic approach from the inexpensive starting material tropylium cation without the need for protecting groups.4 It also includes a very efficient 1,6-conjugate addition of ketene acetals together with oxidation, which provided the targeted lactone with the perfect configurations at C7, C11, and C6.4

1.6.10 Type of Reaction C-C bond formation using ultrasonic irradiation.4

38  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

1.6.11 Synthetic Strategy Using Ultrasonic Irradiation Cycloaddition reaction.4

1.6.12 Synthetic Route Depres and co-workers explored the first total synthesis of geigerin (1) and geigerin acetate (2). They accomplished a highly effective secondgeneration total synthesis of 6-deoxygeigerin (3) using cycloaddition reaction under ultrasonic irradiation as a key step4; cycloaddition reactions play an essential role in synthesizing bioactive secondary metabolites as a green methodology due to their high atom efficiency.14 The investigators initiated the total syntheses of sesquiterpene lactones from commercially available tropylium cation (4) to provide a versatile intermediate12 hydroazulenone (7) over three steps in 43% overall yield involving a highly regio- and stereo-controlled [2+2] cycloaddition/ ring-expansion/elimination sequence.15 The tropylium cation (4) was treated with methyllithium (MeLi) in ether at 0–20 °C to deliver ultrasound precursor 7-methylcyclohepta-1,3,5-triene (5). Next, triene (5) was reacted with trichloroacetyl chloride (Cl3CCOCl) in Et2O using

Scheme 1.6.1.    Ultrasound-assisted total syntheses of (±)-geigerin, (±)-geigerin acetate, and (±)-6-deoxygeigerin.



Geigerin, Geigerin Acetate, and 6-Deoxygeigerin    39

ultrasonication at 25–28 °C for 1–2 h to afford the central intermediate hydroazulenone (7) through the construction of the bicyclo dichloro keto compound (6) (Scheme 1.6.1.). Herein, ultrasonication plays a vital role in constructing a C-C bond through a cycloaddition reaction. The second-generation total synthesis of (±)-6-deoxygeigerin (3) (13.6% overall yield) and the first total synthesis of (±)-geigerin (1) and (±)-geigerin acetate (2) (4.9% overall yield) were completed from key hydroazulenone (7) without protecting-group chemistry as another green methodology.4

References  1. Rimington C, Roets GCS, Steyn DG. (1936) Chemical studies upon the ­vermeerbos, Geigeria aspera Harv.I. Isolation of a bitter principle “geigerin”. Onderstepoort J Vet Sci 7: 485–506.   2. Fouche G, Ackerman LGJ, Annette E et al. (2021) Sesquiterpene lactones from Geigeria aspera Harv. and their cytotoxicity. Nat Prod Res 35: 2353–2359.   3. Barton DHR, Levisalles JED. (1958) 912. Sesquiterpenoids. Part XI. The constitution of geigerin. J Chem Soc 4518–4523.  4. Carret S, Depres JP. (2007) Access to Guaianolides: Highly efficient ­stereocontrolled total synthesis of (±)-Geigerin. Angew Chem Int Ed 46: 6870–6873.  5. Botha CJ, Clift SJ, Ferreira GCH et al. (2017) Geigerin-induced cyto­ toxicity in a murine myoblast cell line (C2C12). Onderstepoort J Vet Res 84: 1465.   6. Rodriguez E, Towers GHN, Mitchell JC. (1976) Review, biological activities of sesquiterpene lactones. Phytochemistry 15: 1573–1580.   7. Fadul E, Nizamani A, Rasheed S et al. (2020) Anti-glycating and anti-oxidant compounds from traditionally used anti-diabetic plant Geigeria alata (DC) Oliv. & Hiern. Nat Prod Res 34: 2456–2464.   8. Bajaj Y. (1989) Biotechnology in Agriculture and Forestry, Medicinal and Aromatic Plants II, vol. 7, pp. 227–244. Springer, Berlin.   9. Hamilton JA, McPhail AT, Sim GA. (1960) The structure of acetylbromogeigerin. Proc Chem Soc 278. 10. Barton DHR, Pinhey TJ, Wells RJ. (1964) 483. Photochemical Transformations. Part X V. Synthetic Studies on Geigerin and its Derivatives. J Chem Soc 2518–2526. doi:https://doi.org/10.1039/JR9640002518. 11. Jacobi PA, Touchette KM, Selnick HG. (1992) Bis-Heteroannulation. 16. A Synthetic Approach to Geigerin. J Org Chem 57: 6305–6313.

40  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

12. Coquerel Y, Greene AE, DeprLs JP. (2003) New Approach to Bicyclo[5.3.0] decanes: Stereoselective Guaiane Synthesis. Org Lett 5: 4453–4455. 13. Hu X, Musacchio AJ, Shen X et al. (2019) Allylative approaches to the synthesis of complex Guaianolide Sesquiterpenes from Apiaceae and ­ Asteraceae. J Am Chem Soc 141: 14904−14915. 14. Sarkar D, Bera N, Ghosh S. (2020) [2+2] Photochemical cycloaddition in organic synthesis. Eur J Org Chem 1310–1326. 15. Greene AE, DeprLs JP. (1979) A versatile three-carbon annelation. Synthesis of cyclopentanones and cyclopentanone derivatives from olefins. J Am Chem Soc 101: 4003–4005.

Chapter 7

Haliclonin A 1.7.1 Natural Source Haliclona sp. (marine sponge) (family: Chalinidae).1

1.7.2 Structure

1.7.3 Structural Features Haliclonin A (1) is a macrocyclic diamide alkaloid of a novel skeletal comprising two aza-macrocycles, a trisubstituted double bond (C1–C10) linked to a carbonyl group, a cyclohexanone moiety bearing an exodouble bond, and six-membered lactam moiety. The unique structural feature of this bioactive natural tetracyclic diamide (1) includes an attractive azabicyclo[3.3.1]nonane core with two bridges that construct 15- and 17-membered rings bearing an E-alkene and a (Z,Z)-skipped diene, and a formamide group (an isolated proton at δ 8.02 and its linked amide carbon at δ 162.9).1 41

42  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

1.7.4 Class of Compounds Alkaloid.1

1.7.5 Pharmaceutical Potential The natural alkaloid haliclonin A (1) shows moderate cytotoxicity against the K562 leukemia cell line, with a half-maximal inhibitory concentration (IC50) of 15.9 μg/mL (0.03 μmol). It also displays moderate antibacterial activity with minimum inhibitory concentrations (MIC) of 25, 6.25, 12.5, 12.5, and >100 μg/mL against diverse microbial strains.1

1.7.6 Conventional Approach In 2009, Shin and co-workers isolated natural tetracyclic diamide alkaloid haliclonin A (1) as a colorless gum, [α]20D –23.6 (c 0.14, MeOH) from a marine sponge Haliclona sp. originated from Korean waters.1 A macrocyclic diamide haliclonin A (1) bearing the molecular formula of C32H48N2O4 was deduced by high-resolution fast atom bombardment mass spectra (HRFABMS) analysis (+0.3 mmu) at m/z 525.3696 [M + H]+ (calcd for C32H49N2O4, 525.3692) for the first time.1 The absolute configuration of this alkaloid remained confusing since it was partially assigned as 1E,3S,4R,6S,11S based on the spectroscopic and chemical analyses. Ishihara and co-workers developed a formal synthesis of (−)-haliclonin A (1), including the highly stereoselective tandem radical transformation to create the extremely functionalized azabicyclo[3.3.1] nonane ring system and the enantioselective construction of an all-carbon quaternary center through the Pd-mediated deracemization as crucial steps in 2020.2 The total synthesis of haliclonin A (1) was also achieved by Yokoshima et al. using the formation of a functionalized cyclohexanone fused to a 17-membered ring, reductive C−N bond construction through an N,O-acetal forged the 3-azabicyclo[3.3.1]nonane ring system, and the formation of an allyl alcohol moiety through a sequence concerning stereoselective α-selenylation of the aldehyde as central steps in 2021.3

1.7.7 Demerits of Conventional Approach Ishihara et al. constructed the key compound selenocarbamate using triphosgene which decomposes to liberate a flammable and/or toxic gas;



Haliclonin A    43

however, it is a safer substitute for phosgene as it is solid at room temperature.2 Moreover, the same group used benzenesulfonyl chloride during a three-step sequence containing Lemieux−Johnson oxidation, reductive amination, and benzenesulfonylation; benzenesulfonyl chloride yields hazardous decomposition products, such as chlorine, hydrogen chloride, carbon monoxide, and oxides of sulfur.

1.7.8 Key Features of Total Synthesis Using Ultrasonic Irradiation The unique features of the first asymmetric total synthesis of the macrocyclic alkaloid (–)-haliclonin A (1) comprise the introduction of the stereochemistry of the all-carbon quaternary stereogenic center through a new organocatalytic asymmetric conjugate addition of nitromethane with 3-substituted cyclohex-2-enone, a SmI2-assisted bimolecular reductive coupling of enone with an aldehyde to generate the requisite secondary chiral alcohol, and direct conversion of enol into enone. The structure of natural alkaloid (–)-haliclonin A (1) has been confirmed by this first asymmetric total synthesis, and its absolute configuration is clarified as 1E,3R,4S,6R,11R,13Z,16Z through this enantioselective total synthesis.4

1.7.9 Type of Reaction N–H bond formation using ultrasonic irradiation.4

1.7.10 Synthetic Strategy Using Ultrasonic Irradiation Desulfonylation reaction.4

1.7.11 Synthetic Route In 2016, Huang and co-workers accomplished the first enantioselective total synthesis of the natural bioactive alkaloid (–)-haliclonin A (1) using desulfonylation reaction using ultrasound irradiation as a key step.4 The investigators began the total synthesis from 3-ethoxycyclohex-2-enone (2) to furnish ultrasound precursor tetracyclic diene (13Z,16Z) (3) over several steps involving Dess–Martin oxidation and Wittig reaction as

44  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Scheme 1.7.1.    Ultrasound-assisted total synthesis of (–)-haliclonin A.

leading steps. Herein, ultrasonic irradiation played an important role in delivering the crucial intermediate diamide (4) from tetracyclic diene (3) through a deprotection protocol. Next, tetracyclic diene (3) was desulfonylated using Mg in methanol under ultrasonication as a green tool,5 and the resulting crude amine was treated with ethyl formate/ pyridine (HCOOEt/Py) to provide diamide ketone (4) in 82% yield through formylation reaction (Scheme 1.7.1). Diamide (4) was efficient to produce the targeted natural alkaloid (–)-haliclonin A (1) finally over several steps; new chemistry has been developed to confirm the absolute configuration of the natural alkaloid (–)-haliclonin A (1) successfully.4

References 1. Jang KH, Kang GW, Jeon J et al. (2009) A new macrocyclic diamide from the sponge Haliclona sp. Org Lett 11: 1713–1716. 2. Komine K, Urayama Y, Hosaka T et al. (2020) Formal synthesis of (−)-haliclonin A: Stereoselective construction of an azabicyclo[3.3.1]nonane ring system by a tandem radical reaction. Org Lett 22: 5046–5050. 3. Jin Y, Orihara K, Kawagishi F et al. (2021) Total synthesis of haliclonin A. Angew Chem Int Ed 60: 9666–9671. 4. Guo LD, Huang XZ, Luo SP et al. (2016) Organocatalytic, asymmetric total synthesis of (−)-haliclonin A. Angew Chem Int Ed 55: 4064–4068. 5. Nyasse B, Grehn L, Ragnarsson U. (1997) Mild, efficient cleavage of arenesulfonamides by magnesium reduction. Chem Commun 1997: 1017–1018.

Chapter 8

Hemiasterlin 1.8.1 Natural Source Hemiasterella minor (Kirkpatrick) (family: Hemiasterellidae).1,2

1.8.2 Structure

1.8.3 Systematic Name (S,E)-2,5-dimethyl-4-((S)-N,3,3-trimethyl-2-((S)-3-methyl-3-(1-methyl-1Hindol-3-yl)-2-(methylamino)butanamido)butanamido)hex-2-enoic acid.

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46  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

1.8.4 Structural Features A potent antimitotic agent hemiasterlin (1) includes three sterically congested amino acids. This natural tripeptide (1) comprises three carbonyls, a double bond, an indole heterocycle, a gem-dimethyl group, one iso-propyl, and one tert-butyl group (out of 11 methyls).1

1.8.5 Class of Compounds Tripeptide.1

1.8.6 Pharmaceutical Potential Hemiasterlin (1) exhibits the potent antimitotic activity3 by disrupting microtubule dynamics causing mitotic arrest as well as cell deaths having low- to sub-nanomolar potencies against various cancer cell lines3,4 and has triggered clinical trials of natural tripeptide (1) as an anticancer agent.5

1.8.7 Conventional Approach Kashman et al. isolated cytotoxic peptide hemiasterlin (1) in 1994 from freshly collected sponge Hemiasterella minor as an amorphous white solid bearing molecular formula C30H47N404 which was established by HRFABMS (“magic bullet”).1 Three synthetic strategies have been disclosed for the total synthesis of bioactive hemiasterlin so far, including Lindel and co-workers’ work using ultrasound irradiation as a green tool.6,7 In 1997, Andersen and co-workers reported the total synthesis of the natural product (–)-hemiasterlin (1) involving Evans’ oxazolidinone to construct an enantiomerically pure tetramethyltryptophan unit, Wittig olefination of a carbonyl compound to furnish the desired acid followed by acid hydrolysis and oxidation through a longest linear sequence of 17 steps (total 23 steps).8 Vedejs et al. achieved a total synthesis of (–)-hemiasterlin (1) involving N-benzothiazole-2-sulfonyl (Bts) protecting group for the construction of the peptide bond, an improved enantiocontrolled pathway for the formation of the tetramethyltryptophan subunit by an asymmetric Strecker synthesis with a longest linear sequence of 13 steps (total 20 steps).9 In 2020, the total synthesis of hemiasterlin (1) was explored by Spring et al. through a four-component

Hemiasterlin    47

Ugi reaction as a central step with a longest linear sequence of 10 steps, in 11% overall yield; the convergent synthetic strategy allows quick access to taltobulin (HTI-286), a similarly potent synthetic analog.7

1.8.8 Demerits of Conventional Approach The potent cytotoxic properties of hemiasterlin (1) and its reported derivatives make them attractive candidates for its total synthesis. Conventional approaches for the total synthesis of peptide hemiasterlin (1) were not free from a few demerits such as (S)-N-Boc-tert-leucine reacted with the amino acid salt to afford the functionalized dipeptide in the presence of the DMAP (4-dimethylaminopyridine) in low yield (22%) by the Andersen group8; besides, a corrosive reagent trifluoroacetic acid (TFA) was used to prepare trifluoroacetate salt from dipeptide.8 Vedejs et al. prepared free amino ester through Bts deprotection by thiophenol, which is highly toxic by inhalation.9 Spring et al. also used trifluoroacetic acid (TFA) to synthesize hemiasterlin.7

1.8.9 Key Features of Total Synthesis Using Ultrasonic Irradiation The key feature in the total synthesis of potently cytotoxic marine peptide hemiasterlin (1) consists of assembling the tetramethyltryptophan moiety by tert-prenylation of indole, after that, the formation of the organocatalyzed ahydrazination of a sterically congested aldehyde in high yield with excellent enantioselectivity. The efficient synthesis also comprises 2-bromoN-ethylpyridinium tetrafluoroborate (BEP)-mediated peptide coupling and a new phenonium-type rearrangement of the indole core.6

1.8.10 Type of Reaction O–H bond formation using ultrasonic irradiation.6

1.8.11 Synthetic Strategy Using Ultrasonic Irradiation Saponification reaction.6

48  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

1.8.12 Synthetic Route Lindel and co-workers developed an efficient total synthesis of the cytotoxic tri-peptide hemiasterlin (1) using a key saponification reaction using ultrasonic irradiation in 2017.6 The investigators initiated the total synthesis of this marine bioactive secondary metabolite from indole (2) to afford ultrasound precursor methyl ester (3) over several steps. Next, this ester (3) underwent saponification reaction to provide carboxylic acid involving the suspension of barium hydroxide [Ba(OH)2·8H 2O] in methanol/water by a temperature-controlled ultrasonic bath for 30 h at room temperature as an unconventional activation technique (Scheme 1.8.1). Herein, ultrasonication plays an important role to create the O–H bond by the cleavage of the ester linkage. The hemiasterlin ethyl ester (6) was obtained efficiently from methyl ester (3) by the coupling of the generated carboxylic acid with dipeptide (4) in the presence of

Scheme 1.8.1.    Ultrasound-assisted total synthesis of hemiasterlin.

Hemiasterlin    49

2-bromo-N-ethyl pyridinium tetrafluoroborate (BEP) (5) in 76% yield for only 15 min. Ethyl ester (6) was again saponified by the lithium hydroxide (LiOH) and after work-up,8 it delivered the targeted bioactive hemiasterlin (1) in 67% yield over two steps.6

References 1. Talpir R, Benayahu Y, Kashman Y. (1994) Hemiasterlin and geodiamolide TA; two new cytotoxic peptides from the marine sponge Hemiasterella minor (Kirkpatrick). Tetrahedron Lett 35: 4453–4456. 2. Coleman JE, de Silva ED, Kong F et al. (1995) Cytotoxic peptides from the marine sponge Cymbastela sp. Tetrahedron 51: 10653–10662. 3. Anderson HJ, Coleman JE, Andersen RJ et al. (1997) Cytotoxic peptides hemiasterlin, hemiasterlin A and hemiasterlin B induce mitotic arrest and abnormal spindle formation. Cancer Chemother Pharmacol 39: 223–226. 4. Nieman JA, Coleman JE, Wallace DJ et al. (2003) Synthesis and antimitotic/ cytotoxic activity of hemiasterlin analogues. J Nat Prod 66: 183–199. 5. Rocha-Lima CM, Bayraktar S, MacIntyre J et al. (2012) A phase 1 trial of E7974 administered on day 1 of a 21-day cycle in patients with advanced solid tumors. Cancer 118: 4262–4270. 6. Lang JH, Jones PG, Lindel T. (2017) Total synthesis of the marine natural product hemiasterlin by organocatalyzed α-hydrazination. Chem Eur J 23: 12714–12717. 7. Charoenpattarapreed J, Walsh SJ, Carroll JS (2020) Expeditious total synthesis of hemiasterlin via a convergent multi-component strategy and its use in targeted cancer therapeutics. Angew Chem Int Ed 59: 23045–23050. 8. Andersen RJ, Coleman JE, Piers E et al. (1997) Total synthesis of (−)-hemiasterlin, a structurally novel tripeptide that exhibits potent cytotoxic activity. Tetrahedron Lett 38: 317–320. 9. Vedejs E, Kongkittingam C. (2001) A total synthesis of (−)-hemiasterlin using N-Bts methodology. J Org Chem 66: 7355–7364.

Chapter 9

(–)-Khayasin 1.9.1 Natural Source Khaya senegalensis (family: Meliaceae).1,2

1.9.2 Structure

1.9.3 Systematic Name (4R,4aR,6aS,7R,8S,10R,11S)-4-(furan-3-yl)-8-(2-methoxy-2-oxoethyl)4a,7,9,9-tetramethyl-2,13-dioxo-2,4,4a,5,6,6a,7,8,9,10,11,12dodecahydro-1H-7,11-methanocycloocta[f]isochromen-10-yl isobutyrate.

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52  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

1.9.4 Structural Features The natural tetranortriterpenoid khayasin (1) includes mexicanolide nucleus, δ-lactone ring, and an isobutyryl group located at C-3. Besides, the pentacyclic khayasin (1) comprises a furyl ring substituent located at C-17 and the existence of a Δ8,14 double bound inside its nucleus is another key feature of this natural limonoid.2

1.9.5 Class of Compounds Tetranortriterpenoid.2,3

1.9.6 Pharmaceutical Potential Khayasin (1) displays potent insecticidal properties against the fifth instar larvae of Brontispa longissima (GESTRO) at a concentration of 10 mg/L.2

1.9.7 Conventional Approach In 1966, Taylor et al. isolated a mexicanolide class of limonoid natural product khayasin (1) from Khaya senegalensis.1 WU and co-workers isolated it from the seeds of an Indian mangrove Xylocarpus moluccensis as a white, amorphous powder and also reported the 13C-NMR data of khayasin for the first time in 2010.2 Khayasin (1) bearing a molecular formula of C31H40O8 was established by HRTOF-MS (m/z 563.2625, calcd for [M+Na]+ 563.2621), suggesting that this bioactive secondary metabolite (1) included 12 degrees of unsaturation. Only one total synthesis of this natural product khayasin (1) has been reported using ultrasonic irradiation as a green tool since its isolation about 55 years ago.1,3

1.9.8 Demerits of Conventional Approach No conventional approach has been disclosed to date for the total synthesis of natural tetranortriterpenoid khayasin (1).3

(–)-Khayasin    53

1.9.9 Key Features of Total Synthesis Using Ultrasonic Irradiation The key feature in the first enantioselective total synthesis of insecticide khayasin (1) includes a ketal Claisen rearrangement; it should be noted that the ketal Claisen precursors were both derived from DIP-Clcontrolled asymmetric aldol transformations. The enantioselective total synthesis of the limonoid khayasin (1) together with other natural limonoids mexicanolide (2) and proceranolide (3) was completed through a convergent strategy employing a tactic aimed at incorporating secondary metabolites as improved intermediates.3 Besides, regio- and stereoselective epoxidation of (−)-cipadonoid B occurred to install β-oxygenation at C-3 to deliver key epoxide (4) as a single enantiomer.3

1.9.10 Type of Reaction C–C bond formation using ultrasonic irradiation.3

1.9.11 Synthetic Strategy Using Ultrasonic Irradiation Cascade reaction.3

1.9.12 Synthetic Route Williams and co-workers achieved the first enantioselective total synthesis of the natural tetranortriterpenoid khayasin (1) along with other secondary metabolites mexicanolide (2) and proceranolide (3), using ultrasonic irradiation as a green tool involving a cascade reaction; one-pot ecofriendly cascade reaction includes single reaction solvent, work-up, and purification step as well as a high atom economy.3 Total syntheses of limonoids were initiated from 2-cyclohexenone (4) to furnish a crucial intermediate epoxide (5) over several steps. Next, natural limonoid proceranolide (3) was synthesized by a cascade reaction of a key epoxide (5) with rarely encountered reagent amalgamated aluminum pieces in the

54  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Scheme 1.9.1.  Ultrasound-assisted total syntheses of khayasin, proceranolide, and mexicanolide.

presence of EtOH/H2O/THF/saturated NaHCO3 (87:48:30:3 v/v, 1 mL) at room temperature for 1 h under ultrasonication as an alternative energy input (Scheme 1.9.1). Herein, the role of ultrasound was important to enhance the reaction rate and open the epoxide ring of the vital epoxide (5) followed by a 6-endo-trig cyclization to afford the secondary metabolite proceranolide (3) through cascade reaction successfully.4 Another natural mexicanolide (2) was obtained from proceranolide (3) through the oxidation using the Jones reagent at room temperature for 15 min in 68% yield and acylation of the proceranolide (3) provided targeted khayasin (1) in 71% yield in the presence of the isobutyric acid, the coupling reagent 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) and 4-dimethylaminopyridine (DMAP) for 4 h.

References 1. Adesogan EK, Bevan CWL, Powell JW et al. (1966) Extractives from West African timbers. Part XV. The structure of the low-melting compound from Khaya senegalensis. Chem Commun 27–27. doi:https://doi.org/10.1039/ C19660000027.

(–)-Khayasin    55

2. Zhang J, Yang SX, Yang XB et al. (2010) Mexicanolides from the seeds of a Krishna mangrove, Xylocarpus moluccensis. Chem Pharm Bull 58: 552–555. 3. Faber JM, Eger WA, Williams CM. (2012) Enantioselective total synthesis of the mexicanolides: Khayasin, proceranolide, and mexicanolide. J Org Chem 77: 8913–8921. 4. Corey EJ, Ensley HE. (1973) Highly stereoselective conversion of prostaglandin A2 to the 10, 11.alpha.-oxido derivative using a remotely placed exogenous directing group. J Org Chem 38: 3187–3189.

Chapter 10

Kopsanone 1.10.1 Natural Source Aspidosperma macrocarpon (family: Apocynaceae).1–3

1.10.2 Structure

1.10.3 Systematic Name (3aR,3a1S,5aR,11R)-2,3,3a1,4,5,6,11,12-octahydro-1H-3a,5a-ethano-5,11methanoindolizino[8,1-cd]carbazol-14-one.

1.10.4 Structural Features The core structure of the indole alkaloid kopsanone (1) shares a unique heptacyclic skeleton bearing six stereogenic centers. The key feature of this rigid and cagelike polycyclic skeleton consists of the cyclopropyl ring in which the carbonyl group is situated at C22 (δC 220.2, C-22).3,4

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58  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

1.10.5 Class of Compounds Alkaloid.3

1.10.6 Pharmaceutical Potential Kopsanone (1) shows monoamine oxidase A (MAO-A) inhibitory activity with a half-maximal inhibitory concentration (IC50) value of 0.48 µM2 and colorectal cancer (CRC) activity against colon cancer cells (HCT-116).5

1.10.7 Conventional Approach Phytochemical investigation of the methanolic extract of the Aspidosperma macrocarpon Mart. revealed the isolation of the indole alkaloid kopsanone (1). It was obtained as a yellowish amorphous solid (mp 161–163 °C) bearing molecular formula C20H22N2O, [α]20D –12.3 (c 0.005 in CHCl3).1–3 1H and 13C NMR data of kopsanone (1) exhibited characteristic signals of an indolic alkaloid having kopsane skeleton. In 1983 and 1984, Magnus et al. reported two total syntheses of indole alkaloid kopsanone (1) using the crucial allylation of the C-11 carbanion, the construction of the basic kopsane skeleton via intramolecular Diels– Alder reaction and a Pummerer reaction, and the elimination of the sulfoxide via the anti-Bredt compound as key steps.6,7 In 1985, Kuehne et al. disclosed a biogenetic derivation-inspired approach involving the construction of pentacyclic diene intermediates and an intermolecular Diels–Alder reaction with phenyl vinyl sulfone as crucial steps.8 The first asymmetric total synthesis of kopsanone (1) was achieved by Macmillan and co-workers through the landmark synthesis in 2011 using organocascade catalysis and collective natural product synthesis to facilitate the formation of useful quantities of a range of structurally diverse secondary metabolites from a common molecular scaffold elegantly.9 A brilliant collective strategy towards the total synthesis of Kopsia alkaloids including (–)-kopsanone was disclosed by Qin and co-workers in 2017 by applying intramolecular cyclopropanation using microwave irradiation, an acyloin condensation/rearrangement sequence as central steps.10

Kopsanone    59

1.10.8 Demerits of Conventional Approach Owing to the fascinating structure and the multiple continuous stereogenic centers as well as promising biological activities, heptacyclic kopsanone (1) has been a captivating synthetic target among the organic synthetic community. Each of the total syntheses in polycyclic kopsia indole alkaloids consisting (–)-kopsanone (1) donated elegant contri­ butions as the construction of the all-carbon-substituted quaternary carbon centers are considered to be one of the most significant challenges in the synthetic community. However, conventional approaches were not free from a few demerits. Magnus and co-workers employed high shocksensitive meta-chloroperbenzoic acid (m-CPBA) to construct the diastereomeric sulfoxides through an oxidation reaction.7 The same investigator used harmful trifluoroacetic anhydride during an acidcatalyzed 1,4-elimination reaction.7 Toxic phosgene and fluorinated trifluoroacetic acid (TFA) were used to produce the unsaturated ester from spiroindoline by the Macmillan group.9 The same group employed a hazard liquid oxalyl chloride to synthesize an important imine.

1.10.9 Key Features of Total Synthesis Using Ultrasonic Irradiation The key features in the concise and asymmetric total synthesis of five kopsane alkaloids, including (–)-kopsanone (1), consist of the formation of polycyclic indolines with an excellent control of diastereoselectivities by a remarkable PtCl2 catalyzed intramolecular [3+2] cycloaddition, the preparation of crucial alkynes each bearing two stereogenic centers on a gram scale, and the construction of the tetrahydrocarbazole through a Mannich-type process.4

1.10.10 Type of Reaction N–H bond formation using ultrasonic irradiation.4

1.10.11 Synthetic Strategy Using Ultrasonic Irradiation Deprotection reaction.4

60  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

1.10.12 Synthetic Route In 2020, Ye and co-workers explored a concise and asymmetric total synthesis of five kopsane alkaloids comprising (–)-kopsanone (1) using deprotection of the tosyl group through ultrasonication as a leading step.4 The investigators commenced the total synthesis of (–)-kopsanone (1) from the known aldehyde (3) to furnish ultrasound precursor amino alcohol (4) in excellent yield over four steps. Next, three steps occurred such as the protection of the primary hydroxyl group of the amino alcohol (4) as its ether of tert-butyldimethylsilyl (TBS), masking the amine group as its benzyloxycarbonyl (Cbz) group derivative, and the construction of the vital secondary amine (5) through the deprotection of the N-Ts (tosyl) group in the presence of the magnesium powder in methanol (MeOH) in 62% yield using ultrasonication as a green tool (Scheme 1.10.1). Herein, the ultrasound sonication’s role was significant in efficiently constructing a new N–H bond. Natural bioactive alkaloids such as (–)-kopsanone (1) and N-methyl kopsanone (2) as well as (+)-kopsanol, (–)-epikopsanol, (+)-10,22-dioxokopsane, and (+)-N-methyl-10,22-dioxokopsane were synthesized from key amino alcohol (4) successfully.4

Scheme 1.10.1.    Ultrasound-assisted total syntheses of (–)-kopsanone and (+)-N-methyl10,22-dioxokopsane.

Kopsanone    61

References  1. Ferreira Filho JM, Gilbert B, Kitagawa M et al. (1966) Four heptacyclic alkaloids from Aspidosperma species. J Chem Soc (C) 1260–1266. doi:https:// doi.org/10.1039/J39660001260.   2. Júnior LCK, Bannwart G, Kato L et al. (2015) Kopsanone and N(4)-oxidekopsanone: Two β-carbolinic indole alkaloids with monoamine oxidase A inhibitory activity. Planta Med 81: PW-119.  3. Peixotoa MA, Katob L, Oliveirab CMA et al. (2020) Kopsanone and N-oxide isolated from Aspidosperma macrocarpon Mart. (Apocynaceae) leaves and their MAOA inhibitory activity. Nat Prod Res 22: 1–5.   4. Jia X, Lei H, Han F, Zhang T et al. (2020) Asymmetric total syntheses of kopsane alkaloids via a PtCl2-catalyzed intramolecular [3+2] cycloaddition. Angew Chem Int Ed 59: 12832–12836.  5. Bonfim DP, Nakamura CV, Júnior JXA et al. (2021) Kopsanone inhibits proliferation and migration of invasive colon cancer cells. Phytother Res 35: 3769–3780.  6. Gallagher T, Magnus P. (1983) Synthesis of (±)-kopsanone and (±)-10, 22-dioxokopsane, heptacyclic indole alkaloids. J Am Chem Soc 105: 2086–2087.  7. Magnus P, Gallagher T, Brown P et al. (1984) Synthesis of (±)-10,22dioxokopsane and (±)-kopsanone, heptacyclic indole alkaloids. Synthetic and mechanistic studies. J Am Chem Soc 106: 2105–2114.   8. Kuehne ME, Seaton PJ. (1985) Studies in biomimetic alkaloids synthesis. 13. Total syntheses of racemic aspidofractine, pleiocarpine, pleiocarpinine, kopsinine, N-methylkopsanone, and kopsanone. J Org Chem 50: 4790–4796.  9. Jones SB, Simmons B, Mastracchio A et al. (2011) Collective synthesis of natural products by means of organocascade catalysis. Nature 475: 183–188. 10. Leng L, Zhou X, Liao Q et al. (2017) Asymmetric total syntheses of Kopsia indole alkaloids. Angew Chem Int Ed 56: 3703–3707.

Chapter 11

Nosiheptide (Also known as RP9617) 1.11.1 Natural Source Streptomyces actuosus 40037 (NRRL 2954) (family: Streptomycetaceae).1

1.11.2 Structure

1.11.3 Structural Features A sulfur-containing polypeptidic antibiotic nosiheptide (1) comprises a unique 3-hydroxypyridine core, a sterically hindered aromatic B-ring thiolactone, and five thiazole rings. Structurally, the key feature of this natural series e thiopeptide nosiheptide (1) includes an indolylmethyl 63

64  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

ester, all embedded within a bismacrocyclic scaffold possessing with a pendant dehydroaminoacid side chain.2,3

1.11.4 Class of Compounds Polypeptidic antibiotic.1,2

1.11.5 Pharmaceutical Potential Thiopeptide antibiotic nosiheptide (1) displays highly potent activity against all contemporary methicillin-resistant Staphylococcus aureus (MRSA) strains tested comprising multiple drug-resistant clinical isolates, with minimum inhibitory concentration (MIC) values ≤0.25 mg/L. It exhibits high activity against Enterococcus spp. and the contemporary hypervirulent BI strain of Clostridium difficile; however, it was inactive against most Gram-negative strains tested.4 Historically, bismacrocyclic nosiheptide has been employed as a growth-promoting additive in animal (pigs and poultry) feed5; various thiopeptide antibiotics comprise nosiheptide block protein synthesis through the inhibition of elongation factors Tu and G.6

1.11.6 Conventional Approach In 1948, the first thiopeptide micrococcin was isolated, and the proto­ typical and easily generated thiopeptide thiostrepton has rapidly become the most studied molecule in this group.2,7 Their intriguing structures unified them, which were always constructed on a common central pyridine-derived heterocycle (out of seven heterocyclic rings, such as five thiazoles, one indole, and one pyridine in nosiheptide). A macrocyclic array with several thiazole and oxazole rings and other specific residues, namely dehydroamino acids, are formed by this common core (pyridinederived heterocycle).8 Hensler and co-workers identified a potent fraction obtained from strain CNT-373, a Streptomycetes species originated from marine sediment collected in Nacula Island, Fiji, during the screen of marine-derived actinomycete extract libraries due to anti-MRSA property.4 Purification, as well as identification by NMR of the 1221.16 mol wt active component, considered it as the thiopeptide antibiotic nosiheptide



Nosiheptide (Also known as RP9617)    65

(1).4 Historically, nosiheptide (1) was also referred to as multhiomycin isolated from Streptomyces antibioticus 8446-CC1 in 1970 because 13C NMR and IR spectroscopy, as well as thin-layer chromatography, revealed that it was structurally identical with nosiheptide.2 The oldest known thiopeptide antibiotic nosiheptide, also called RP9671 bearing molecular formula C51H43N13O12S6, was initially isolated from Streptomyces actuous 40037 in the early 1960s by French workers.1 However, the total synthesis of antibiotic nosiheptide (1) was challenging due to its complex structure consisting of six fragments traditionally, such as dehydroalanine, 2,3,5,6-tetrasubstituted pyridine, threonine, threonine–cysteine-derived propenylthiazole, modified glutamate, and 2,3,4-trisubstituted indole.9 Hence, synthetic work on nosiheptide (1) has focused first to create building blocks as well as to develop synthetic methods10–16 such as Moody et al. disclosed the synthesis of the northern-hemisphere fragments involving the construction of the macrolactone/thiolactone from a suitable indole in 21.8% and 16.8% overall yields with appropriate orthogonal protecting groups in 2006.9 The typical A- and B-ring systems of nosiheptide (1) have been synthesized in model studies also such as Arndt et al. went on to report the synthesis of the A ring of the antibiotic nosiheptide (1) using a mild aza-Wittig thiazole ring closure, a novel ScIIIassisted regioselective ester hydrolysis, and a highly effective construction of a macrolactam as key steps in 2009.17 In another study, Moody and co-workers developed the strategy of successive amide, ester, and thioester bond construction between orthogonally protected dicarboxylate, hydroxy-acid, and amino-thiol fragments as a model for the southern hemisphere of the antibiotic nosiheptide (1).18

1.11.7 Demerits of Conventional Approach The total synthesis of antibiotic nosiheptide (1) has been richly inspired by the intricate molecular architectures of thiopeptide. Conventional approaches for synthesizing it were not free from a few demerits, although several groups were involved in its synthesis.9–18 A corrosive reagent trifluoroacetic acid (TFA) in a chlorinated solvent (DCM) was used to prepare the dipeptide and ‘northern-hemisphere’ fragment by the Moody group.9 In another study, the same investigators used a hazardous chemical N,N′-dicyclohexylcarbodiimide to construct the desired indole fragment and ester, yielding up to 40% as the targeted macrocycle.18

66  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

1.11.8 Key Features of Total Synthesis Using Ultrasonic Irradiation A viable total synthesis of the bismacrocyclic thiopeptide antibiotic nosiheptide (1) comprises late-stage construction of a dehydroalanine residue, a demanding macrothiolactonization, and finely tuned depro­ tection of the 3-hydroxypyridine core as key steps.3

1.11.9 Type of Reaction O–H bond formation under ultrasonic irradiation.3

1.11.10 Synthetic Strategy Using Ultrasonic Irradiation Deprotection reaction.3

1.11.11 Synthetic Route Total synthesis of the thiopetide antibiotic nosiheptide (1) was accomplished by Arndt and co-workers through the assembly of an entirely functionalized linear precursor, subsequently consecutive critical macrocyclizations in 2016.3 The total synthesis of natural bismacrocyclic nosiheptide (1) was initiated from 3-nitro-2-methylbenzylalcohol (2) to provide ultrasound precursor trichloro ethyl ester (Tce ester, 3) over eight steps. Next, Tce ester (3) was reacted with Zn in the presence of the 1 M KH2PO4 in THF to furnish the desired acid (4) at 45 °C for 10 h in 95% yields using ultrasonication as a non-polluting source of energy (Scheme 1.11.1). Herein, the role of the ultrasound irradiation was significant in constructing a new –O–H bind of the targeted acid (4) during the deprotection of the trichloro ethyl ester. The bioactive natural antibiotic nosiheptide (1) was finally obtained from key acid (4). This route should be applied in synthesizing the highly potent and structurally surprising antibiotic as it permits the successful exchange of building blocks.3



Nosiheptide (Also known as RP9617)    67

Scheme 1.11.1.    Ultrasound-assisted total syntheses of nosiheptide.

References   1. Benazet F, Cartier M, Florent J et al. (1980) Nosiheptide, a sulfur-containing peptide antibiotic isolated from Streptomyces actuosus 40037. Experientia 36: 414–416.   2. Bagley MC, Dale JW, Merritt EA et al. (2005) Thiopeptide antibiotics. Chem Rev 105: 685–714.   3. Wojtas KP, Riedrich M, Lu JY et al. (2016) Total synthesis of nosiheptide. Angew Chem Int Ed 55: 9772–9776.   4. Haste NM, Thienphrapa W, Tran DN et al. (2012) Activity of the thiopeptide antibiotic nosiheptide against contemporary strains of methicillin-resistant Staphylococcus aureus. J Antibiot 65: 593–598.  5. Benazet F, Cartier JR. (1980) Effect of nosiheptide as a feed additive in chicks on the quantity, duration, prevalence of excretion, and resistance to antibacterial agents of Salmonella typhimurium on the proportion of Escherichia coli and other coliforms resistant to antibacterial agents on their degree of resistance. Poult Sci 59: 1405–1415.

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  6. Cundliffe E, Thompson J. (1981) The mode of action of nosiheptide (multhiomycin) and the mechanism of resistance in the producing organism. J Gen Microbiol. 126: 185–192.  7. Anderson B, Crowfoot-Hodgkin D, Viswamitra MA. (1970) Landmark structure determination of thiostrepton. Nature 225: 233–235.  8. Arndt HD, Schoof S, Lu JY. (2009) Thiopeptide antibiotic biosynthesis. Angew Chem Int Ed 48: 6770–6773.  9. Belhadj T, Nowicki A, Moody CJ. (2006) Synthesis of the ‘northern-­ hemisphere’ fragments of the thiopeptide antibiotic nosiheptide. Synlett 2006: 3033–3036. 10. Iwakawa M, Kobayashi Y, Ikuta SJ et al. (1982) A facile synthetic approach to the fragment D of antibiotic nosiheptide, 2-[1-amino-3-carboxy3-hydroxy-(1S,3S)-propyl]-thiazole-4-carboxylic acid. Chem Lett 11: 1975–1978. 11. Koerber-Ple K, Massiot G. (1995) Total synthesis of nosiheptide. Synthesis of thiazole fragments. J Heterocycl Chem 32: 1309–1315. 12. Umemura K, Tate T, Yamaura MJ et al. (1995) A facile synthesis of fragment D of antibiotic, nosiheptide. Synthesis 11: 1423–1426. 13. Shin C-G, Yamada Y, Hayashi K et al. (1996) Convenient synthesis of fragment E of antibiotic, nosiheptide. Heterocycles 43: 891–898. 14. Umemura K, Noda H, Yoshimura J et al. (1997) The synthesis of fragment A of an antibiotic, nosiheptide. Tetrahedron Lett 38: 3539–3542. 15. Bentley DJ, Fairhurst J, Gallagher PT et al. (2004) Synthesis of the 2,3,4-trisubstituted indole fragments of nosiheptide and glycothiohexide. Org Biomol Chem 2: 701–708. 16. Yonezawa Y, Konn A, Shin CG. (2004) Useful synthesis of 2,3,6-tri- and 2,3,5,6-tetrasubstituted pyridine derivatives from aspartic acid. Heterocycles 63: 2735–2746. 17. Lu JY, Riedrich M, Mikyna M et al. (2009) Aza-Wittig-supported synthesis of the A ring of nosiheptide. Angew Chem Int Ed 48: 8137–8140. 18. Kimber MC, Moody CJ. (2008) Construction of macrocyclic thiodepsipeptides: Synthesis of a nosiheptide ‘southern hemisphere’ model system. Chem Commun 2008: 591–593.

Chapter 12

Psymberin 1.12.1 Natural Source Psammocinia sp. (marine sponge) (family: Irciniidae).1–3

1.12.2 Structure

1.12.3 Systematic Name (2S,3S)-N-((S)-((2S,4R,6R)-6-((2S,3R)-3-((R)-6,8-dihydroxy-5-methyl-1oxoisochroman-3-yl)-2-hydroxybutyl)-4-hydroxy-5,5-dimethyltetrahydro2H-pyran-2-yl)(methoxy)methyl)-2-hydroxy-3-methoxy-5-methylhex5-enamide.

1.12.4 Structural Features The unique structural features of an architecturally complex marine antitumor agent psymberin (1) comprise the pentasubstituted 69

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dihydroisocoumarin unit and a psymberic acid side chain; dihydroisocoumarin unit is characterized by its improved substitution pattern and this unit as well as psymberic acid distinguish this bioactive natural product (1) from the other pederins and result in magnificent cytotoxicity values which overcome the others.1,4 Structurally, it also includes a densely functionalized 2,6-trans-tetrahydropyran skeleton, an  N,O-hemiaminal subunit, and eight stereogenic centers (5S,8S,9S, 11R,13R,15S,16R,17R).5

1.12.5 Class of Compounds Polyketide.5

1.12.6 Pharmaceutical Potential A potent cytotoxin, psymberin (1), shows the selective activity against many tumor types such as various melanoma, breast, and colon cancer cell lines [lethal concentration 50 (LC50) < 2.5 × 10–9 M], and all six of the leukemia cell lines are comparatively immune to it (LC50 > 2.5 × 10–5 M).1

1.12.7 Conventional Approach The isolation of polyketide psymberin (1) was reported by Crews and co-workers in 2004 from the marine sponge Psammocinia sp. accumulated from the waters of Papua New Guinea.1 Independently, Pettit et al. disclosed the isolation of constitutionally identical cytotoxin polyketide irciniastatin A from the extract of dichloromethane/methanol mixture (1:1) of the marine sponge Ircinia ramose in the same year, which was collected in Malaysia.2 De Brabander et al. achieved the first total synthesis of psymberin (1) in 2005 with the fully stereochemical assignment of psymberin/irciniastatin A involving a syn-selective aldol reaction as a key step and confirmed that psymberin and irciniastatin A are structurally identical; the C8-aminal configuration in irciniastatin A was reverse to the corresponding center ascribed for psymberin (1).6 The synthetic community is motivated in the total synthesis of psymberin (1) due to its architecturally intriguing structure and potent biological activity, namely antitumor activity.1 Several groups have reported the total

Psymberin    71

synthesis of psymberin (1)7–12; recent total synthesis has been highlighted herein. In 2011, Floreancig et al. reported concise synthetic routes for the synthesis of psymberin and pederin involving a late-stage multicomponent approach to build the N-acyl aminal linkages.13 In 2012, De Brabander et al. accomplished two synthetic approaches in the total syntheses of psymberin with full structure elucidation; the highlights of the highly convergent first-generation synthesis include a diastereoselective aldol coupling, a new one-pot procedure to transform an amide to the N-acyl aminal reminiscent of secondary metabolite psymberin, and the key features of the second-generation synthesis comprise an effective iridiumcatalyzed enantioselective bisallylation of neopentyl glycol as well as a stepwise Sonogashira coupling/cycloisomerization/reduction sequence to build the dihydroisocoumarin unit.14 In 2013, Smith et al. accomplished a convergent synthetic strategy to access two cytotoxic natural products (+)-irciniastatin A (a.k.a. psymberin) and (−)-irciniastatin B; highlights of this efficient synthetic strategy include a boron-assisted aldol union to install the C(15)–C(17) syn–syn triad, reagent control for the introduction of four stereocenters out of eight stereogenic centers into the tetrahydropyran skeleton, and a late-stage important Curtius rearrangement to introduce the acid-sensitive stereogenic N,O-aminal moiety.15 In 2015, Iwabuchi and co-workers disclosed the total synthesis of irciniastatin A (a.k.a. psymberin) and irciniastatin B, as well as the investigators also conducted a biological evaluation of members of the pederin natural product family, which have significant antitumor activity ((+)-irciniastatin A, half-maximal inhibitory concentration (IC50) (HeLa) 0.49 ± 0.10 nM and (–)-irciniastatin B, 0.25 ± 0.02 nM) and intriguing structural complexity. The key features of the total synthesis of (+)-irciniastatin A and (–)-irciniastatin B comprise Sharpless asymmetric epoxidation-regioselective epoxide ring-opening, an efficient protocol for highly regioselective epoxide ring-opening transformation employing Eu(OTf)3/DTBMP, wide application of AZADO (2-azaadamantane N-oxyl), and its connected nitroxyl radical/oxoammonium salt-catalyzed alcohol oxidation.16

1.12.8 Demerits of Conventional Approach The fascinating structure of the bioactive natural product psymberin (1) possessed an unstable N,O-aminal moiety, stereochemical complexity

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(eight stereogenic centers, 5S,8S,9S,11R,13R,15S,16R,17R), the pentasubstituted dihydroisocoumarin unit, and a highly substituted 2,6-trans-tetrahydropyran core.5 So, it was not easy to prepare this cytotoxic polyketide psymberin (1). Hence, conventional approaches were not free from a few demerits. Iwabuchi et al. used flammable liquid 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl, which causes severe skin burns and eye damage and may cause cancer) to prepare important primary alcohol from the 1,2-diol through a protection–deprotection sequence, neurotoxin dichloromethane was employed several times as a solvent, and the Grignard reagent was used to prepare ketone to install the ethyl ketone moiety which is not safe for green chemistry because Grignard reagent comprises a heat-generating metal (volatile metal magnesium), as well as flammable solvent, namely ether.16 Flammable 2-(trimethylsilyl)ethoxymethyl chloride (SEMCl) was also employed several times by Smith et al.15

1.12.9 Key Features of Total Synthesis Using Ultrasonic Irradiation The key features in the total synthesis of cytotoxic polyketide psymberin (1) comprise a new and effective transannular Michael addition/lactone reduction sequence for the formation of the highly substituted 2,6trans-tetrahydropyran core. Other crucial features in convergent, stereocontrolled total syntheses of natural cytotoxin (1) include a diastereoselective IBr-induced iodocarbonate cyclization to install the C17 stereogenic center and a Diels−Alder/aromatization transformation to introduce the extremely substituted aromatic system.5

1.12.10 Type of Reaction C–C bond formation using ultrasonic irradiation.5

1.12.11 Synthetic Strategy Using Ultrasonic Irradiation Barbier-type reaction.5

Psymberin    73

1.12.12 Synthetic Route Ye and co-workers executed a highly convergent strategy for the completion of the total synthesis of bioactive polyketide psymberin (1) involving a Barbier-type reaction under ultrasonic irradiation as a key step in 20195; the Barbier-type transformation is a powerful tool to generate a new carbon–carbon bond in the total synthesis of several complex secondary metabolites and it is possible in several cases to run the reaction in water, making the method part of sustainable chemistry as relatively inexpensive, water insensitive metals or metal compounds are dedicated in the Barbier reaction.17 First, a separable mixture (1.7:1) of (4) and (5) was prepared by a Barbier-type reaction of the known starting aldehyde (2) with prenyl bromide (3) using freshly activated zinc powder under ultrasound sonication as a green tool (Scheme 1.12.1).18 Herein, ultrasonication plays a key role in providing a new C–C bond during the Barbier-type reaction.18 Next, undesired epimer secondary alcohol (5) was readily transformed into desired alcohol (4) in 85% yield through a twostep sequence using Swern oxidation along with a chelation-controlled reduction. The targeted cytotoxic psymberin (1) was synthesized from alcohol (4) over several steps finally; a highly convergent strategy was conducted to finish the total synthesis under ultrasonication using Barbier

Scheme 1.12.1.    Ultrasound-assisted total synthesis of psymberin.

74  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

reaction as a key step. Total synthesis has been achieved from aldehyde (2) in 27 steps, providing an avenue for synthesizing the natural products and analogs.

References   1. Cichewicz RH, Valeriote FA, Crews P. (2004) Psymberin, a potent spongederived cytotoxin from Psammocinia distantly related to the pederin family. Org Lett 6: 1951–1954.  2. Pettit GR, Xu JP, Chapuis JC et al. (2004) Antineoplastic agents. 520. Isolation and structure of irciniastatins A and B from the Indo-Pacific marine sponge Ircinia ramosa. J Med Chem 47: 1149–1152.   3. Pöppe J, Sutcliffe P, Hooper JNA et al. (2010) CO I barcoding reveals new clades and radiation patterns of Indo-Pacific sponges of the family Irciniidae (Demospongiae: Dictyoceratida). PLoS ONE 5: e9950.   4. Bielitza M, Pietruszka J. (2013) The psymberin story — Biological properties and approaches towards total and analogue syntheses. Angew Chem Int Ed 52: 10960–10985.   5. Yu J, Yang M, Guo Y et al. (2019) Total synthesis of psymberin (irciniastatin A). Org Lett 21: 3670−3673.   6. Jiang X, Garcia-Fortanet J, De Brabander JK. (2005) Synthesis and complete stereochemical assignment of psymberin/irciniastatin A. J Am Chem Soc 127: 11254–11255.   7. Huang X, Shao N, Palani A et al. (2007) The total synthesis of psymberin. Org Lett 9: 2597–2600.   8. Smith ABIII, Jurica JA Walsh SP. (2008) Total synthesis of (+)-psymberin (irciniastatin A): Catalytic reagent control as the strategic cornerstone. Org Lett 10: 5625–5628.   9. Crimmins MT, Stevens JM, Schaaf GM. (2009) Total synthesis of irciniastatin A (psymberin). Org Lett 11: 3990–3993. 10. Shao N, Huang X, Palani A et al. (2009) New applications of PhI(OAc)2 in synthesis: Total synthesis and SAR development of potent antitumor natural product psymberin/irciniastatin A. Synthesis 17: 2855–2872. 11. Watanabe T, Imaizumi T, Chinen T et al. (2010) Syntheses and biological evaluation of irciniastatin A and the C1−C2 alkyne analogue. Org Lett 12: 1040–1043. 12. Byeon SR, Park H, Kim H et al. (2011) Stereoselective synthesis of 2,6-trans-tetrahydropyran via primary diamine-catalyzed oxa-conjugate addition reaction of α,β-unsaturated ketone: Total synthesis of psymberin. Org Lett 13: 5816–5819.

Psymberin    75

13. Wan S, Wu F, Rech JC et al. (2011) Total synthesis and biological evaluation of pederin, psymberin, and highly potent analogs. J Am Chem Soc 133: 16668–16679. 14. Feng Y, Jiang X, De Brabander JK. (2012) Studies toward the unique pederin family member psymberin: Full structure elucidation, two alternative total syntheses, and analogs. J Am Chem Soc 134: 17083–17093. 15. An C, Jurica JA, Walsh SP et al. (2013) Total synthesis of (+)-irciniastatin A (a.k.a. psymberin) and (−)-irciniastatin B. J Org Chem 78: 4278–4296. 16. Uesugi S, Watanabe T, Imaizumi T et al. (2015) Total synthesis and biological evaluation of irciniastatin A (a.k.a. psymberin) and irciniastatin B. J Org Chem 80: 12333–12350. 17. Zhou F, Li CJ. (2014) The Barbier–Grignard-type arylation of aldehydes using unactivated aryl iodides in water. Nat Commun 5: 4254. 18. Rychnovsky SD, Skalitzky DJ. (1990) Stereochemistry of alternating polyol chains: 13C NMR analysis of 1,3-diol acetonides. Tetrahedron Lett 31: 945–948.

Chapter 13

Schilancitrilactone C 1.13.1 Natural Source Schisandra lancifolia (family: Schisandraceae).1

1.13.2 Structure

1.13.3 Structural Features The unique structural feature of two nortriterpenoids schilancitrilactones B (2) and C (1) includes a 5/7/5/5/5-fused pentacyclic ring system bearing a C27 skeleton as well as nine stereogenic centers. Highly oxygenated terpenoids (1) and (2) comprise the three cis-fused five-membered rings having seven contiguous chiral centers and all with the envelope conformations construct a structurally rigid tricyclic ring system1,2; their structures characterize with an α-orientation hydrogen and an α-orientation methyl at C-8 and C-13 positions, which are inappropriate with those of a normal cycloartane triterpenoid.3

77

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1.13.4 Class of Compounds Nortriterpenoid.1

1.13.5 Pharmaceutical Potential Schilancitrilactone C (1) displays anti-HIV-1 activity with a half-maximal effective concentration (EC50) value of 27.54 μg/mL and a therapeutic index (TI) higher than 7.26.1

1.13.6 Conventional Approach In 2012, Sun and co-workers isolated highly oxygenated nortriter­ penoids schilancitrilactone B (2) as colorless chunk crystals and schilancitrilactone C (1) from the stems of Schisandra lancifolia. Both terpenoids (1) and (2) bear the same molecular formula C27H34O8, which was established by HRESIMS analysis ([M+Na]+, m/z 509.2168). The CD spectrum of schilancitrilactone B (2) exhibited a negative Cotton effect at 268 nm (Δε = –9.64), suggesting an R configuration of C-20 in 2. The NMR data of both terpenoids (2) and (1) were very similar; minor differences may arise from the distinctness of the side chains in the eastern hemisphere of (1) and (2); the double bond between C-22 and C-23 of schilancitrilactone C (1) was Z geometry, establishing from the ROESY correlation of H-22 with H-24. Only one total synthesis of this natural product schilancitrilactone C (1) has been reported using ultrasonic irradiation as a non-polluting source of energy since its isolation about 9 years ago.2

1.13.7 Demerits of Conventional Approach No conventional approach has been reported to date for the total synthesis of bioactive natural product schilancitrilactone C (1).2

1.13.8 Key Features of Total Synthesis Using Ultrasonic Irradiation The first total syntheses of natural terpenoids schilancitrilactones B (2) and C (1) have been completed in 17 steps (longest linear sequence) by



Schilancitrilactone C    79

using an intramolecular radical cyclization to deliver the sevenmembered ring as a key step. Besides, late-stage iodination and intermolecular radical addition took place to finish the total syntheses as central steps.2

1.13.9 Type of Reaction C–C bond formation under ultrasonic irradiation.2

1.13.10 Synthetic Strategy Using Ultrasonic Irradiation Cyclization reaction.2

1.13.11 Synthetic Route Tang and co-workers explored the first total syntheses of schilancitrilactone C (1) and schilancitrilactone B (2) from commercially available materials under ultrasonic irradiation as a green tool using intramolecular cyclization as a central step.2 The intramolecular cyclization protocol has presently attracted much attention due to its high efficiency, atom economy, and operational simplicity in the total synthesis of medicinally important molecules and bioactive secondary metabolites.4 The total synthesis was started from L-carvone (3) and 1,3-cyclohexadiene (5); L-carvone (3) provided key intermediate (4) and another starting material 1,3cyclohexadiene (5) delivered another building block (6). Then, treatment of the iodo compound (4) with important tricyclo lactone (6) furnished an ultrasound precursor diene lactone (7) in 83% yield over two steps. The targeted seven-membered cyclization product (8) in 55% yields along with its isomer (9) in 4% yield were synthesized by intramolecular cyclization of the lactone (7) with CuI using Zn in pyridine/water (1:4) under ultrasonication as a green tool (Scheme 1.13.1).5 Two natural products schilancitrilactone C (1) and schilancitrilactone B (2) were obtained from the cyclization product (8) finally; 17 steps (longest linear sequence) were needed from known starting materials to provide secondary metabolites schilancitrilactone C (1) and schilancitrilactone B (2) that open a pathway for the preparations of other compounds associated with these terpenoids, as well as their analogs.

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Scheme 1.13.1.  Ultrasound-assisted total syntheses of schilancitrilactone B and schilancitrilactone C.



Schilancitrilactone C    81

References 1. Luo X, Shi YM, Luo RH et al. (2012) Schilancitrilactones A–C: Three unique nortriterpenoids from Schisandra lancifolia. Org Lett 14: 1286–1289. 2. Wang L, Wang H, Li Y et al. (2015) Total synthesis of schilancitrilactones B and C. Angew Chem Int Ed Engl 54: 5732–5735. 3. Xiao WL, Li RT, Huang SX et al. (2008) Triterpenoids from the Schisandraceae family. Nat Prod Rep 25: 871–891. 4. Amiri SS, Vessally E, Babazadeh M et al. (2017) Intramolecular cyclization of N-allyl propiolamides: A facile synthetic route to highly substituted γ-lactams (a review). RSC Adv 7: 28407–28418. 5. Luche JL, Allavena C. (1988) Ultrasound in organic synthesis 16. Optimisation of the conjugate additions to α,β-unsaturated carbonyl compounds in aqueous media. Tetrahedron Lett 29: 5369–5372.

Chapter 14

(–)-Stenine 1.14.1 Natural Source Stemona species, Stemona sessilifolia (family: Stemonaceae).1,2

1.14.2 Structure

1.14.3 Systematic Name (31R,7aR,8R,8aS,11S,11aS,11bR)-8-ethyl-11-methyldodecahydroazepino [3,2,1-hi]furo[3,2-e]indol-10(2H)-one.

1.14.4 Structural Features The key structural feature of stenine (1) includes central cyclohexane fused to three other rings carrying a stereogenic center at every carbon (total of seven contiguous stereogenic centers), and the presence of a

83

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pyrrolo[1,2-a]azepine nucleus along with a highly substituted perhydroindole ring system is another interesting feature of this alkaloid.1–3

1.14.5 Class of Compounds Alkaloid.1,2

1.14.6 Pharmaceutical Potential Stenine (1) displays significant antiacetylcholinesterase activity with the half-maximal inhibitory concentration (IC50) value of 19.8 ± 2.5 μM.2

1.14.7 Conventional Approach Chinese and Japanese traditional medicines have employed extracts of Stemona and Croomia species as insecticides, which are drugs for the treatment of respiratory ailments.4 In folk Chinese medicines, the roots of Stemonaceae plants are utilized for the treatment of several respiratory diseases. The roots of the Chinese medicinal plant Stemona tuberosa (Stemonaceae) are the source of the interesting secondary metabolite stenine (1), and its structure and absolute configuration were obtained by comparison to the key Stemona alkaloid tuberostemonine.5 Only two asymmetric syntheses have been developed to date9 such as Wipf et al. accomplished the first enantioselective total synthesis of bioactive natural product (–)-stenine (1) by a strategy that takes benefit of a diastereoselective end-group-differentiating cyclization in the crucial oxidation of L-tyrosine in 1995. The unique feature in the total synthesis of the (–)-stenine (1) comprises the transformation of the cis-fused indolone to the trans-fused core of stenine by the reduction of a π-allylpalladium complex and the introduction of four additional stereocenters in a stereoselective way.5 The second asymmetric synthesis has been completed by Morimoto and co-workers involving an intramolecular asymmetric Diels–Alder transformation of the triene synthesized in a convergent manner from three commercially available components and the effective formation of the tricyclic A, B, D ring system as leading steps in 1996.6 Besides, the Stemona alkaloids have attracted substantial interest from synthetic chemists and biological community due to their biological activity and structural complexity and

(–)-Stenine    85

hence this bioactive secondary metabolite stenine has been the focus of various successful synthetic efforts. In 2002, Padwa et al. achieved total synthesis of (±)-stenine involving the construction of the azepinoindole skeleton by the intramolecular [4+2]-cycloaddition of a 2-methylthio-5amidofuran, iodolactonization, and a Keck allylation as key steps.7 In 2005, Aube and co-workers explored an expeditious total synthesis of (±)-stenine using the Diels–Alder/Schmidt reaction sequence for complex synthesis as the leading step.3 The same investigators also reported total syntheses of (±)-stenine and (±)-neostenine by applying a tandem Diels– Alder/azido Schmidt reaction sequence to provide quick access to the core skeleton of various Stemona alkaloids including stenine and neostenine as a central step in 2008.8

1.14.8 Demerits of Conventional Approach Stenine (1) has provided researchers with a synthetic challenge as the difficulty of the total synthesis of the desired stenine (1) arises due to the presence of the central cyclohexane fused to three other rings and having a stereogenic center at every carbon, and hence conventional approaches are not free from a few demerits. Corrosive meta-chloroperoxybenzoic acid was used by the Morimoto group to prepare a key tricyclic ring system from bicyclic trimethylsilyl enol ether6 and Aube et al. also prepared sulfone intermediate using corrosive meta-chloroperoxybenzoic acid.8 Chloroform, dichloromethane, and potent liver toxin DMF were employed by several groups in the total synthesis of this natural product which is not a green solvent.5,6

1.14.9 Key Features of Total Synthesis Using Ultrasonic Irradiation Total synthesis of (–)-stenine (1) provided a catalytic, enantioselective strategy to establish the required stereogenic centers through a highly stereocontrolled and one-pot cyclization. The double Michael addition plays a crucial role in this total synthesis to secure the needed configuration with high enantioselectivity and diastereoselectivity; the first Michael addition provided the desired Michael addition product in the presence of the Evans catalyst using solvent-free conditions in 96% yield and the pivotal cyclization was achieved through the second Michael addition

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with high diastereoselectivity using ultrasonic irradiation as a green protocol.9

1.14.10 Type of Reaction C–C bond formation using ultrasonic irradiation.9

1.14.11 Synthetic Strategy Using Ultrasonic Irradiation Michael addition reaction.9

1.14.12 Synthetic Route An efficient enantioselective total synthesis of (–)-stenine (1) was achieved by Zhang et al. involving classical Michael addition under ultrasound as crucial steps in 20129; the Michael addition is one of the most important reactions for the construction of carbon–carbon bonds which is extensively employed to synthesize all kinds of natural products and drugs with great efficiency, simplicity, and greenness.10 A catalytic, enantioselective total synthesis of (–)-stenine (1) was initiated from commercially available diethoxybutene (2) to furnish a crucial inter­ mediate α,β-unsaturated keto ester (3) over several stages including first Michael addition as a key step. Then, second Michael addition of keto ester (3) took place to afford a valuable Michael addition product (4) with high diastereoselectivity; Michael addition product (4) includes the correct relative configuration in the enol form for the synthesis of (–)-stenine (1). Hence, α,β-unsaturated keto ester (3) undergoes intramolecular Michael addition in the presence of potassium hydroxide (KOH) that was supported on silica gel (KOH/SiO2) in anhydrous THF under ultrasonic irradiation to provide Michael addition product (4) as a crucial intermediate in 80% yield along with β-ketoester (5) in 11% yield (Scheme 1.14.1); the keto form of cyclohexanone derivative (5) comprises five continuous stereogenic centers. Herein, the role of ultrasound was important to increase the yield of the desired product (4) with the extension of time. The targeted natural bioactive alkaloid (–)-stenine (1) was obtained from the valuable intermediate (4) finally;

(–)-Stenine    87

Scheme 1.14.1.    Ultrasound-assisted total synthesis of (–)-stenine.

the total synthesis was completed in 14 steps from readily available material with an overall yield of 5.9%.9

References   1. Uyeo S, Irie H, Haroda H. (1967) The structure of stenine, a new alkaloid occurring in Stemona tuberosa. Chem Pharm Bull 15: 768–770.  2. Lai DH, Yang ZD, Xue WW et al. (2013) Isolation, characterization and acetylcholinesterase inhibitory activity of alkaloids from roots of Stemona sessilifolia. Fitoterapia 89: 257–264.   3. Zeng Y, Aubé J. (2005) An expeditious total synthesis of (±)-stenine. J Am Chem Soc 127: 15712–15713.  4. Götz M, Srunz M. (1975) Tuberostemonine and related compounds: The chemistry of stemona alkaloids. In The Alkaloids, vol. 9. Wiesner G (Ed.). MTP, International Review of Sciences, Organic Chemistry, Series one. Butterworths, London, 143–160.  5. Wipf P, Kim Y, Goldstein DM. (1995) Asymmetric total synthesis of the Stemona alkaloid (-)-stenine. J Am Chem Soc 117: 11106–11112.   6. Morimoto Y, Iwahashi M, Nishida K et al. (1996) Studies on the asymmetric synthesis of Stemona alkaloids: Total synthesis of (-)-stenine. Angew Chem Int Ed Engl 35: 904–906.   7. Ginn JD, Padwa A. (2002) Total synthesis of (±)-stenine using the IMDAF cycloaddition of a 2-methylthio-5-amido-substituted furan. Org Lett 4: 1515–1517.

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  8. Frankowski KJ, Golden JE, Zeng Y et al. (2008) Syntheses of the Stemona alkaloids (±)-stenine, (±)-neostenine, and (±)-13-epineostenine using a stereodivergent Diels-Alder/azido-Schmidt reaction. J Am Chem Soc 130: 6018–6024.  9. Chen J, Chen J, Xie Y et al. (2012) Enantioselective total synthesis of (−)-stenine. Angew Chem Int Ed 51: 1024–1027. 10. Huang G, Li X. (2017) Applications of Michael addition reaction in organic synthesis. Curr Org Synth 14: 568–571.

Chapter 15

Strictinin and Tellimagrandin II 1.15.1 Natural Source of Strictinin Casuarina stricta (family: Casuarinaceae).1,2

1.15.2 Natural Source of Tellimagrandin II Geum japonicum (family: Rosaceae)3,4 and Syzygium aromaticum (family: Myrtaceae).3,4

1.15.3 Structure

1.15.4 Systematic Name (11aR,13S,14R,15R,15aS)-2,3,4,5,6,7,14,15-octahydroxy-9,17-dioxo-9, 11,11a,13,14,15,15a,17-octahydrodibenzo[g,i]pyrano[3,2-b][1,5]dioxa­ cycloundecin-13-yl 3,4,5-trihydroxybenzoate.

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1.15.5 Systematic Name (11aR,13S,14R,15S,15aR)-2,3,4,5,6,7-hexahydroxy-9,17-dioxo9,11,11a,13,14,15,15a,17-octahydrodibenzo[g,i]pyrano[3,2-b][1,5] dioxacycloundecine-13,14,15-triyl tris(3,4,5-trihydroxybenzoate).

1.15.6 Structural Features Ellagitannin is one of the broad types of plant polyphenolic hydrolysable tannins; strictinin (1) is an interesting hydrolysable tannin of the ellagitannin family and tellimagrandin II (2) (eugeniin) is the first of the ellagitannins constructed from 1,2,3,4,6-pentagalloyl-glucose. The unique structural feature of strictinin (1), as well as tellimagrandin II (2) (eugeniin), comprises a central sugar core, usually D-glucose, to which galloyl (esterified 3,4,5-trihydroxybenzoic acid) and hexahydroxy diphenoic acid (HHDP) moieties are added.1,5

1.15.7 Class of Compounds Polyphenols.1,3,5

1.15.8 Pharmaceutical Potential Strictinin (1) exhibits 50% inhibitory concentrations (IC50) for IAVs (influenza A virus) from 0.09 ± 0.021 to 0.28 ± 0.037 μM (mean ± S.E.M.).6



Strictinin and Tellimagrandin II    91

Polyphenol strictinin (1) shows antiallergic activity,7 antiTNBC (triple negative breast cancer) effect with minimal effects on non-malignant tissue,8 and antiviral activity.9 Another ellagitannin tellimagrandin II (2) (eugeniin) displays antiviral efficacy against acyclovir and phosphonoacetic acid (PAA)-resistant herpes simplex virus type 1 (HSV-1) and the wild-type HSV-1.10 Besides, tellimagrandin II (2) displays potent inhibitory activity against MRSA (methicillin-resistant Staphylococcus aureus) having a minimum inhibitory concentration of 128 µg/mL.4

1.15.9 Conventional Approach The architecturally intriguing and biologically active natural glycosides strictinin (1) and tellimagrandin II (2) have spurred interest in the organic synthetic and biological community. 1-O-galloyl-4,6-O-(S)hexahydroxydiphenoyl (HHDP)-β-D-glucopyranose (–)-strictinin (1) was first originated from the leaves of Casuarina stricta and the structure of this natural polyphenol was characterized by Okuda and co-workers in 1983.1,2 Hence, pioneering work on the total synthesis of natural bioactive strictinin (1) was accomplished by Khanbabaee and co-workers involving diastereoselective esterification of benzyl protected hexa­hydroxy­diphenic acid by the D-glucose derived sugar as a leading step elegantly in 1997.11 Yamada et al. achieved a total synthesis of (–)-strictinin (1) in 13 steps and a 78% overall yield from D-glucose using improvements of the 4-O-selective benzylation of methyl gallate, fully diastereoselective synthesis of the 4,6-(S)-HHDP (1-O-galloyl-4,6-O-(S)-hexahydroxydiphenoyl) in quantitative yield, and efficient elimination of the disarmed ethylthio group as key steps in 2013.12 Feldman et al. disclosed the first chemical synthesis of the naturally occurring ellagitannin tellimagrandin II (2) in 1999, involving the atropselective oxidative coupling of appropriately protected galloyl rings and the stereoselective acylation of the derived anomeric alcohol in the presence of a galloyl chloride as key steps.13 Kawabata and co-workers achieved a short-step total synthesis of the natural glycoside tellimagrandin II (2) (eugeniin) using a β-selective glycosidation of a gallic acid derivative and catalyst-controlled site-selective insertion of a galloyl group as central steps in 2017.14

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1.15.10 Demerits of Conventional Approach Although Khanbabaee et al. completed the total synthesis of strictinin (1) using double esterification, the yield of the 4,6-(S)-HHDP (1-O-galloyl4,6-O-(S)-hexahydroxydiphenoyl) compound was only 24% because (R)-protected diphenic acid includes intermolecular esterification yielding dimers (and perhaps higher oligomers), the production of which wastes 1-O-(o-nitrobenzyl)-2,3-di-O-benzyl β-D-glucopyranoside.11 Kawabata et al. and Feldman et al. employed corrosive thionyl chloride to prepare the key diacid chloride from diacid during the total synthesis of tellimagrandin II (2).13,14

1.15.11 Key Features of Total Synthesis Using Ultrasonic Irradiation Short total syntheses of natural glycosides strictinin (1) and tellima­ grandin II (2) were conducted through the sequential and regioselective insertion of galloyl(oxy) groups to unprotected glucose as a key step. Total syntheses of ellagitannins also comprise β-selective glycosidation of a gallic acid derivative and catalyst-controlled regioselective functionalization of a galloyl group into the fundamentally little active hydroxy group of the glucoside as other central steps.5

1.15.12 Type of Reaction C–O bond formation under ultrasonic irradiation.5

1.15.13 Synthetic Strategy Using Ultrasonic Irradiation Stereoselective glycosidation.5

1.15.14 Synthetic Route In 2015, Kawabata and co-workers explored short total syntheses of natural glycosides strictinin (1) and tellimagrandin II (2) by applying the sequential and regioselective introduction of galloyl(oxy) groups into



Strictinin and Tellimagrandin II    93

Scheme 1.15.1.    Ultrasound-assisted total syntheses of strictinin and tellimagrandin II.

unprotected glucose using ultrasonication as a key step.5 Total syntheses of natural bioactive polyphenols strictinin (1) and tellimagrandin II (2) were initiated from glucose as a cheap starting material. Gallic acid trimethoxymethyl ether (4) underwent stereoselective glycosidation with finely ground unprotected glucose powder (3) in 1,4-dioxane as a glycosyl donor in the presence of the diisopropyl azodicarboxylate and triphenylphosphine at room temperature for 30 min to afford the desired β-glycoside (5) in 78% yield with high stereoselectivity (β/α = 99/1) under ultrasound sonication as an alternative source of energy (Scheme 1.15.1). Herein, ultrasound irradiation was used to provide an ester linkage as a key step via Mitsunobu conditions for the smooth development of glycosylation.15 β-Glycoside (5) was effective to deliver strictinin (1) and another ellagitannin tellimagrandin II (2) over several steps, including the catalytic regioselective introduction of a galloyl group as a crucial step.

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Bioactive strictinin (1) was prepared from naturally abundant glucose in five overall steps in 21% overall yield, and natural tellimagrandin II (2) was synthesized from the same starting material in six overall steps in 18% overall yield; the idea of catalyst-controlled regioselective functionalization should motivate the further improvement of direct methods for the synthesis of the architecturally intriguing and biologically potent secondary metabolites with minimal application of protective groups.5

References   1. Okuda T, Yoshida T, Ashida M et al. (1982) Casuariin, stachyurin and strictinin, new ellagitannins from Casuarina stricta and Stachyurus praecox. Chem Pharm Bull 30: 766–769.  2. Okuda T, Yoshida T, Ashida M et al. (1983) Tannis of Casuarina and Stachyurus species. Part 1. Structures of pendunculagin, casuarictin, strictinin, casuarinin, casuariin, and stachyurin. J Chem Soc Perkin Trans 1 1983: 1765–1772.   3. Kurokawa M, Hozumi T, Basnet PM et al. (1998) Purification and characterization of eugeniin as an anti-herpesvirus compound from Geum japonicum and Syzygium aromaticum. J Pharmacol Exp Ther 284: 728–735.   4. Chang YW, Huang WC, Lin CY et al. (2019) Tellimagrandin II, a type of plant polyphenol extracted from Trapa bispinosa inhibits antibiotic resistance of drug-resistant Staphylococcus aureus. Int J Mol Sci 20: 5790.   5. Takeuchi H, Mishiro K, Ueda Y et al. (2015) Total synthesis of ellagitannins through regioselective sequential functionalization of unprotected glucose. Angew Chem Int Ed 54: 6177–6180.   6. Saha RK, Takahashi T, Kurebayashi Y et al. (2010) Antiviral effect of strictinin on influenza virus replication. Antiviral Res 88: 10–18.   7. Tachibana H, Kubo T, Miyase T et al. (2001) Identification of an inhibitor for interleukin 4-induced ε germline transcription and antigen-specific IgE production in vivo. Biochem Biophys Res Commun 280: 53–60.  8. Fultang N, Illendula A, Chen B et al. (2019) Strictinin, a novel ROR1inhibitor, represses triple negative breast cancer survival and migration via modulation of PI3K/AKT/GSK3ß activity. PLOS ONE 14: e0217789.   9. Chen GH, Lin YL, Hsu W et al. (2015) Significant elevation of antiviral activity of strictinin from Pu’er tea after thermal degradation to ellagic acid and gallic acid. J Food Drug Anal 23: 116–123. doi:10.1016/j. jfda.2014.07.007.



Strictinin and Tellimagrandin II    95

10. Kurokawa M, Hozumi T, Tsurita M et al. (2001) Biological characterization of eugeniin as an anti-herpes simplex virus type 1 compound in vitro and in vivo. J Pharmacol Exp Ther 297: 372–379. 11. Khanbabaee K, Schulz C, Lçtzerich K. (1997) Synthesis of enantiomerically pure strictinin using a stereoselective esterification reaction. Tetrahedron Lett 38: 1367–1368. 12. Michihata N, Kaneko Y, Kasai Y et al. (2013) High-yield total synthesis of (–)-strictinin through intramolecular coupling of gallates. J Org Chem 78: 4319–4328. 13. Takeuchi H, Ueda Y, Furuta T et al. (2017) Total synthesis of ellagitannins via sequential site-selective functionalization of unprotected D-glucose. Chem Pharm Bull 65: 25–32. 14. Feldman KS, Sahasrabudhe K. (1999) Ellagitannin chemistry. Syntheses of tellimagrandin II and a dehydrodigalloyl ether-containing dimeric gallotannin analogue of coriariin A. J Org Chem 64: 209–216. 15. Besset C, Chambert S, Fenet B et al. (2009) Direct azidation of unprotected carbohydrates under Mitsunobu conditions using hydrazoic acid. Tetrahedron Lett 50: 7043–7047.

Chapter 16

Tubulysins U and V 1.16.1 Natural Source Archangium gephyra and Angiococus disciformis (tubulysins) (family: Archangiaceae).1,2

1.16.2 Structure

1.16.3 Systematic Name (2S,4R)-4-(2-((1R,3R)-1-acetoxy-4-methyl-3-((2S,3R)-3-methyl-2-((R)1-methylpiperidine-2-carboxamido)pentanamido)pentyl)thiazole-4carboxamido)-2-methyl-5-phenylpentanoic acid (tubulysin U). (2S,4R)-4-(2-((1R,3R)-1-hydroxy-4-methyl-3-((2S,3R)-3-methyl-2-((R)1-methylpiperidine-2-carboxamido)pentanamido)pentyl)thiazole4-carboxamido)-2-methyl-5-phenylpentanoic acid (tubulysin V).

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1.16.4 Structural Features The unique molecular architecture of tubulysins includes four unusual or hydrophobic amino acid fragments such as N-methylpipecolic acid (Mep) at the N terminus, isoleucine (Ile, the only proteinogenic amino acid), and a thiazole-bearing amino acid that features two stereogenic centers dubbed tubuvaline (Tuv), and tubuphenylalanine (Tup) or Tubutyrosine (Tut), with an N- to C-terminal distance of nearly 18 Å (angstrom), bears an aromatic amino acid at the C terminus. Moreover, the N-terminal residue of Tuv is functionalized by a highly uncommon N,O-acetal substituent having different ester functions.3

1.16.5 Class of Compounds Tetrapeptides.1,3

1.16.6 Pharmaceutical Potential Tubulysins display extraordinary anticancer properties and many members of this family are active with growth inhibition of 50% (GI50) values in the low picomolar range against the NCI-60 cancer cell-line panel, as well as some representatives are very antiangiogenic.4 Biologically, tubulysin U (1) was found to show highly potent antiproliferative activity in 1A9 ovarian cancer cells with a half-maximal inhibitory concentration (IC50) value of 0.65 nM, MCF-7 breast cancer cells with an IC50 value of 0.4 nM, and for in vitro inhibition of tubulin polymerization having an IC50 value of 1.9 μM.5

1.16.7 Conventional Approach Hofle, Reichenbach, and co-workers first described the structure, stereochemistry, and biosynthetic pathway of tubulysins and also disclosed the potent cytotoxic property of these compounds. Hence, the total synthesis of tubulysins has been reported by several groups due to their molecular architecture and remarkable biological activities. In 2020, a concise and effective procedure for the total synthesis of tubulysin U (1) and N14-desacetoxytubulysin H was disclosed by Wu et al. involving the installation of the challenging thiazole through an elegant cascade one-pot



Tubulysins U and V    99

process under mild conditions, the application of the stereoselective reductions to secure stereochemistry, reaction scale, and the yield on gram scale as key steps.6 Nicolaou and co-workers accomplished improved, streamlined total syntheses of natural tubulysins U (1) and V (2), pretubulysin D, and permitted quick and effective syntheses of several tubulysin analogs in 2018; these works led to a set of useful structure− activity relationships that furnish powerful path pointing guidance for further optimization of the newest tubulysin analogs.7 Wei et al. achieved an enantioselective total synthesis of tubulysin V (2) from the units of dipeptide, Tuv (non-proteinogenic tubuvaline) and Tup (tubuphenylalanine), involving the preparation of the Tuv unit diastereoselectively from the D-malic acid, the construction of Tup unit by the asymmetric reduction as well as methylation, the elimination of the epimerization, and by deprotection with hydrogenation as central steps in 2016.8 Fecik et al. developed a stereoselective total synthesis of the bioactive natural products tubulysin U (1), tubulysin V (2), its unnatural epimer epitubulysin V, and a series of simplified analogs in 2009 through the biological evaluation of the secondary metabolites which established the significance of the acetate and hydroxyl groups in the Tuv residue and the existence of the tertiary amide between the Ile and Tuv residues for the extraordinarily potent antiproliferative activity of tubulysin U (1).5 Zanda et al. went on to report the efficient total synthesis of tubulysins U (1) and V (2) in chemically/stereochemically pure form and with the perfect stereochemistry in 2007.9

1.16.8 Demerits of Conventional Approach Several conventional approaches were developed for the total synthesis of tubulysins U and V, analog design, and synthesis as well as biological exploration as part of anticancer drug discovery and development programs.7 However, conventional approaches were not free from a few demerits. Wu et al. employed a corrosive reagent trifluoroacetic acid (TFA) to generate dipeptide from the key Tuv fragment and a hazard chemical 2-iodoxybenzoic acid was used to prepare the aldehyde for Tuv fragment and Tup fragment by the same investigators.6 Nicolaou also used TFA several times to prepare tubulysin U methyl ester as well as pretubulysin D and their various analogs.7 Moreover, a highly corrosive chemical acetic anhydride was used to synthesize various

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tubulysin analogs by the same group. Wei et al. applied corrosive benzylbromomagnesium to obtain ketone in comparatively low yield (38%) and TFA was used to generate optically pure amide.8 Fecik et al. also employed a highly corrosive chemical acetic anhydride to synthesize tubulysin U (1).5

1.16.9 Key Features of Total Synthesis Using Ultrasonic Irradiation The key features in a short, stereoselective, and convergent route include coupling between suitably monoprotected Tup and Tuv without racemization, a selective methyl ester hydrolysis without epimerization. The total synthesis of tubulysins also discloses the structure–activity relationship for tubulysins as these compounds can be obtained by a fermentation process that yields less than 10 mg/L.4

1.16.10 Type of Reaction N–H bond formation using ultrasonic irradiation.4

1.16.11 Synthetic Strategy Using Ultrasonic Irradiation Deprotection reaction.4

1.16.12 Synthetic Route Wessjohann and co-workers explored the first stereoselective, convergent total synthesis of two members of the tubulysin family such as tubulysins U (1) and V (2) involving deprotection reaction ultrasound as a key step.4 The investigators planned for a short total synthesis of tubulysins U (1) and V (2) to express the structure–activity relationship for these compounds as tubulysins can be derived by a fermentation process in very low yields (less than 10 mg/L) by various rather tedious chromatographic purification steps.4 The total synthesis of tubulysins U (1) and V (2) was initiated from commercially available (S)-N-Ts-2-benzylaziridine (3) to



Tubulysins U and V    101

Scheme 1.16.1.    Ultrasound-assisted total syntheses of tubulysins U and V.

furnish the ultrasound precursor methylphenylsulfonamido ester (4) over four steps. The key secondary amine (5) was obtained from phenyl ester (4) in the presence of the Mg powder in methanol in a 70% yield using ultrasound irradiation as a green tool (Scheme 1.16.1). Herein, ultrasonication plays an important role to generate a new N–H bond through a deprotection reaction. The targeted bioactive natural products tubulysins U (1) and V (2) were obtained finally from the secondary amine (5) over several steps; the route permits for further structure– activity relationship and biological evaluations of this promising type of anticancer natural products.4

References 1. Sasse F, Steinmetz H, Heil J et al. (2000) Tubulysins, new cytostatic peptides from myxobacteria acting on microtubuli. J Antibiot 53: 879–885. 2. Steinmetz H, Glaser N, Herdtweck E et al. (2004) Isolation, crystal and solution structure determination, and biosynthesis of tubulysins — Powerful inhibitors of tubulin polymerization from myxobacteria. Angew Chem Int Ed 43: 4888–4892. 3. Neri D, Fossati G, Zanda M. (2006) Efforts toward the total synthesis of tubulysins: New hopes for a more effective targeted drug delivery to tumors. ChemMedChem 1: 175–180. 4. Dmling A, Beck B, Eichelberger U et al. (2006) Total synthesis of tubulysin U and V. Angew Chem Int Ed 45: 7235–7239.

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5. Balasubramanian R, Raghavan B, Begaye A et al. (2009) Total synthesis and biological evaluation of Tubulysin U, Tubulysin V, and their analogues. J Med Chem 52: 238–240. 6. Long B, Tao C, Li Y et al. (2020) Total synthesis of tubulysin U and N14desacetoxytubulysin H. Org Biomol Chem 18: 5349–5353. 7. Nicolaou KC, Erande RD, Yin J et al. (2018) Improved total synthesis of tubulysins and design, synthesis, and biological evaluation of new tubulysins with highly potent cytotoxicities against cancer cells as potential payloads for antibody−drug conjugates. J Am Chem Soc 140: 3690−3711. 8. Tao W, Zhou W, Zhou Z et al. (2016) An enantioselective total synthesis of tubulysin V. Tetrahedron 72: 5928–5933. 9. Sani M, Fossati G, Huguenot F et al. (2007) Total synthesis of tubulysins U and V. Angew Chem Int Ed 46: 3526–3529.

Chapter 17

WF-1360F 1.17.1 Natural Source Rhizopus sp. No. F-1360 (ATCC 20577 or FERM P-5362) (family: Mucoraceae).1,2

1.17.2 Structure

1.17.3 Systematic Name (1R,2R,3E,5R,7R,8S,10S,13E,16R)-8-hydroxy-10-((2S,3R,4E,6E,8E)-3methoxy-4,8-dimethyl-9-(2-methyloxazol-4-yl)nona-4,6,8-trien-2-yl)-2,7dimethyl-6,11,19-trioxatricyclo[14.3.1.05,7]icosa-3,13-diene-12,18-dione.

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1.17.4 Structural Features Structural studies of antimitotic WF-1360F (1) revealed that it comprises a 16-membered-ring lactone skeleton bearing an oxazole ring at the side chain (C23–C24) in its structure. Tubulin inhibitor WF-1360F (1), a congener of the antitumor antibiotic rhizoxin (a 16-membered macrolide) includes the conjugated polyene system (UV absorbance maxima at 298, 310, and 324 nm), and the presence of hydroxyl and carboxyl groups are supported by IR spectra (νmax = 3400 and 1700 cm–1); structurally, WF-1360F (1) is a deoxy derivative, 2,3-conjugated lactone derivative, as well as a homolog of the rhizoxin.1–3

1.17.5 Class of Compounds Macrolide.1–3

1.17.6 Pharmaceutical Potential WF-1360F (1) exhibits the growth inhibitory activity1,2; it shows antiproliferative activity against the human pancreatic and colon cancer cell lines with half-maximal inhibitory concentration (IC50) values 5.1 ± 0.74 (MiaPaCa) and 4.5 ± 0.38 (HCT116).4

1.17.7 Conventional Approach Tubulin inhibitor WF-1360F (1) was isolated from Rhizopus sp. as a pale yellow powder ([α]23D + 970); from its molecular formula, C35H47O8N, it was considered to be a deoxy derivative of the antitumor macrolide rhizoxin. Only a single synthesis of natural rhizoxin has been reported to date5; no conventional total synthesis of WF-1360F (1) has been disclosed so far.4 Ohno and co-workers accomplished the first total synthesis of the potent antimitotic polyketide macrolide rhizoxin through a highly stereocontrolled way involving the control of the stereochemistry of the two epoxidations (C2–C3 and C11–C12 double bonds) after the construction of the unsaturated 16-membered macrocyclic lactone as a key step in 1993.5 However, majority of the work described total syntheses of rhizoxin D as the final target structure.6

WF-1360F    105

1.17.8 Demerits of Conventional Approach Okuda and co-workers isolated an unusual 16-membered macrolide from the fungus Rhizopus chinensis Rh-2 as a pale yellow powder in 1984 and named it rhizoxin which displays remarkable antimitotic properties.3 Only one total synthesis of rhizoxin has been completed to date; it was not free from a few demerits, such as Ohno et al. prepared key monoepoxide in comparatively low yields (49%) for four days from the macrocyclic lactone.5 Besides, halogenated solvent dichloromethane (DCM) was employed several times, which is not a green solvent. Moreover, green tools such as ultrasonic irradiation, microwave irradiation, visible-light photochemistry, organic electrochemistry, and flow chemistry were not used as key steps in its total synthesis.5

1.17.9 Key Features of Total Synthesis Using Ultrasonic Irradiation The unique step of the first total synthesis of the antimitotic natural product WF-1360F (1) comprises the construction of the macrocycle through ring-closing alkyne metathesis (RCAM) and it also includes the subsequent effective transformation of the ensuing alkyne moiety into the needed E-configured double bond as a crucial step.4

1.17.10 Type of Reaction C–Sn bond formation using ultrasonic irradiation.4

1.17.11 Synthetic Strategy Using Ultrasonic Irradiation Barbier-type reaction.4

1.17.12 Synthetic Route Altmann and co-workers developed the first total synthesis of the antimitotic WF-1360F (1) using an ultrasound-promoted Barbier-type reaction as a key step in 20134; the widely utilized Barbier-type reaction

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includes the transformation of a carbonyl compound with an alkyl halide (chloride, bromide, and iodide) using magnesium, tin, zinc, aluminum, indium, or its salts. It bears a close similarity to the Grignard reaction, but the key difference is that the organometallic species in the Barbier transformation are created in situ, whereas a Grignard reagent is prepared separately before adding the carbonyl compound. The total synthesis of a 16-membered macrolide WF-1360F (1) was initiated from monobenzyl ether (2) to afford allylic chloride (3) over two steps, including the Appel reaction as a leading step. The targeted stannane (4) was prepared by the ultrasound-promoted Barbier-type reaction of the allylic chloride (3) with tributyltin chloride (Bu3SnCl) using Mg turnings in tetrahydrofuran (THF) using ultrasonication as a non-polluting tool at 0 °C to room temperature in quantitative yield (Scheme 1.17.1).7 Herein, ultrasonic irradiation plays a key role to construct the new C–Sn bond through Barbier-type reaction which comprises inexpensive, water insens­ itive metals or metal compounds, making the method part of sustainable chemistry. The stannane (4) was efficient in furnishing bioactive natural product WF-1360F (1) finally over several steps based on macrocyclization by ring-closing alkyne metathesis as an alternative approach to macrocycle formation; this effective access to vinyl iodide can provide a common precursor for the preparation of side-chainmodified rhizoxin derivatives for structure-activity works and lead optimization.4

Scheme 1.17.1.    Ultrasound-assisted total synthesis of WF-1360F.

WF-1360F    107

References 1. Kiyoto S, Kawai Y, Kawakita T et al. (1986) A new antitumor complex, WF-1360, WF-1360A, B, C, D, E and F. J Antibiot 39: 762–772. 2. Scherlach K, Partida-Martinez LP, Dahse HM et al. (2006) Antimitotic rhizoxin derivatives from a cultured bacterial endosymbiont of the rice pathogenic fungus Rhizopus microspores. J Am Chem Soc 128: 11529–11536. 3. Iwasaki S, Kobayashi H, Furukawa J et al. (1984) Studies on macrocyclic lactone antibiotics. VII. Structure of a phytotoxin “rhizoxin” produced by Rhizopus chinensis. J Antibiot 37: 354–362. 4. Neuhaus CM, Liniger M, Stieger M et al. (2013) Total synthesis of the tubulin inhibitor WF-1360F based on macrocycle formation through ring-closing alkyne metathesis. Angew Chem Int Ed 52: 5866–5870. 5. Nakada M, Kobayashi S, Iwasaki S et al. (1993) The first total synthesis of the antitumor macrolide, rhizoxin. Tetrahedron Lett 34: 1039–1042. 6. Hong J, White JD. (2004) The chemistry and biology of rhizoxins, novel antitumor macrolides from Rhizopus chinensis. Tetrahedron 60: 5653–5681. 7. Naruta Y, Nishigaichi Y, Maruyama K. (1986) Extremely facile and stereoselective preparation of allylstannanes with use of ultrasound. Chem Lett 15: 1857–1860.

Part 2

Application of Microwave in Total Synthesis of Bioactive Natural Products: An Unconventional Activation Technique

Chapter 1

α- and β-Amanitin 2.1.1 Natural Source Amanita phalloides (Vaill. ex Fr.) Link, the notorious “death-cap” mushrooms (family: Amanitaceae).1–3

2.1.2 Structure

2.1.3 Structural Features The unique structural features of an extremely toxic bicyclic octapeptide α-amanitin (1) include posttranslationally modified isoleucine and a 6-hydroxy-tryptathionine-(R)-sulfoxide bridge separating the macrocycle 111

112  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

into two rings.4 Structurally, it also comprises trans-4-hydroxy-proline (Hyp) and notably (2S,3R,4R)-4,5-dihydroxy-isoleucine (DHIle) oxidized amino acids which are responsible for its toxicity.5 β-Amanitin, in which aspartic acid (Asp) substitutes the asparagine (Asn), provides a crystal structure that was suitable to the 1H NMR solution structure of α-amanitin.2,3 A study confirms that all eight peptide groups are situated in the trans conformation; β-amanitin includes distinct regions of hydrophilic and hydrophobic residues as well as two 18-membered rings which were evident from a single crystal X-ray diffraction analysis.3

2.1.4 Class of Compounds Bicyclic polypeptides.2

2.1.5 Pharmaceutical Potential A potent inhibitor of RNA polymerase II (α-amanitin, LD50 = 50−100 μg/ kg, Kd = 10–9 M).6–8

2.1.6 Conventional Approach In 1941, Wieland and Hallermayer isolated the fungal toxins, and their structures were determined in the 1950s and 1960s.9,10 For over 60 years, the only source of α-amanitin is Amanita phalloides, the poisonous “death-cap” mushroom, which has been employed for murder and suicide dating to Roman times.11 “A poisonous mushroom has a peculiar color or odor.” “It will turn a silver coin black.” “It has a devil’s cup.”1 Two conventional approaches are available in the total synthesis of α-amanitin. In 2018, the total synthesis of the death-cap mushroom toxin α-amanitin was achieved by Perrin and coworkers for the first time, involving a sophisticated Savige–Fontana methodology for the construction of the tryptathionine bridge as a crucial step.5 Salient points of this total synthesis comprise an enantioselective synthesis of (2S,3R,4R)4,5-dihydroxy-isoleucine and solvent-dependent diastereoselective sulfoxidation. The convergent and robust total synthesis of one of the deadliest toxins α-amanitin was also accomplished by Sussmuth et al. in 2020 using a [5+1+2]-strategy under the preformation of the thioether



α- and β-Amanitin    113

bond as a key step.12 The synthesis of α-amanitin was conducted entirely in the solution phase by this group which is another key feature of this death cap toxin.

2.1.7 Demerits of Conventional Approach The total synthesis of an extremely toxic α-amanitin remained challenging because its unique structural features resisted synthesis. It comprises three implicit challenges: a synthetic way to the oxidatively delicate 6-hydroxytryptathionine, the preparation of (2S,3R,4R)-4,5-dihydroxy-isoleucine via an enantioselective manner, and the synthesis of the (R)-sulfoxide through a diastereoselective sulfoxidation.4,5 Hence, conventional approaches were not free from a few demerits, such as Perrin et al. employed high shock-sensitive meta-chloroperbenzoic acid (mCPBA) to prepare (R)-sulfoxide (α-amanitin) from very toxic S-deoxy amanitin as a bulkier oxidant through sulfoxidation.5 Besides, a potent liver toxin N,Ndimethylformamide (DMF) was used to produce the octapeptide. The Sussmuth group used a highly corrosive chemical acetic anhydride (Ac2O) to prepare tryptophan.12 Moreover, green tools such as microwave, ultrasonic irradiation, visible-light photochemistry, flow chemistry, and organic electrochemistry were not applied as a central step in its total synthesis.4

2.1.8 Key Features of Total Synthesis Using Microwave Irradiation The key features for the total syntheses of bicyclic octapeptides alphaand beta-amanitin (1 and 2) comprise the construction of the solid phase assembling of a linear octamer following two important consecutive cyclization steps in the solution. The vital non-proteinogenic amino acids such as 6-hydroxy tryptophan and (3R,4R)-dihydroxyisoleucine are obtainable through multistep synthesis on a multigram scale for a scalable synthetic route towards the total syntheses of natural secondary metabolites (1 and 2). To assemble the octapeptide precursor through a coupling reaction under microwave irradiation as a non-polluting source of energy is another salient feature in total syntheses of natural polypeptides (1 and 2).4

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2.1.9 Type of Reaction C–N bond formation using microwave irradiation.4

2.1.10 Synthetic Strategy Using Microwave Irradiation Coupling reaction.4

2.1.11 Synthetic Route In 2020, a facile route for the total syntheses of natural alpha- and betaamanitin (1 and 2) was developed by Muller and co-workers, involving a coupling reaction using microwave irradiation as a leading step.4 The total syntheses of highly toxic bicyclic octapeptides alpha- and beta-amanitin

Scheme 2.1.1.    Microwave-assisted total synthesis of α- and β-amanitin.



α- and β-Amanitin    115

(1 and 2) were initiated from (S)-1-tert-butyl 4-methyl 2-aminosuccinate (3) to furnish microwave precursor tetrahydropyranyl (THP) resin (4) over several steps. Herein, the role of microwave irradiation was crucial to assemble the octapeptide precursor through a coupling transformation. In this crucial step, 4,5-dihydroxyisoleucine (DHIL) was coupled with C-terminal under microwave conditions for 10 min by benzotriazol-1yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP)/N,Ndiisopropylethylamine (DIEA) activation with the N2 bubbling to deliver a key intermediate (5) (Scheme 2.1.1). Finally, the key intermediate (5) was effective in producing natural cyclic peptides (1 and 2) via a scalable synthetic route which makes alpha-amanitin and analogs now accessible for the commercial development of novel payload linkers for antibodydrug conjugates (ADC).4

References   1. Block SS, Stephens RL, Barreto A et al. (1955) Chemical identification of the Amanita toxin in mushrooms. Science 121: 505−506.   2. Tonelli AE, Patel DJ, Wieland T et al. (1978) The structure of a-amanitin in dimethylsulfoxide solution. Biopolymers 17: 1973–1986.   3. Kostansek EC, Lipscomb WN, Yocum RR et al. (1978) Conformation of the mushroom toxin β-amanitin in the crystalline state. Biochemistry 17: 3790–3795.   4. Lutz C, Simon W, Werner-Simon S et al. (2020) Total synthesis of α- and β-amanitin. Angew Chem Int Ed 59: 11390–11393.   5. Matinkhoo K, Pryyma A, Todorovic M et al. (2018) Synthesis of the deathcap mushroom toxin α-amanitin. J Am Chem Soc 140: 6513–6517.  6. Wienland T, Faulstich H. (1991) Fifty years of amanitin. Experientia 47: 1186−1193.   7. Vetter J. (1998) Toxins of Amanita phalloides. Toxicon 36: 13−24.   8. Walton JD, Hallen-Adams HE, Luo H. (2010) Ribosomal biosynthesis of the cyclic peptide toxins of Amanita mushrooms. Biopolymers 94: 659–664.   9. Wieland T, Schmidt G. (1952) Über die Giftstoffe des Knollenblätterpilzes VIII. Justus Liebigs Ann Chem 577: 215–233. 10. Wieland T, Gebert U. (1966) [On the ingredients of the green amanita. XXX. Structures of amanatines]. Justus Liebigs Ann Chem 700: 157–173. 11. Marmion VJ, Wiedemann TEJ. (2002) The death of Claudius. J R Soc Med 95: 260−261. 12. Siegert M-AJ, Knittel CH, Sussmuth RD. (2020) A convergent total synthesis of the death cap toxin a-amanitin. Angew Chem Int Ed 59: 5500–5504.

Chapter 2

(–)-Ambiguine P 2.2.1 Natural Source Cyanobacterium Fischerella ambigua (UTEX 1903).1

2.2.2 Structure

2.2.3 Systematic Name (5aS,8R)-5,5,8,11,11-pentamethyl-8-vinyl-5,5a,6,7,8,11-hexahydro-1H1-azacyclohepta[mno]aceanthrylen-5a-ol.

2.2.4 Structural Features The intriguing structure of hapalindole-related alkaloid ambiguine P comprises a fused pentacyclic scaffold attributing a characteristic 117

118  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

seven-membered ring moiety. It represents a different variant lacking the typical isonitrile or less common nitrile functionality in its structure, found among natural ambiguines.1,2 The most important structural feature of this cyanobacterial alkaloid is that it is the only ambiguine derivative carrying a hydroxyl group at C-15.1

2.2.5 Class of Compound Alkaloid.1

2.2.6 Pharmaceutical Potential Antimicrobial activity against Candida albicans (MIC 32.9 μM).1

2.2.7 Conventional Approach In 2010, a cycloheptane-containing member of the hapalindole alkaloids (–)-ambiguine P was identified from the cultured cyanobacterium Fischerella ambigua (UTEX 1903) as a white amorphous solid first.1 Only one conventional total synthesis of (–)-ambiguine P is available to date since its isolation due to its intriguing structural complexity. Rawal et al. completed a conventional concise total synthesis of it through a [4+3] cycloaddition reaction-inspired strategy and the introduction of the crucial C-15 tertiary hydroxy group by an N-bromosuccinimide (NBS)mediated bromination-nucleophilic substitution sequence.4

2.2.8 Demerits of Conventional Approach Presumably, the additional synthetic challenge for the total synthesis of the more intricate alkaloid (–)-ambiguine P arises due to the indole-fused seven-membered ring in the pentacyclic ambiguines.3 This difficulty has resisted total synthesis efforts.5 A conventional total synthesis of it was disclosed by the Rawal group using a [4+3] cycloaddition reaction as a key step. However, the major product of the reaction was enone through the formal [4+3] cycloaddition reaction conditions rather than tetracycle cycloadduct containing a key seven-membered ring as expected in the model studies during the reaction between diene and alcohol. Moreover,



(–)-Ambiguine P    119

the yield of the formation of the desired tetracycle was comparatively low (56%).4 Besides, green tools such as visible-light photochemistry, flow chemistry, organic electrochemistry, microwave, and ultrasonic irradiation were not employed as a central step in its total synthesis.

2.2.9 Key Features of Total Synthesis Using Microwave Irradiation The salient feature of the first total synthesis of alkaloid ambiguine P includes sequential alkylations of an indole core to build the secondary metabolite’s pentacyclic framework rapidly. Other key features comprise a characteristic-fused seven-membered ring formation through cobaltmediated Nicholas alkylation at C2, the construction of tetrahydro furanimine ring, and the pentacyclic amide formation using the microwave as a green technique.3

2.2.10 Type of Reaction C–O bond-forming reaction under microwave irradiation.3

2.2.11 Synthetic Strategy Using Microwave Irradiation Olefination and nitrile hydration.3

2.2.12 Synthetic Route Sarpong and co-workers accomplished a protecting-group-free (PGF) total synthesis of a pentacyclic alkaloid (–)-ambiguine P (1) by sequential alkylations of indole core and fused seven-membered ring formation via cobalt-mediated Nicholas alkylation.3,6 Microwave irradiation is crucial in affording tetrahydro furan-imine core and pentacyclic amide as the main steps. The total synthesis was started with the elegant Cu(II)-mediated oxidative coupling of indole (2) with (S)-carvone (3) to deliver pentamethylaceanthrylene-8a-carbonitrile (4) over several steps. Next, the treatment of the pentacyclic carbonitrile (4) with trimethylsilylmethyllithium– lithium dimethylaminoethoxide (TMSCH2Li) in THF provided the

120  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Scheme 2.2.1.    Microwave-assisted total synthesis of (–)-ambiguine P.

secondary alcohol, which engaged the nitrile group by pyridinium p-toluenesulfonate (PPTS) in DCE to give key intermediate furan-imine (5) at 120 °C using microwave irradiation as a non-polluting source of energy (Scheme 2.2.1). Then, subsequent cleavage of the TMS group by the tetrabutylammonium fluoride (TBAF) in tetrahydrofuran (THF) delivered amide (6) at 100 °C in 52% yield over three steps using the microwave as another crucial step. Finally, the targeted bioactive secondary metabolite (1) was obtained from important amide (6), and the first total synthesis was finished elegantly in 20 steps from C3-functionalized indole (2).3

References 1. Mo S, Krunic A, Santarsiero BD et al. (2010) Hapalindole-related alkaloids from the cultured cyanobacterium Fischerella ambigua. Phytochemistry 71: 2116–2123.



(–)-Ambiguine P    121

2. Walton K, Berry JP. (2016) Indole alkaloids of the Stigonematales (Cyanophyta): Chemical diversity, biosynthesis and biological activity. Mar Drugs 14: 73. 3. Johnson RE, Ree H, Hartmann M et al. (2019) Total synthesis of pentacyclic (−)-ambiguine P using sequential indole functionalizations. J Am Chem Soc 141: 2233−2237. 4. Xu J, Rawal VH. (2019) Total synthesis of (−)-ambiguine P. J Am Chem Soc 141: 4820−4823. 5. Rafferty RJ, Williams RM. (2011) Synthetic studies on the ambiguine family of alkaloids: Construction of the ABCD ring system. Tetrahedron Lett 52: 2037–2040. 6. Fernandes RA, Kumar P, Choudhary P. (2021) Evolution of strategies in ­protecting-group-free synthesis of natural products: A recent update. Eur J Org Chem 5: 711–740.

Chapter 3

Antibiotic CJ-16,264 2.3.1 Natural Source Fungus CL39457.1

2.3.2 Structure

2.3.3 Systematic Name (2aS,2a1S,7S,7aR)-2a1-hydroxy-7-((1S,2S,4aR,6S,8aR)-2,3,4a,6-tetramethyl1,2,4a,5,6,7,8,8a-octahydronaphthalene-1-carbonyl)tetrahydrofuro[2,3,4-gh]pyrrolizine-2,6(2aH,2a1H)-dione.

123

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2.3.4 Structural Features Structurally, antibiotic CJ-16,264 (1) includes a pyrrolizidinone skeleton with an amide carbonyl group at C-6′, a ketone at C-8′, and its antibacterial activity is supposed to be the presence of the gamma-lactone.1 This natural antibiotic comprises a challenging unique tetramethylated decalin system, which is its most significant structural feature because of the organic synthetic community.2

2.3.5 Class of Compound Antibiotic.1

2.3.6 Pharmaceutical Potential Impressive antibacterial activities against Staphylococcus aureus 01A1120 (MIC = 0.78 μg/mL), Moraxella catarrhalis 87A1055 (MIC = 0.39 μg/mL), and Escherichia coli 51A1051 with altered permeability (MIC = 6.25 μg/mL) and cytotoxic activities (IC90 = 8.0 μg/mL against HeLa cells).1

2.3.7 Conventional Approach Antibiotic CJ-16,264 (1) was first obtained from the fermentation broth of fungus CL39457 as a white amorphous powder bearing molecular formula C23H31NO5 by positive ion HRFAB-MS in 2009.1 Only one conventional approach in the total synthesis of the antibiotic CJ-16,264 (1) is available to date.3 In 2017, Nicolaou and co-workers developed an improved and practical total synthesis of natural antibiotic CJ-16,264 (1) involving an enantioselective preparation of the pyrrolizidine structural domain of the compound as a crucial step.3 Design and the synthesis of a series of racemic and enantiopure derivatives of antibiotic CJ-16,264 (1) were performed by the same group efficiently via the developed synthetic technologies. The biological evaluation was also carried out against drugresistant bacterial strains, which provide fascinating structure–activity relationships and identify several more potent derivatives than the natural product.3



Antibiotic CJ-16,264    125

2.3.8 Demerits of Conventional Approach The organic synthetic community faces a great challenge for the total synthesis of the more complicated antibiotic CJ-16,264 (1) due to a challenging unique tetramethylated decalin system and a complex pyrrolizidinone skeleton presumably. The Nicolaou group achieved a brilliant total synthesis of the antibiotic CJ-16,264 (1); it was not free from a few demerits such as harmful 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) which was employed to produce key amide in comparatively low yield (45%). Furthermore, green tools such as microwave, ultrasonic irradiation, and visible-light photochemistry were not applied as a key step in its total synthesis.3

2.3.9 Key Features of Total Synthesis Using Microwave Irradiation The key features for the first total synthesis of antibiotic CJ-16,264 (1) include the formation of the vinyl iodide through reductive ozonolysis and the preparation of the 26-membered macrolide under Shiina conditions, a new bis-transannular Diels–Alder reaction to construct the highly substituted decalin system. Reductive removal of the sulfonate functionality using microwave irradiation as a green tool is another salient feature of the total synthesis of natural antibiotic CJ-16,264 (1).

2.3.10 Type of Reaction Removal of the sulfonate group using microwave irradiation.2

2.3.11 Synthetic Strategy Using Microwave Irradiation Desulfonation reaction.2

2.3.12 Synthetic Route Nicolaou et al. achieved an enantioselective total synthesis as well as structural revision of the architecturally intriguing and biologically potent

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Scheme 2.3.1.    Microwave-assisted total synthesis of antibiotic CJ-16,264.

antibiotic CJ-16,264 (1) using reductive removal of the sulfonate group under microwave irradiation as a key step in 2015.2 The authors commenced the total synthesis from less costly (R)-citronellal (2) to generate microwave precursor tricyclic lactone (3) over several steps. Next, the key gamma-lactone (3) was converted into the desired ether decalin (4) under microwave irradiation via a four-step sequence, including a reductive removal of the sulfonate group as a crucial step (Scheme 2.3.1). The central step for removing the sulfonate group was conducted with lithium triethylborohydride (LiEt3BH) in THF for 10 min at 80 °C in an 82% yield. The ether decalin (4) was very effective in delivering the natural antibiotic CJ-16,264 (1) finally, which also sets the foundation for the complete structural elucidation of other members of this progressive type of antitumor antibiotics.2

References 1. Sugie Y, Hirai H, Kachi-Tonai H et al. (2001) New pyrrolizidinone antibiotics CJ-16,264 and CJ-16,367. J Antibiot 54: 917–925.



Antibiotic CJ-16,264    127

2. Nicolaou KC, Shah AA, Korman H et al. (2015) Total synthesis and structural revision of antibiotic CJ-16,264. Angew Chem Int Ed 54: 9203–9208. 3. Nicolaou KC, Pulukuri KK, Rigol S et al. (2017) Enantioselective total synthesis of antibiotic CJ-16,264, synthesis and biological evaluation of designed analogues, and discovery of highly potent and simpler antibacterial agents. J Am Chem Soc 139: 15868–15877.

Chapter 4

Echinoside A (Holothurin A2) 2.4.1 Natural Source Okinawa sea cucumber Actinopyga echinites (Jaeger) (family: Holothuriidae).1,2

2.4.2 Structure

2.4.3 Systematic Name (3R,5R,6S)-6-(((3S,3aR,5aS,5bS,7aR,9S,11aS,13R,13aS)-3a,13-dihydroxy3,5a,8,8,11a-pentamethyl-3-(4-methylpentyl)-1-oxo-1,3,3a,4,5,5a,5b, 6,7,7a,8,9,10,11,11a,13-hexadecahydronaphtho[2′,1′:4,5]indeno[1,7a-c] furan-9-yl)oxy)-5-(((2S,3R,5S,6R)-5-(((2S,3R,4S,5R,6R)-4-(((2S,3R,5R,6R)3,5-dihydroxy-6-(hydroxymethyl)-4-methoxytetrahydro-2H-pyran-2-yl) oxy)-3,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)

129

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oxy)-3,4-dihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-4hydroxytetrahydro-2H-pyran-3-yl sulfate.

2.4.4 Structural Features Structurally, the presence of a lanostane-18(20)-lactone (holostane) as the aglycone is the most significant feature of echinoside A and most of its congeners; these secondary metabolites also bear Δ9,11 double bond and 12 α-hydroxy group. Interestingly, the glycans of these compounds are linked solely at the lanostane 3-OH position; it initiates with D-xylose (Xyl) unit first and is extended at its 2-OH position with D-quinovose (Qui) and D-glucose (Glc) finally. The other common features include the existence of the sulfonyl residue at the 4-OH position of the xylose unit and the methyl substituent at the 3-OH position of the final glucose unit.3

2.4.5 Class of Compound Triterpene glycoside.1,3

2.4.6 Pharmaceutical Potential Anticancer4–6 and antifungal activity.1,2

2.4.7 Conventional Approach In 1980, a sulfonylated holostane tetrasaccharide echinoside A was originally isolated from sea cucumber Actinopyga echinites as a potent antifungal agent.1,2 Later on, this typical triterpene glycoside with a molecular formula of C54H87O26SNa·2H 2O (mp 228–230 °C) was also originated from other species of sea cucumbers.1,4,7 Only one total synthesis of this bioactive marine natural product echinoside A was reported in 2017, applying microwave irradiation as a non-polluting source of energy since its isolation about 40 years ago. However, the highly complex architecture of the tetrasaccharide echinoside A has retarded in-depth studies on its total synthesis.3



Echinoside A (Holothurin A2 )    131

2.4.8 Demerits of Conventional Approach No conventional approach has been reported to date for the total synthesis of complex marine metabolite echinoside A.3

2.4.9 Key Features of Total Synthesis Using Microwave Irradiation The main feature of the first total synthesis of complex sulfonylated holostane tetrasaccharide echinoside A comprises glycosylation of 3-hydroxyholostane by the protected xylosyl o-hexynylbenzoate with [PPh3Au]NTf2 at room temperature. 18-Iodo-20-oxo derivative formation with 125-W tungsten lamp as a green methodology, selective oxidation of the primary 18-OH group in triol to provide 18(20)-lactone by Swern oxidation, transposition of the Δ8(9) double bond to Δ9(11), and the 4′-O-sulfonyl derivative formation under microwave irradiation are the salient feature of this total synthesis.3

2.4.10 Type of Reaction S–O bond-forming reaction under microwave irradiation.3

2.4.11 Synthetic Strategy Using Microwave Irradiation Sulphonation using sulfur trioxide–pyridine.

2.4.12 Synthetic Route Total synthesis of a complex marine metabolite echinoside A (1) was reported by Yu and co-workers in 2017 in an efficient way from lanosterol (2) under microwave irradiation as a green tool. The starting material lanosterol (2) was converted into desired microwave precursor (3) over several steps. Next, holostane tetrasaccharide acetate (3) in dimethylformamide (DMF) was reacted with sulfur trioxide (SO3)– pyridine at 50 °C for 10 min to afford the 4′-O-sulfonyl derivative under

132  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

º

º

Scheme 2.4.1.    Microwave-assisted total synthesis of echinoside A.

microwave irradiation as an unconventional activation technique (Scheme 2.4.1), which was then reacted with potassium hydroxide (KOH) in methanol (MeOH) to eliminate all of the acyl groups to deliver bioactive secondary metabolite echinoside A (1) in high yield (85% for two steps). The total synthesis of echinoside A (1) was completed with 0.6% overall yield, and the longest linear sequence (in a total of 63 steps) included 35 operations from commercially available materials (i.e., lanostanol, glucose, and xylose); the present synthesis demonstrates the feasibility of synthetic access to the synthesis of other complex triterpene glycosides and congeners as well as analogs.3

References 1. Kitagawa I, Inamoto T, Fuchida M et al. (1980). Structures of echinoside A and B, two antifungal oligoglycosides from the sea cucumber Actinopyga echinites (JAEGER). Chem Pharm Bull 28: 1651–1653. 2. Kitagawa I, Kobayashi M, Inamoto T et al. (1985). Marine natural products. XIV. Structures of echinosides A and B, antifungal lanostane-oligosides from the sea cucumber Actinopyga echinites (JAEGER). Chem Pharm Bull 33: 5214–5224.



Echinoside A (Holothurin A2 )    133

3. Chen X, Shao X, Li W et al. (2017) Total synthesis of echinoside A, a representative triterpene glycoside of sea cucumbers. Angew Chem Int Ed 56: 7648–7652. 4. Li M, Miao ZH, Chen Z et al. (2010) Echinoside A, a new marine-derived anticancer saponin, targets topoisomerase2alpha by unique interference with its DNA binding and catalytic cycle. Ann Oncol 21: 597–607. 5. Wang J, Han H, Chen X et al. (2014) Cytotoxic and apoptosis-inducing activity of triterpene glycosides from Holothuria scabra and Cucumaria frondosa against HepG2 cells. Mar Drugs 12: 4274–4290. 6. Zhao Q, Xue Y, Wang J-F et al. (2012) In vitro and in vivo anti-tumour activities of echinoside A and ds-echinoside A from Pearsonothuria graeffei. J Sci Food Agric 92: 965–974. 7. Ivanchina NV, Kalinovsky AI, Malyarenko TV et al. (2019) A holothurian triterpene glycoside holothurin A2 (= echinoside A) isolated from the starfish Choriaster granulatus. Nat Prod Commun 14: 1–3.

Chapter 5

(–)-Englerin A 2.5.1 Natural Source Phyllanthus engleri (family: Euphorbiaceae).1

2.5.2 Structure

2.5.3 Systematic Name (1R,3aR,4S,5R,7R,8S,8aR)-5-(2-hydroxyacetoxy)-7-isopropyl-1,4-dimethyldecahydro-4,7-epoxyazulen-8-yl cinnamate.

2.5.4 Structural Features The englerin A comprises a challenging tricyclic structure attributing a trans-fused bicyclo[5.3.0]-guaiane-type moiety and an oxabicyclo[3.2.1]135

136  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

heptane core system having six contiguous stereogenic centers out of seven stereogenic centers as well as a characteristic biologically relevant seven-membered ring.2

2.5.5 Class of Compound Sesquiterpene.1,2

2.5.6 Pharmaceutical Potential A potent renal cancer inhibitor1–4; englerin A selectively inhibits renal cancer cell lines’ growth bearing 50% cell growth inhibition (GI50) between 1 and 87 nM.5

2.5.7 Conventional Approach The interesting molecular structure and fascinating biological activity of englerin A attracted the attention of the organic synthetic and biological community. As a result, various total syntheses have been reported so far since the first reported isolation of it in 2009 from the stem bark of P. engleri, a plant indigenous to East Africa.1 Several groups disclosed its total syntheses; most of them focused on how to effectively construct the characteristic tricyclic framework with several approaches toward the total syntheses of this bioactive secondary metabolite 2,6 In 2019, Tchabanenko and co-workers accomplished total synthesis of (±)-englerin A, and its truncated analogs based on a 1,3-dipolar cycloaddition of a highly substituted pyrylium ylide.7 Wang et al. achieved the total synthesis of (–)-englerin A through intramolecular [3+2] cross cycloaddition between cyclopropane and ketone in 2018.8 The total synthesis of (–)-englerin A was explored by the López group in 2016 via platinum-catalyzed intramolecular [4+3] cycloaddition of allenediene.9 Hashimoto et al. efficiently used diastereo- and enantio-selective carbonyl ylide cycloaddition for the total synthesis of guaiane sesquiterpenetype natural product (–)-englerin A in 2015.10 The total synthesis of (–)-englerin A was completed by Shen and co-workers using ring-closing olefin metathesis and intramolecular iodoetherification in 2014.11 Metz and co-workers went on to report the total synthesis of (–)-englerin A in 2013 involving ring-closing olefin metathesis as a key step.12 In 2012, the



(–)-Englerin A    137

total synthesis of (–)-englerin A was disclosed by Hatakeyama and co-workers involving epoxynitrile cyclization and ring-closing olefin metathesis to make the five- and seven-membered rings of this bioactive sesquiterpene.13 Chain et al. reported the elegant and short total synthesis of (–)-englerin A that leverages simple carbonyl-enabled carbon–carbon bond generations in 2011.14 Echavarren et al. were able to construct the tricyclic moiety of (–)-englerin A through gold(I)-catalyzed [2+2+2] cyclization from a linear precursor in 2010.15 In 2009, the first total synthesis of englerin A was achieved by Christmann and co-workers and they also determined its absolute configuration effectively.16

2.5.8 Demerits of Conventional Approach As most reported total syntheses of englerin A relied on the use of cycloaddition as the crucial step, it needs a conceptually novel total synthesis of it.2 Moreover, most of the reported total syntheses could not apply microwave irradiation as a greener technology. Microwave irradiation has emerged as a greener tool to reduce reaction times dramatically, enhance product yields and purities, promote reproducibility, and decrease unwanted side reactions.

2.5.9 Key Features of Total Synthesis A conceptually novel total synthesis of englerin A includes an asymmetric organocatalytic decarboxylative aldol reaction, neighboring group participation, and the construction of the cyclopentane motif via a sequential Pd-catalyzed Heck reaction-1,4-hydrosilylation-Tamao– Fleming oxidation, and an asymmetric Corey–Bakshi–Shibata (CBS) reduction.2

2.5.10 Type of Reaction C–C bond-forming reaction under microwave irradiation.2

2.5.11 Synthetic Strategy Using Microwave Irradiation Alkylation and decarboxylation reactions.2

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2.5.12 Synthetic Route In 2019, Plietker et al. explored the conceptually novel enantioselective total synthesis of (–)-englerin A (1) involving microwave-assisted Krapcho-condition as a central step.3 They started the total synthesis of (–)-englerin A (1) with the decarboxylative aldol condensation between methylglyoxal (2) and β-ketoacid (3) to furnish important intermediate oxabicyclic β-ketoester (4) over several steps. Alkylation of β-ketoester (4) occurred with the 4-bromo-1-butene in tetrahydrofuran (THF) in the presence of the lithium bis(trimethylsilyl)amide (LiHMDS) and N,N′dimethylpropyleneurea (DMPU) at –78 °C to room temperature and decarboxylation took place with the lithium chloride (LiCl) in wet dimethyl sulfoxide (DMSO) to afford key ketone (5) under microwave irradiation as a non-polluting source of energy at 140 °C in 74% yield with full control of diastereoselectivity (Scheme 2.5.1). The target (–)-englerin A (1) was obtained finally from the important intermediate ketone (5) over eight steps; the total enantioselective synthesis permits the synthesis of the natural product in 6.7% overall yield within 12 steps starting from methylglyoxal (2).2

Scheme 2.5.1.    Microwave-assisted total synthesis of (–)-englerin A.



(–)-Englerin A    139

References   1. Ratnayake R, Covell D, Ransom TT et al. (2009) Englerin A, a selective inhibitor of renal cancer cell growth, from Phyllanthus engleri. Org Lett 11: 57–60.   2. Guo L, Plietker B. (2019) β-Ketoesters as mono‐ or bisnucleophiles: A concise enantioselective total synthesis of (−)-englerin A and B. Angew Chem Int Ed 131: 8434–8438.   3. Wu Z, Zhao S, Fash DM et al. (2017) Englerins: A comprehensive review. J Nat Prod 80: 771–781.  4. Sulzmaier FJ, Li Z, Nakashige ML et al. (2012) Englerin A selectively induces necrosis in human renal cancer cells. PLoS One 7: e48032.   5. Rodrigues T, Sieglitz F, Somovilla VJ et al. (2016) Unveiling (−)-englerin A as a modulator of L-type calcium channels. Angew Chem Int Ed 55: 11077–11081.  6. Hagihara S, Hanaya K, Sugai T et al. (2019) Syntheses of englerin A, a potent renal cancer inhibitor. Asian J Org Chem 8: 48–62.   7. Reagan C, Trevitt G, Tchabanenko K. (2019) Total synthesis of (±)-englerin A and its tuncated analogues. Eur J Org Chem 2019: 1027–1037.  8. Liu P, Cui Y, Chen K et al. (2018) Total syntheses of (−)-englerins A/B, (+)-orientalols E/F, and (−)-oxyphyllol. Org Lett 20: 2517–2521.   9. Nelson R, Gulías M, Mascareñas JL et al. (2016) Concise, enantioselective, and versatile synthesis of (−)-englerin A based on a platinum-catalyzed [4C+3C] cycloaddition of allenedienes. Angew Chem Int Ed 55: 14359–14363. 10. Hanari T, Shimada N, Kurosaki Y et al. (2015) Asymmetric total synthesis of (−)-englerin A through catalytic diastereo- and enantioselective carbonyl ylide cycloaddition. Chem Eur J 21: 11671–11676. 11. Zhang J, Zheng S, Peng W et al. (2014) Total synthesis of (−)-englerin A. Tetrahedron Lett 55: 1339–1341. 12. Zahel M, Keßberg A, Metz P. (2013) A short enantioselective total synthesis of (−)-englerin A. Angew Chem Int Ed 52: 5390–5392. 13. Takahashi K, Komine K, Yokoi Y. (2012) Stereocontrolled total synthesis of (−)-englerin A. J Org Chem 77: 7364−7370. 14. Li Z, Nakashige M, Chain WJ. (2011) A brief synthesis of (−)-englerin A. J Am Chem Soc 133: 6553–6556. 15. Molawi K, Delpont N, Echavarren AM. (2010) Enantioselective synthesis of (−)-englerins A and B. Angew Chem Int Ed 49: 3517–3519. 16. Willot M, Radtke L, Könning D et al. (2009) Total synthesis and absolute configuration of the guaiane sesquiterpene englerin A. Angew Chem Int Ed 48: 9105–9108.

Chapter 6

(+)-Erogorgiaene 2.6.1 Natural Source Pseudopterogorgia elisabethae Bayer (family: Gorgoniidae).1

2.6.2 Structure

2.6.3 Systematic Name (1S,4R)-1,6-dimethyl-4-((S)-6-methylhept-5-en-2-yl)-1,2,3,4-tetrahydronaphthalene.

2.6.4 Structural Features The relatively simple structure of erogorgiaene (1) contains 1,2,4-trisubstituted benzene ring with an aromatic methyl. Other features of the serrulatane skeleton of this bicyclic diterpene included three 141

142  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

stereogenic centers and one olefin of the isobutylene group at the side chain.1

2.6.5 Class of Compound Diterpene.1

2.6.6 Pharmaceutical Potential Potential antitubercular activity (96% growth inhibition of Mycobacterium tuberculosis H37Rv at 12.5 µg/mL concentration).1

2.6.7 Conventional Approach The antimycobacterial serrulatane diterpene erogorgiaene (1) was obtained from the West Indian sea whip P. elisabethae in 2001 for the first time as an optically active colorless oil, [α]25D +24.4° having a molecular formula of C20H30.1 The total syntheses of serrulatane diterpenes comprise chiral reagents/chiral substrates,2 chiral pool,3 and asymmetric catalysis4 to control the desired stereochemistry of important natural products. There are some successful strategies for controlling the stereochemistry of diterpene erogorgiaene (1), an inhibitor of mycobacterium tuberculosis, which are provided herein. The first enantioselective total synthesis of marine diterpene (+)-erogorgiaene (1) was achieved by Hoveyda and co-workers in 2004 involving the chiral-catalyst-controlled conjugate addition in a sequential way to install both the methyl stereogenic centers as key steps.4 Davies et al. disclosed the total synthesis of (+)-erogorgiaene (1) involving the combination of C–H activation and Cope rearrangement protocol to establish the three stereogenic centers as the key steps.5 Yadav et al. demonstrated a total synthesis of erogorgiaene based on an extremely diastereoselective intramolecular Friedel–Crafts transformation of an oxetane obtained through a non-Evans syn aldol coupling in 16 steps.3 Aggarwal and co-workers accomplished the total synthesis of erogorgiaene involving lithiation/borylation methodology as a crucial step in 2011.2 An enantioselective brilliant total synthesis of (–)-erogorgiaene along with its C-11 epimer was completed by Malkov and co-workers using catalytic asymmetric crotylation and anionic oxy-Cope rearrangement as central steps in 2016.6

(+)-Erogorgiaene    143

2.6.8 Demerits of Conventional Approach The total synthesis of diterpene erogorgiaene (1) makes it an attractive synthetic target because of its relatively simple structure and potential antitubercular activity. However, a major challenge related to its stereoselective synthesis is due to the lack of functional groups near the three stereogenic centers of erogorgiaene (1).5,6 Hence, there are a few demerits related to the conventional approach, such as the Hoveyda method that used carcinogenic benzene to prepare β-methyl ketone from enone,4 desired unsaturated ester along with a mixture of the cyclopropane and the diastereomer was obtained from the Davies method,5 and the Malkov methodology that used chloroform as a solvent which is not an example of green solvent.6

2.6.9 Key Features of Total Synthesis Using Microwave Irradiation The Pinnick oxidation of the chiral aldehyde, the stereoselective Cope rearrangement in the presence of the gold catalyst (BINAP(AuCl)2/ AgNTf2), and the elongation of the side with 9-BBN hydroboration followed by palladium-catalyzed Suzuki coupling are key features of the total synthesis of erogorgiaene (1). The other salient feature of this total synthesis includes a cascade intermolecular Diels–Alder reaction of the α-pyrone and norbornadiene microwave irradiation as a green tool.7

2.6.10 Type of Reaction C–C bond-forming reaction under microwave irradiation.7

2.6.11 Synthetic Strategy Using Microwave Irradiation A cascade intermolecular Diels–Alder reaction.7

2.6.12 Synthetic Route Luo and co-workers were intrigued to prepare serrulatane diterpenoids including (+)-erogorgiaene (1) in 2016 by invoking a cascade including an

144  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Scheme 2.6.1.    Microwave-assisted total synthesis of (+)-erogorgiaene.

intermolecular Diels–Alder reaction under microwave irradiation as a key step.7 The authors commenced the total synthesis from cyclohexenone (2) to generate chiral keto ester (3); microwave precursor α-pyrone (4) was obtained from this key keto ester (3) successfully over several steps. Herein, the role of microwave irradiation was crucial to afford bioactive natural product erogorgiaene (1) from α-pyrone (4) in one step. Microwave precursor α-pyrone (4) was heated at 200 °C with 2,5-norbornadiene through a cascade intermolecular Diels–Alder reaction followed by the removal of carbon dioxide and cyclopentadiene using microwave irradiation conditions to furnish (+)-erogorgiaene (1) in 75% yield (Scheme 2.6.1).7

References 1. Rodriguez AD, Ramirez C. (2001) Serrulatane diterpenes with antimycobacterial activity isolated from the West Indian sea whip Pseudopterogorgia elisabethae. J Nat Prod 64: 100–102. 2. Elford TG, Nave S, Sonawane RP et al. (2011) Total synthesis of (+)-erogorgiaene using lithiation-borylation methodology, and stereoselective synthesis of each of its diastereoisomers. J Am Chem Soc 133: 16798–16801. 3. Yadav JS, Basak AK, Srihari P. (2007) An aldol approach to the synthesis of the anti-tubercular agent erogorgiaene. Tetrahedron Lett 48: 2841–2843. 4. Cesati RR, Armas JD, Hoveyda AH. (2004) Enantioselective total synthesis of erogorgiaene: Applications of asymmetric Cu-catalyzed conjugate additions of alkylzincs to acyclic enones. J Am Chem Soc 126: 96–101. 5. Davies HML, Walji AM. (2005) Direct synthesis of (+)-erogorgiaene through a kinetic enantiodifferentiating step. Angew Chem Int Ed 44: 1733–1735.

(+)-Erogorgiaene    145

6. Incerti-Pradillos CA, Kabeshov MA, O’Hora PS et al. (2016) Asymmetric total synthesis of (−)-erogorgiaene and its C-11 epimer and investigation of their antimycobacterial activity. Chem Eur J 22: 14390–14396. 7. Yu X, Su F, Liu C et al. (2016) Enantioselective total syntheses of various amphilectane and serrulatane diterpenoids via cope rearrangements. J Am Chem Soc 138: 6261–6270.

Chapter 7

Fidaxomicin (Tiacumicin B or Lipiarmycin A3 or Clostomicin B1) 2.7.1 Natural Source Actinoplanes deccanensis (family: Micromonosporaceae).1,2

2.7.2 Structure

147

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2.7.3 Systematic Name (2R,3S,4S,5S,6R)-6-(((3E,5E,8S,9E,11S,12R,13E,15E,18S)-12-(((2R,3S, 4R,5S)-3,4-dihydroxy-5-(isobutyryloxy)-6,6-dimethyltetrahydro-2H-pyran2-yl)oxy)-11-ethyl-8-hydroxy-18-((R)-1-hydroxyethyl)-9,13,15trimethyl-2-oxooxacyclooctadeca-3,5,9,13,15-pentaen-3-yl)methoxy)4-hydroxy-5-methoxy-2-methyltetrahydro-2H-pyran-3-yl 3,5-dichloro-2ethyl-4,6-dihydroxybenzoate.

2.7.4 Structural Features Fidaxomicin is structurally attractive due to an 18-membered aglycon macrolactonic core decorated with two unusual sugars, D-noviose and D-rhamnose, which are linked through β-glycosidic bonds, where the eastern glycoside bears a fully substituted dichlororesorcinol unit. The molecule also comprises 14 stereogenic centers and various polysubstituted alkenes.3

2.7.5 Class of Compound Macrolide antibiotic.3,4

2.7.6 Pharmaceutical Potential Antibacterial activity against tuberculosis, an inhibitor of bacterial ribonucleic acid (RNA) polymerase, FDA-approved for the treatment of Clostridium difficile infections in 2011.5–8

2.7.7 Conventional Approach The clinically used antibiotic fidaxomicin originated through fermentation of Actinoplanes deccanensis for the first time in 1975, bearing molecular formula C52~54H74~76Cl2O19 (M.W. = 1073~1099); the exact molecular weight could not be ascertained since no molecular ion is noticeable in the mass spectrum.2 Various research groups have been inspired by the adventure of its total synthesis because of its daunting structure. Gademann et al. reported the first total synthesis of potent bioactive fidaxomicin using an efficient Suzuki coupling of largely functionalized substrates, quick access to the rhamnosyl side chain, and the first



Fidaxomicin (Tiacumicin B or Lipiarmycin A3 or Clostomicin B1)    149

β-selective noviosylation as crucial steps in 2015.9 A β-selective rhamnosylation and the stereoselective construction of both 1,2-cis diols in the β-connected carbohydrate units are also a remarkable feature of this successful approach. In 2020, Roulland and co-workers documented a total synthesis of natural macrolide tiacumicin B (fidaxomicin) based on the extraordinary selectivity of both glycosylations depending on an H-bond directed effect. The remarkable facial β-selective rhamnosylation, a Suzuki cross-coupling reaction to assemble the rhamnoside by the aglycone fragment, and the noviolysation step by the virtually total β-selectivity as central steps provided antibiotic fidaxomicin finally.4

2.7.8 Demerits of Conventional Approach The 18-membered macrolactone core of the natural antibiotic fidaxomicin includes an architecturally complex synthetic target presenting 14 stereogenic centers and diverse polysubstituted alkenes. The challenges in the total synthesis of macrolide fidaxomicin include two inspiring β-selective glycosylations (complication regarding the cis-1,2-diol β-mannose), quick and high-yielding access to the carbohydrate together with orsellinate building blocks, and an acceptable protecting group strategy permitting for selective deprotection.9 So, conventional protocols are not free from a few demerits, such as Gademann group and Roulland group employed highly corrosive and toxic thionyl chloride to prepare the protected resorcylate and TBS-protected product, respectively.4,9 Moreover, the tertiary alcohol was prepared using Grignard reagent (MeMgBr), which is not safe compared to the Barbier reaction, as comparatively inexpensive water-insensitive metals or metal compounds are included in the Barbier reaction. Therefore, it is possible to run the transformation in water, making the protocol more sustainable in various cases. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was employed to prepare tetraol from key alcohol by the Roulland group4; DDQ can decompose in water to release poisonous hydrogen cyanide (HCN).

2.7.9 Key Features of Total Synthesis Using Microwave Irradiation The highly convergent synthetic route for the first enantioselective total synthesis of the protected aglycon of fidaxomicin (1) comprises a diastereoselective vinylogous Mukaiyama aldol conversion, Yamaguchi

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esterification together with a Stille coupling transformation of sterically demanding substrates. The ring-closing metathesis (RCM) of a terminal olefin for macrocyclization under the microwave is another important salient feature for the target product (1), which was successfully synthesized in 14 steps (longest linear sequence) through three mediumsized fragments.3

2.7.10 Type of Reaction C–C bond-forming reactions under microwave irradiation.3

2.7.11 Synthetic Strategy Using Microwave Irradiation Ring-closing metathesis (RCM).3

2.7.12 Synthetic Route An efficient total synthesis of the protected aglycon of fidaxomicin (1) was completed by Gademann et al. in 2015, involving ring-closing metathesis (RCM) of a terminal olefin for macrocyclization under a microwave as a leading step.3 Herein, the known building block (2) acted as a starting material to deliver microwave precursor ester (3) over several steps for the first enantioselective total synthesis of it (1). Next, the unsaturated ester (3) undergoes the crucial RCM smoothly with the second-generation Grubbs catalyst under microwave irradiation as a key step. The central step afforded a mixture of E/Z macrocycles (4a and 4b) at 40 °C in 10 min with an overall yield of 90% (Scheme 2.7.1).10 Finally, the key E-isomer (4a) was able to provide the desired macrocycle diol (1) in 65% yield together with triethylsilane (TES)-deprotected intermediate in a 32% yield, thus permitting a substantial amount of flexibility in developing the points of diversity for preparation of derivatives. The first enantioselective total synthesis of clinically used antibiotic fidaxomicin was also achieved by the same group successfully using acetal formation from the tertiary alcohol under microwave irradiation as a key step.9



Fidaxomicin (Tiacumicin B or Lipiarmycin A3 or Clostomicin B1)    151

Scheme 2.7.1.    Microwave-assisted total synthesis of aglycon of fidaxomicin.

References   1. Parenti F, Pagani H, Beretta G. (1975) Lipiarmycin, a new antibiotic from actinoplanes. J Antibiot 28: 247–252.   2. Coronelli C, White RJ, Lancini GC et al. (1975) Lipiarmycin, a new antibiotic from actinoplanes. J Antibiot 28: 253–259.   3. Miyatake-Ondozabal H, Kaufmann E, Gademann K. (2015) Total synthesis of the protected aglycon of fidaxomicin (tiacumicin B, lipiarmycin A3). Angew Chem Int Ed Engl 54: 1933–1936.   4. Norsikian S, Tresse C, François-Eude M et al. (2020) Total synthesis of tiacumicin B: Implementing H-bond-directed acceptor delivery for highly selective β-glycosylations. Angew Chem Int Ed Engl 59: 6612–6616.   5. Kurabachew M, Lu SHJ, Krastel P et al. (2008) Lipiarmycin targets RNA polymerase and has good activity against multidrug-resistant strains of Mycobacterium tuberculosis. Antimicrob Chemother 62: 713–719.   6. Duggan ST. (2011) Fidaxomicin. Drugs 71: 2445–2456.

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  7. Bedeschi A, Fonte P, Fronza G et al. (2014) The co-identity of lipiarmycin A3 and tiacumicin B. Nat Prod Commun 9: 237–240.   8. Goldstein EJC, Babakhani F, Citron DM. (2012) Antimicrobial activities of fidaxomicin. Clin Infect Dis 55: S143–S148.   9. Kaufmann E, Hattori H, Miyatake-Ondozabal H et al. (2015) Total synthesis of the glycosylated macrolide antibiotic fidaxomicin. Org Lett 17: 3514–3517. 10. Nicolaou KC, Bulger PG, Sarlah D. (2005) Metathesis reactions in total synthesis. Angew Chem Int Ed 44: 4490–4527.

Chapter 8

(−)-Glaucocalyxin A (Leukamenin F) 2.8.1 Natural Source Isodon japonica var. glaucocalyx or Rabdosia japonica var. galucocalyx (family: Labiatae = Lamiaceae).1–4

2.8.2 Structure

2.8.3 Systematic Name (4aS,6R,11aS,11bR,12R)-6,12-dihydroxy-4,4,11b-trimethyl-8-methylenedecahydro-6a,9-methanocyclohepta[a]naphthalene-3,7(2H,8H)-dione.

2.8.4 Structural Features Natural tetracyclic ent-kaurane diterpenoid glaucocalyxin A includes the 14-oxygenated bicyclo[3.2.1]octane core system with exo-methylene

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cyclopentanone ring.5 The presence of oxygen- and stereochemistry-rich chemical skeleton as well as α,β-unsaturated ketone moiety in the D-ring is the common structural feature of this bioactive diterpenoid.6

2.8.5 Class of Compound Diterpenoid.1

2.8.6 Pharmaceutical Potential Cytotoxicity and antitumour activity,1,7 immunosuppressive activity,8 inhibi­ tion of platelet-activating factor (PAF)-induced platelet aggregation,9 and antioxidative and DNA damage protective activity.10 Glaucocalyxin A has been investigated to inhibit the proliferation of a wide variety of tumor cells.11 It is interesting to be noted that the α-methylene cyclopentanone system in D-ring was believed to be related to their diversity of biological properties.12

2.8.7 Conventional Approach Natural ent-kaurane diterpenoid Glaucocalyxin A (7α,14β-dihydroxy-entkaur-16-en-3,15-dione) or leukamenin F (synonym) was isolated from the leaves of Rabdosia umbrosa var. leucantha f. Kameba with a molecular formula of C20H28O4.2,3 In 2020, only one total synthesis of (–)-glaucocalyxin A has been completed using microwave irradiation as a green tool since its isolation nearly 40 years ago.5 Synthetic efforts toward the total synthesis of this diterpenoid have been especially limited, perhaps due to the presence of a highly oxygenated bicyclo[3.2.1]octane ring system.5 Moreover, it is a tremendous challenge for chemical synthesis to introduce the C14-OH by applying the previously reported strategies.13–15

2.8.8 Demerits of Conventional Approach No conventional approach was available for the total synthesis of (–)-glaucocalyxin A.5



(−)-Glaucocalyxin A (Leukamenin F)    155

2.8.9 Key Features of Total Synthesis A practically effective method for the preparation of the highly 14-oxygenated bicyclo[3.2.1]octane ring system was performed by Mn(OAc)3-mediated oxidative cyclization of alkynyl ketone under microwave irradiation as an unconventional technique. An extremely enantioselective conjugate addition/acylation cascade transformation, a Yamamoto aldol conversion, and an important intramolecular Diels– Alder reaction to construct the A/B ring system were other salient features of this total synthesis.5

2.8.10 Type of Reaction C–C bond-forming reaction under microwave irradiation.5

2.8.11 Synthetic Strategy Using Microwave Irradiation Oxidative cyclization.5

2.8.12 Synthetic Route In 2020, the first total synthesis of a highly oxygenated ent-kaurene bioactive diterpenoid (–)-Glaucocalyxin A (1) was completed by Jia and co-workers involving microwave irradiation as a central step.5 They commenced the total synthesis from commercially available starting material cyclohexenone (2) to prepare chiral cyclization micro­ wave precursor (3) over three steps only. Alkynyl ketone (3) in 1,2-dichloroethane (DCE) undergoes crucial oxidative cyclization to furnish the highly 14-oxygenated bicyclo[3.2.1]octane (4) in 53% yield in the presence of the manganese(III) acetate [Mn(OAc)3] at 125 °C using microwave irradiation as a green technique (Scheme 2.8.1). Herein, the role of the DCE as a solvent was very significant in giving the highest yield instead of acetic acid and ethanol as they were the most familiar solvent in Mn(OAc)3-mediated reaction. Moreover, microwave irradiation dramatically reduces reaction time from 3 d to 3 h in this key step as an unconventional technique. The key intermediate bicyclo[3.2.1]octane (4)

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Scheme 2.8.1.    Microwave-assisted total synthesis of (–)-glaucocalyxin A.

was efficient in delivering the target diterpenoid glaucocalyxin A (1) in several steps finally; this practically useful method could also be employed for the synthesis of other secondary metabolites having the highly oxygenated bicyclo[3.2.1]octane ring system.5

References   1. Xiang Z, Wu X, Liu X et al. (2014) Glaucocalyxin A: A review. Nat Prod Res 28: 2221–2236.   2. Xu YL, Sun XC, Sun HD et al. (1981) Chemical structure of glaucocalyxin A and B. Acta Bot Yunnanica 3: 283–286.   3. Takeda Y, Fujita T, Ueno A. (1981) Structures of leukamenins. Chem Lett 10: 1229–1232.   4. Li W, Tang X, Yi W et al. (2013) Glaucocalyxin A inhibits platelet activation and thrombus formation preferentially via GPVI signaling pathway. PLoS One 8: e85120.   5. Guo J, Li B, Ma W et al. (2020) Total synthesis of (−)-glaucocalyxin A. Angew Chem Int Ed 59: 15195–15198.   6. Yang J, Liu Y, Xue C et al. (2014) Synthesis and biological evaluation of glaucocalyxin A derivatives as potential anticancer agents. Eur J Med Chem 86: 235–241.   7. Xiao X, Cao W, Jiang X et al. (2013) Glaucocalyxin A, a negative Akt regulator, specifically induces apoptosis in human brain glioblastoma U87MG cells. Acta Biochim Biophys Sin 45: 946–952.



(−)-Glaucocalyxin A (Leukamenin F)    157

  8. Chen ZJ, Li YS, Zhou JY et al. (2006) Effects of glaucocalyxin A on level of Th1/Th2 type cytokines in mice. China J Chin Mater Med 31: 1257–1260.   9. Zhang B, Long K. (1992) Inhibition by glaucocalyxin A of aggregation of rabbit platelets induced by AKP, arachidonic acid and platelet activating factor, and inhibition of (3H)-PAF binding. Thromb Haemost 67: 458–460. 10. Liu GA, Ding L, Yang Y, et al. (2006) Anti-oxidative action of ent-kaurene diterpenoids. Res Chem Intermed 32: 787–794. 11. Shen XD, Cao L, Dong X et al. (2011) Study on the cytotoxic effect of glaucocalyxin A in vitro. Chin Arch Tradit Chin Med 29: 1334–1335. 12. Fujita E, Nagao KK, Nakazawa S et al. (1976) The antitumor and antibacterial activity of the isodon diterpenoids. Chem Pharm Bull 24: 2118–2127. 13. Liu M, Wang W-G, Sun H-D et al. (2017) Diterpenoids from Isodon species: An update. Nat Prod Rep 34: 1090–1140. 14. Wang J, Hong B, Hu D et al. (2020) Protecting-group-free syntheses of entkaurane diterpenoids: [3+2+1] Cycloaddition/cycloalkenylation approach. J Am Chem Soc 142: 2238–2243. 15. Turlik A, Chen Y, Scruse AC et al. (2019) Convergent total synthesis of principinol D, a rearranged kaurane diterpenoid. J Am Chem Soc 141: 8088–8092.

Chapter 9

(–)-Halenaquinone 2.9.1 Natural Source Marine sponge Xestospongia exigua (family: Petrosiidae).1

2.9.2 Structure

2.9.3 Systematic Name (R)-12b-methyl-1H-tetrapheno[5,4-bc]furan-3,6,8,11(2H,12bH)tetraone.

2.9.4 Structural Features A rare polyketide secondary sponge metabolite halenaquinone (1) includes a unique fused tricyclic ABC core with a 2,4-diketofuran moiety and a benzylic quaternary carbon center. Pentacyclic quinone-type

159

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bioactive metabolite halenaquinone (1) comprises a naphtha[1,8-bc]furan core responsible for their efficient biological activity because of the presumed strain in the ring system along with the pendant electronwithdrawing moiety.1–3

2.9.5 Class of Compound Polyketide.1

2.9.6 Pharmaceutical Potential Antibiotic activity against both Staphylococcus aureus and Bacillus subtilis, antileukemic activity, and potent inhibition of topoisomerase and histone deacetylase (HDAC) activity having IC50 values at 0.0055 and 2.905 μg/mL, respectively.1,4

2.9.7 Conventional Approach In 1983, secondary metabolite halenaquinone (1) was isolated from marine sponge Xestospongia exigua as a yellow solid (mp >250 °C) bearing molecular formula C20H12O5, which was secured by highresolution mass spectrometry (m/z 332.06847; calcd for C20H12O5, 332.06847) for the first time.1 In 1988, the first total synthesis of pentacyclic polyketide halenaquinone (1) was achieved by Harada et al. using the Diels–Alder reaction of 3,6-dimethoxybenzocyclobutene with cyclohexene as a crucial step.5 Shibasaki and co-workers disclosed the catalytic asymmetric synthesis of halenaquinone (1) from commercially available 6,7-dimethoxy-1-tetralone involving a cascade Suzuki crosscoupling, an asymmetric Heck transformation along with the one-pot establishment of a pentacyclic ring system as central steps in 1996.6 Rodrigo et al. have concentrated to develop a short synthesis of (±)-halenaquinone in eight steps using Diels–Alder methodology with methylguaiacol and [bis(trifluoroacetoxy)iodo]benzene, Cope rearrangement of the adduct alkene ether as the key steps in 2001.7 In 2008, Trauner et al. completed a concise synthesis of (–)-halenaquinone based on a crucial intramolecular inverse-electron-demand Diels–Alder conversation including a vinyl quinone.8

(–)-Halenaquinone    161

2.9.8 Demerits of Conventional Approach Although an uncommon polyketide secondary sponge metabolite halenaquinone (1) has generated significant interest among medicinal, synthetic chemists, and marine ecologists because of the combination of a fascinating chemical structure and potent biological property yet, the establishments of the C6 all-carbon quaternary stereocenter as well as the all-fused tricyclic ABC core bearing a reactive furan ring are two serious challenges in the total synthesis of pentacyclic halenaquinone (1). So, conventional approaches are not free from a few demerits, such as Harada group that employed corrosive p-toluene sulfonic acid to deliver monoacetal from optically pure (8aR)-(–)-Wieland–Miescher ketone through the protection selectively. 5 Besides, Harada and Shibasaki groups used carcinogenic benzene as a solvent.5,6 In Trauner methodology, hydroquinone ether was able to yield the desired product (–)-halenaquinone in the presence of the 2,3-dichloro-5,6-dicyano-1,4benzoquinone (DDQ) in low yield (12%) through the heating of quinone.8

2.9.9 Key Features of Total Synthesis Using Microwave Irradiation The efficient total synthesis of pentacyclic (–)-halenaquinone (1) contains proline sulfonamide-catalyzed, Yamada–Otani transformation to construct the C6 all-carbon quaternary stereocenter, multiple, new Pd-mediated oxidative cyclizations to install an important furan A ring, the formation of a key alkene using microwave irradiation and oxidative Bergman cyclization to provide the vital quinone ring as crucial steps.2

2.9.10 Type of Reaction Cleavage of C–S bond under microwave irradiation.2

2.9.11 Synthetic Strategy Using Microwave Irradiation Desulfonation reaction.2

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Scheme 2.9.1.    Microwave-assisted total synthesis of halenaquinone.

2.9.12 Synthetic Route In 2018, Carter et al. accomplished a scalable, enantioselective total synthesis of pentacyclic polyketide (–)-halenaquinone (1) by applying the formation of a key alkene (4) using microwave irradiation as a leading step.2 The investigators commenced the total synthesis from methyl ketone (2) to deliver the vital sulfoxide (3) as a microwave precursor over several steps. Next, an important alkene (4) was prepared from sulfoxide (3) over two steps when thermal elimination of it (3) in p-xylene occurred at 130 °C under microwave heating as an unconventional activation technique in 57% yield with calcium carbonate (CaCO3) to neutralize the phenylsulfanol (PhSOH). Subsequent formylation of the cyclohexe­ none took place in the presence of the lithium bis(trimethylsilyl)amide (LiHMDS) and the benztriazole formaldehyde surrogate to provide primary alcohol (4) in excellent yield (86% yield) and stereoselectivity (Scheme 2.9.1).9 The enantioselective total synthesis of halenaquinone (1) bearing a naphtha[1,8-bc]furan core was completed in 12–14 steps using a late-stage oxidative Bergman cyclization to build the quinone moiety successfully.2

References 1. Roll DM, Scheuer PJ, Matsumoto GK et al. (1983) Halenaquinone, a pentacyclic polyketide from a marine sponge. J Am Chem Soc 105: 6177–6178. 2. Goswami S, Harada K, El-Mansy MF et al. (2018) Enantioselective synthesis of (−)‐halenaquinone. Angew Chem Int Ed 57: 9117–9121. 3. Wipf P, Halter RJ. (2005) Chemistry and biology of wortmannin. Org Biomol Chem 3: 2053–2061. 4. Shih S-P, Lee M-G, El-Shazly M et al. (2015) Tackling the cytotoxic effect of a marine polycyclic quinone-type metabolite: Halenaquinone induces molt 4 cells apoptosis via oxidative stress combined with the inhibition of HDAC and topoisomerase activities. Mar Drugs 13: 3132–3153.

(–)-Halenaquinone    163

5. Harada N, Sugioka T, Ando Y et al. (1988) Total synthesis of (+)-halenaquinol and (+)-halenaquinone. Experimental proof of their absolute stereostructures theoretically determined. J Am Chem Soc 110: 8483–8487. 6. Kojima A, Takemoto T, Sodeoka M et al. (1996) Catalytic asymmetric synthesis of halenaquinone and halenaquinol. J Org Chem 61: 4876–4877. 7. Sutherland HS, Souza FES, Rodrigo RGA. (2001) A short synthesis of (±)-halenaquinone. J Org Chem 66: 3639–3641. 8. Kienzler MA, Suseno S, Trauner D et al. (2008) Vinyl quinones as Diels-Alder dienes: Concise synthesis of (−)-halenaquinone. J Am Chem Soc 130: 8604–8605. 9. Deguest G, Bischoff L, Fruit C et al. (2007) Anionic, in situ generation of formaldehyde: A very useful and versatile tool in synthesis. Org Lett 9: 1165–1167.

Chapter 10

Harzianic Acid 2.10.1 Natural Source Trichoderma harzianum, SY-307 (family: Hypocreaceae).1

2.10.2 Structure

2.10.3 Systematic Name (2S)-2-hydroxy-2-(((E)-4-((2E,4E)-1-hydroxyocta-2,4-dien-1-ylidene)-1methyl-3,5-dioxopyrrolidin-2-yl)methyl)-3-methylbutanoic acid.

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2.10.4 Structural Features Harzianic acid (1a), a tetramic acid derivative, comprises an unnatural 4,4-disubstituted glutamic acid unit. Other features of this secondary metabolite of Trichoderma, structurally relating to the dienyltetramic acid subgroup of the tetramic acids, contain two stereogenic centers (5′S,7′S), conjugated olefinic double bonds at the side chain, three intramolecular H-bonds between hydroxyl functionalities, as well as carboxyl acid and carbonyl oxygen atoms [H(1) and O(2′), H(7′) and O(4′), and H(13′) and O(7′)].1–3

2.10.5 Class of Compound Antibiotic.1,2

2.10.6 Pharmaceutical Potential Antibiotic activity against Pythium irregulare, Sclerotinia sclerotiorum, and Rhizoctonia solani and plant growth-promoting activity.1,2

2.10.7 Conventional Approach No synthetic routes to the total synthesis of harzianic acid (1a) have been reported to date, although a novel antibiotic harzianic acid (1a) was isolated from a culture filtrate of a strain Trichoderma harzianum, SY-307, in 1994 as orange powder bearing molecular formula of C19H27NO6 which was determined by HRFAB-MS and elemental analysis.4

2.10.8 Demerits of Conventional Approach No conventional approach was available in the total synthesis of harzianic acid (1a) so far.4

2.10.9 Key Features of Total Synthesis Using Microwave Irradiation The first total synthesis of harzianic acid (1a) and its three stereoisomers involving isoharzianic acid (1b) was conducted with a good overall yield



Harzianic Acid    167

of 22% through the longest linear sequence in just six steps. This short, stereoselective route includes an extremely diastereoselective aldol condensation of the tert-butanesulfinamide imine, a Horner−Wadsworth− Emmons transformation of aldehyde with the dianion, the silver trifluoroacetate mediated coupling of β-ketothioester with a key masked 4,4-disubstituted glutamic acid, and ester hydrolysis of harzianic acid ethyl ester under microwave irradiation are other salient features of the first total synthesis of bioactive harzianic acid (1a).

2.10.10 Type of Reaction Cleavage of the C–O bond under microwave irradiation.4

2.10.11 Synthetic Strategy Using Microwave Irradiation Ester hydrolysis reaction.4

2.10.12 Synthetic Route The first total synthesis of bioactive secondary metabolite harzianic acid (1a) and its three stereoisomers involving bioactive isoharzianic acid (1b) was reported by Westwood and co-workers in 2015 by applying ester hydrolysis as a central step under microwave irradiation.4 The short, stereoselective total synthesis was initiated from ethyl pyruvate (2) and commercially available (E)-2-hexenol to provide microwave precursor harzianic acid ethyl ester (3) as a targeted product. Next, the hydrolysis of

º

Scheme 2.10.1.    Microwave-assisted total synthesis of harzianic acid.

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the harzianic acid ethyl ester (3) in ethanol (EtOH) with the sodium hydroxide (NaOH) took place to deliver a readily separable 3:1 mixture of naturally occurring harzianic acid (1a) and its important stereo­ isomer 5′-isoharzianic acid (1b) using microwave irradiation as an unconventional activation technique at 110 °C in 71% yield in one step (Scheme 2.10.1). Thus, the first total synthesis of harzianic acid (1a) was finished for the first time in just six steps via the longest linear sequence with an overall yield of 22%.4

References 1. Sawa R, Mori Y, Iinuma H et al. (1994) Harzianic acid, a new antimicrobial antibiotic from a fungus. J Antibiot 47: 731–732. 2. Vinale F, Flematti G, Sivasithamparam K et al. (2009) Harzianic acid, an antifungal and plant growth promoting metabolite from Trichoderma harzianum. J Nat Prod 72: 2032−2035. 3. Tommaso GD, Salvatore MM, Nicoletti R et al. (2020) Bivalent metal-­ chelating properties of harzianic acid produced by Trichoderma pleuroticola associated to the gastropod Melarhaphe neritoides. Molecules 25: 2147. 4. Healy AR, Vinale F, Lorito M et al. (2015) Total synthesis and biological evaluation of the tetramic acid based natural product harzianic acid and its stereoisomers. Org Lett 17: 692–695.

Chapter 11

Hyperforin 2.11.1 Natural Source Hypericum perforatum Linn. (also called St. John’s wort) (family: Hypericaceae).1

2.11.2 Structure

2.11.3 Systematic Name (1R,5R,7S,8R)-4-hydroxy-1-isobutyryl-8-methyl-3,5,7-tris(3-methylbut2-en-1-yl)-8-(4-methylpent-3-en-1-yl)bicyclo[3.3.1]non-3-ene-2,9-dione.

2.11.4 Structural Features Structurally, hyperforin (1) is related to the family of polycyclic polyprenylated acylphloroglucinol (PPAP) secondary metabolites. The 169

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cage structure of the bicyclic phloroglucinol derivative hyperforin (1) is characterized by a highly oxidized bicyclo[3.3.1]nonane core extremely substituted with terpenoid side chains, as well as it comprises a C8 quaternary stereocenter. The presence of a β-hydroxy enone moiety in its structure is responsible for its instability as meroterpene hyperforin (1) undergoes quick tautomeric interconversion and stays as a tautomeric mixture.2,3

2.11.5 Class of Compound Prenylated phloroglucinol derivative, a type-A polycyclic polyprenylated acylphloroglucinol (PPAP).1,4

2.11.6 Pharmaceutical Potential Antidepressant, anticancer, antibiotic, and precognitive activities.4

2.11.7 Conventional Approach (+)-Hyperforin (1) was originated first in 1971 from Hypericum perforatum Linn. as a colorless oil, [α]18D +41.0 (C2H5OH, c 5.0) having a molecular formula C35H52O4. It is the main component of H. perforatum also called St. John’s wort, an attractive medicinal plant due to its antidepressant properties and has invoked great interest in the organic sciences as well as the biological community as it was identified as the active agent accountable for the antidepressant property with the highly decorated bicyclo[3.3.1]nonane core.1,5 About four decades after its isolation, the first catalytic asymmetric total synthesis of ent-hyperforin was documented by Shibasaki and co-workers in 50 steps using an ironcatalyzed asymmetric Diels–Alder transformation to generate contiguous C7 and C8 stereocenters as a key step in 2010.6 The other key features of this total synthesis include the formation of the bridgehead quaternary carbon atom at C1 through a stereoselective Claisen rearrangement and the introduction of the oxygen functionality at the C2-position via a vinylogous Pummerer rearrangement. In 2013, the research group of Nakada disclosed the total synthesis of the racemic version of hyperforin (1) in 35 steps for the first time by applying the preparation of a bicyclo[3.3.1]nonane derivative through a three-step sequence.7

Hyperforin    171

The features of this three-step sequence include intramolecular cyclopropanation, creation of the C-8 all-carbon quaternary stereogenic center, as well as successive regioselective ring-opening of cyclopropane. Barriault et al. accomplished the short and scalable total syntheses of hyperforin along with three secondary metabolites PPAPs papuaforins A–C and also the formal synthesis of nemorosone in 17 steps involving a gold(I)-catalyzed 6-endo-dig carbocyclization of cyclic enol ethers as the vital step in 2014.8 Maimone and co-workers disclosed a 10-step total synthesis of hyperforin straightforwardly and systematically by a diketene annulation transformation and an oxidative ring expansion strategy in 2015.9

2.11.8 Demerits of Conventional Approach Hyperforin is an unstable molecule due to the presence of a β-hydroxy enone moiety; it exists as a tautomeric mixture since it undergoes rapid tautomeric interconversion.2,3 NMR spectra supported this fact where 1Hand 13C-NMR signals appeared as broad and poorly resolved peaks; however, the enol interconversion is blocked in the case of the analogs of the hyperforin. The therapeutic potential of hyperforin is seriously handicapped due to its poor water solubility and instability when exposed to light and air.3 However, hyperforin exhibits several biological applications as its dicyclohexylammonium salt is stable, and the compound is fairly stable in protic solvents as well as in vivo systems.10 As a result, the total synthesis of hyperforin, especially its enantioselective total synthesis, was not a simple task. Hence, the conventional approach to the total synthesis of hyperforin faces some demerits. The yield of the highly substituted cyclopentanone from 2-methylcyclopent-2-en-1-one was comparatively low (2nd step, yield 40%) as reported by the Maimone group.9 Asymmetric total synthesis of ent-hyperforin needs about 50 steps disclosed by Shibasaki et al.; moreover, microwave-assisted Claisen rearrangement provided a trace amount of the product. Besides, chloroform was employed to prepare enol acetate from allyl ether.6

2.11.9 Key Features of Total Synthesis Using Microwave Irradiation The key features of the convergent total synthesis of the natural enantiomer of (+)-hyperforin (1.4% overall yield, 40 mg of hyperforin) include the high

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level of synthetic efficiency, which opened the route to analogs of hyperforin that will definitely be useful in the deciphering of the structure– activity relationships of the compound. The other salient feature in the total synthesis of natural hyperforin (1) involves the construction of the bicyclo[3.3.1]-nonane core through Lewis acid-catalyzed epoxide-opening cascade cyclization and the installation of two key quaternary stereocenters, specifically in the transformation of epoxide to ketal.3

2.11.10 Type of Reaction Removal of a substituted silyl group (cleavage of the C–Si bond) using microwave irradiation.3

2.11.11 Synthetic Strategy Using Microwave Irradiation Desilytion reaction.3

Scheme 2.11.1.    Microwave-assisted total synthesis of hyperforin.

Hyperforin    173

2.11.12 Synthetic Route An enantioselective total synthesis of hyperforin (1) was developed by Shair et al. in 2013 using one-pot desilylation and elimination using microwave-assisted conditions as a leading step.3 The investigators commenced the total synthesis from geraniol (2) to afford microwave precursor ketone (3) over several steps. Next, ketone (3) undergoes one-pot desilylation and elimination reactions in the presence of the p-toluenesulfonic acid (p-TsOH·H 2O) and acetic acid (HOAc) with 2-methyl-2-butene under microwave as an unconventional activation technique at 100 °C to deliver key bicyclic unsaturated ether (4) in 65% yield (Scheme 2.11.1). The key ether (4) was effective in generating the targeted bioactive natural hyperforin (1) finally over two steps in a 55% yield; in this practical and modular way, they were able to create diverse hyperforin analogs that will definitely be effective in deciphering the structure–activity relationships of the molecule.

References   1. Gurevich AI, Dobrynin VN, Kolosov MN et al. (1971) Hyperforin, an antibiotic from Hypericum perforatum. Antibiotiki 16: 510–513.   2. Verotta L, Appendino G, Belloro E et al. (1999) Furohyperforin, a prenylated phloroglucinol from St. John’s wort (Hypericum perforatum). J Nat Prod 62: 770–772.   3. Sparling BA, Moebius DC, Shair MD. (2013) Enantioselective total synthesis of hyperforin. J Am Chem Soc 135: 644–647.   4. Richard J-A. (2014) Chemistry and biology of the polycyclic polyprenylated acylphloroglucinol hyperforin. Eur J Org Chem 2014: 273–299.   5. Bystrov NS, Chernov BK, Dobrynin VN et al. (1975) The structure of hyperforin. Tetrahedron Lett 16: 2791–2794.   6. Shimizu Y, Shi S-L, Usuda H et al. (2010) Catalytic asymmetric total synthesis of ent-hyperforin. Angew Chem Int Ed 49: 1103–1106.   7. Uwamori M, Nakada M. (2013) Stereoselective total synthesis of (±)-hyperforin via intramolecular cyclopropanation. Tetrahedron Lett 54: 2022–2025.   8. Bellavance G, Barriault L. (2014) Total syntheses of hyperforin and papuaforins A–C, and formal synthesis of nemorosone through a gold(I)-catalyzed carbocyclization. Angew Chem Int Ed 53: 6701–6704.   9. Ting CP, Maimone TJ. (2015) Total synthesis of hyperforin. J Am Chem Soc 137: 10516−10519. 10. Beerhues L. (2006) Hyperforin. Phytochemistry 67: 2201–2207.

Chapter 12

Kirkamide 2.12.1 Natural Source Psychotria kirkii Hiern (family: Rubiaceae).1

2.12.2 Structure

2.12.3 Systematic Name N-((1S,2S,5R,6R)-2,5,6-trihydroxy-4-(hydroxymethyl)cyclohex-3-en-1-yl) acetamide.

2.12.4 Structural Features Since kirkamide (1) is C7N aminocyclitol, its key structural motif contains three hydroxyl groups and one amino group (N-acetyl) on the cyclic ring system.2 Structurally, it also comprises hydroxymethyl substituent and 175

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one endocyclic olefinic bond, and it is an N-acetyl derivative of β-valienamine, a lead molecule for the improvement of novel biologically active β-glycosidase inhibitors.3

2.12.5 Class of Compound Aminocyclitol (amino carbasugar).1,2

2.12.6 Pharmaceutical Potential Cytotoxic activity against insects and arthropods.1

2.12.7 Conventional Approach Kirkamide (1) originated from the bacterial leaf symbiont of the Rubiaceous shrub Psychotria kirkii by applying a genome-driven 1HNMRguided fractionation procedure in 2015 first via a combination of RP-HPLC and CuII-coated preparative thin-layer chromatography. An exact mass of m/z 240.0844 of the new C7N-aminocyclitol kirkamide (1) was determined by the high-resolution ESI-MS which confirms the molecular formula C9H15NO5Na for the [M+Na]+ pseudomolecular ion. Only one conventional approach to date includes the total synthesis of kirkamide (1) by the Sagar group in 2020, involving stereoselective epoxidation as a crucial step. Acid-mediated regioselective epoxide ringopening and regioselective tertiary alcohol removal through global deprotection are key steps in the second total synthesis of natural bioactive kirkamide (1).2 It should be noted that in 2015, the first total synthesis of kirkamide (1) was achieved by Gademann and co-workers using microwave irradiation as a green tool.1

2.12.8 Demerits of Conventional Approach Only one conventional approach was available yet as kirkamide (1) was isolated recently, which probably makes a short time to the synthetic community. Few demerits of the conventional approach were observed, such as α,β-unsaturated ketone was obtained in low yield (40%) from epoxide through Swern oxidation along with an unidentified mixture of

Kirkamide    177

compounds.2 Chloro compound was prepared with the help of the corrosive thionyl chloride which can irritate and harm the skin, nose, and eyes with possible eye damage. Besides, flow chemistry, visible-light photochemistry, organic electrochemistry, microwave, and ultrasonic irradiation were not employed as green tools.

2.12.9 Key Features of Total Synthesis Using Microwave Irradiation The key features for the first enantioselective total synthesis of kirkamide (1) comprise a Garegg–Samuelsson reaction of methyl-N-acetyl-Dglucosamine and the formation of the benzyl-protected enol ether as a vital intermediate through acetylation along with the exchange of the protecting groups from acetyl to benzyl. The Ferrier carbocyclization of the exocyclic enol ether and the Stille cross-coupling transformation of the cyclohexene triflate under microwave irradiation as an alternative means of activation are other salient features of the total synthesis of natural kirkamide (1).1

2.12.10 Types of Reaction C–O and C–C bond-forming reactions using microwave irradiation.1

2.12.11 Synthetic Strategy Using Microwave Irradiation Ferrier carbocyclization and Stille cross-coupling reaction.1

2.12.12 Synthetic Route In 2015, Gademann et al. disclosed the first total synthesis and isolation of C7N-aminocyclitol kirkamide (1) by applying a Ferrier carbocycli­ zation and Stille coupling reaction using microwave irradiation as a green tool. Microwave precursor exocyclic enol ether (2) was prepared from the known methyl-N-acetyl-D-glucosamine (1) as the starting material.1 Next, a Ferrier carbocyclization of the enol ether (2) was conducted to deliver the cyclohexanone (3) with excellent diastereoselectivity (94:6) at

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Scheme 2.12.1.    Microwave-assisted total synthesis of kirkamide.

C-2 under microwave conditions in the presence of the sulfuric acid (H2SO4) and mercury sulfate (HgSO4) as a catalyst at 60 °C for 15 min. Then, the cyclohexene triflate (4) in dioxane undergoes the Stille crosscoupling reaction to afford the primary alcohol (5) in 85% yield using microwave irradiation with tributylstannyl-methanol (Bu3SnCH2OH), tetrakis(triphenylphosphine)palladium(0) [Pd(PPh3)4], and LiCl at 105 °C for 60 min via an important Pd-mediated hydroxymethylation (Scheme  2.12.1). The key intermediate of the primary alcohol (5) was effective to provide bioactive kirkamide (1) finally through deprotection in the presence of the tetra-n-butylammonium fluoride (TBAF) in 98% yield and then Birch conditions in 59% yield which also suggested that this secondary metabolite (1) was synthesized by Candidatus Burkholderia kirkii.1

References 1. Sieber S, Carlier A, Neuburger M et al. (2015) Isolation and total synthesis of kirkamide, an aminocyclitol from an obligate leaf nodule symbiont. Angew Chem Int Ed 54: 7968–7970. 2. Narayana C, Khanna A, Kumari P et al. (2021) Total syntheses of kirkamide and N-acetyl ent-conduramine B-1. Asian J Org Chem 10: 392–399. 3. Cui L, Zhu Y, Guan X et al. (2016) De novo biosynthesis of β-valienamine in engineered Streptomyces hygroscopicus 5008. ACS Synth Biol 5: 15−20.

Chapter 13

Kopsanone 2.13.1 Natural Source Aspidosperma macrocarpon Mart. (family: Apocynaceae).1–3

2.13.2 Structure

2.13.3 Systematic Name (3aR,3a1S,5aR,11R)-2,3,3a1,4,5,6,11,12-octahydro-1H-3a,5a-ethano-5,11methanoindolizino[8,1-cd]carbazol-14-one.

2.13.4 Structural Features Representative complex Kopsia alkaloids comprise a unique heptacyclic kopsanone; structurally, kopsanone and related Kopsia indole alkaloids include a rigid and cagelike polycyclic skeleton which are highly conserved through a pentacyclic core. The significant structural feature of 179

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the heptacyclic indole alkaloid kopsanone includes six stereogenic centers containing three all-carbon quaternary stereocenters at C2, C7, and C20 as well as the carbonyl group of the cyclopropyl ring at C22.4,9

2.13.5 Class of Compound Alkaloid.1–3

2.13.6 Pharmaceutical Potential Monoamine oxidase A (MAO-A) inhibitory activity (IC50 = 0.48 µM)3 and antitumor activity (colorectal cancer).5

2.13.7 Conventional Approach The first racemic total synthesis of heptacyclic indole alkaloid kopsanone was completed by Magnus et al. in 1983 using an intramolecular Diels–Alder reaction to construct the core ring system as a key step,6 although isolation and identification of Kopsia alkaloids such as kopsine and kopsanone have a long history.1,2 In 1985, Kuehne and co-workers developed a biogenetic derivation-inspired approach featuring an intermolecular Diels–Alder reaction and a possibly biomimetic rearrangement as the central steps.7 In 2011, the landmark synthesis of (–)-kopsanone was accomplished by Macmillan et al. involving natureinspired organocascade catalysis, an intermolecular Diels–Alder reaction as the crucial steps, executing the first asymmetric total synthesis of it.8 Recently, the concise and asymmetric total synthesis of five Kopsia indole alkaloids including (–)-kopsanone was achieved by the Ye group involving a remarkable PtCl2-catalyzed intramolecular [3+2] cycloaddition as a crucial step.10

2.13.8 Demerits of Conventional Approach Each of the total syntheses in polycyclic Kopsia indole alkaloids including (–)-kopsanone provided elegant contributions because of the extraordinary complex structures and the multiple continuous

Kopsanone    181

stereogenetic centers of alkaloids. The presence of a rigid and cagelike heptacyclic skeleton of (–)-kopsanone alkaloid creates great challenges in synthetic organic chemistry.11,12 Furthermore, the construction of the allcarbon-substituted quaternary carbon centers is considered to be one of the most significant challenges in synthetic chemistry. There are some demerits of conventional approach, such as Magnus et al. employed carcinogenic benzene to prepare kopsine-type skeleton from homo­ annular diene involving intramolecular Diels–Alder reaction as a key step,6 comparatively low yields (33%) of key intermediate was obtained during the condensation of tricyclic indole core with α-phenylselenyl aldehyde by the Kuehne group,7 acceptable yields of pyrroloindolines (58%), and the yield of the cleavage of the TBS ether by mesylation and hydrolysis was comparatively low (43%) from the Ye group,10 although this group used ultrasonic successfully as a green tool.

2.13.9 Key Features of Total Synthesis Using Microwave Irradiation The asymmetric total synthesis of Kopsia alkaloids including kopsanone comprises the intramolecular cyclopropanation reaction under microwave irradiation to set the second and third quaternary carbon centers at C2 and C7, respectively, as the key steps.9 An asymmetric Tsuji–Trost rearrangement to install the first quaternary carbon center at C20, a samarium iodide (SmI2)-promoted acyloin condensation to construct the molecular complexity in the target alkaloid, and a radical decarbonylation to deliver N-decarbomethoxyisokopsine and N-decarbomethoxykopsine are other salient features of this total synthesis.9

2.13.10 Type of Reaction C–C bond-forming reaction using microwave irradiation.9

2.13.11 Synthetic Strategy Using Microwave Irradiation Intramolecular cyclopropanation reaction.9

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2.13.12 Synthetic Route In 2017, Qin and co-workers disclosed the asymmetric total synthesis of  Kopsia indole bioactive alkaloid kopsanone (1) by applying the intramolecular cyclopropanation reaction under microwave irradiation as a key step with a brilliant collective strategy.9 The commercially available starting material tetrahydrocarbazolone (2) was transformed into tetracyclic diazo compound (3) as a microwave precursor over several stages. Herein, the role of the microwave irradiation was most significant as the decomposition of diazo (3) in dichloromethane (DCM) with various metal salts as catalysts such as copper(II) trifluoromethanesulfonate [Cu(OTf)2], rhodium(II) acetate [Rh(OAc)2], and bis(N-tert-butyl salicylaldiminato)copper(II) [Cu(TBS)2] gave extremely disappointing results for the intramolecular cyclopropanation reaction through traditional heating. However, the decomposition of diazo (3) in 1,2-dichloroethane (DCE) took place using microwave irradiation as a green tool at 120 °C for 5 min to furnish the desired pentacyclic key intermediate (4) in the presence of the hexafluoroacetylacetone [Cu(hfacac)2] catalyst to install the second and third quaternary carbon centers at C2 and C7 as a crucial step (Scheme 2.13.1). The bioactive natural alkaloid (–)-kopsanone (1) was obtained from key intermediate (4) finally which provided a basis for the synthesis of the various subtype core structures of the important individual alkaloids.9 Synthesis of

Scheme 2.13.1.    Microwave-assisted total synthesis of (–)-kopsanone.

Kopsanone    183

kopsanone and N-methuyl kopsanone under ultra sound irradiation has been discussed in Part 1, Chapter 10 (Scheme 1.10.1).

References   1. Filho JMF, Gilbert B, Kitagawa M et al. (1966) Four heptacyclic alkaloids from Aspidosperma species. J Chem Soc C 1260–1266. doi:https://doi. org/10.1039/J39660001260.  2. Mitaine A-C, Mesbah K, Richard B et al. (1996) Alkaloids from Aspidosperma species from Bolivia. Planta Med 62: 458–461.  3. Peixotoa MA, Katob L, Oliveirab CMA et al. (2020) Kopsanone and N-oxide isolated from Aspidosperma macrocarpon Mart. (Apocynaceae) leaves and their MAOA inhibitory activity. Nat Prod Res 22: 1–5.   4. Qin B, Wang Y, Wang X et al. (2021) Total synthesis of kopsine, fruticosine, and structurally related polycyclic caged Kopsia indole alkaloids. Org Chem Front 8: 369–383.  5. Bonfim DP, Nakamura CV, Júnior JXA et al. (2021) Kopsanone inhibits proliferation and migration of invasive colon cancer cells. Phytother Res. doi:10.1002/ptr.7078.   6. Gallagher T, Magnus P. (1983) Synthesis of (±)-kopsanone and (±)-10,22dioxokopsane, heptacyclic indole alkaloids. J Am Chem Soc 105: 2086–2087.   7. Kuehne ME, Seaton PJ. (1985) Studies in biomimetic alkaloids synthesis. 13. Total syntheses of racemic aspidofractine, pleiocarpine, pleiocarpinine, kopsinine, N-methylkopsanone, and kopsanone. J Org Chem 50: 4790–4796.  8. Jones SB, Simmons B, Mastracchio A et al. (2011) Collective synthesis of natural products by means of organocascade catalysis. Nature 475: 183–188.   9. Leng L, Zhou X, Liao Q et al. (2017) Asymmetric total syntheses of kopsia indole alkaloids. Angew Chem Int Ed 56: 3703–3707. 10. Jia X, Lei H, Han F et al. (2020) Asymmetric total syntheses of kopsane alkaloids via a PtCl2-catalyzed intramolecular [3+2] cycloaddition. Angew Chem 59: 12832–12836. 11. Buschleb M, Dorich S, Hanessian S et al. (2016) Synthetic strategies toward natural products containing contiguous stereogenic quaternary carbon atoms. Angew Chem Int Ed 55: 4156–4186. 12. Zeng XP, Cao ZY, Wang YH et al. (2016) Catalytic enantioselective desymmetrization reactions to all-carbon quaternary stereocenters. Chem Rev 116: 7330–7396.

Chapter 14

Luotonin A 2.14.1 Natural Source Peganum nigellastrum Bunge (family: Nitrariaceae, formerly known as Zygophyllaceae).1,2

2.14.2 Structure

2.14.3 Systematic Name Quinolino[2′,3′:3,4]pyrrolo[2,1-b]quinazolin-11(13H)-one.

2.14.4 Structural Features Luotonin A includes a five-ring planar structure; it comprises a heterofused pentacyclic structure carrying a characteristic quinazolinone moiety. The major structural feature includes a 6,5-membered fused B, C-ring structure instead of a 5,6-membered fused B, C-ring structure like rutaecarpine quinazolinone alkaloid.3

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2.14.5 Class of Compound Alkaloid.1

2.14.6 Pharmaceutical Potential Cytotoxic activity toward the murine leukemia P-388 cell line (IC50 = 1.8 μg/mL), inhibitory activity on topoisomerase I and topoisomerase II, and antiviral activity against tobacco mosaic virus.4–7

2.14.7 Conventional Approach Numerous synthetic endeavors toward the synthesis of luotonin A (1) have been disclosed to date due to a wide range of attractive biological activities; some promising total synthesis of luotonin A is provided herein.3,8 Ganesan et al. accomplished the first total synthesis of naturally occurring alkaloid luotonin A in 1998 by applying the coupling between dihydro-[1H]-pyrrolo[3,4-b]quinolin-3-one and 2-sulfinylaminobenzoyl chloride as a key step.9 Malacria et al. developed the total synthesis of bioactive alkaloid luotonin A involving the cascade radical cyclization of N-acylcyanamides as the alternative methodology for the formation of the 4(3H)-quinazolinone nucleus.10 Short and efficient total synthesis of secondary metabolite luotonin A was accomplished by Yao and co-workers using a mild cascade procedure as a common strategy.11 Bergman et al. reported a novel and concise synthesis of luotonin A and 14-substituted derivatives involving 14-chloroluotonin A as the central intermediate.12 An effective and practical synthesis of alkaloid luotonin A and also luotonins B and E was achieved by Nagarapu and co-workers from o-nitrobenzaldehyde as a starting material in 2012 by employing a phase-transfer catalyst and Mitsunobu cyclization as key steps.13

2.14.8 Demerits of Conventional Approach A conventional strategy includes the design of a desired natural product through an independent synthetic route for the total synthesis of secondary metabolite. Presently, a divergent strategy instead of the traditional targetoriented total synthesis has been accepting considerable attention; various secondary metabolites, namely luotonin A (1) alkaloid, can be synthesized



Luotonin A    187

from the common intermediate via a divergent strategy. The total synthesis of bioactive alkaloid luotonin A (1) carrying both indole and quinoline scaffolds has not been investigated to date from the same intermediate through a divergent strategy because of the lack of effective methodologies to build a divergent skeleton from the common intermediate probably.14 Furthermore, a conventional method such as the Yao method needs high temperature (185–186 °C) for 5 h via a classical heating process during the formation of the quinazolinone derivative from anthranilamide11; an extremely hazardous substance phosphorus oxychloride (POCl3) was used at reflux condition during the preparation of the key intermediate 14-chloroluotonin A via chlorination reaction by the Bergman group.12

2.14.9 Key Features of Total Synthesis Using Microwave Irradiation The key feature of the total synthesis of luotonin A (1) along with another alkaloid rutaecarpine bearing a quinazolinone moiety comprises a novel skeletal-divergent synthesis from a common aldimine intermediate instead of the conventional strategy. A microwave-assisted thermal 6π-electrocyclization reaction and the generation of a 5-membered C-ring by intramolecular Mitsunobu reaction are other salient features of this total synthesis.3

2.14.10 Type of Reaction C–C bond-forming reaction under microwave irradiation.3

2.14.11 Synthetic Strategy Using Microwave Irradiation Thermal 6π-electrocyclization reaction.3

2.14.12 Synthetic Route A new path for the total synthesis of the bioactive alkaloid luotonin A (1) was achieved by Cheon and co-workers in 2016 involving a microwaveassisted thermal 6π-electrocyclization reaction as a key step.3 At first,

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Scheme 2.14.1.    Microwave-assisted total synthesis of luotonin A.

microwave precursor aldimine (4) was prepared in 95% yield by the reaction between ethyl 2-aminocinnamate (2) and quinazolinone-2carbaldehyde (3) in one step. The key intermediate aldimine (4) was efficient to construct the quinoline scaffold (5) in 42% yield via a thermal 6π-electrocyclization reaction under microwave irradiation as a nonpolluting source of energy at 160 °C for 10 h as a crucial step (Scheme 2.14.1). The total synthesis of naturally occurring alkaloid luotonin A (1) was finished in four steps from the vital intermediate aldimine (4) successfully with a 34% yield.3

References   1. Nomura T, Ma Z-Z, Hano Y et al. (1997) Two new pyrroloquinazolinoquinoline alkaloids from Peganum nigellastrum. Heterocycles 46: 541−546.   2. Ma Z-Z, Hano Y, Nomura T et al. (2000) Alkaloids and phenylpropanoids from Peganum nigellastrum. Phytochemistry 53: 1075–1078.   3. Kwon SH, Seo H-A, Cheon C-H. (2016) Total synthesis of luotonin A and rutaecarpine from an aldimine via the designed cyclization. Org Lett 18: 5280−5283.   4. Cagir A, Jones SH, Gao R et al. (2003) A naturally occurring human DNA topoisomerase I poison. J Am Chem Soc 125: 13628–13629.   5. Cagir A, Eisenhauer BM, Gao R et al. (2004) Synthesis and topoisomerase I inhibitory properties of luotonin A analogues. Bioorg Med Chem Lett 12: 6287−6299.



Luotonin A    189

  6. Almansour AI, Arumugam N, Suresh Kumar R et al. (2017) Design, synthesis and antiproliferative activity of decarbonyl luotonin analogues. Eur J Med Chem 138: 932−941.   7. Hao Y, Wang K, Wang Z et al. (2020) Luotonin A and its derivatives as novel antiviral and antiphytopathogenic fungus agents. J Agric Food Chem 68: 8764–8773.   8. Liang JL, Cha HC, Jahng Y. (2011) Recent advances in the studies on luotonins. Molecules 16: 4861–4883.   9. Wang H, Ganesan A. (1998) Total synthesis of the cytotoxic alkaloid luotonin A. Tetrahedron Lett 39: 9097–9098. 10. Servais A, Azzouz M, Lopes D et al. (2007) Radical cyclization of N-acylcyanamides: Total synthesis of luotonin A. Angew Chem Int Ed 46: 576–579. 11. Zhou H-B, Liu G-S, Yao Z-J. (2007) Short and efficient total synthesis of luotonin A and 22-hydroxyacuminatine using a common cascade strategy. J Org Chem 72: 6270–6272. 12. Mason JJ, Bergman J. (2007) Total synthesis of luotonin A and 14-substituted analogues. Org Biomol Chem 5: 2486–2490. 13. Nagarapu L, Gaikwad HK, Bantu R. (2012) TBAHS-catalyzed synthesis of 2-dihydroquinazolin-2-ylquinoline: An efficient and practical synthesis of naturally occurring alkaloids luotonin A, B, and E. Synlett 23: 1775–1778. 14. Bowman WR, Elsegood MRJ, Stein T et al. (2007) Radical reactions with 3H-quinazolin-4-ones: Synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin. Org Biomol Chem 5: 103–113.

Chapter 15

(±)-Phyllantidine (Phyllanthidine) 2.15.1 Natural Source Phyllanthus discoides (family: Euphorbiaceae).1

2.15.2 Structure

2.15.3 Systematic Name (6S,12aS,12bS)-6,9,10,11,12,12a-hexahydro-2H-6,12b-methanofuro[2,3d]pyrido[1,2-b][1,2]oxazocin-2-one.

2.15.4 Structural Features Phyllantidine possesses the tetrahydro-1,2-oxazine ring (N–O bond) which is an uncommon heterocyclic motif in natural products; it is the most significant structural feature of it.2 Structurally, it includes a unique

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oxazabicyclo[3.3.1]nonane core with an additional oxygen atom between the N and C7 atoms compare to another securinega alkaloid (namely securinine, allosecurinine, viroallosecurinine, virosecurinine, etc.) and butenolide moiety also.3

2.15.5 Class of Compound Alkaloid.1,3

2.15.6 Pharmaceutical Potential Anti-inflammatory activity [(+)-phyllanthidine displayed inhibitory effects on NO production with IC50 value of 12.1 μM)]4 and leishmanicidal activity [(+)-phyllanthidine exhibited also leishmanicidal activity against Leishmania (L.) amazonensis (IC50 value of 82.37 µg/mL or 353 μM)].5

2.15.7 Conventional Approach The securinega rarer alkaloid phyllantidine was first isolated from the root bark of Phyllanthus discoides in 1965,1 although its structure was not correctly assigned upon isolation.3 Later, its correct structure was proposed as (–)-phyllantidine in 1972.6 Its enantiomer, a bioactive alkaloid (+)-phyllantidine, was originated from the leaves of Breynia coronate in 1992.7 It is interesting to be noted that this compound can be prepared from another alkaloid allosecurinine by oxidation with hydrogen peroxide. Only two total syntheses of phyllantidine have been reported to date since its isolation over five decades ago due to its unusual structure bearing an N–O bond.2,3 The presence of the uncommon heterocyclic motif tetrahydro-1,2-oxazine ring makes phyllantidine an intangible target since there are few ways to directly synthesize tetrahydro-1,2-oxazines. In 2006, Carson and Kerr completed the total synthesis of the structurally complex and demanding alkaloid (+)-phyllantidine for the first time involving a homo [3+2] dipolar cycloaddition instead of a classical 1,3-dipolar cycloaddition.3 Coupling of hydroxylamine, aldehyde, and cyclopropane, Krapcho decarboxylation, and intramolecular Horner– Emmons reaction were employed as central steps for the first total synthesis of this bioactive secondary metabolite.2



(±)-Phyllantidine (Phyllanthidine)    193

2.15.8 Demerits of Conventional Approach The tetrahydro-1,2-oxazine occupying the core of the infrequent alkaloid phyllantidine is not approachable via a classical 1,3-dipolar cycloaddition. The traditional approach included an analogous homo [3+2] cycloaddition between a nitrone and an electron-deficient, chiral cyclopropane. As this ring system has limited accessibility, its total synthesis needs an innovative, modular approach that permits the installation of N–O bonds embedded in functionally dense architectures of bioactive phyllantidine.8,9 Moreover, green technologies such as visible-light photochemistry, organic electrochemistry, flow chemistry, microwave, and ultrasonic irradiation were not applied as a key step in the total synthesis of it.

2.15.9 Key Features of Total Synthesis Using Microwave Irradiation An innovative, modular approach was developed for the total synthesis of phyllantidine.3 It comprises a novel ring expansion for the installation of embedded N–O bonds into densely functionalized core structures, an early-stage diastereoselective aldol transformation to construct the substituted cyclopentanone, a mild reduction of an amide intermediate without cleavage of interesting N–O bond, and the quick assembly of the butenolide using microwave irradiation as a green tool.3

2.15.10 Types of Reaction C–C and C–O bond-forming reactions using microwave irradiation.3

2.15.11 Synthetic Strategy Rapid assembly of the butenolide via the use of the Bestmann ylide using microwave irradiation as a key step.3

2.15.12 Synthetic Route In 2020, an innovative, modular approach was disclosed by Wood et al. for the total synthesis of (±)-phyllantidine (1) using the rapid assembly of

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Scheme 2.15.1.    Microwave-assisted total synthesis of (±)-phyllantidine.

the butenolide as a key step under microwave irradiation.3 The investigators commenced the total synthesis from commercially available 1,4-cyclohexadiene (2). The relatively unstable microwave precursor enone (3) was obtained from 1,4-cyclohexadiene (2) over several steps and enone (3) was taken immediately to the next step to minimize decomposition. Next, exposure of enone (3) to Bestmann ylide (Ph3P=C=C=O) with microwave heating as a green tool at 90 °C for 6 h using high dilution conditions delivered the structurally uncommon and demanding alkaloid phyllantidine (1) in 62% yield over the two steps (Scheme 2.15.1). Overall, the total synthesis needs 14-steps from readily available 1,4-cyclohexadiene (2) to prepare securinega rarer alkaloid phyllantidine (1) and is completed in 9% yield from known mono TBSprotected diol.3

References 1. Parello J, Munavalli S. (1965) Phyllantin and phyllantidin, alkaloids of Phyllantus discouides Muell. Arg. (Euphorbiaceae). Compt C R Hebd Seances Acad Sci 260: 337–340. 2. Carson CA, Kerr MA. (2006) Total synthesis of (+)-phyllantidine. Angew Chem Int Ed 45: 6560–6563. 3. Lambert KM, Cox JB, Liu L et al. (2020) Total synthesis of (±)-phyllantidine: Development and mechanistic evaluation of a novel ring expansion for installation of embedded nitrogen-oxygen bonds. Angew Chem Int Ed 59: 9757–9766. 4. Park KJ, Kim CS, Khan Z et al. (2019) Securinega alkaloids from the twigs of Securinega suffruticosa and their biological activities. J Nat Prod 82: 1345–1353. 5. Moraes LS, Donza MR, Rodrigues AP et al. (2015) Leishmanicidal activity of (+)-phyllanthidine and the phytochemical profile of Margaritaria nobilis (Phyllanthaceae). Molecules 20: 22157–22169.



(±)-Phyllantidine (Phyllanthidine)    195

6. Horii Z, Imanishi T, Yamauchi M et al. (1972) Structure of phyllantidine. Tetrahedron Lett 13: 1877–1880. 7. Lajis NH, Guan OB, Sargent MV et al. (1992) Viroallosecurinine and entphyllanthidine from the leaves of Breynia coronata (Euphorbiaceae). Aust J Chem 45: 1893–1897. 8. Young IS, Kerr MA. (2003) A homo [3+2] dipolar cycloaddition: The reaction of nitrones with cyclopropanes. Angew Chem Int Ed 42: 3023–3026. 9. Wehlauch R, Gademann K. (2017) Securinega alkaloids: Complex structures, potent bioactivities, and efficient total syntheses. Asian J Org Chem 6: 1146–1159.

Chapter 16

(+)-Rubriflordilactone A 2.16.1 Natural Source Schisandra rubriflora (Franch.) Rehd. et Wils. (family: Schisandraceae).1

2.16.2 Structure

2.16.3 Systematic Name (3aR,5aS,9aR,10S,11S,14aR)-5,5,10-trimethyl-11-((S)-4-methyl-5-oxo-2,5dihydrofuran-2-yl)-3,3a,5,5a,6,7,8,9,9a,10,11,14-dodecahydro-2Hcyclopenta[de]furo[3″,2″:2′,3′]furo[3′,4′:4,5]cyclohepta[1,2-g]chromen2-one.

2.16.4 Structural Features Rubriflordilactone A (1) comprises a bisnortripenoid backbone obtained from cycloartane and features a fused AB ring system including a 197

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γ-lactone and gem-dimethyl-substituted tetrahydrofuran, and a neighboring characteristic heptacyclic framework. Structurally, it also includes a biosynthetically modified pentasubstituted aromatic D ring, which happened in cycloartane triterpenoid first. The attractive architectures of the nortriterpenoid rubriflordilactone A (1) are characterized by a high degree of oxygenation, densely arrayed stereochemistry, and the butenolide G ring.1,2

2.16.5 Class of Compound Bisnortriterpenoid.1

2.16.6 Pharmaceutical Potential Anti-HIV-1 activity.1

2.16.7 Conventional Approach Rubriflordilactone A (1) was isolated from the leaves and stems of Schisandra rubriflora as colorless crystals in 2006. A quasi-molecular ion peak at m/z 463 ([M–H–]) of a novel bisnortriterpenoid rubriflordilactone A (1) in its negative ESI mass spectrum supports the molecular formula C28H32O6, corresponding to 13 degrees of unsaturation in the compound.1 The first elegant asymmetric total synthesis of natural bisnortriterpenoid rubriflordilactone A (1) was accomplished by Li and co-workers in 2014, involving a 6π-electrocyclization/aromatization sequence to construct the challenging pentasubstituted D-ring arene, the preparation of a functionalized cis-triene, and the formation of the butenolide side chain through a formal vinylogous Mukaiyama aldol reaction as the key steps.3

2.16.8 Demerits of Conventional Approach Bromoenone was prepared with the help of the toxic bromoform (CHBr3), a demerit of the conventional approach. Moreover, ketone was treated with a Grignard reagent, which is unsafe for green chemistry since the Grignard reaction includes a heat-generating metal (volatile metal magnesium) and flammable solvent ether.3 Besides, green tools were not used as key steps in the total synthesis of natural rubriflordilactone A (1).



(+)-Rubriflordilactone A    199

2.16.9 Key Features of Total Synthesis Using Microwave Irradiation The key features for two enantioselective total syntheses of the nortriterpenoid secondary metabolite rubriflordilactone A (1) comprise the formation of the vital CDE rings through palladium- or cobaltcatalyzed cyclizations, Ireland–Claisen rearrangement of the ester, the construction of the AB-ring aldehyde through oxy-Michael addition, and the installation of the butenolide G ring via the addition of a siloxyfuran.2 It is interesting to note that the same group (Anderson et al.) disclosed a series of model studies that gave a firm synthetic footing for the construction of the CDE rings of this natural product (1) in 2017. It includes palladium- and cobalt-catalyzed polycyclizations to build the central pentasubstituted arene as crucial steps.4

2.16.10 Type of Reaction C–H activation under microwave irradiation.2

2.16.11 Synthetic Strategy Using Microwave Irradiation Cyclotrimerization.2

2.16.12 Synthetic Route The total synthesis of the oxygenated Schisandraceae bisnortriterpenoid rubriflordilactone A (1) was achieved by Anderson and co-workers in 2015 using cyclotrimerization under microwave irradiation as a key step. The total synthesis of this secondary metabolite (1) was started from pentanoic acid (3) to provide bicycle triyne (4) over several steps. The authors were excited to build the key intermediate pentacycle (5) from microwave precursor bicycle triyne (4) under microwave heating at 150 °C for 25 min as a green tool. The crucial step was conducted with the cyclopentadienylcobalt dicarbonyl [CpCo(CO)2], chlorobenzene (PhCl), and triphenylphosphine (PPh3) via cyclotrimerization in 67% yield (Scheme 2.16.1). The microwave-assisted condition was also helpful to construct another pentacycle (6) in 54% yield from the key bicycle triyne (4).

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Scheme 2.16.1.    Microwave-assisted total synthesis of rubriflordilactone A.

The targeted nortriterpenoid secondary metabolite rubriflordilactone A (1) and 23-epi-rubriflordilactone A (2) was synthesized successfully which offers a high degree of flexibility for the synthetic exploration of other members of this family and the synthesis of rubriflordilactone analogs.

References 1. Xiao W-L, Yang L-M, Gong N-B et al. (2006) Rubriflordilactones A and B, two novel bisnortriterpenoids from Schisandra rubriflora and their biological activities. Org Lett 8: 991–994. 2. Goh SS, Chaubet G, Gockel B et al. (2015) Total synthesis of (+)-rubriflordilactone A. Angew Chem Int Ed 54: 12618–12621. 3. Li J, Yang P, Yao M et al. (2014) Total synthesis of rubriflordilactone A. J Am Chem Soc 136: 16477–16480. 4. Chaubet G, Goh SS, Mohammad M et al. (2017) Total synthesis of the Schisandraceae nortriterpenoid rubriflordilactone A. Chem Eur J 23: 14080–14089.

Chapter 17

Yaku’amide B 2.17.1 Natural Source Marine sponge Ceratopsion sp.1

2.17.2 Structure

NTA-OHIle1-ΔIle2-Ala3-ΔIle4-Val5-alloIle6-OHVal7-OHVal8-ΔIle9-Ala10Val11-Val12-ΔVal13-CTA.

2.17.3 Systematic Name (S)-2,2,4,6-tetramethyl-3-oxo-N-((4S,10S,13R,16R,19Z,22S,25R,28R, 31R,34E,37S,40Z,43S,44R)-19,34,40-tri(butan-2-ylidene)-28-((S)-secbutyl)-44-hydroxy-22,25-bis(2-hydroxypropan-2-yl)-4,10,13,31-tetra isopropyl-2,16,37,44-tetramethyl-6,9,12,15,18,21,24,27,30,33,36,39,42tridecaoxo-7-(propan-2-ylidene)-2,5,8,11,14,17,20,23,26,29,32,35,38,41tetradecaazahexatetracontan-43-yl)heptanamide.

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2.17.4 Structural Features A structurally unique cytotoxic peptide yaku’amide B (1, molecular weight = 1655) possesses four β,β-dialkylated α,β-unsaturated amino acids [(Z)-ΔIle-2/9, (E)-ΔIle-4, and ΔVal-13] in its linear tridecapeptide sequence, seven other non-proteinogenic α-amino acids are characterized by (L-OHIle-1, D-Val-5/11, D-allo-Ile-6, D-OHVal-7, L-OHVal-8, and D-Ala-10), and is capped with an N-terminal acyl group (NTA) together with a C-terminal amine (CTA). Yaku’amides A and B differ by one amino acid in their residue-3 with Gly-3 for Yaku’amides A and L-Ala-3 for Yaku’amides B.1,2

2.17.5 Class of Compounds Peptide.2

2.17.6 Pharmaceutical Potential Potent cell-growth inhibitory activity against a P388 murine leukemia cell line (IC50 = 4 ng/mL),1 Yaku’amide B also displays potent growth inhibitory activity against various cancer cell lines (GI50 = 26 nM for the JFCR39 cancer panel).2

2.17.7 Conventional Approach Two natural linear peptides Yaku’amides A (molecular formula C83H145N15O18) and B (molecular formula C84H147N15O18, one CH2 unit larger) were isolated for the first time from a rare deep-sea sponge Ceratopsion sp. in 2010 as minute components and were reported to display extraordinarily potent cytotoxicity toward P388 murine leukemia cells (IC50 = 8.5 and 2.4 nM, respectively).1 Further evaluation of the biological activities of two cytotoxic peptides as well as their complete structural elucidation has been hampered as only minute amounts of two highly unsaturated linear tridecapeptides have been obtained from natural sources (Yaku’amides A: 1.3 mg; Yaku’amides B: 0.3 mg). To address these issues, organic synthetic chemists have extended their hands in preparing two natural complex peptides in the laboratory for further investigations of their structures along with biological activities.



Yaku’amide B    203

In this context, the contributions of the Inoue group were remarkable3–7; to perform structure–activity relationship (SAR) studies on biologically more potent Yaku’amides B rather than Yaku’amides A, the established synthetic strategy was very efficient.3 In 2015, Inoue and co-workers disclosed the structural revision and total synthesis of highly unsaturated complex peptides Yaku’amides A and B using a judicious combination of secondary metabolite degradation, MS, and chromatographic analyses, as well as chemical synthesis.4 In 2018, the same group completed the target identification of Yaku’amide B and uncovered the cellular target and biological mode of action of this peptide first based on their established route, and enantiomeric analogs were assembled for cell imaging studies.5

2.17.8 Demerits of Conventional Approach Among the peptide secondary metabolites, natural linear peptide yaku’amide B (1) includes four β,β-dialkylated α,β-unsaturated amino acids, which represents a particularly unusual structural feature and it generates the additional synthetic challenge for their efficient assembly.8 Hence, the conventional approach faces a few demerits, such as a potent liver toxin dimethylformamide (DMF) was used by the Inoue group several times.4 The same investigators employed fluorinated trifluoroacetic acid (TFA) to remove the Boc groups5; the –CF3 group is resistant to degradation in the environment due to the strength of the carbon-fluorine bond in TFA.9

2.17.9 Key Features of Total Synthesis Using Microwave Irradiation An Fmoc-based solid-phase total synthesis of structurally unique dehydropeptide yaku’amide B (1) includes three key methods for forming the enamide, deprotection of the enamide, as well as C-terminal modification. First of all, the construction of the three dipeptides took place through stereoselective traceless Staudinger ligation which enabled enamide formation. Second, the use of Eu(OTf)3 was effective for chemoselective removal of the enamide, and lastly, resin cleavage and C-terminus modification occurred to furnish yaku’amide B (1) in 9.1% overall yield efficiently (24 steps from the resin).2

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2.17.10 Type of Reaction C–N bond formation under microwave irradiation.2

2.17.11 Synthetic Strategy Using Microwave Irradiation Tetrapeptide formation.2

2.17.12 Synthetic Route In 2020, Inoue and co-workers developed a solid-phase strategy for the total synthesis of the cytotoxic peptide yaku’amide B (1) through tetrapeptide formation.2 The investigators preferred solid-phase peptide synthesis (SPPS) over classical solution-phase synthesis due to its higher operational simplicity and larger flexibility for creating derivatives. Motivated by its unusual structure and potential activity, the authors conducted a solid-phase total synthesis of the natural linear peptide (1) involving a crucial C–N bond formation under microwave irradiation as a green technique. The total synthesis of this bioactive peptide (1) was commenced from resin (2) to deliver microwave precursor (3) over two cycles and two steps. Two vital repeats of Nα-deprotection in the presence of the piperidine in N-methyl-2-pyrrolidone (NMP) and amide coupling in the presence of the Nα-Fmoc-amino acids (5) and (6)

Scheme 2.17.1.    Microwave-assisted total synthesis of yaku’amide B.



Yaku’amide B    205

were conducted with 1-hydroxy-7-azabenzotriazole (HOAt)/hexafluoro­ phosphate azabenzotriazole tetramethyl uronium (HATU)/N,Ndiisopropylethylamine (iPr2Net) at 40 °C using microwave-irradiation conditions to transform (3) into tetrapeptide (4) (Scheme 2.17.1). The desired product yaku’amide B (1) was obtained from the key intermediate (4) successfully over several steps. The established route allows efficient access to natural yaku’amide B (1) as it needs only one purification and is useful for the solid-phase synthesis of its derivatives and several other natural peptides with non-proteinogenic amino acid structures.2

References 1. Ueoka R, Ise Y, Ohtsuka S et al. (2010) Yaku’amides A and B, cytotoxic linear peptides rich in dehydroamino acids from the marine sponge Ceratopsion sp. J Am Chem Soc 132: 17692–17694. 2. Itoh H, Miura K, Kamiya K et al. (2020) Solid-phase total synthesis of yaku’amide B enabled by traceless Staudinger ligation. Angew Chem Int Ed 59: 11390–11393. 3. Mutoh H, Sesoko Y, Kuranaga T et al. (2016) The total synthesis and functional evaluation of fourteen stereoisomers of yaku’amide B. The importance of stereochemistry for hydrophobicity and cytotoxicity. Org Biomol Chem 14: 4199–4204. 4. Kuranaga T, Mutoh H, Sesoko Y et al. (2015) Elucidation and total synthesis of the correct structures of tridecapeptides yaku’amides A and B. Synthesisdriven stereochemical reassignment of four amino acid residues. J Am Chem Soc 137: 9443–9451. 5. Kitamura K, Itoh H, Sakurai K et al. (2018) Target identification of yaku’amide B and its two distinct activities against mitochondrial FoF1-ATP synthase. J Am Chem Soc 140: 12189–12199. 6. Kamiya K, Miura K, Itoh H et al. (2021) Divergent solid-phase synthesis and biological evaluation of yaku’amide B and its seven E/Z isomers. Chem Eur J 27: 1088–1093. 7. Kuranaga T, Sesoko Y, Sakata K et al. (2013) Total synthesis and complete structural assignment of yaku’amide A. J Am Chem Soc 135: 5467–5474. 8. Ma Z, Jiang J, Luo S et al. (2014) Selective access to E- and Z-ΔIle-containing peptides via a stereospecific E2 dehydration and an O → N acyl transfer. Org Lett 16: 4044–4047. 9. Solomona KR, Veldersb GJM, Wilsonc SR et al. (2016) Sources, fates, toxicity, and risks of trifluoroacetic acid and its salts: Relevance to substances regulated under the Montreal and Kyoto Protocols. J Toxicol Environ Health B Crit Rev 19: 289–304.

Part 3

Visible-Light Photochemistry as a Greener Approach for the Total Synthesis of Bioactive Natural Products

Chapter 1

Ambiguine H 3.1.1 Natural Source Cyanobacterium strain Fischerella sp. (family: Hapalosiphonaceae).1

3.1.2 Structure

3.1.3 Systematic Name (6aS,9R,10R,10aS)-10-isocyano-6,6,9-trimethyl-1-(2-methylbut-3-en-2-yl)9-vinyl-2,6,6a,7,8,9,10,10a-octahydronaphtho[1,2,3-cd]indole.

3.1.4 Structural Features Alkaloid ambiguine H (1) consists of tetra-carbon skeletons obtained from tryptophan and geranyl diphosphate; the ambiguine isonitriles comprise an additional 1,1-dimethylallyl moiety at the two positions of the indole skeleton.1,2 209

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3.1.5 Class of Compounds Alkaloid.1

3.1.6 Pharmaceutical Potential Ambiguine H isonitrile displays antibacterial and antifungal activities against test organisms such as Escherichia coli ESS K-12, Saccharomyces cerevisiae, Candida albicans ATCC 90028, Staphyloccocus albus, and Bacillus subtilis in vitro with MIC values (µg/mL) of 10, 5, 6.25, 0.625, and 1.25, respectively.1

3.1.7 Conventional Approach Carmeli and co-workers isolated bioactive alkaloid ambiguine H isonitrile (1) as an amorphous white solid bearing molecular formula C26H32N2 from bioassay-leaded fractionation of a cultured cyanobacterium strain recognized as Fischerella sp. in 2007. Baran et al. achieved the first total synthesis of (+)-ambiguine H involving an isonitrile-promoted prenylation of indole and, afterward, a photo fragmentation cascade as crucial steps in 2015.3

3.1.8 Demerits of Conventional Approach No conventional approach has been reported to date.3,4

3.1.9 Key Features of Total Synthesis Using Visible-Light Irradiation The unique feature for the enantioselective total synthesis of bioactive ambiguine H (1) includes the formation of the single enantiomer in impressive quantities instead of small milligram amounts, completed in 10 steps or less rather than 20 or more steps from commercially available materials without the need for protecting groups. Photoexcitation of the chloroimidate (6) was carried out by a Norrish-type cleavage and fragmentation cascade as another green protocol in this total synthesis.4



Ambiguine H    211

3.1.10 Types of Reactions C–C and C–N bond formation under visible-light irradiation.4

3.1.11 Synthetic Strategy Using Visible-light Irradiation Norrish-like cleavage.4

3.1.12 Synthetic Route Reducing the use of protecting groups and the number of steps in a total synthesis of complex natural products carries a more significant impact than the corresponding longer routes.5 The total synthesis of the marine alkaloid (+)-ambiguine H (1) was started by the direct coupling between

Scheme 3.1.1.    Visible-light-assisted total synthesis of ambiguine H.

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commercially available terpene (2) and 4-bromoindole (3) to afford the brominated indole (4) as a single diastereomer in 50% yield on a gram scale without using protecting groups, a reaction that was explicitly discovered for constructing this type of C–C bond.6 Next, Baran and co-workers synthesized an alkaloid (–)-hapalindole U (5) from the brominated indole (4) as a single diastereomer over four steps in 60% overall yield.4 Next, hapalindole U (5) effectively produced chloroimidate (6) over four steps involving Danishefsky’s protocol as a vital step. Ultimately, irradiation of chloroimidate (6) in Et3N (triethylamine) provided the targeted alkaloid ambiguine H (1) for 5 h in 63% yield based on recovered starting material (6) through constructions of important intermediates (7) and (8), followed by a fragmentation cascade to elimi­ nate the BBN (9-borabicyclo[3.3.1]nonane) functionality (Scheme 3.1.1). The elimination of protecting groups from the synthetic design facilitated the improvement and invention of novel chemical transformations by harvesting the intrinsic reactivity within organic compounds.4

References 1. Raveh A, Carmeli S. (2007) Antimicrobial ambiguines from the cyanobacterium Fischerella sp. collected in Israel. J Nat Prod 70: 196–201. 2. Moore RE, Cheuk C, Patterson GML. (1984) Hapalindoles: New alkaloids from the blue-green alga Hapalosiphon fontinalis. J Am Chem Soc 106: 6456–6457. 3. Maimone TJ, Ishihara Y, Baran PS. (2015) Scalable total syntheses of (−)-hapalindole U and (+)-ambiguine H. Tetrahedron 71: 3652–3665. 4. Baran PS, Maimone TJ, Richter JM. (2007) Total synthesis of marine natural products without using protecting groups. Nature 446: 404–408. 5. Hudlicky T. (1996) Design constraints in practical syntheses of complex molecules: Current status, case studies with carbohydrates and alkaloids, and future perspectives. Chem Rev 96: 3–30. 6. Baran PS, Richter JM. (2004) Direct coupling of indoles with carbonyl compounds: Short, enantioselective, gram-scale synthetic entry into the hapalindole and fischerindole alkaloid families. J Am Chem Soc 126: 7450–7451.

Chapter 2

Aspergillide A 3.2.1 Natural Source Aspergillus ostianus strain 01F313 (family: Trichocomaceae).1

3.2.2 Structure

3.2.3 Systematic Name (1R,5S,11R,14S,E)-14-hydroxy-5-methyl-4,15-dioxabicyclo[9.3.1]pentadec9-en-3-one.

3.2.4 Structural Features From a structural perspective, the 14-membered macrocyclic structure of aspergillide A (1) comprises of trisubstituted tetrahydropyran unit as a non-hemiacetal form decorated with four stereocenters and a 213

214  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

hydroxy group. The distinctive molecular architecture of bioactive natural aspergillide also studded a 12-membered macrolactone bearing a disubstituted E-alkene.1,2

3.2.5 Class of Compounds Macrolide.1

3.2.6 Pharmaceutical Potential The first example of a 14-membered macrolide, aspergillide A (1), displays potent cytotoxic properties towards mouse lymphocytic leukemia cell (L1210) with a lethal dose 50 (LD50) value of 2.1 μg/mL.1

3.2.7 Conventional Approach Kusumi and co-workers isolated cytotoxic macrolides aspergillides A−C from the marine fungus Aspergillus ostianus strain 01F313 in 2008, having a molecular formula of C14H22O4; comprehensive spectroscopic studies confirmed their structures, X-ray crystallography together with the modified Mosher method determined their absolute configurations.1 Because of their trans-substituted tetrahydro- or dihydropyran core and attractive biological profile, 14-membered macrolides promptly captured the interest of the organic synthetic community as targets for total synthesis.2 Kuwahara et al. accomplished the first synthesis of the natural cytotoxin aspergillide A (1) from 3,7-trans-substituted lactone, a synthetic intermediate of natural epimer aspergillide B. The unique feature of the synthesis includes a retro-oxy-Michael/oxy-Michael sequence and the construction of the critical cis-isomer from the corresponding 3,7-transsubstituted intermediate by the proline-assisted epimerization.3 Fuwa et al. achieved the total enantioselective syntheses of natural macrolides aspergillide A (1) and aspergillide B through a unified synthetic approach using stereodivergent intramolecular oxa-conjugate cyclization together with Yamaguchi macrolactonization as main steps.4 Marco et al. went on to report the synthesis of the cytotoxic aspergillide A (1) in a stereoselective manner for the first time. The total synthesis establishes its stereostructure and absolute configuration successfully. The key features



Aspergillide A    215

of the synthesis comprise the formation of the macrocyclic lactone ring via ring-closing metathesis and the construction of the cis-2,6disubstituted tetrahydropyran core through a stereoselective reduction.5 Sasaki et al. disclosed enantioselective total syntheses of 14-membered macrolides aspergillide A (1) and aspergillide B, which consist of the preparation of the 2,6-substituted tetrahydropyran framework by the diastereoselective intramolecular oxa-conjugate cyclization and chemoselective olefin cross-metathesis transformation as central steps.6 Shishido and co-workers demonstrated the total synthesis of naturally occurring aspergillides A and B through a most extended linear sequence involving the formation of the syn- and anti-tetrahydropyrans by the transannular oxy-Michael reaction for the first time and transformation of the syn-pyran into the anti-isomer for a short period; it was completed in 17 steps from easily approachable bicyclic chiral building blocks in 30% and 28% yield, respectively, in 2011.7 Marco et al. evolved total syntheses of biologically active natural macrolides aspergillides A and B in a stereoselective way by utilizing olefin metatheses along with asymmetric allylations as crucial steps. The investigators also conducted cytotoxicity assays for two natural macrolides and several synthetic intermediates against various tumor cell lines. One intermediate was noticeably active against the human leukemia cancer cell line HL-60; the value of an IC50 is similar to the clinical drug fludarabine.8 Loh et al. described the synthesis of bioactive macrolides aspergillides A (1) and B in which all the carbon atoms are developed from biomass gained platform chemicals including ethanol, 5-hydroxymethylfurfural together with levulinic acid in 2015. The unique features consist of the first use of Achmatowicz rearrangement with Lipshutz’s micellar Negishi coupling.9

3.2.8 Demerits of Conventional Approach From the view of green chemistry, conventional approaches were not free from a few demerits. The Kuwahara group used a hazardous reagent 2,4,6-trichlorobenzoyl chloride to construct key cis-isomer through macrolactonization3; Fuwa et al. also used 2,4,6-trichlorobenzoyl chloride to prepare a vital diene by the coupling of the alcohol with a carboxylic acid.4 Marco et al. used the same reagent to produce key ester under the Yamaguchi method. Besides, the yield of (Z)-lactone was comparatively low (28%) during the cyclization reaction5; the same group applied

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photochemical isomerization as a green tool in 56% yield for 6 h for the preparation of naturally occurring aspergillide A (1). The Sasaki group used acute toxic triphenylphosphine and renal damaging chloroform solvent to generate the 2,6-trans-tetrahydropyran core.6

3.2.9 Key Features of Total Synthesis Using VisibleLight Irradiation The unique feature of the stereoselective total synthesis of natural macrolide consists of atom transfer radical addition followed by lactonization to construct the critical tetrahydropyran core. For the success of this total synthesis, stereoselective alkynylation, a cross-metathesis, and a Yamaguchi macrolatonization also played a vital role.10

3.2.10 Type of Reaction C–C bond formation using visible-light irradiation.10

3.2.11 Synthetic Strategy Using Visible-Light Irradiation Atom transfer radical addition.10

3.2.12 Synthetic Route In 2019, Cordero-Vargas et al. explored the stereoselective total synthesis of bioactive natural product aspergillide A (1) by applying a visible lightpromoted photoredox transformation as a key step.10 The total synthesis commenced from a known epoxide (2) to provide the allylic alcohol (3) in 95% yield in the presence of the trimethyl sulfonium iodide and n-butyllithium. Next, the allylic alcohol (3) was treated with iodoacetic acid (4) using [Ru(bpy)3]Cl2 and sodium ascorbate in acetonitrile/ methanol using blue LED irradiation as a green protocol to afford the critical atom transfer product (5) through atom transfer radical addition (Scheme 3.2.1). The atom transfer product (5) was not isolated; it was reacted in situ with trifluoroacetic acid in DCM at room temperature to furnish a key iodolactone (6) in 65% yield as a 1:1 mixture of



Aspergillide A    217

Scheme 3.2.1.    Visible-light-assisted total syntheses of aspergillide A.

diastereoisomers. The obtained key iodolactone (6) comprises the three functionalized sites in the final targeted product. Finally, cytotoxic natural macrolide aspergillide A (1) was originated from iodolactone (6) over several steps; this study discloses that the radical-ionic iodolactonization is an efficient protocol for the formation of substituted lactones as well as tetrahydropyrans.10

References  1. Kito K, Ookura R, Yoshida S et al. (2008) New cytotoxic 14-membered macrolides from marine-derived fungus Aspergillus ostianus. Org Lett 10: 225−228.   2. Nagasawa T, Kuwahara S. (2012) Total synthesis of aspergillides A, B, and C. Heterocycles 85: 587–613.   3. Nagasawa T, Kuwahara S. (2010) Synthesis of aspergillide A from a synthetic intermediate of aspergillide B. Tetrahedron Lett 51: 875–877.   4. Fuwa H, Yamaguchi H, Sasaki M. (2010) An enantioselective total synthesis of aspergillides A and B. Tetrahedron 66: 7492–7503.   5. Diaz-Oltra S, Angulo-Pachon CA, Murga J et al. (2010) Stereoselective synthesis of the cytotoxic 14-membered macrolide aspergillide A. J Org Chem 75: 1775–1778.

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6. Fuwa H, Yamaguchi H, Sasaki M. (2010) A unified total synthesis of aspergillides A and B. Org Lett 12: 1848−1851. 7. Kanematsu M, Yoshida M, Shishido K. (2011) Total synthesis of aspergillide A and B based on the transannular oxy-Michael reaction. Angew Chem Int Ed 50: 2618–2620. 8. Diaz-Oltra S, Angulo-Pachon CA, Murga J et al. (2011) Synthesis and biological properties of the cytotoxic 14-membered macrolides aspergillide A and B. Chem Eur J 17: 675–688. 9. Koha P-F, Loh T-P. (2015) Synthesis of biologically active natural products, aspergillides A and B, entirely from biomass derived platform chemicals. Green Chem 17: 3746–3750. 10. Mateus-Ruiz JB, Cordero-Vargas A. (2019) Stereoselective total synthesis of aspergillide A: A visible light-mediated photoredox access to the trisubstituted tetrahydropyran core. J Org Chem 84: 11848−11855.

Chapter 3

Drimentines A, F, and G and Their Congener Indotertine A 3.3.1 Natural Source Streptomyces sp. CHQ-64 (family: Streptomycetaceae).1–3

3.3.2 Structure

3.3.3 Systematic Name (3S,5aS,10bS)-3-isopropyl-2-methyl-10b-(((1S,4aS,8aS)-5,5,8a-trimethyl2-methylenedecahydronaphthalen-1-yl)methyl)-2,3,5a,6,11,11ahexahydro-1H-pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4(10bH)-dione (Drimentine F). 219

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(3S,5aS,10bS)-3-isobutyl-10b-(((1S,4aS,8aS)-5,5,8a-trimethyl-2methylenedecahydronaphthalen-1-yl)methyl)-2,3,5a,6,11,11a-hexahydro1H-pyrazino[1′,2′:1,5]pyrrolo[2,3-b]indole-1,4(10bH)-dione (Drimentine A). (6S)-6-isopropyl-1-methyl-3-(((4aS,7aR,12bS,13aS,13bS)-4,4,13btrimethyl-2,3,4,4a,5,6,7a,8,12b,13,13a,13b-dodecahydro-1H-naphtho[2,1-b]carbazol-12b-yl)methyl)piperazine-2,5-dione (Indotertine A).

3.3.4 Structural Features From a structural perspective, a hybrid isoprenoid indotertine A (4) possesses a condensed pentacyclic skeleton bearing a tryptophan-derived indole moiety along with a sesquiterpene unit and represents a novel type of hybrid isoprenoids merging amino acid and mevalonate pathways.1 Drimentines belong to a new type of antibiotics characterized by the novel terpenylated diketopiperazine structure having proline or leucine residues; in contrast to the known derivatives drimentine F (3) and drimentine G (2) comprise valine residues, the ascertainment of the absolute configurations of drimentines was not disclosed definitely.1–3

3.3.5 Class of Compounds Alkaloids.1–4

3.3.6 Pharmaceutical Potential Hybrid isoprenoid drimentines belong to a new class of antibiotics containing a novel terpenylated diketopiperazine structure, which displayed anticancer, antibiotic, antifungal, and anthelmintic properties.3 Drimentine G (2) exhibited potent cytotoxicity against human cancer cell lines with IC50s down to 1.01 μM.1 Indotertine B shows activities against A549 and HCT-8 tumor cell lines with IC50 values of 4.88 and 6.96 μM, respectively.2

3.3.7 Conventional Approach Li and co-workers isolated optically active indotertine A (4) from actinomycete Streptomyces sp. CHQ-64 as a colorless amorphous powder with molecular formula C32H45N3O2 deduced by HRESIMS at m/z



Drimentines A, F, and G and Their Congener Indotertine A    221

504.3583 [M+H]+, needing 12 degrees of unsaturation.1 The same group also isolated two linked hybrid isoprenoids of indotertine A, such as drimentines F and G, from the same Streptomyces sp. in 2012; drimentine F (3) bears the same molecular formula of C32H45N3O2 suggesting that it is an isomer of drimentine A (1). The key differences were ascribed to the diketopiperazine ring, in which the leucine of hybrid isoprenoid drimentine A (1) was substituted by N-Me-valine residue.1 Another alkaloid drimentine G (2) was found to have a molecular formula C31H43N3O2 which was determined by HRESIMS at m/z 490.3446 [M+H]+ analysis, indicating its smaller molecular weight than that of drimentine F (3) by a CH2.1 In 2020, Li et al. stretched the structural diversity of drimentines through the investigation of the promiscuity of two N-methyltransferases since the methylation steps throughout drimentines biosynthesis were not demonstrated; setting the stage for searching the structural diversity of diketopiperazine derivatives for drug design.5 However, only one concise route is available to complete the first total synthesis of drimentines A (1), F (3), and G (2), along with indotertine A (4) using visible-light irradiation as a green tool in 2013.4

3.3.8 Demerits of Conventional Approach No conventional approach has been described to date.4

3.3.9 Key Features of Total Synthesis Using Visible-Light Irradiation The key feature for the short and sweet route of total syntheses of natural bioactive alkaloids, drimentines A (1), F (3), and G (2), and indotertine A (4), includes a crucial intermolecular radical conjugate addition. For the success of this transformation, photoredox catalysis played a vital role in the total syntheses of natural hybrid isoprenoids.4 For the transformation of drimentine F into indotertine A, a biology-inspired iminium–olefin cyclization played a determining role.4

3.3.10 Type of Reaction C–C bond formation using visible-light irradiation.4

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3.3.11 Synthetic Strategy Using Visible-Light Irradiation Radical conjugate addition.4

Scheme 3.3.1.  Visible-light-assisted total syntheses of drimentines A, F, and G and indotertine A.



Drimentines A, F, and G and Their Congener Indotertine A    223

3.3.12 Synthetic Route Li et al. accomplished the total syntheses of bioactive alkaloids drimentines A (1), F (3), and G (2) together with indotertine A (4), involving visible light-assisted radical conjugate addition as a powerful tool in C–C bond formation reaction.4 The investigators initiated total synthesis with sclareolide (5) to deliver precursor (6) on a multigram scale over several steps in high yield. Meanwhile, another precursor (8) was originated from L-tryptophan derivative (7) through bromocyclization on a decagram scale in 96% yield.6 Now, the authors explored the radical conjugate addition under visible-light irradiation as a green tool instead of the conventional radical conditions because the application of a significant excess of toxic Bu3SnH was not suitable in this vital transformation. The substrate (6) was subjected to the key radical 1,4-addition with precursor (8) using visible-light irradiation (blue LED, λmax = 454 nm) in the presence of [Ir(ppy)2(dtbbpy)PF6] in triethylamine in 89% yield to produce important intermediate (9) (Scheme 3.3.1); X-ray crystallographic analysis confirmed the structure of crucial intermediate (9). Herein, photoredox catalysis was significant in enhancing the efficiency of the conjugate addition by forming the new C–C bond. With key intermediate (9) in hand, the authors entered the final stage of alkaloid drimentine G (2) synthesis as well as drimentines A (1) and F (3) syntheses since intermediate (9) was transformed into the desired natural hybrid isoprenoids efficiently. Ultimately, hybrid isoprenoid drimentine F (3) was treated with Bi(OTf)3 in the presence of the KPF6 to furnish another hybrid isoprenoid indotertine A (4) in 78% yields.

References 1. Che Q, Zhu T, Qi X et al. (2012) Hybrid isoprenoids from a reeds rhizosphere soil derived actinomycete Streptomyces sp. CHQ-64. Org Lett 14: 3438–3441. 2. Che Q, Zhu T, Keyzers RA et al. (2013) Polycyclic hybrid isoprenoids from a reed rhizosphere soil derived Streptomyces sp. CHQ-64. J Nat Prod 76: 759–763. 3. Lacey, E., Power, M., Wu, Z. & Rickards, R. W. Terpenylated Diketopiperazines, (Drimentines). WO 1998/009968, March 12, 1998. 4. Sun Y, Ruofan L, Zhang W et al. (2013) Total synthesis of indotertine A and drimentines A, F, and G. Angew Chem Int Ed 52: 9201–9204.

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Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

5. Yao T, Liu J, Jin E et al. (2020) Expanding the structural diversity of drimentines by exploring the promiscuity of two N-methyltransferases. iScience 23: 101323. 6. Lopez CS, Perez-Balado C, Rodriguez-Grana P et al. (2008) Mechanistic insights into the stereocontrolled synthesis of hexahydropyrrolo[2,3-b]indoles by electrophilic activation of tryptophan derivatives. Org Lett 10: 77–80.

Chapter 4

(−)-FR901483 and (+)-TAN1251C 3.4.1 Natural Source Cladobotryum sp. No. 11231 (family: Hypocreaceae)1 for FR901483 and Penicillium thomii RA-89 (family: Trichocomaceae)2 for TAN1251C.

3.4.2 Structure

3.4.3 Systematic Name (2S,5S,6S,7R,8S,10aS)-6-hydroxy-5-(4-methoxybenzyl)-2-(methylamino) octahydro-1H-7,10a-methanopyrrolo[1,2-a]azocin-8-yl dihydrogen phosphate ((−)-FR901483). (5S)-4-methyl-2-(4-((3-methylbut-2-en-1-yl)oxy)benzyl)-1,4-diazaspiro[bicyclo[3.2.1]oct[2]ene-7,1′-cyclohexan]-4′-one ((+)-TAN1251C).

225

226  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

3.4.4 Structural Features The intriguing structure of the immunosuppressive alkaloid FR901483 includes a phosphate ester along with a highly strained 5-azatricyclo[6.3. 1.0]dodecane framework, which was extraordinary in nature.3 From a structural perspective, TAN1251C consists of a unique tricyclic scaffold bearing 1,4-diazabicyclo[3.2.1]octane and spiro-fused cyclohexanone moieties.4

3.4.5 Class of Compounds Alkaloids.5

3.4.6 Pharmaceutical Potential FR901483 displays an exceedingly potent immunosuppressant property (>100 times more active than cyclosporine).6 The fascinating structure of FR901483 consists of a phosphate ester which may play a vital role in its immunosuppressive activity in vitro as the desphosphoryl molecule is devoid of this activity.1 TAN1251 A and B show cholinergic activity and inhibit the acetylcholine-induced contraction of guinea pig ileum, having ED50 (median effective dose) values of 8.0 and 10.0 nM, respectively; the former (TAN1251A) is also called a selective muscarinic M1 subtype receptor antagonist.7

3.4.7 Conventional Approach In 1996, a novel immunosuppressant FR901483 (1) was invented by scientists at Fujisawa Pharmaceutical Company Ltd.1 It was isolated from the fermentation broth of Cladobotryum sp. No. 11231 bearing molecular formula C20H31N2O6P as colorless needles (melting point 210–213 °C). Several elegant and inventive syntheses of FR901483 (1) have been reported to date; only the first reported synthesis and recent critical syntheses have been highlighted herein. Snider et al. achieved the first synthesis of the alkaloid (–)-FR901483 (1) from O-methyltyrosine methyl ester in a 2% overall yield in 1999 and demonstrated the absolute stereochemistry of the secondary metabolite.8 The investigators completed total synthesis in 22 steps involving a 1,3-dipolar cycloaddition of nitrone,



(−)-FR901483 and (+)-TAN1251C    227

the construction of the azaspirolactam, and the intramolecular aldol reaction as key steps. In 2005, Brummond et al. accomplished an effective formal total synthesis of FR901483 (1) from readily available ketone in 18 steps with 2.5% overall yield using an aldol condensation reaction and a tandem aza-Cope/Mannich reaction, monitoring the stereochemistry of the oxygen-carrying stereocenters as crucial steps.9 Ma and co-workers conducted the total synthesis of the immunosuppressive natural product (–)-FR901483 starting from readily available ketone in 16 steps in 3.5% overall yield by applying intramolecular Schmidt reaction as well as semipinacol-type rearrangement as vital steps in 2012.10 Huang and co-workers disclosed a new enantioselective total synthesis of FR901483 (1) and 8-epi-FR901483 from (R)-3-benzyloxyglutarimide as the starting material with an overall yield of 1.3% and 2.4%, respectively, in 21 steps by utilizing the formation of the chiral aza-quaternary center, intra­ molecular aldol reaction in regio- and diastereo-selective manner, and the construction of 3-pyrrolin-2-one ring through RCM as key steps in 2013.11 Kawahara et al. reported the first synthesis of another alkaloid (±)-TAN1251A involving Curtius rearrangement, selective tosylation of the primary alcohol, the formation of the pyrrolidine ring, and Mitsunobu reaction as central steps in 1998.12 Snider et al. developed biomimetic first total syntheses of muscarinic antagonists (+)-TAN1251B and (+)-TAN1251C together with (+)-TAN1251D enantiospecifically and the first synthesis of (–)-TAN1251A confirming the relative stereochemistry of TAN1251D and establishing the absolute stereochemical assignments based on CD investigations in 2000.13 Ciufolini and co-workers completed total syntheses of tricyclic azaspirane secondary metabolites FR901483 and TAN1251C through oxazoline chemistry to solve the long-standing problem regarding the oxidative cyclization of a phenolic 3arylpropionamide in 2001.14 Honda et al. disclosed an enantiospecific total synthesis of TAN1251C along with TAN1251D from the dimeric tyrosine derivative as the starting material by utilizing an aromatic oxidation of a secondary amine with hypervalent iodine reagent as a central step in 2005.15 In 2017, Kan executed a practical total synthesis of TAN1251C by involving an Ugi four-component accumulation transformation as well as a Dieckmann condensation for the construction of the spiro-fused cyclohexanone and γ-lactam ring. The formation of the amino group with the targeted stereochemistry was also achieved through diastereoselective reduction or Zn reduction of the oxime.16

228  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

3.4.8 Demerits of Conventional Approach The concise and effective formation of the amino-substituted azaspirocyclic skeleton of alkaloids FR901483 and TAN1251 remains a daunting synthetic challenge.5 Hence, various conventional approaches suffer from a few demerits regarding green chemistry as hazardous chemicals were used to synthesize natural products that are not safe for our environment and living organisms. Snider employed corrosive chemical trifluoroacetic acid in volatile solvent dichloromethane to furnish aldol adduct in comparatively low yield (36%) during the total synthesis of FR901483 (1).8 Acute toxic thionyl chloride was used to construct ketene from the major diastereomer of amino alcohol through oxidation by the Brummond group, providing the corresponding amino acid, and harmful benzene was also applied to generate key aldehyde from the aminoketone.9 Ma et al. prepared a benzyl protected diol derivative from the known diol using a highly corrosive benzyl bromide in potent liver toxin DMF.10 Eye-damaging chemical oxalyl chloride was applied to construct piperidin-3-one by the Huang group.11 A modest toxic DDQ in DCM (an LD50 of 82 mg/kg3, liberating highly toxic hydrogen cyanide with water) was used to prepare an essential eniminium salt from ketal through oxidation by the Snider group during the total synthesis of alkaloid TAN1251 (2).13

3.4.9 Key Features of Total Synthesis Using VisibleLight Irradiation The key feature for the concise total synthesis of natural alkaloids (−)-FR901483 (1) and (+)-TAN1251C (2) includes a divergent synthetic methodology that provides access to both secondary metabolites and new chiral spirolactam scaffolds through a crucial common spirolactam intermediate (3). The targeted spirolactam precursor (3) was obtained on a gram scale in a single operation by the visible light-assisted photocatalytic olefin hydroaminoalkylation.5

3.4.10 Type of Reaction C–N bond formation using visible-light irradiation.5



(−)-FR901483 and (+)-TAN1251C    229

3.4.11 Synthetic Strategy Using Visible-Light Irradiation Photocatalytic olefin hydroaminoalkylation reaction.5

3.4.12 Synthetic Route In 2019, Gaunt and co-workers developed a common strategy for the concise total syntheses of the polycyclic alkaloids (−)-FR901483 (1) and (+)-TAN1251C (2) through a pivotal spirolactam intermediate in the presence of the blue LED as a green protocol.5 The investigators were delighted to prepare the novel spirolactam precursor (6) from three commercially available building blocks such as 1,4-cyclohexanedione monoethylene acetal (3), L-tyrosine methyl ester (4), and dehydroalanine derivative (5) in 73% yield on gram scale by a variation of the visible lightassisted photocatalytic olefin hydroaminoalkylation method, following an easy filtration as the only purification step (Scheme 3.4.1). The unification of monoethylene acetal (3), ester (4), and dehydroalanine derivative (5) was executed to afford the targeted spirolactam precursor (6) using a catalytic amount of TFA, 1 mol% fac-Ir(ppy)3, Hantzsch ester in the presence of visible light irradiation (40 W blue LED light for 2 h) as a green methodology in DCM (dichloromethane) solution at room temperature, followed by acid-mediated (aqueous HCl) cyclization without deterioration of stereochemical integrity at the C2 position of key spirolactam (6). Herein, the role of a 40 W blue LED light was significant to construct the new C–N bond effectively in a single operation, providing concise total syntheses. The crucial spirolactam precursor (6) was effective to generate bioactive alkaloid (−)-FR901483 (1) as its HCl salt, in 85% yield over several steps. With the concise total synthesis of (−)-FR901483 (1) (total number of steps to 1 is 12) in hand, the investigators turned their attention to exploring the divergence of the synthetic methodology for the synthesis of (+)-TAN1251C (2) in a typical fashion from the same crucial spirolactam precursor (6). The construction of the vital alkene from spirolactam precursor (6) proceeded in 97% yield to complete the synthesis of (+)-TAN1251C (2) in seven steps (Scheme 3.4.2). Beyond its application in total synthesis, the authors recognized that the photocatalytic

230  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Scheme 3.4.1.    Visible-light-assisted total syntheses of (−)-FR901483 and (+)-TAN1251C.

Scheme 3.4.2.  Visible-light-assisted rapid stereocontrolled synthesis of chiral spirolactams and synthesis of analogs of TAN1251C.



(−)-FR901483 and (+)-TAN1251C    231

hydroaminoalkylation–cyclization strategy could be effective for the quick stereocontrolled preparation of a diversity of chiral spirolactams. Hence, the geminal difluoro analog of TAN1251C (10) was synthesized from spirolactam (8) to follow the same synthetic pathway initiating from the commercial ketone; this synthetic strategy provides direct access to a new chiral spirolactam skeleton that is likely to be of engrossment to early-stage drug design programs.5

References   1. Sakamoto K, Tsujii E, Abe F et al. (1996) FR901483, a novel immunosuppressant isolated from Cladobotryum sp. No. 11231. Taxonomy of the producing organism, fermentation, isolation, physicochemical properties, and biological activities. J Antibiot 49: 37–44.   2. Shirafuji H, Tsubotani S, Ishimaru T, Harada S, (1991) PCT Int. Appl., WO 91 13,887 [Chem. Abstr., 116, 39780h].   3. Ma A-J, Tu Y-Q, Peng J-B et al. (2012) Total synthesis of (-)-FR901483. Org Lett 14: 3604–3607.  4. Nagasaka Y, Shintaku S, Matsumura K et al. (2017) Total synthesis of TAN1251C via diastereoselective construction of the azaspiro skeleton. Org Lett 19: 3839−3842.   5. Reich D, Trowbridge A, Gaunt MJ. (2020) Rapid syntheses of (−)-FR901483 and (+)-TAN1251C enabled by complexity-generating photocatalytic olefin hydroaminoalkylation. Angew Chem Int Ed 59: 2256–2261.  6. Ciufolini MA. (2005) Synthetic studies on heterocyclic natural products. Il Farmaco 60: 627–641.  7. Widzowski D, Helander HF, Wu ESC. (1997) Selective muscarinic M1 antagonists: Drug design and discovery. Drug Discov Today 2: 341–350.   8. Snider BB, Lin H (1999) Total synthesis of (−)-FR901483. J Am Chem Soc 121: 7778–7786.   9. Brummond KM, Hong S-p. (2005) A formal total synthesis of (-)-FR901483, using a tandem cationic aza-Cope rearrangement/Mannich cyclization approach. J Org Chem 70: 907–916. 10. Ma A-J, Tu Y-Q, Peng J-B et al. (2012) Total synthesis of (−)-FR901483. Org Lett 14: 3604–3607. 11. Huo H-H, Xia X-E, Zhang H-K et al. (2013) Enantioselective total syntheses of (−)-FR901483 and (+)-8-epi-FR901483. J Org Chem 78: 455–465. 12. Nagumo S, Nishida A, Yamazaki C et al. (1998) Total synthesis of (±)-TAN1251A. Tetrahedron Lett 39: 4493–4496. 13. Snider BB, Lin H. (2000) Biomimetic total syntheses of (-)-TAN1251A, (+)-TAN1251B, (+)-TAN1251C, and (+)-TAN1251D. Org Lett 2: 643–646.

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14. Ousmer M, Braun NA, Bavoux C et al. (2001) Total synthesis of tricyclic azaspirane derivatives of tyrosine: FR901483 and TAN1251C. J Am Chem Soc 123: 7534–7538. 15. Mizutani H, Takayama J, Honda T. (2005) Enantiospecific total synthesis of TAN1251C and TAN1251D. Synlett 2005: 328–330. 16. Nagasaka Y, Shintaku S, Matsumura K et al. (2017) Total synthesis of TAN1251C via diastereoselective construction of the azaspiro skeleton. Org Lett 19: 3839–3842.

Chapter 5

(+)-Fusarisetin A 3.5.1 Natural Source Fusarium sp. FN080326 (family: Nectriaceae).1

3.5.2 Structure

3.5.3 Systematic Name (3S,3aR,5S,5aS,5bS,7aS,9R,11aR,11bS,12aR)-3a-hydroxy-3-(hydroxymethyl)-2,5,9,11b-tetramethyl-3,3a,5,5a,5b,7a,8,9,10,11,11a,11b-dodecahydro-1H-benzo[4′,5′]indeno[2′,1′:3,4]furo[2,3-c]pyrrole-1,12 (2H)-dione.

233

234  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

3.5.4 Structural Features The unique structural feature of the acinar morphogenesis inhibitor fusarisetin A comprises an unprecedented carbon skeleton with a fused pentacyclic ring system (A, B, C, D, E), including 10 stereocenters.2 The key structural characteristics of the fungal metabolite fusarisetin A consist of a trans-decalin (A, B) and a crucial tetramic acid moiety combined with a tetrahydrofuran ring (D, E) along with a spiroskeleton (C, E).1

3.5.5 Class of Compounds Tetramic acid.2

3.5.6 Pharmaceutical Potential The fungal metabolite fusarisetin A significantly inhibits acinar morphogenesis (77 μM), cell invasion (26 μM), and cell migration (7.7 μM) without significant cytotoxicity during tests of cell growth and cell death employing MDAMB-231 cells.1

3.5.7 Conventional Approach Ahn and co-workers isolated bioactive fusarisetin A from the fungus Fusarium sp. FN080326 as a white powder bearing molecular formula C22H31NO5, deduced by high-resolution electrospray ionization mass spectrometry (ESIMS) analysis together with NMR data.1 The same investigators also established the absolute stereochemistries of 10 stereogenic centers in the fungal metabolite fusarisetin A; the absolute stereochemistries were ascertained as 1S, 3R, 4S, 5R, 6R, 7R, 11R, 12S, 15S, and 16R.1 Li et al. achieved the first total synthesis of (−)-fusarisetin A using a Lewis acid-assisted intramolecular Diels−Alder reaction (IMDA) and a key chemoselective Wacker oxidation along with a crucial Pd-catalyzed O→C allylic rearrangement; they revised the absolute configuration of the secondary metabolite and completed total synthesis in 13 steps in 2012.3 Theodorakis et al. accomplished a short, efficient synthesis of (−)-fusarisetin A, the enantiomer of bioactive natural product through protecting group-free manner in nine steps from readily available (S)-(–)-citronellal; the critical steps of this synthesis include a facile formation of the decalin moiety through a stereoselective intramolecular



(+)-Fusarisetin A    235

Diels−Alder reaction, TEMPO-promoted radical cyclization/aminolysis via a one-pot operation for the construction of the C ring of (−)-fusarisetin A in 2012.4 Gao et al. developed an efficient strategy for an asymmetric total synthesis of (+)-fusarisetin A (1) for the first time involving the formation of the trans-decalin through a one-pot IMDA/Roskamp transformation and biosynthetic oxidation of equisetin assisted by MnIII/ O22; the same group was also able in its total synthesis through visiblelight-promoted oxidation as a green protocol.5

3.5.8 Demerits of Conventional Approach A highly corrosive chemical acetic anhydride was used to prepare key triene from the resulting primary alcohol through acetylation by the Li group; moreover, the same group employed highly toxic methane sulfonyl chloride to synthesize O-allylation compound from unsaturated primary alcohol.3 The irritating lungs causing coughing chemical ethyl bromoacetate was used to prepare bicyclic motif from decalin by the Theodorakis group; besides, an organolithium reagent toxic n-BuLi was used to synthesize the desired triene.4 BF3 is toxic by inhalation, and it is hydrolyzed by cold water to produce a corrosive material, hydrofluoric acid. BF3·OEt 2 in neurotoxin dichloromethane solvent was employed by the Gao group to produce the key aldehyde.2

3.5.9 Key Features of Total Synthesis Using Visible-Light Irradiation The key feature of the biomimetic total synthesis of the acinar morpho­ genesis inhibitor fusarisetin A comprises the formation of equisetin, a biogenetically linked acyl tetramic acid, which possesses a basic framework of a fungal metabolite (+)-fusarisetin A through a cyclization sequence including an intramolecular Diels–Alder reaction afterward a Dieckmann cyclization of polyenoylamino acid. Construction of peroxyfusarisetin through aerobic oxidation of equisetin by visible light and reduction of peroxyfusarisetin are other key steps of this synthesis.5

3.5.10 Type of Reaction C–O bond formation under visible-light irradiation.5

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3.5.11 Synthetic Strategy Using Visible-Light Irradiation Bio oxidation (radical cascade reaction).5

3.5.12 Synthetic Route Gao et al. disclosed a biomimetic synthesis of (+)-fusarisetin A (1) promoted by a reactive oxygen species (ROS) with visible light via a radical cascade reaction.5 Chlorophyll behaves as a photosensitizer in photosynthesis and has a profound role in accumulating solar energy in the form of chemical energy. It effectively initiates single-electron transfer (SET) during the process; the investigators applied this concept in the first asymmetric synthesis of fungal metabolite (+)-fusarisetin A (1). The authors initiated total synthesis of (+)-fusarisetin A (1) with the (+)-citronellal (2) to afford the aldehyde (3) on a large scale over two steps with good yield. Initially, a biogenetically linked acyl tetramic acid

Scheme 3.5.1.    Visible-light-assisted total synthesis of (+)-fusarisetin A.



(+)-Fusarisetin A    237

equisetin (4) was prepared from the aldehyde (3) over several steps. Next, the visible-light-assisted oxidation of equisetin (4) provided peroxyfusarisetin (5) along with its C5-epi-isomer (6) (d.r. = 2:1) in 68% combined yield. A solution of equisetin (4) in acetonitrile was irradiated with compact fluorescence lamp (CFL) in the presence of a catalytic amount of [Ru(bpy)3]Cl2 (photocatalyst) and Et3N under air or oxygen to provide targeted peroxide (Scheme 3.5.1). Similar results originated when the reaction was executed under sunlight as the photo source. The oxidation of equisetin (4) was also conducted using methylene blue as a photocatalyst to obtain peroxyfusarisetin (5) and C5-epi-isomer (6) in 70% combined yield. Finally, the reduction of peroxide bonds of peroxyfusarisetin (5) and (6) took place in the presence of the P(OMe)3 in acetonitrile at 80 °C to deliver the desired (+)-fusarisetin A (1) together with C5-epi-1 in 75% combined yield.5

References 1. Jang J-H, Asami Y, Jang J-P et al. (2011) Fusarisetin A, an acinar morphogenesis inhibitor from a soil fungus, Fusarium sp. FN080326. J Am Chem Soc 133: 6865–6867. 2. Yin J, Wang C, Kong L et al. (2012) Asymmetric synthesis and biosynthetic implications of (+)-fusarisetin A. Angew Chem Int Ed 51: 7786–7789. 3. Deng J, Zhu B, Lu Z et al. (2012) Total synthesis of (−)-fusarisetin A and reassignment of the absolute configuration of its natural counterpart. J Am Chem Soc 134: 920−923. 4. Xu Jing, Caro-Diaz EJE, Trzoss L et al. (2012) Nature-inspired total synthesis of (−)-fusarisetin A. J Am Chem Soc 134: 5072−5075. 5. Jun Y, Kong L, Wang C et al. (2013) Biomimetic synthesis of equisetin and (+)-fusarisetin A. Chem Eur J 19: 13040–13046.

Chapter 6

(+)-Gliocladin C 3.6.1 Natural Source Gliocladium roseum Bionectriaceae).1

OUPS-N132

(Aplysia

kurodai)

(family:

3.6.2 Structure

3.6.3 Systematic Name (5aR,10bS)-10b-(1H-indol-3-yl)-2-methyl-5a,6-dihydro-1H-pyrazino [1′,2′:1,5]pyrrolo[2,3-b]indole-1,3,4(2H,10bH)-trione.

3.6.4 Structural Features From a structural perspective, the marine alkaloid gliocladin C (1) is linked closely in structure to epidithiodiketopiperazine congeners gliocladine A and leptosin D, along with T988A.2 A fungal-derived 239

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metabolite gliocladin C (1) consists of a rare trioxopiperazine fragment, despite the core skeleton in gliocladin C (1) is common to other hexahydropyrrolo[2,3-b]indole diketopiperazine alkaloids.1,3

3.6.5 Class of Compounds Alkaloid.1,2

3.6.6 Pharmaceutical Potential Gliocladin C (1) displays potent cytotoxicity against P388 lymphocytic leukemia cells in vitro with an ED50 value of 2.4 μg/mL.1,4

3.6.7 Conventional Approach In 2004, Usami et al. isolated cytotoxic marine alkaloid from a strain Gliocladium roseum, which initially originated from the sea hare Aplysia kurodai carrying molecular formula C22H16N4O3.1 Natural gliocladin C (1) has been the focus of plentiful synthetic efforts, owing to its structural complexity and potent biological activities. Overman et al. achieved the first asymmetric total synthesis of natural bioactive alkaloid gliocladin C (1) in 21 steps from isatin with nearly 4% overall yield in 2007; this enantioselective synthesis confirms the absolute configuration of this structurally new secondary metabolite also.2 The key feature of the total synthesis comprises an asymmetric formation of the critical quaternary carbon stereocenter by an important Mukaiyama aldol reaction between enantiopure aldehyde and siloxyindole.5 A second-generation total synthesis of the epipolythiodioxopiperazine natural alkaloid (+)-gliocladine C has been executed by the Zhang group from the same isatin in 10 steps with 11% overall yield involving a convergent formation of oxopiperazinefused pyrrolidinoindolines in 2011 through two short synthetic sequences.6 In 2017, Martin and co-workers developed a unique approach for the syntheses of bioactive natural gliocladin C (1) and related alkaloids using an unusual nucleophilic addition of a diketopiperazine to an isatin analog followed by an important Friedel−Crafts alkylation of the tertiary alcohol in the presence of the indole to construct the vital quaternary center. Another central feature of this synthesis includes chemoselective oxindole reduction and cyclization to form the crucial hexahydropyrrolo[2,3-b]



(+)-Gliocladin C    241

indole diketopiperazine intermediate.3 Recently, formal total synthesis of racemic gliocladin C was described by Bisai et al. along with a new entry to direct incorporation of a nitrile functionality by applying a cyano-1,2benziodoxol-3(1H)-one reagent under a transition-metal free condition in 2020.7

3.6.8 Demerits of Conventional Approach Several conventional approaches were reported to complete the total synthesis of cytotoxic marine alkaloids despite classical approaches suffering from a few demerits with respect to green or clean chemistry. Overman et al. employed highly flammable carcinogenic benzene to prepare amino oxindole from Mukaiyama aldol adduct oxindole by forming the key hydroxymethyl pyrrolidinoindoline.2 Highly toxic and irritant methane sulfonyl chloride or mesyl chloride was used by the Martin group to construct the crucial addition product as a single regioisomer and diastereomer during the total synthesis of alkaloid gliocladin C (1).3 Zhang et al. applied a corrosive reagent trifluoroacetic acid in volatile organic solvent dichloromethane to synthesize key intermediate oxindole during the total synthesis of alkaloid gliocladin (+)-gliocladine C.6

3.6.9 Key Features of Total Synthesis Using Visible-Light Irradiation The unique feature for the total synthesis of natural alkaloid gliocladin C (1) consists of a visible-light-assisted coupling of indoles with bromopyrroloindolines, catalytic decarbonylation of an aldehyde, acylation/cyclization by microwave irradiation, and intramolecular amidation to install the triketopiperazine. The total synthesis of gliocladin C (1) was completed in 10 steps in 30% overall yield through the formation of a common imine intermediate for the synthesis of other members of the monumental type of indole alkaloids.8

3.6.10 Type of Reaction C–C bond formation under visible-light irradiation.8

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3.6.11 Synthetic Strategy Using Visible-Light Irradiation Coupling reaction.8

3.6.12 Synthetic Route Stephenson and co-workers explored photoredox chemistry in the total synthesis of cytotoxic alkaloid gliocladin C (1) using a visible-lightassisted coupling of indoles with bromopyrroloindolines in 2011.8

º º

º

Scheme 3.6.1.    Visible-light-assisted total synthesis of gliocladin C.



(+)-Gliocladin C    243

The total synthesis was initiated from readily available Boc-D-tryptophan methyl ester (2) to provide bromopyrroloindoline (3) over three steps involving methylamidation as a key step. Next, the resulted methylamide (3) was subjected to the crucial visible-light-mediated indole coupling reaction with indole-2-carboxaldehyde (4) as the most suitable coupling partner to generate coupling product (5) using 1 mol% of [Ru(bpy)3Cl2] in DMF and Bu3N (2.0 equiv) using blue-light irradiation for 12 h in 82% yield (Scheme 3.6.1). The key intermediate (5) was very efficient to furnish bioactive natural alkaloid gliocladin C (1) over several steps ultimately. Optical rotation along with spectroscopic data for synthetic gliocladin C (1) correlates well to the reported data for the natural alkaloid sample.8

References 1. Usami Y, Yamaguchi J, Numata A. (2004) Gliocladins A - C and glioperazine; cytotoxic dioxo- or trioxopiperazine metabolites from a Gliocladium sp. separated from a sea hare. Heterocycles 63: 1123–1129. 2. Overman LE, Shin Y. (2007) Enantioselective total synthesis of (+)-gliocladin C. Org Lett 9: 339–341. 3. Hodges TR, Benjamin NM, Martin SF. (2017) Syntheses of gliocladin C and related alkaloids. Org Lett 19: 2254−2257. 4. Bertinetti BV, Rodriguez MA, Godeas AM et al. (2010) 1H,1′H-[3,3′]biindolyl from the terrestrial fungus Gliocladium catenulatum. J Antibiot 63: 681−683. 5. Adhikari S, Caille S, Hanbauer M et al. (2005) Asymmetric construction of quaternary carbon stereocenters: High stereoselection in Mukaiyama aldol reactions of 2-siloxyindoles with chiral aldehydes. Org Lett 7: 2795–2798. 6. DeLorbe JE, Jabri SY, Mennen SM. (2011) Enantioselective total synthesis of (+)-gliocladine C: Convergent construction of cyclotryptamine-fused polyoxopiperazines and a general approach for preparing epidithiodioxopiperazines from trioxopiperazine precursors. J Am Chem Soc 133: 6549−6552. 7. Maity A, Roy A, Das MK et al. (2020) Oxidative cyanation of 2-oxindoles: Formal total synthesis of (±)-gliocladin C. Org Biomol Chem 18: 1679–1684. 8. Furst L, Narayanam JMR, Stephenson CRJ. (2011) Total synthesis of (+)-gliocladin C enabled by visible-light photoredox catalysis. Angew Chem Int Ed 50: 9655–9659.

Chapter 7

Grandilodine and Lapidilectine Family of Alkaloids 3.7.1 Natural Source Kopsia grandifolia (grandilodines) and Kopsia lapidilecta (lapidilectines) (family: Apocynaceae).1–3

3.7.2 Structure

3.7.3 Systematic Name (6aR,11aR,12R,13aR)-methyl 3-methylene-16-oxo-5,6,12,13-tetrahydro6a,12-(epoxymethano)-11a,13a-ethanopyrrolo[1′,2′:1,8]azocino[5,4-b]indole11(3H)-carboxylate: (+)-Lapidilectine B (1). (6aR,11aR,12R,13aR)-methyl 3,16-dioxo-5,6,12,13-tetrahydro-6a,12(epoxymethano)-11a,13a-ethanopyrrolo[1′,2′:1,8]azocino[5,4-b]indole-11(3H)carboxylate: (+)-Grandilodine C (2).

245

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(6aS,11aR,12R,13aR)-trimethyl 3-methylene-6,6a,12,13-tetrahydro3H-11a,13a-ethanopyrrolo[1′,2′:1,8]azocino[5,4-b]indole-6a,11,12(5H)tricarboxylate: (–)-Lapidilectine A (3). (6aS,11aR,12R,13aR)-trimethyl 3-oxo-6,6a,12,13-tetrahydro-3H-11a,13aethanopyrrolo[1′,2′:1,8]azocino[5,4-b]indole-6a,11,12(5H)-tricarboxylate: (–)-Lapidilectam (4). (6aS,11aR,12R,13aR)-trimethyl 3-methylene-2,3,6,6a,12,13-hexahydro1H-11a,13a-ethanopyrrolo[1′,2′:1,8]azocino[5,4-b]indole-6a,11,12(5H)tricarboxylate: (–)-Grandilodine A (5). (6aS,11aR,12S,13aR)-trimethyl 3-methylene-6,6a,12,13-tetrahydro3H-11a,13a-ethanopyrrolo[1′,2′:1,8]azocino[5,4-b]indole-6a,11,12(5H)tricarboxylate: (+)-Isolapidilectine A (6). (6aS,11aR,12S,13aR)-trimethyl 3-oxo-6,6a,12,13-tetrahydro-3H-11a,13aethanopyrrolo[1′,2′:1,8]azocino[5,4-b]indole-6a,11,12(5H)-tricarboxylate: (+)-Grandilodine B (7).

3.7.4 Structural Features From a structural perspective, (+)-lapidilectine B (1) and (+)-grandilodine C (2) comprise lactone motif as well as (–)-lapidilectine A (3) to (+)-grandilodine B (7) include diester motif. Indole alkaloids lapidilectines and grandilodines consist of pyrroloazocine skeleton; pentacyclic indole lapidilectine A (3) is characterized by the existence of a 1-azabicyclo[6.3.0] decane unit and lapidilectine B (1) is characterized by the presence of a urethane.1–3

3.7.5 Class of Compounds Alkaloids.1–3

3.7.6 Pharmaceutical Potential Kam et al. isolated grandilodines A–C along with five known compounds from Kopsia grandifolia. The authors also examined biological properties



Grandilodine and Lapidilectine Family of Alkaloids    247

of indole alkaloids; grandilodines A and C together with lapidilectine B were found to reverse multidrug resistance in vincristine-resistant KB cells (IC50 4.35, 4.11, and 0.39 μg/mL, respectively, in the presence of 0.1 μg/mL vincristine).1

3.7.7 Conventional Approach The synthetic and biological community was attracted to total syntheses of indole alkaloids because of their interesting structures and biological properties. Pearson et al. developed the first total synthesis of (±)-lapidilectine B, an azocino[5,4-b]indole type of alkaloids, which comprises indoxyl preparation through Smalley’s method, the construction of the perhydroazocine nucleus by intramolecular N-alkylation as central steps.4 In another work, the same group also demonstrated the total synthesis of the natural alkaloid (±)-lapidilectine B from 4-benzyloxycyclohexanone by applying the Smalley azido-enolate cyclization for the first time and the formation of the eight-membered perhydroazocine core through the intramolecular SN2 replacement of a mesylate as vital steps.5 Nishida et al. explored the total synthesis of Kopsia alkaloid (+)-grandilodine C for the first time as well as the enantioselective total synthesis of (+)-lapidilectine B with the establishment of the absolute configuration of both alkaloids in 2016. The unique features of total syntheses include the trouble-free construction of a key intermediate spiroenone and the formation of novel stereocenters through the stereoselective vinylation–allylation sequence. The total synthesis of alkaloid (+)-lapidilectine B was achieved by the crucial selective reduction of a lactam carbonyl, and the total synthesis of another bioactive (+)-grandilodine C was executed by palladium-catalyzed intramolecular allylic amination and ring-closing metathesis.6 Zu et al. evolved the total synthesis of the naturally occurring opened-class Kopsia alkaloid grandilodine B for the first time in 2017. The key points in this synthesis consist of a Diels−Alder reaction for forming C16 stereocenter and establishing the C7 quaternary carbon center through a diastereoselective cyanation as well as regioselective nitrone 1,3-dipolar cycloaddition.7

3.7.8 Demerits of Conventional Approach From the view of clean chemistry, conventional approaches suffer from a few demerits. The Pearson group used volatile liquid and highly toxic

248  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

osmium tetroxide to prepare diol from amino ketone as a 6:1 mixture of diastereomers.4,5 The same group employed the toxic PCC (pyridinium chlorochromate, the presence of chromium (VI)) in volatile organic solvent dichloromethane to produce an important ketone and lactone.5 A corrosive reagent p-toluene sulfonic acid and toxic chemical acetic anhydride were applied in constructing acetate and lactone from the corresponding azide by the Nishida group.6 Zu used a toxic organosulfur molecule mesyl chloride to yield an alkyl mesylate from alcohol although they used microwave irradiation as a green tool to prepare grandilodine B.7

3.7.9 Key Features of Total Synthesis Using VisibleLight Irradiation Total syntheses of indole alkaloids were completed without any need for protection/deprotection of functional groups. The key features of syntheses comprise two effective gold-catalyzed cyclization protocols, a 6-exo-trig photoredox cyclization as well as an 8-endo-dig hydroarylation.

3.7.10 Type of Reaction C–C bond formations using visible-light irradiation.3

3.7.11 Synthetic Strategy Using Visible-Light Irradiation Photoredox cyclization.

3.7.12 Synthetic Route In 2018, Echavarren and co-workers achieved total syntheses of enantiomerically pure indole alkaloids lapidilectines and grandilodines in 11–19 steps using a 6-exo-trig photoredox cyclization as a crucial step. Total syntheses of pyrroloazocine indole alkaloids were initiated from readily available tryptamine (8) with oxoester (9) to deliver the targeted bromide (10) over several steps, including Au-catalyzed cyclization as a key step. The challenging rigid azabicyclic [4.2.2] core was constructed



Grandilodine and Lapidilectine Family of Alkaloids    249

by the photoredox transformation since it includes a rare 6-exo-trig radical spirocyclization, the absence of driving force for the cyclization owing to the relative stability of an α-CO2Me radical compared to the strained benzyl radicals. The bromide (10) was irradiated with 365 nm UV LEDs to produce an important elimination product (13) using [(dppmAuCl)2] as a digold photoredox catalyst and sodium carbonate in acetonitrile in 91% yield through the construction of two intermediates (11 and 12) (Scheme 3.7.1). The alkene (13) was very effective to generate (–)-lapidilectine A (3), (+)-lapidilectine B (1), (–)-lapidilectam (4), (+) isolapidilectine A (6), (–)-grandilodine A (5), (+)-grandilodine B (7), and (+)-grandilodine C (2).

Scheme 3.7.1.  Visible-light-assisted total syntheses of lapidilectine and grandilodine family of alkaloids.

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References 1. Yap W-S, Gan C-Y, Low Y-Y et al. (2011) Grandilodines A-C, biologically active indole alkaloids from Kopsia grandifolia. J Nat Prod 74: 1309–1312. 2. Awang K, Sevenet T, Pais M. (1993) Alkaloids of Kopsia lapidilecta. J Nat Prod 56: 1134–1139. 3. Awang K, Sevenet T, Hadi AHA et al. (1992) Lapidilectine A and lapidilectine B, two new alkaloids from Kopsia lapidilecta. Tetrahedron Lett 33: 2493–2496. 4. Pearson WH, Mi Y, Lee IY et al. (2001) Total synthesis of the Kopsia lapidilecta alkaloid (±)-lapidilectine B. J Am Chem Soc 123: 6724–6725. 5. Pearson WH, Lee IY, Mi Y et al. (2004) Total synthesis of the Kopsia lapidilecta alkaloid (±)-lapidilectine B. J Org Chem 69: 9109–9122. 6. Nakajima M, Arai S, Nishida A. (2016) Total syntheses of (+)-grandilodine C and (+)-lapidilectine B and determination of their absolute stereochemistry. Angew Chem Int Ed 55: 3473–3476. 7. Wang C, Wang Z, Xie X (2017) Total synthesis of (±)-grandilodine B. Org Lett 19: 1828–1830. 8. Miloserdov FM, Kirillova MS, Muratore ME et al. (2018) Unified total synthesis of pyrroloazocine indole alkaloids sheds light on their biosynthetic relationship. J Am Chem Soc 140: 5393–5400.

Chapter 8

(+)-Jungermatrobrunin A 3.8.1 Natural Source Jungermannia atrobrunnea (family: Jungermanniaceae).1

3.8.2 Structure

3.8.3 Systematic Name (3S,3aS,4S,5R,8S,8aR,12S,12aS,12bS)-3,4-dihydroxy-9,9,12a-trimethyl13-methylene-3,3a,4,5,6,8,8a,9,10,11,12,12a-dodecahydro-3,5-methanophenanthro[4a,4-c][1,2]dioxole-8,12-diyl diacetate.

3.8.4 Structural Features The fascinating architecture of (+)-jungermatrobrunin A (1) comprises an unusual peroxide bridge, an exo-methylene, and an extremely oxidized scaffold having a distinctive bicyclo[3.2.1]octene ring skeleton.2 The key 251

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feature of a rearranged ent-kaurane diterpenoid (+)-jungermatrobrunin A (1) includes the two oxygenated quaternary carbons C-9 (δC 94.3) and C-15 (δC 113.2), α-oriented two O-acetyl groups at C-1 and C-6, and β-oriented hydroxy group at C-12.1

3.8.5 Class of Compounds Diterpenoid.1

3.8.6 Pharmaceutical Potential (+)-Jungermatrobrunin A (1) displayed antifungal activity.2

3.8.7 Conventional Approach In 2008, Lou et al. isolated a novel rearranged ent-kaurane-type diterpenoid (+)-jungermatrobrunin A (1) from the liverwort Jungermannia atrobrunnea (Jungermanniaceae) for the first time as colorless needles having molecular formula C24H32O8.1 The molecular formula of jungermatrobrunin A (1) was established by the [M+NH4]+ ion peak at m/z 466.2430 within the HRESIMS (calcd, 466.2441), suggesting that this natural bioactive secondary metabolite (1) consists of nine degrees of unsaturation. Only one enantioselective total synthesis of natural (+)-jungermatrobrunin A (1) has been reported employing visible-light irradiation as a green tool.2

3.8.8 Demerits of Conventional Approach No conventional approach has been reported to date.2

3.8.9 Key Features of Total Synthesis Using VisibleLight Irradiation The unique feature for the concise total synthesis of (+)-jungermatrobrunin A (1) consists of the radical-assisted reductive cyclization, formation of the trans-decalin from cis-decalin, Schenck ene reaction, and construction of a jungermannenone-type scaffold through reductive cyclization.2



(+)-Jungermatrobrunin A    253

3.8.10 Type of Reaction C–O bond formation using visible-light irradiation.2

3.8.11 Synthetic Strategy Using Visible-Light Irradiation Schenck ene reaction.2

3.8.12 Synthetic Route In 2019, Lei and co-workers completed the first enantioselective total synthesis of natural (+)-jungermatrobrunin A (1) in 13 steps using a latestage visible-light-assisted Schenck ene reaction as a central step.2

Scheme 3.8.1.    Visible-light-assisted total synthesis of (+)-jungermatrobrunin A.

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The total synthesis was initiated from readily available 4,4-dimethylcyclo­ hex-2-enone (2) and 2-bromo-4-methoxy-1-vinylbenzene (3) to furnish the targeted cyclohexanone (4) on decagram scale in 78% yield with 88% ee through Fletcher’s protocol.3 A single recrystallization was effective in enhancing the yield of cyclohexanone (4) to 94% ee, and single-crystal X-ray analysis confirmed its absolute configuration.2 Next, the desired product (5) was obtained from cyclohexanone (4) efficiently over several steps including the regio- along with diastereo-selective methylation of the cyclohexanone skeleton, construction of the trans-decalin from cis-decalin through ketone–enol tautomerization, and formation of a jungermannenone-type scaffold by the tri-n-butyltin hydride as key steps. Finally, the targeted natural ent-kaurene diterpenoid (+)-jungermatrobrunin A (1) was prepared from (5) through an essential photo-induced singlet oxygen Schenck ene transformation to build the peroxide bridge. Herein, the role of a 24-W white LED lamp was significant in constructing a peroxide bridge effectively through the construction of the new C–O bond (Scheme 3.8.1). Compound (5) was irradiated with a 24-W white LED lamp in the presence of the rose bengal (10 mol%) as a photosensitizer in a solvent mixture (MeCN/pyridine 40:1 v/v) using O2 to afford jungermatrobrunin A (1) as a sole product in 57% yield (65% conversion).

References 1. Qu J-B, Zhu R-L, Zhang YL et al. (2008) ent-Kaurane diterpenoids from the liverwort Jungermannia atrobrunnea. J Nat Prod 71: 1418–1422. 2. Wu J, Kadonaga Y, Hong B et al. (2019) Enantioselective total synthesis of (+)-jungermatrobrunin A. Angew Chem Int Ed 58: 10879–10883. 3. Maksymowicz RM, Roth PMC, Fletcher SP. (2012) Catalytic asymmetric carbon–carbon bond formation using alkenes as alkylmetal equivalents. Nat Chem 4: 649–654.

Chapter 9

Kuwanons 3.9.1 Natural Source A variety of Morus alba L., mulberry tree (kuwanons I, J, G, and H) (family: Moraceae).1–4

3.9.2 Structure

3.9.3 Systematic Name (E)-1-((2′R,3′R)-2′-(2,4-dihydroxy-3-(3-methylbut-2-en-1-yl)benzoyl)2,2″,4″,6-tetrahydroxy-5′-methyl-1′,2′,3′,4′-tetrahydro-[1,1′:3′,1″terphenyl]-3-yl)-3-(2,4-dihydroxyphenyl)prop-2-en-1-one. 255

256  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

3.9.4 Structural Features From a structural perspective, prenylflavonoid Diels–Alder secondary metabolites kuwanon I (1) and kuwanon J (2) include at least one 2′-hydroxy chalcone moiety along with polyphenol structures. Kuwanon I (1) in solution stays as an equilibrium mixture of conformational isomers established by the variable temperature NMR examinations; it is the earliest instance considered a Diels–Alder adduct of a prenylchalcone derivative as well as a dehydroprenylchalcone derivative biogenetically.1 The unique carbon skeleton kuwanon J (2) consists of two prenylchalcone derivatives.2

3.9.5 Class of Compounds Dehydroprenylchalcone type.1,2

3.9.6 Pharmaceutical Potential Most mulberry Diels−Alder-type adducts (MDAAs) display various biological activities, including antibacterial, hypotensive, antiinflammation, antioxidation, antivirus, and antiphlogistic properties.5–9 For example, kuwanon G exhibits antibacterial activity with a MIC value of 8.0 mg/mL10; kuwanons G and H have emerged as powerful multitargeted agents for Alzheimer’s disease, which showed influential inhibitory property of tau aggregation as well as good blood−brain barrier permeability, respectively.11

3.9.7 Conventional Approach Nomura and co-workers isolated a new natural Diels–Alder adduct from the root bark of the mulberry tree as a yellow amorphous powder having molecular formula C40H38O10 and named kuwanon I (1).1 Another novel natural Diels–Alder adduct kuwanon J (2) was isolated by Ueda et al. from seedlings of Morus alba L. as a yellow powder bearing the same molecular formula in 1982.2 Total syntheses of mulberry Diels−Aldertype adducts (MDAAs) have been achieved by several groups due to their attractive structures and interesting biological properties. Rahman and co-workers developed the first synthesis of (±)-kuwanon V, a mulberry

Kuwanons    257

Diels–Alder adduct through the biomimetic [4+2] Diels–Alder cycloaddition reaction between the largely electron-rich dienophile and a Lewis acid impressible diene in 2011.12 In 2016, Lei et al. demonstrated the first enantioselective total syntheses of (−)-kuwanon X, (+)-kuwanon Y, as well as (+)-kuwanol A involving an asymmetric Diels−Alder cycloaddition assisted by (R)-VANOL (L2) or boron Lewis acid. Greater exo selectivity (exo/endo = 13/1) was exhibited by the biosynthesisinspired asymmetric Diels−Alder cycloaddition, which was unexampled in the previous total syntheses of Diels−Alder secondary metabolites.13 Calcaterra Lei et al. executed the total synthesis of (±)-kuwanol E, the Diels−Alder-type adducts and (±)-kuwanon Y, the heptamethyl ether analog through a convergent approach by utilizing 2′-hydroxychalcone as well as dehydroprenylstilbene in nine steps; the formation of the cyclohexene framework was achieved by a Lewis acid-promoted biomimetic [4+2] cycloaddition in 2016.14 Recently, in 2021, Tang et al. went on to report the total syntheses of bioactive natural kuwanons G and H through a biomimetic manner for the first time by applying the Baker−Venkataraman rearrangement, intramolecular cyclization, Suzuki− Miyaura coupling along with the alkylation of β-diketone as crucial steps.15

3.9.8 Demerits of Conventional Approach Conventional approaches were not free from a few demerits. Rahman et al. used flammable and reactive liquid acetyl chloride in carcinogenic benzene to construct key diene.12 Lei and co-workers used a highly corrosive reagent acetic anhydride in volatile organic solvent DCM to prepare a vital iodide together with diene.13 Possible eye-damaging chemical phosphorus tribromide in DCM was applied to synthesize benzyl bromide by the Calcaterra group.14 Tang et al. used a corrosive chemical, thionyl chloride, which irritates the lungs in preparing benzoyl chloride from 2,4-dimethoxybenzoic acid.15

3.9.9 Key Features of Total Synthesis Using VisibleLight Irradiation The salient features for total syntheses of kuwanons I (1) and J (2) as well as brosimone A (12) and brosimone B (13) comprise a new asymmetric

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Diels–Alder cycloaddition, regioselective Schenck ene reaction, and the construction of six stereogenic centers in a single operation through a new tandem inter/intramolecular asymmetric Diels–Alder cycloaddition methodology.16

3.9.10 Type of Reaction C–O bond formation using visible-light irradiation.16

3.9.11 Synthetic Strategy Using Visible-Light Irradiation Schenck ene reaction.16

3.9.12 Synthetic Route Lei and co-workers explored the first enantioselective total syntheses of mulberry Diels−Alder-type adducts kuwanons I (1) and J (2) in 2014 using a visible-light-promoted Schenck ene reaction as a key step.16 The authors initiated total syntheses with readily available chalcone (3) to furnish the prenyl chalcone (4) in excellent yield (95%); the common intermediate (4) underwent the montmorillonite-K-10-assisted sigmatropic rearrangement to deliver the ortho-prenylated chalcone (5) (37%) and a para-prenylated chalcone (6) (27%). Interestingly, an orthoprenylated product (5) is a suitable synthetic precursor for the syntheses of prenylflavonoid natural products kuwanons I (1) and J (2), while paraprenylated chalcone (6) is a worthy synthetic precursor for the syntheses of natural products brosimones A and B. Next, the desired dienophile triacetate (7) was obtained from a MOM-protected molecule (5); the dienophile triacetate (7) was subjected to visible-light promoted Schenck ene reaction to generate the tertiary alcohol (8) and secondary allylic alcohol (9) in 71% combined yield with a 2:1 ratio. The authors conducted the first [Ru(bpy)3Cl2·6H 2O]-assisted regioselective Schenck ene reaction in methanol solvent employing rose bengal as a photosensitizer (Scheme 3.9.1). Finally, the tertiary allylic alcohol (8) was effective in producing the targeted natural products kuwanon I (1) and kuwanon J (2), including asymmetric Diels–Alder reaction as a crucial step. The investigators also

Kuwanons    259

α β

Scheme 3.9.1.    Visible-light-assisted total syntheses of kuwanons I and J.

achieved enantioselective total syntheses of (–)-brosimone A and (–)-brosimone B (Scheme 3.9.2); total syntheses were completed in seven steps from the common precursor prenyl chalcone (4) based on a biosynthesis-inspired strategy.16

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Scheme 3.9.2.  Visible-light-assisted total syntheses of (–)-brosimone A and (–)brosimone B.

References   1. Nomura T, Fukai T, Matsumoto J et al. (1982) Constituents of the cultivated mulberry tree. Planta Med 46: 167–174.   2. Ueda S, Nomura T, Fukai T et al. (1982) Kuwanon J, a new Diels–Alder adduct and chalcomoracin from callus culture of Morus alba L. Chem Pharm Bull 30: 3042–3045.

Kuwanons    261

  3. Nomura T, Fukai T. (1980) Kuwanon G, a new flavone derivative from the root barks of the cultivated mulberry tree (Morus alba L.). Chem Pharm Bull 28: 2548–2552.   4. Nomura T, Fukai T, Narita T. (1980) Hypotensive constituent, kuwanon H, a new flavone derivative from the root bark of the cultivated mulberry tree (Morus alba L.). Heterocycles 14: 1943–1951.   5. Yang Y, Tan YX, Chen RY et al. (2014) The latest review on the polyphenols and their bioactivities of Chinese Morus plants. J Asian Nat Prod Res 16: 690−702.   6. Gao L, Han J, Lei X. (2016) Enantioselective total syntheses of kuwanon X, kuwanon Y, and kuwanol A. Org Lett 18: 360−363.   7. Zelová H, Hanáková Z, Čermáková Z. (2014) Evaluation of anti-inflammatory activity of prenylated substances isolated from Morus alba and Morus nigra. J Nat Prod 77: 1297−1303.   8. Zheng ZP, Cheng KW, Zhu Q et al. (2010) Tyrosinase inhibitory constituents from the roots of Morus nigra: A structure−activity relationship study. J Agric Food Chem 58: 5368−5373.  9. Zhang QJ, Tang YB, Chen RY et al. (2007) Three new cytotoxic Diels− Alder-type adducts from Morus australis. Chem Biodivers 4: 1533−1540. 10. Park KM, You JS, Lee HY et al. (2003) Kuwanon G: An antibacterial agent from the root bark of Morus alba against oral pathogens. J Ethnopharmacol 84: 181–185. 11. Xia C-L, Tang G-H, Guo Y-Q et al. (2019) Mulberry Diels-Alder-type adducts from Morus alba as multi-targeted agents for Alzheimer’s disease. Phytochemistry 157: 82–91. 12. Chee CF, Lee YK, Buckle MJC et al. (2011) Synthesis of (±)-kuwanon V and (±)-dorsterone methyl ethers via Diels–Alder reaction. Tetrahedron Lett 52: 1797–1799. 13. Gao L, Han J, Lei X. (2016) Enantioselective total syntheses of kuwanon X, kuwanon Y, and kuwanol A. Org Lett 18: 360–363. 14. Iovine V, Benni I, Sabia R et al. (2016) Total synthesis of (±)-kuwanol E. J Nat Prod 79: 2495−2503. 15. Luo S-Y, Tang Z-Y, Li Q et al. (2021) Total synthesis of mulberry Diels− Alder-type adducts kuwanons G and H. J Org Chem 86: 4786−4793. 16. Han J, Li X, Guan Y et al. (2014) Enantioselective biomimetic total syntheses of kuwanons I and J and brosimones A and B. Angew Chem Int Ed 53: 9257–9261.

Chapter 10

Lactacystin 3.10.1 Natural Source Streptomyces sp. OM-6519 (family: Streptomycetaceae).1,2

3.10.2 Structure

3.10.3 Systematic Name (R)-2-acetamido-3-(((2R,3S,4R)-3-hydroxy-2-((S)-1-hydroxy-2-methyl­ propyl)-4-methyl-5-oxopyrrolidine-2-carbonyl)thio)propanoic acid.

3.10.4 Structural Features From a structural perspective, bioactive lactacystin (1) contains a thioester structure that is decorated by N-acetylcysteine along with γ-lactam 263

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moieties possessing a quaternary carbon; the existence of a hydroxy­ isobutyl group was confirmed by the 1H–1H COSY spectrum (400 MHz, pyridine-d5).1,2

3.10.5 Class of Compounds Carboxylic acid.1,2

3.10.6 Pharmaceutical Potential A microbial metabolite lactacystin (1) displays significant neurotrophic activity1,2; it was shown to inhibit cellular growth. It induced neurite outgrowth in the mouse neuroblastoma cell line Neuro-2a (the least concentration of lactacystin needed for the changes was 1.3 µm). A Streptomyces metabolite lactacystin (1) also inhibits proliferation of other cell types, indicating that its target is not dedicated to Neuro-2a cells; a detailed examination of the mode of biological action expressed that lactacystin (1) inhibits the proteolytic activity of the 20S proteasome in an irreversible manner.3

3.10.7 Conventional Approach In 1991, Omura and co-workers identified lactacystin (1) from Streptomyces sp. OM-6519 as colorless needles (melting point 237~238 °C) having molecular formula C15H24N2O7S, after screening various thousand culture samples.1 1H and 13C NMR spectroscopy together with singlecrystal X-ray analysis determined the relative and absolute stereochemistry of a powerful proteasome inhibitor (+)-lactacystin successfully.2 Due to its glamorous biological activity and fascinating structure, lactacystin (1) has attracted significant attention as a synthetic target, and hence various conventional approaches have been reported.4–12 Corey et al. developed the first total synthesis of a bioactive metabolite lactacystin (1) in 1992 using aldol couplings for the construction of the diastereo, enantiomerically pure secondary alcohol, and the targeted aldol stereoisomer under the Pirrung–Heathcock antialdol conditions; synthetic lactacystin was prepared utilizing very little chromatography so that a substantial amount of the desired bioactive Streptomyces metabolite

Lactacystin    265

lactacystin (1) can be synthesized.4 Ogawa et al. achieved the total synthesis of a lactacystin (1) stereoselectively from readily available D-glucose utilizing the allylic trichloroacetimidate rearrangement as a crucial step.5 Panek et al. accomplished the total synthesis of a potent proteasome inhibitor (+)-lactacystin which comprises the formation of a γ-lactam methyl ester through the hydrogenation of the oxazoline functionality, the construction of the dihydroxy acid via saponification, and the transformation of the β-lactone from dihydroxy acid as key steps.6 Adams et al. went on to report an effective synthesis of clasto-lactacystin β-lactone composed of a doubly diastereoselective aldol reaction as a vital step; the synthesis provided multigram quantities of lactone; it completed only 10 synthetic steps from isobutyraldehyde as a starting material with an overall yield exceeding 20%.7 Hatakeyama et al. developed an efficient total synthesis of lactacystin (1) through a chromatography-free route. The key step in the concise synthesis includes the preparation of Kang’s intermediate, completed in 16 steps and 13% overall yield from 2-amino2-(hydroxymethyl)propane-1,3-diol.8 Jacobsen et al. explored the total synthesis of a bioactive (+)-lactacystin in which a single protecting group as well as only five chromatographic purifications are needed. The total synthesis also comprises an application of an unusual spiro β-lactone as an intermediate first and the use of the catalytic Michael additions as crucial steps.9 Shibasaki et al. explored the total synthesis of a bioactive (+)-lactacystin by applying a catalytic enantioselective Strecker transformation of a ketoimine, Meerwein-like reduction of ketone, and Tamao oxidation along with Donohoe methylation as central steps.10 Hayes et al. conducted an enantioselective total synthesis of a microbial metabolite (+)-lactacystin by utilizing an alkylidene carbene 1,5-CH introduction and a regioselective dimethyldioxirane (DMDO)-assisted oxidative cleavage as vital steps.11 Silverman and co-workers disclosed the total synthesis of a natural bioactive (+)-lactacystin through the construction of a key intermediate aldehyde by Dess–Martin periodinane oxidation.12

3.10.8 Demerits of Conventional Approach From the view of green chemistry, conventional approaches suffer from a few demerits during the total synthesis of a microbial natural product (+)-lactacystin. Corey et al. employed a hazardous liquid oxalyl chloride

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to construct key intermediate aldehyde from ester and important acid from alcohol; moreover, carcinogenic benzene was also used to prepare oxazolidine system.4 Toxic trichloroacetonitrile [LD50 (lethal dose 50) for acute oral toxicity in rats was 250 mg/kg]13 was applied to generate trichloroacetimidate from allylic alcohol by Ogawa et al.5 Adams et al. employed a highly flammable liquid, and vapor toxic n-butyllithium was used to prepare acyloxazolidinone.7 A highly corrosive reagent acetic anhydride was used to construct key ester, and corrosive trifluoroacetic acid was used to prepare important alcohol by Silverman et al.12

3.10.9 Key Features of Total Synthesis Using Visible-Light Irradiation The key features for the total synthesis of a microbial product lactacystin (1) composed of the construction of the tetra- and tri-substituted carbon centers through the photo-promoted intermolecular C(sp3)−H alkynylation as well as intramolecular C(sp3)−H acylation stereoselectively.14

3.10.10 Type of Reaction C–C bond formations using visible-light irradiation.14

3.10.11 Synthetic Strategy Using Visible-Light Irradiation C(sp3)−H alkynylation and Norrish–Yang cyclization.14

3.10.12 Synthetic Route Inoue and co-workers explored a total synthesis of a powerful inhibitor of the 20S proteasome (+)-lactacystin (1) involving important photoinduced intermolecular C−H alkynylation along with intramolecular C−H acylation for the formations of the tetra- and tri-substituted carbon centers stereoselectively as crucial steps in 2015.14 The investigators started total synthesis from commercially available (S)-pyroglutaminol (2) to afford the bicyclic (3) for the improvement of the stereoselectivity. Next, the bicycle (3) underwent a photoinduced intermolecular C(sp3)−H

Lactacystin    267

alkynylation with a mercury lamp using 1-tosyl-2-(trimethylsilyl)acetylene, benzophenone in t-BuOH to construct the C5-tetrasubstituted carbon of (4) stereoselectively, followed by the desilylation of alkyne (4) which provided the targeted terminal alkyne (5) in 54% yield over two steps. The terminal alkyne (5) was effective in delivering diketone (6) for another stereoselective C(sp3)−H functionalization. Next, 1,2-diketone (6)

Scheme 3.10.1.    Visible-light-assisted total synthesis of (+)-lactacystin.

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was irradiated by a mercury lamp to produce monoketone (9) through the construction of the intermediate (7) and 1,4-diradical (8). However, a complex mixture was obtained during photoirradiation with UV light (380 nm, 300 W) to produce key intermediate spiroether (14) for 1 h at room temperature in 65% yield over two steps through the construction of the diradical (12) and zwitterion (13) involved



Spiroxin A and Spiroxin C    291

Scheme 3.14.1.    Visible-light-assisted total synthesis of (–)-spiroxin A.

intramolecular 1,5-hydrogen shift and single-electron transfer (SET) as vital steps (Scheme 3.14.2). The first enantioselective total synthesis of natural antibiotic (–)-spiroxin C (2) was completed from spiroether (14) ultimately.

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Scheme 3.14.2.    Visible-light-assisted total synthesis of (–)-spiroxin C.

References  1. McDonald LA, Abbanat DR, Barbieri LR et al. (1999) Spiroxins, DNA cleaving antitumor antibiotics from a marine-derived fungus. Tetrahedron Lett 40: 2489–2492.   2. Wang T, Shirota O, Nakanishi K et al. (2001). Absolute stereochemistry of the spiroxins. Can J Chem 79: 1786–1791.   3. Ando Y, Tanaka D, Sasaki R et al. (2019) Stereochemical dichotomy in two competing cascade processes: Total syntheses of both enantiomers of spiroxin A. Angew Chem Int Ed 58: 12507–12513.   4. Miyashita K, Sakai T, Imanishi T. (2003) Total synthesis of (±)-spiroxin C. Org Lett 5: 2683–2686.  5. Shu X, Chen, C-C, Yu T et al. (2021) Enantioselective total synthesis of (–)-spiroxins A, C and D. Angew Chem Int Ed 60: 18514–18518.   6. Ando Y, Hanaki A, Sasaki R et al. (2017) Stereospecificity in intramolecular photoredox reactions of naphthoquinones: Enantioselective total synthesis of (–) spiroxin C. Angew Chem Int Ed 56: 11460–11465.   7. Ando Y, Matsumoto T, Suzuki K. (2021) Photoredox reaction of naphthoquinone C-glycoside revisited: Insight into stereochemical aspect. Helv Chim Acta 104: e2100008.



Spiroxin A and Spiroxin C    293

  8. Ando Y, Matsumoto T, Suzuki K (2017) Intramolecular photoredox reaction of naphthoquinone derivatives. Synlett 28: 1040–1045.   9. Wakita F, Ando Y, Ohmori K (2018) Model reactions for the enantioselective synthesis of γ-rubromycin: Stereospecific intramolecular photoredox cyclization of an ortho-quinone ether to a spiroacetal. Org Lett 20: 3928–3932. 10. Ando Y, Wakita F, Ohmori K et al. (2018) Intramolecular photoredox reactions of 1,2-naphthoquinone derivatives. Bioorg Med Chem Lett 28: 2663–2666. 11. Ando Y, Suzuki K. (2018) Photoredox reactions of quinones. Chem Eur J 24: 15955–15964.

Chapter 15

Thymarnicol 3.15.1 Natural Source Arnica sachalinensis (family: Asteraceae).1,2

3.15.2 Structure

3.15.3 Systematic Name (2S,2′S,4a′R,9a′S)-6,7′-dimethyl-3′,4′,4a′,9a′-tetrahydro-2H-spiro [benzofuran-3,2′-pyrano[2,3-b]benzofuran]-2,4a′-diol.

3.15.4 Structural Features A natural thymarnicol (1), a dimeric thymol derivative, contains spiro[benzofuran-3(2H),2′-pyrano[2,3-b]benzofuran] ring system with a dense array of oxygen functionalities together with four stereogenic centers; it (1) is stereodynamic which lies as a single epimer in the solid state and can stays as a mixture of lactol epimers in solution. It consists of 295

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two triple substituted benzene rings, one pyranobenzofuran and two benzofuran moieties.1,3

3.15.5 Class of Compounds Terpenoid.1

3.15.6 Pharmaceutical Potential Thymarnicol (1) showed antifeedant activity against 5th instar larvae of Spodoptera litura1 and phytotoxic effect was exhibited by it (inhibited radical growth of Amaranthus hypochondriacus with IC50 1.2 × 10–5 M; the inhibitory effect of thymarnicol (1) on the calmodulin (CaM) was also carried out and it was observed that thymarnicol (1) inhibited activation of phosphodiesterase type 1 (PDE1) in the presence of CaM with halfmaximal inhibitory concentration IC50 values of 4.2 ± 0.5 μM).4 Thymarnicol (1) also displayed anti-inflammatory activity (IC50 (μM) 4.37 ± 3.37, superoxide anion generation).5

3.15.7 Key Features of Total Synthesis Using Visible-Light Irradiation The key features for the total synthesis of natural thymarnicol (1) include biomimetic Diels–Alder dimerization at ambient temperature and visiblelight-mediated oxidative cyclization. It was interesting to note that a sixstep total synthesis of this bioactive secondary metabolite has been completed through the construction of nine novel bonds (three C–C and six C–O), three new rings, and four novel stereogenic centers.3

3.15.8 Type of Reaction C–O bond formation using visible-light irradiation.3

3.15.9 Synthetic Strategy Using Visible-Light Irradiation Oxidative cyclization.3

Thymarnicol    297

Scheme 3.15.1.    Visible-light-assisted total synthesis of thymarnicol.

3.15.10 Synthetic Route Lawrence and co-workers accomplished a total synthesis of natural thymarnicol (1) in six steps using visible-light-promoted final oxidative cyclization as a key step in 2017.3 The total synthesis was initiated from readily available acetophenone (2) to afford important lactol (3) over five steps including hetero-Diels–Alder dimerization as a crucial step. The investigators could identify novel peaks corresponding to the desired dimeric thymarnicol (1) from unstable dihydropyran (3). Finally, lactol (3) underwent visible-light-assisted oxidative cyclization to furnish bioactive thymol derivative thymarnicol (1) when simply exposed to air along with visible light as a green tool; no oxidation occurred in the dark when the dihydropyran (3) was exposed to the atmosphere. Herein, the role of the visible light was significant in providing a new C–O bond when a solution of the dihydropyran (3) was irradiated with visible light in the presence of the air from an 11-W compact fluorescent lamp at room temperature for 72 h in NMR 57% yield over final three steps (Scheme 3.15.1). Interestingly, the authors conducted the final three-step sequence without column chromatographic purification of key intermediates on a more than 100 mg scale.

References 1. Passreiter CM, Willuhn G, Weber H et al. (1999). A dimeric thymol derivative from Arnica sachalinensis. Tetrahedron 55: 2997–3006. 2. Passreiter CM, Weber H, Bl-ser D et al. (2002) Stereochemistry and oxidative degradation of a dimeric thymol derivative from Arnica sachalinensis. Tetrahedron 58: 279–282. 3. Silvestro ID, Drew SL, Nichol GS et al. (2017) Total synthesis of a dimeric thymol derivative isolated from Arnica sachalinensis. Angew Chem Int Ed 56: 6813–6817.

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4. Pérez-Vásquez A, Reyes A, Linares E et al. (2005) Phytotoxins from Hofmeisteria schaffneri: Isolation and synthesis of 2′-(2′-hydroxy-4″-methyl­ phenyl)-2′-oxoethyl acetate. J Nat Prod 68: 959–962. 5. Chen J-J, Tsai Y-C, Hwang T-L et al. (2011) Thymol, benzofuranoid, and phenylpropanoid derivatives: Anti-inflammatory constituents from Eupatorium cannabinum. J Nat Prod 74: 1021–1027.

Chapter 16

Trehazolin 3.16.1 Natural Source Micromonospora strain SANK 62390 (family: Micromonosporaceae).1,2

3.16.2 Structure

3.16.3 Systematic Name (3aR,4R,5S,6S,6aS)-4-(hydroxymethyl)-2-(((2S,3R,4S,5S,6R)-3,4,5-trihy droxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)amino)-4,5,6,6atetrahydro-3aH-cyclopenta[d]oxazole-4,5,6-triol.

3.16.4 Structural Features A particular inhibitor of trehalase aminocyclopentitol pseudosugar of natural trehazolin (1) includes a pseudo-disaccharide architecture decorated by α-D-glucopyranosylamine, and it closely assimilates α,αtrehalose, a sugar comprising of two molecules of glucose.1,2 299

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3.16.5 Class of Compounds Pseudodisaccharide.1

3.16.6 Pharmaceutical Potential A pseudosugar trehazolin (1) strongly inhibited silkworm along with porcine trehalase (half-maximal inhibitory concentration (IC50) 52 nM for silkworm trehalase).1 A specific as well as potent trehalase inhibitor trehazolin (1) displays the pesticidal activities; it inhibited trehalase of Rhizoctonia solani having an IC50 value of 66 nM and the insecticidal activity is exhibited by it toward silkworms by injecting 50–100 µg.3

3.16.7 Conventional Approach Ando and coworkers first isolated a potent trehalase inhibitor, pseudosugar trehazolin (1), as an amorphous white powder from a culture broth of Micromonospora strain SANK 62390 in 1991.1 So, it is not surprising that the total synthesis of trehazolin (1) has received much interest by the organic synthetic community. Ogawa et al. demonstrated the total syntheses of pseudodisaccharide trehazolin (1) and trehalostatin; the authors established the absolute configuration of trehazolin (1) and disclosed the biological assay of the inhibitors as well as their derivatives.4 The structure–inhibitory activity correlation of inhibitors of this type was also examined by the same group. Giese et al. evolved a short and practical synthesis of trehazolin together with carbocyclic sugar trehazolamine.5 The preparation of trehazolin from trehazolamine was completed in 63% over three steps; the synthesis of trehazolamine from D-glucose comprises two highly stereoselective sequences, such as pinacol-like coupling transformations as well as an oxidation–reduction step. Crimmins et al. focused on the asymmetric synthesis of natural pseudodisaccharide trehazolin involving the formation of the fivemembered ring through an asymmetric aldol-ring closing metathesis route with control of both the relative together with absolute stereochemistry.6

3.16.8 Demerits of Conventional Approach Conventional approaches were not free from a few demerits, such as Ogawa et al. used a severe eye-damaging chemical dicyclohexylcarbodiimide

Trehazolin    301

(DCC) in organic volatile solvent dichloromethane (DCM) to produce the diastereoisomeric mixture of the (S)-acetylmandelates.4 The construction of the oxime ether from methoxyamine was executed by Giese et al. using acetic anhydride; a chemical can cause acute lung damage in high concentrations.5 Crimmins et al. employed a hazard liquid trichloroacetonitrile to construct a key intermediate imidate from the alcohol; moreover, carcinogenic benzene was used to prepare a cyclic carbamate from iodide in the presence of the DBU at 80 °C.6

3.16.9 Key Features of Total Synthesis Using Visible-Light Irradiation The key feature for the enantioselective total synthesis of natural pseudodisaccharide trehazolin comprises the construction of the optically active spirocycloheptadien, the entire functionalized aminocyclopentitol scaffold in 14 steps, the introduction of the wanted 1,4-aminocarbinol in a single step, and a photochemical intramolecular γ-hydrogen abstraction.7

3.16.10 Type of Reaction C–C bond cleavage using visible-light irradiation.7

3.16.11 Synthetic Strategy Using Visible-Light Irradiation Norrish type II reaction.7

3.16.12 Synthetic Route An enantioselective total synthesis of strong trehalase inhibitor aminocyclopentitol pseudodisaccharide of trehazolin (1) was executed by Carreira and co-workers by applying a photochemical intramolecular γ-hydrogen abstraction as a central step.7 The investigators commenced the total synthesis with non-racemic spirocycloheptadien (3); it was derived from (R)-epichlorohydrin (2) in multigram quantities in the presence of the lithium cyclopentadienide and sodium hydride in THF. Next, an important aryl ketone (4) was obtained from spirocycloheptadien (3) over several steps involving the installation of the

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Scheme 3.16.1.    Visible-light-assisted total synthesis of trehazolin (1).

targeted 1,4-aminocarbinol in a single step. The key aryl ketone (4) underwent intramolecular γ-H atom abstraction (Norrish type II reaction) to furnish the desired alkene (6) in quantitative yield through the construction of the 1,4-diradical (5) (Scheme 3.16.1). A specific and powerful trehalase inhibitor trehazolin (1) was originated from the crucial alkene (6) over several steps finally.7

References 1. Ando O, Satake H, Itoi K et al. (1991) Trehazolin, a new trehalase inhibitor. J Antibiot 44: 1165–1168. 2. Ando O, Nakajima M, Hamano K et al. (1993) Isolation on trehalamine, the aglycon of trehazolin, from microbial broths and characterization of trehazolin related compounds. J Antibiot 46: 1116–1125. 3. Ando O, Kifune M, Nakajima M. (1995) Effects of trehazolin, a potent trehalase inhibitor, on Bombyx mori and plant pathogenic fungi. Biosci ­ Biotechnol Biochem 59: 711–712. 4. Uchida C, Yamagishi T, Ogawa S. (1994) Total synthesis of the trehalase inhibitors trehalostatin and trehazolin, and of their diastereoisomers. Final structural confirmation of the inhibitor. J Chem Soc Perkin Trans 1 1994: 589–602.

Trehazolin    303

5. Boiron A, Zillig P, Faber D (1998) Synthesis of trehazolin from D-glucose. J Org Chem 63: 5877–5882. 6. Crimmins MT, Tabet EA. (2001) Formal total synthesis of (+)-trehazolin. Application of an asymmetric aldol-olefin metathesis approach to the synthesis of functionalized cyclopentenes. J Org Chem 66: 4012–4018. 7. Ledford BE, Carreira EM. (1995) Total synthesis of (+)-trehazolin: Optically active spirocycloheptadienes as useful precursors for the synthesis of aminocyclopentitols. J Am Chem Soc 117: 11811–11812.

Chapter 17

Xiamycins A, C, F, H and Oridamycin A 3.17.1 Natural Source Streptomyces species (family: Streptomycetaceae)1–3 for xiamycins and  Streptomyces sp. strain KS84 (family: Streptomycetaceae)4 for oridamycin A.

3.17.2 Structure

3.17.3 Systematic Name (3S,4S,4aR,13bS)-3-hydroxy-4,13b-dimethyl-2,3,4,4a,5,6,8,13b-octahydro1H-naphtho[2,1-b]carbazole-4-carboxylic acid (xiamycin A).

3.17.4 Structural Features From a structural perspective, indolosesquiterpenoids xiamycin A and oridamycin A include a challenging pentacyclic scaffold decorated by a carbazole nucleus fused to a trans-decalin ring system comprising four 305

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contiguous stereocenters.1–5 The natural antibiotic oridamycin A consists of a similar framework to that of xiamycin A, though with the reverse stereochemistry at quaternary C16.4

3.17.5 Class of Compounds Indolosesquiterpene.1–4

3.17.6 Pharmaceutical Potential Natural pentacyclic indolosesquiterpene xiamycin A (1) exhibits anti­ biotic and selective anti-HIV activity6; xiamycin A (1) includes no effects on X4 tropic HIV-1 infection, but it can block R5 specifically. In a panel of cytotoxicity assays, it has been observed that the methyl ester of xiamycin A (1) displays more powerful activity (geometric mean IC50 = 10.13 mM) than that of xiamycin A (1) (geometric mean IC50 > 30 mM).6 Oridamycin A (2), C-16 epimer of xiamycin A (1), shows anti-S. parasitica activity with a MIC value of 3.0 μg/mL.4

3.17.7 Conventional Approach A new pentacyclic indolosesquiterpene xiamycin and its methyl ester were isolated by the Hertweck group from Streptomyces sp. GT2002/1503 in 2010 as a pale yellow powder bearing molecular formula C23H25NO3, which provides a strong violet color reaction in the presence of the anisaldehyde–sulfuric acid.1 Imamura et al. isolated anti-Saprolegnia antibiotics oridamycins A (1) and B (2) from the fermentation broth of Streptomyces sp. strain KS84 in 2010 for the first time having molecular formula C23H25NO3 and C23H25NO4 respectively as pale yellow solids.4 Several groups completed total syntheses of xiamycins and oridamycins successfully as these molecules have drawn remarkable attention from synthetic chemists and biological community due to their potent biological property and challenging pentacyclic framework. Li et al. achieved total syntheses of indolosesquiterpenoids xiamycin A along with oridamycins A and B using two unified strategies to construct the carbazole core by 6π-electrocyclization/aromatization as well as indole C2–H bond



Xiamycins A, C, F, H and Oridamycin A    307

activation/Heck annulation as crucial steps in 2015.6 Baran et al. developed total synthesis of indoloterpenoid natural product dixia­ mycin B through electrochemical oxidation of xiamycin A using N−N dimerization of substituted carbazoles as well as β-carbolines.7 Trotta explored the total synthesis of indolosesquiterpenes oridamycins A and B from a common synthetic intermediate involving the formation of the trans-decalin ring system through an oxidative radical cyclization, one-pot setting three contiguous stereocenters out of four as vital steps, completed in six and nine steps, respectively, from a known molecule.8 In 2016, Krische et al. disclosed the total synthesis of oridamycin A from a common precursor to follow a modular and step-economic strategy by utilizing ridium-catalyzed alcohol C−H tert-(hydroxy) prenylation.9 Trotta described the total synthesis of the xiamycin as well as oridamycin families by applying a Mn(III)-mediated oxidative radical cyclization, late-stage C−H oxidation, chelated radical intermediate formation, and photoredox-catalyzed radical cyclizations as vital steps in 2017.10 Very recently, Dethe et al. accomplished first enantioselective total syntheses of marine pentacyclic natural prod­ ucts xiamycins D and E involving Michael addition, regioselective sp3(C–H) activation, Heck-type annulation/aromatization together with functionalization of enantiopure Wieland–Miescher ketone as central steps in 2021.11

3.17.8 Demerits of Conventional Approach Various conventional approaches were not free from a few demerits concerning green or clean chemistry as hazardous chemicals were employed in the total synthesis of pentacyclic indolosesquiterpene xiamycin A (1) and oridamycin A (2). Li et al. used acute toxic organosulfur molecule methanesulfonyl chloride or mesyl chloride to produce important triene through dehydration during the total synthesis of xiamycin A.6 A moderately toxic chlorinating and oxidizing agent N-chlorosuccinimide (probable oral lethal dose (human) 0.5–5 g/kg) was used by the Baran group to furnish xiamycin A from pentacycle using Pinnick oxidation as another key step.7 A corrosive chemical trifluoroacetic acid (TFA) in volatile organic solvent dichloromethane was applied by Trotta to generate key carbazole during the total syntheses of oridamycins A and B.8

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3.17.9 Key Features of Total Synthesis Using Visible-Light Irradiation The unique feature for divergent as well as enantiospecific total syntheses of natural indolosesquiterpenoids xiamycins A, C, F, H along with oridamycin A composed of a crucial photo-assisted benzannulation sequence to build the characteristic 2,3-fused carbazole moiety and desulfonylation for the construction of the key aldehyde. An unanticipated one-pot oxidative decarboxylation, Pinnick oxidation, and Mukaiyama hydration are other key features of total syntheses of natural indolosesquiterpenoids.5

3.17.10 Type of Reaction C–C bond formation using visible-light irradiation.5

3.17.11 Synthetic Strategy Using Visible-Light Irradiation Photocyclization (photochemical benzannulation).5

3.17.12 Synthetic Route Sarpong and co-workers disclosed enantiospecific total syntheses of natural products xiamycins A (1), C (3), F (4), H (5) together with oridamycin A (2) from (R)-carvone (6) as a starting material using a crucial photoinduced benzannulation sequence to construct the carbazole moiety.5 The investigators commenced the divergent total syntheses of the indolosesquiterpenoids (1-5) from a cyclic “chiral pool” carvone (6) due to its commercial availability and its highly modifiable cyclic structure.12,13 The authors also executed fungicidal activity of all synthetic intermediates along with secondary metabolites; assessment of these molecules disclosed that xiamycin H shows 100% growth inhibition of wheat leaf blotch and 50% and 40% inhibition of rice blast and corn smut, as well as some of the synthetic intermediates, exhibit notable inhibition of agriculturally relevant pathogens. The total syntheses were initiated to afford known trans-decalin C-16 epimers (7a) and (7b) via a known four-step sequence from (R)-carvone (6).14 After forming the vital trans-decalin system, the



Xiamycins A, C, F, H and Oridamycin A    309

authors desired to prepare triene (8) from keto-alcohol (7a) over several steps. Next, they started to explore the photochemical benzannulation sequence instead of the thermal 6π-electrocyclization/aromatization sequence to forge the 2,3-fused carbazole because the thermal protocol was unsuccessful. Triene (8) underwent photochemical benzannulation by irradiation with UVA light (350 nm) in aqueous ethanol to deliver

Scheme 3.17.1.  Visible-light-assisted total syntheses of xiamycins A, C, F, H and oridamycin A.

310  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

desulfonylated carbazole (9) in 44% yield (Scheme 3.17.1). The investigators desired to install the aldehyde group first for the construction of the key aldehyde (15) in 21% yield over three steps involving Martin’s sulfurane, oxidation of the primary alcohol under TEMPO/PIDA conditions, and the crucial photocyclization/desulfonylation because the formation of desired aldehyde (11) was not successful under standard conditions. Ultimately, the total synthesis of xiamycin A (1) was finished from the aldehyde (15) through Pinnick oxidation followed by hydrogenation in the presence of the Pd/C in 55% yield over two steps in a total of 14 steps from the starting material (6). The total synthesis of oridamycin A (2) was also completed from the minor keto-alcohol diastereomer (7b), and xiamycin C (3), xiamycin F (4), and xiamycin H (5) in a maximum of 10 steps were successfully completed from inexpensive and readily available (R)-carvone (6).5

References   1. Ding L, Münch J, Goerls H et al. (2010) Xiamycin, a pentacyclic indolosesquiterpene with selective anti-HIV activity from a bacterial mangrove endophyte. Bioorg Med Chem Lett 20: 6685–6687.   2. Kim S, Ha T, Oh WK et al. (2016) Antiviral indolosesquiterpenoid xiamycins C–E from a halophilic actinomycete. J Nat Prod 79: 51–58.   3. Ding L, Maier A, Fiebig H-H et al. (2011) A family of multicyclic indolosesquiterpenes from a bacterial endophyte. Org Biomol Chem 9: 4029–4031.   4. Takada K, Kajiwara H, Imamura N. (2010) Oridamycins A and B, anti-Saprolegnia parasitica indolosesquiterpenes isolated from Streptomyces sp. KS84. J Nat Prod 73: 698–701.   5. Pfaffenbach M, Bakanas I, O’Connor NR et al. (2019) Total syntheses of xiamycins A, C, F, H and oridamycin A and preliminary evaluation of their anti-fungal properties. Angew Chem Int Ed 58: 15304–15308.   6. Meng Z, Yu H, Li L et al. (2015) Total synthesis and antiviral activity of indolosesquiterpenoids from the xiamycin and oridamycin families. Nat Commun 6: 6096.   7. Rosen B, Werner E, O’Brian A et al. (2014) Total synthesis of dixiamycin B by electrochemical oxidation. J Am Chem Soc 136: 5571–5574.  8. Trotta A. (2015) Total synthesis of oridamycins A and B. Org Lett 17: 3358–3361.  9. Feng J, Noack F, Krische MJ. (2016) Modular terpenoid construction via catalytic enantioselective formation of all-carbon quaternary centers:



Xiamycins A, C, F, H and Oridamycin A    311

Total synthesis of oridamycin A, triptoquinones B and C, and isoiresin. J Am Chem Soc 138: 12364–12367. 10. Trotta A. (2017) Toward a unified total synthesis of the xiamycin and oridamycin families of indolosesquiterpenes. J Org Chem 82: 13500−13516. 11. Dethe DH, Shukla M. (2021) Enantioselective first total syntheses of the antiviral natural products xiamycins D and E. Chem Commun 57: 10644–10646. 12. Brill ZG, Condakes ML, Ting CP et al. (2017) Navigating the chiral pool in the total synthesis of complex terpene natural products. Chem Rev 117: 11753–11795. 13. Boger DL, Brotherton CE. (1984) Total synthesis of azafluoranthene alkaloids: Rufescine and imeluteine. J Org Chem 49: 4050–4055. 14. Zhong Z, Zhao G, Xu D et al. (2016) Bioinspired total syntheses of ­isospongian-type diterpenoids (−)-kravanhins A and C. Chem Asian J 11: 1542–1547.

Chapter 18

Zaragozic Acid C 3.18.1 Natural Source Leptodontium elatius (strain of Leptodontium elatius var. elatius, ATCC 70411).1,2

3.18.2 Structure

3.18.3 Systematic Name (1S,3S,4S,5R,6R,7R)-1-((4R,5R)-4-acetoxy-5-methyl-6-phenylhexyl)4,7-dihydroxy-6-(((R,E)-6-methyl-9-phenylnon-4-enoyl)oxy)-2,8dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid.

3.18.4 Structural Features From a structural perspective, polyketide zaragozic acid C (1) comprises a 2,8-dioxabicyclo[3.2.1]octane skeleton containing six stereogenic 313

314  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

centers and hydrophobic one acyloxy group, decorated with two hydroxyls, three hydroxycarbonyl (C3,4,5) along with one alkyl side chain.1,3

3.18.5 Class of Compounds Polyketide.4,5

3.18.6 Pharmaceutical Potential Zaragozic acid C (1) is a potent inhibitor of squalene synthase. Natural zaragozic acids A, B, and C were significant competitive inhibitors of rat liver squalene synthase, having noticeable Ki values of 78 pM, 29 pM, and 45 pM, respectively. They inhibited cholesterol synthesis in Hep G2 cells. Natural polyketide zaragozic acid A inhibited hepatic cholesterol synthesis in mice with an ED50 (median effective dose) of nearly 0.2 mg/kg.2

3.18.7 Conventional Approach Dufresne and co-workers isolated new zaragozic acid C (1) from the fungus Leptodontium elatius as a white powder bearing molecular formula C40H50O14. Several creative strategies and tactics have been examined for the total synthesis of zaragozic acid C (1) because of its complex architecture and potential advantage for human medicine.6–10 Evans et al. accomplished an asymmetric synthesis of zaragozic acid C (1) utilizing enolization of ketal to form the silylketene acetal, a key stereoselective Lewis acid-catalyzed aldol addition with aldehyde, the addition of vinylmagnesium bromide for the construction of the stereocenter at C5 as crucial steps.6 The Carreira strategy entailed an enantioselective synthesis of natural product zaragozic acid C (1); it includes the establishment of the quatemary center at C(5) through a highly diastereoselective route, an important stereoselective reduction of an α,β-ynone, regioselective protection of the C(7) as central steps.7 Armstrong et al. developed a stereoselective synthesis of the fungal metabolite (+)-zaragozic acid C (1) in which unique features of the total



Zaragozic Acid C    315

synthesis are the application of a double Sharpless asymmetric dihydroxylation transformation to manage stereochemistry at four contiguous stereocenters from C3 to C6 efficiently, the installation of the C1-side chain, and the introduction of the tricarboxylic acid through a new triple oxidation protocol.8 In a study, Hashimoto and co-workers disclosed the total synthesis of bioactive zaragozic acid C through a convergent strategy involving the construction of the C4 and C5 quaternary stereogenic centers concurrently by a Sn(OTf)2-assisted aldol reaction. Other unique features comprise the direct installation of lithium acetylide and the formation of the bicyclic skeleton with the help of an acid-catalyzed internal ketalization.9 In another study, the same group accomplished total syntheses of polyketides zaragozic acids A and C through the carbonyl ylide cycloaddition approach; internal ketalization was not included in this synthesis for the construction of the 2,8-dioxabicyclo[3.2.1]octane framework for the first time.10 Johnson and co-workers reported a self-consistent synthesis of bioactive zaragozic acid C using the idea of controlled oligomerization in 2008. The key feature of this synthesis is the use of silyl glyoxylates as the curious geminal dipolar glycolic acid synthons.11

3.18.8 Demerits of Conventional Approach Conventional approaches were not free from a few demerits if we consider the concept of green chemistry. Evans et al. and Carreira et al. used a hazardous chemical oxalyl chloride in a chlorinated volatile organic solvent (DCM) to construct protected unsaturated aldehyde from aldol adduct. In addition, an expensive osmium tetroxide, which is volatile toxic, was employed to prepare unsaturated lactone from vinyl carbinol. The same group used benzene several times, which is carcinogenic to humans and originates acute myeloid leukemia.6,7 Carreira et al. used a corrosive reagent trifluoroacetic acid to synthesize (+)-zaragozic acid C from an important carboxylic acid,7 and Armstrong et al. also applied the same reagent to produce a mixture of two isomeric ketals in 38% yield from the ketone; a highly corrosive reagent acetic anhydride was employed to yield C7-epimer by the same group.8 Hashimoto et al. also employed acetic anhydride to deliver key triacetate from tetraol.9

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3.18.9 Key Features of Total Synthesis Using Visible-Light Irradiation The unique features for the total synthesis of fungal metabolite zaragozic acid C (1) comprise selective photoactivation of the 1,2-diketone functionality, the formation of the contiguous entirely substituted C4,5carbons, and stereoselective reduction of the key C3-ketone.3

3.18.10 Type of Reaction C–O bond formations under visible-light irradiation.3

3.18.11 Synthetic Strategy Using Visible-Light Irradiation Norrish–Yang cyclization.3

3.18.12 Synthetic Route Zaragozic acids originated as a potent squalene synthase inhibitor; they are considered auspicious lead structures for the evolution of cholesterollowering drugs since squalene synthase includes a profound role in catalyzing the transformation of presqualene pyrophosphate into squalene at the final branching point of cholesterol biosynthesis. Hence, Inoue et al. achieved the total synthesis of a bioactive fungal metabolite zaragozic acid C (1) utilizing a two-step photochemical C(sp3)–H acylation in 2017. The investigators initiated the total synthesis from gluconolactone derivative (2) to produce the key precursor (3) over several steps involving the insertion of the C1-alkyl, C5-alkynyl chains, the substitution of the proper protective groups, as well as the oxidation of the alkyne into the 1,2-diketone. Next, a highly oxygenated substrate (3) underwent a crucial photochemical C(sp3)–H functionalization employing a microflow reactor over a batch reactor since light penetration can be performed more efficiently in a fixed microreaction space, and the constant microflow conditions are comfortably used to a large scale transformation.12 Initially, blue LED light (460 nm) was used to generate the targeted C4,5-cis-fused cyclobutanone (6) from 1,2-diketone (3) in 26% yield only, despite Norrish–Yang cyclization taking place regio- and



Zaragozic Acid C    317

stereo-selectively at C4. However, violet LED irradiation using the microflow system enhanced the effectiveness and scalability of the reaction without any need for extra reagents. A benzene solution of diketone (3) was irradiated at violet LED (405 nm) that matches λmax of 1,2-diketone to afford cis-fused cyclobutanone (6) at 25 °C after optimization of the flow rate (50 µL/min) as the exclusive isomer in 85% yield confirmed on the 1H NMR analysis through the construction of vital 1,2-biradical (4) and 1,4-biradical (5) (Scheme 3.18.1). The cis-fused bicycle (6) was reacted with Pb(OAc)4 in MeOH to yield ketoester (7) in 62% yield over two steps without purification due to the chemical instability of (6). The cis-fused bicycle (6) was effective in furnishing natural zaragozic acid C (1) over several steps by applying the photochemical C(sp3)–H functionalization for the construction of the unique molecular structure that is difficult to be obtained by classical polar transformations.3

º

Scheme 3.18.1.    Visible-light-assisted total synthesis of zaragozic acid C.

318  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

References   1. Dufresne C, Wilson KE, Zink D et al. (1992) The isolation and structure elucidation of zaragozic acid C, a novel potent squalene synthase inhibitor. Tetrahedron 48: 10221–10226.   2. Bergstrom JD, Kurtz MM, Rew DJ et al. (1993) Zaragozic acids: A family of fungal metabolites that are picomolar competitive inhibitors of squalene synthase. Proc Natl Acad Sci USA 90: 80–84.   3. Kawamata T, Nagatomo M, Inoue M. (2017) Total synthesis of zaragozic acid C: Implementation of photochemical C(sp3)–H acylation. J Am Chem Soc 139: 1814–1817.   4. Byme KM, Arison BH, Nallin-Omstead M et al. (1993) Biosynthesis of the zaragozic acids. 1. Zaragozic acid A. J Org Chem 58: 1019–1024.   5. Liu N, Hung Y-S, Gao S-S et al. (2017) Identification and heterologous production of a benzoyl-primed tricarboxylic acid polyketide intermediate from the zaragozic acid A biosynthetic pathway. Org Lett 19: 3560–3563.   6. Evans DA, Barrow JC, Leighton JL et al. (1994) Asymmetric synthesis of the squalene synthase inhibitor zaragozic acid C. J Am Chem Soc 116: 12111–12112.   7. Carreira EM, Bois JD. (1995) (+)-Zaragozic acid C: Synthesis and related studies. J Am Chem Soc 117: 8106–8125.  8. Armstrong A, Barsanti PA, Jones LH et al. (2000) Total synthesis of (+)-zaragozic acid C. J Org Chem 65: 7020–7032.   9. Nakamura S, Sato H, Hirata Y et al. (2005) Total synthesis of zaragozic acid C by an aldol-based strategy. Tetrahedron 61: 11078–11106. 10. Hirata Y, Nakamura S, Watanabe N et al. (2006) Total syntheses of zaragozic acids A and C by a carbonyl ylide cycloaddition strategy. Chem Eur J 12: 8898–8925. 11. Nicewicz DA, Satterfield AD, Schmitt DC et al. (2008) Self-consistent synthesis of the squalene synthase inhibitor zaragozic acid C via controlled oligomerization. J Am Chem Soc 130: 17281–17283. 12. Fukuyama T, Rahman MT, Sato M et al. (2008) Adventures in inner space: Microflow systems for practical organic synthesis. Synlett 2: 151–163.

Part 4

Organic Electrochemistry: A Promising Window for the Development of Total Synthesis of Bioactive Natural Products

Chapter 1

Alliacol A 4.1.1 Natural Source Marasmius alliaceus (family: Marasmiaceae).1,2

4.1.2 Structure

4.1.3 Systematic Name (1aR,2R,4aS,7aS,9aR)-4a-hydroxy-2,9,9-trimethyl-5-methylene hexahydro-8H-oxireno[2′,3′:1,7a]indeno[3a,4-b]furan-6(2H)-one.

4.1.4 Structural Features The alliacols are associated with the group of α,β-unsaturated sesquiterpene lactones. A natural sesquiterpene hydroxy-epoxy-lactone alliacol A (1) includes a tricyclic skeleton, five contiguous stereogenic atoms, and three contiguous tetrasubstituted carbons.1,2 321

322  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

4.1.5 Class of Compounds Sesquiterpene.1,2

4.1.6 Pharmaceutical Potential Alliacol A (1) shows antimicrobial activity and cytotoxicity.2 This antibiotic revealed efficient inhibition of DNA synthesis in ascitic Ehrlich carcinoma at concentrations of about 10 μg/mL.2

4.1.7 Conventional Approach Two antimicrobial and cytotoxic crystalline metabolites alliacols A and B were detected from the fermentation broth of Marasmius alliaceus; the structures of the two natural antibiotics were determined by spectroscopic methods.2 Sesquiterpene lactone alliacol A (1) is isomeric with alliacol B bearing molecular formula C15H20O4. Clair et al. achieved the total synthesis of alliacol A (1) involving both syn- and anti-modes of intramolecular SN′ substitution. The improvement of this synthesis decorates that fine changes in molecular structure can largely control the diastereoselectivity of carbonyl addition reactions.3

4.1.8 Demerits of Conventional Approach The conventional approach was not free from a few demerits with respect to the angle of the green chemistry. A corrosive reagent lithium aluminum hydride in a highly flammable liquid diethyl ether was used to prepare vital primary alcohol during the synthesis of racemic alliacol A.3 An important alkene was synthesized through annulations using mildly toxic hexamethylphosphoramide, found to cause cancer in rats.3

4.1.9 Key Features of Total Synthesis Under Electrochemistry The key features of the total synthesis of natural alliacol A (1) consisted of a sequential anodic cyclization–Friedel–Crafts alkylation of mono­ cyclic furan substrate for constructing the core ring skeleton of this



Alliacol A    323

sesquiterpene lactone (1).4 The electrochemical reaction involves a strong Umpolung methodology that permitted the coupling of two nucleophiles, such as a silylenol ether and a furan ring.

4.1.10 Type of Reaction C–C bond formation under electrochemistry.4

4.1.11 Synthetic Strategy Under Electrochemistry Anodic cyclization reaction.4

4.1.12 Synthetic Route Moeller et al. reported a creative synthesis of tricyclic natural antibiotic alliacol A (1) involving a sequential anodic cyclization–Friedel–Crafts alkylation as a crucial step.4 The total synthesis was initiated from known hydroxy ketone (2) to afford the targeted substrate monocyclic furan (3) over several steps including the bromination of a methyl carbon with

Scheme 4.1.1.    The total synthesis of alliacol A using electrochemistry.

324  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

respect to a keto group, protection of the alcohol, generation of the phosphonate ester, and then a Horner–Emmons–Wadsworth reaction as key steps.4–6 Next, monocyclic furan substrate (3) was oxidized in an undivided cell employing an RVC (reticulated vitreous carbon anode), a carbon cathode, a 0.4 M LiClO4 in methanol/dichloromethane (1:4) as an electrolyte solution, 2,6-lutidine which acts as a proton scavenger, and a constant current of 15–20 mA to produce bicyclic acetal (4) involving electrochemistry as a green technique (Scheme 4.1.1). Primary alcohol (5) was obtained in 88% yield from the sequence. Thus, the cyclization led to a bicyclic compound (4) without the need for specialized equipment that included all of the carbons and functional groups necessary for quickly completing the synthesis of the bioactive sesquiterpene natural product alliacol A (1). The same group applied a tandem anodic coupling–Friedel– Crafts alkylation strategy for the swift asymmetric synthesis of (–)-alliacol A for the first time.4 The anodic oxidation reaction permitted the formation of a novel bond between two nucleophiles also.

References 1. King T, Farrell K, Halsall T et al. (1977) Alliacolide, a new bicyclic sesquiterpene epoxy-lactone with a novel carbon skeleton from cultures of the fungus Marasmius alliaceus (Jacques ex Fr.)Fr; X-ray structure. J Chem Soc Chem Commun 20: 727–728. 2. Anke T, Watson W, Giannetti B et al. (1981) Antibiotics from basidiomycetes. XIII. The alliacols A and B from Marasmius alliaceus (Jacq. ex Fr.) Fr. J Antibiot 34: 1271–1277. 3. La Clair JJ, Lansbury PT, Zhi B-x et al. (1995) A stereoselective total synthesis of (±)-alliacol A and congeners of Marasmius alliaceus. J Org Chem 60: 4822–4833. 4. Mihelcic J, Moeller KD. (2003) Anodic cyclization reactions: The total synthesis of alliacol A. J Am Chem Soc 125: 36–37. 5. Boeykens M, De Kimpe N, Tehrani KA. (1994) Synthesis of 1-amino-2,2-dialkylcyclopropanecarboxylic acids via base-induced cyclization of .gamma.chloro-.alpha.-imino esters. J Org Chem 59: 6973–6985. 6. New DG, Tesfai Z, Moeller KD. (1996) Intramolecular anodic olefin coupling reactions and the use of electron-rich aryl rings. J Org Chem 61: 1578–1598.

Chapter 2

Diazonamide A 4.2.1 Natural Source Diazona angulata (initially misidentified as Diazona chinensis) (family: Diazonidae).1

4.2.2 Structure Me Me HO

Me H N

Me N

N

HN O

Cl

Cl

O O

N H

Me Me

O

Me

O

O

Me

OH

Me HN

O

N

HN O

OH

N

O

F

NH O

Diazonamide A

N H

DZ-2384 (1)

4.2.3 Structural Features Structurally, the marine natural product diazonamide A comprises two 12-membered macrocycles conjoined via a triaryl substituted quaternary carbon stereocenter attached in an uncommon furanoindoline core. It bears a high degree of unsaturation. The structural elements include an extremely compact and rigid skeleton whose inner atoms contain almost no rotational degrees of freedom.1–3 DZ-2384 (1) is the synthetic derivative of the complex peptide diazonamide A.

325

326  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

4.2.4 Class of Compounds Macrocyclic peptide.1–3

4.2.5 Pharmaceutical Potential An unusual halogenated cyclic peptide diazonamide A displays potent in vitro activity against HCT-116 human colon carcinoma with an IC50 value of less than 15 ng/mL.1 DZ-2384 (1) is the new synthetic derivative of the marine natural product diazonamide A, which is 10- to 50-fold more efficient than diazonamide A as a cancer therapy in vivo because of its improved pharmacokinetics.4

4.2.6 Conventional Approach Fenical et al. isolated a structurally unique class of natural products, diazonamides A and B, from the colonial marine ascidian Diazona angulate.1 The remarkable molecular structure of the halogenated cyclic cytotoxic peptide diazonamide A was revised after the synthesis of a biologically potent analog of diazonamide A in which a single nitrogen atom was substituted by an oxygen atom; the structure of diazonamide A was corrected by Harran et al. in 2001.5 Several groups such as Nicolaou,6–9 Haran,10 Magnus,11 MacMillan,3 and Sammakia12 have contributed their research toward the total syntheses and formal syntheses of diazonamide A effectively. DZ-2384 (1), a novel synthetic analog of the diazonamide A, was selected as an improvement candidate in 2012 (http:// www.therillia.com).

4.2.7 Demerits of Conventional Approach Conventional approaches suffer from a few demerits from the angle of sustainable chemistry as most of the traditional approaches employed toxic reagents and solvents. Nicolaou and co-workers accomplished the first total synthesis of diazonamide A brilliantly.7 However, the investigators synthesized peptide-based macrocycle using toxic TFA, and this reagent was also applied during the final stages and completion of the synthesis of this bioactive natural product. The compound carrying both macrocyclic domains of the revised structure of this peptide



Diazonamide A    327

(diazonamide A) was constructed by POCl3, which is very toxic by inhalation and corrosive to tissues although the same authors employed photochemistry to create key intermediates as a green technique.7 Many groups synthesized diazonamide A successfully; attention turned to constructing a practical preparation of the molecule.4 As DZ-2384 lacked the right-hand macrocycle of diazonamide A, the major issue to be aimed at was building the skeleton triarylacetaldehyde in an appropriate diarylaminal form. Various groups developed diastereoselective chemistry for this motive. However, Harran et al. synthesized 280 g DZ-2384 (1) from 1 kg of L-tert-leucine (2) by electrolysis as a green technique.4

4.2.8 Key Features of Total Synthesis Under Electrochemistry The concise and scalable synthesis of DZ-2384 (1) includes the construction of a large ring-forming dehydrogenation through anodic oxidation at a graphite surface.4 The crucial transformation needs no tailoring of the substrate and takes place at ambient temperature in aqueous DMF using an undivided cell open to the air.

4.2.9 Types of Reactions C–C and C–N bond formations under electrochemistry.4

4.2.10 Synthetic Strategy Under Electrochemistry Large ring-forming dehydrogenation by anodic oxidation.4

4.2.11 Synthetic Route Harran et al. reported synthesis for a core macrolactam of natural peptide diazonamides involving an electrochemical method as a central step in 2015.4 Electrochemistry, a sustainable technique, was efficient for the concise synthesis of DZ-2384 (1) through the large ring forming dehydrogenation. The total synthesis was initiated from L-tert-leucine (2) to generate dipeptide (4) through the formation of L-serine (3).

328  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

O Me Me

Me

H N

O O OH

N H

O

NH2

OH HN

OH O

OH

NHZ

((S)-2-(((benzyloxy)carbonyl) amino)-3,3-dimethylbutanoyl)-L-serine (3)

L-tert-leucine (2) or

F

O

O

NH

4

(S)-2-(((benzyloxy)carbonyl) amino)-3,3-dimethylbutanoic acid starting material

Me

O

N

HN ZHN

1.6 V, Et4NBF4, (NH4)2CO3 1.8% aq. DMF, 5 d, 35%, 43% based on recovered 5, d.r.=2.7:1

Me Me

N

O

O

OH

N

HN ZHN

electrochemistry

O OH

O O

N F

F HO O

N H

N H

5

6 i) H2 (1 atm), Pd/C (10 mol%), tBuNH2 (1.5 equiv), MeOH, 4 h ii) (S)-(-)-hydroxyisovaleric acid, EDC, HOBT iPr2NEt, DMF, 4 h, 91% Me

OH

O

N

HN Me HN

Z=

Me Me

O

Me

O O

O

OH

N

O

F

O

N H

(S)-N-((15aS,110bS,3S,6S)-3-(tert-butyl)-19-fluoro-24-(4-(hydroxymethyl) oxazol-2-yl)-5-oxo-15a,110b-dihydro-16H-4-aza-1(10b,2)-benzofuro[2,3b]indola-2(5,2)-oxazolacycloheptaphane-6-yl)-2-hydroxy-3methylbutanamide (1)

1

Scheme 4.2.1.    Scalable synthesis of a diazonamide-based drug improvement candidate using electrochemistry.

An electrolysis substrate (5) was obtained from peptide (4) over several steps. Then, an electrochemical methodology was applied for the construction of the key carbamate (6) from compound (5) at a potential of +1.6 V in the presence of the (NH4)2CO3, Et4NBF4, and 1.8% aqueous DMF for 5 d (yield of the macrocyclization 35%, 43% based on recovered (5), d.r. = 2.7:1) in an undivided cell (Scheme 4.2.1). The electrochemical synthesis of diazonamide A analog was completed in 13 steps from starting material (2) with a 5.7% overall yield. It is interesting to note that this concise and practical synthesis provided 280 g of the desired product DZ-2384 (1) from 1 kg of starting material L-tert-leucine (2).4



Diazonamide A    329

References   1. Lindquist N, Fenical W, Van Duyne GD et al. (1991) Isolation and structure determination of diazonamides A and B, unusual cytotoxic metabolites from the marine ascidian Diazona chinensis. J Am Chem Soc 113: 2303–2304.   2. Fernandez R, Martin MJ, Rodriguez-Acebes R et al. (2008) Diazonamides C–E, new cytotoxic metabolites from the ascidian Diazona sp. Tetrahedron Lett 49: 2282–2285.   3. Knowles RR, Carpenter J, Blakey SB et al. (2011) Total synthesis of diazonamide A. Chem Sci 2: 308–311.   4. Ding H, DeRoy PL, Perreault C et al. (2015) Electrolytic macrocyclizations: Scalable synthesis of a diazonamide-based drug development candidate. Angew Chem Int Ed 54: 4818–4822.   5. Li J, Jeong S, Esser L et al. (2001) Total synthesis of nominal diazonamides Part 1: Convergent preparation of the structure proposed for (−)-diazonamide A. Angew Chem Int Ed 40: 4765–4769.   6. Nicolaou KC, Bella M, Chen DY-K et al. (2002) Total synthesis of diazonamide A. Angew Chem Int Ed 41: 3495–3499.   7. Nicolaou KC, Chen DY-K, Huang X et al. (2004) Chemistry and biology of diazonamide A: First total synthesis and confirmation of the true structure. J Am Chem Soc 126: 12888–12896.   8. Nicolaou KC, Rao PB, Hao J et al. (2003) The second total synthesis of diazonamide A. J Angew Chem Int Ed 42: 1753–1758.  9. Nicolaou KC, Hao J, Reddy MV et al. (2004) Chemistry and biology of diazonamide A: Second total synthesis and biological investigations. J Am Chem Soc 126: 12897–12906. 10. Burgett AWG, Li Q, Wei Q et al. (2003) A concise and flexible total synthesis of (−)-diazonamide A. Angew Chem Int Ed 42: 4961–4966. 11. Cheung C-M, Goldberg FW, Magnus P et al. (2007) An expedient formal total synthesis of (−)-diazonamide A via a powerful, stereoselective O-aryl to C-aryl migration to form the C10 quaternary center. J Am Chem Soc 129: 12320–12327. 12. Mai C-K, Sammons MF, Sammakia T et al. (2010) A concise formal synthesis of diazonamide A by the stereoselective construction of the C10 quaternary center. Angew Chem Int Ed 49: 2397–2400.

Chapter 3

Dixiamycin B 4.3.1 Natural Source Streptomyces sp. SCSIO 02999 (family: Streptomycetaceae).1

4.3.2 Structure

4.3.3 Systematic Name (3S,3′S,4S,4aR,4′S,4′aR,13bS,13′bS)-3,3′-dihydroxy-4,4′,13b,13′btetramethyl-1,1′,2,2′,3,3′,4,4a,4′,4′a,5,5′,6,6′,13b,13′b-hexadecahydro[8,8′-binaphtho[2,1-b]carbazole]-4,4′-dicarboxylic acid.

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4.3.4 Structural Features The atropisomeric indoloterpenoid natural product dixiamycin B (1) contains a dimeric indolo-sesquiterpene core, a carbazole fused to a transdecalin skeleton with four contiguous stereocenters, three of which are quaternary.1–3 The bioactive secondary metabolite dixiamycin B (1) is a dimer of an indole diterpenoid, xiamycin A, and it includes a stereogenic N–N axis between sp3-hybridized nitrogen atoms.1

4.3.5 Class of Compounds Indolo-sesquiterpene (oligomeric indole alkaloid).1,2

4.3.6 Pharmaceutical Potential The dimeric compound dixiamycin B (1) displayed greater antibacterial activities against various bacteria, including E. coli, S. auereus, B. subtilis, and B. thuringensis with MIC values of 8–16 μg/mL, compared to the monomeric siblings.1,4

4.3.7 Conventional Approach Two novel indolo-sesquiterpenes dixiamycins A and B were isolated independently by Zhang and Hertweck from a marine-derived Actinomycete in 2012.1 These bioactive natural compounds are the first examples of atropisomerism of N–N-coupled atropo-diastereomers having molecular formula C46H48N2O6. The similar ECD spectra of dixiamycins A and B are the result of the symmetry of the 9-carbazole chromophore. It suggests that the orientations of the two interacting 9-carbazole chromophores do not vary greatly in the two atropodiastereomers dixiamycins A and B. The principal difference in their ECD spectra is demonstrated in the intense 297 nm positive Cotton effect (CE) of dixiamycin B (1) with a positive shoulder, whereas it was absent from the ECD spectrum of dixiamycin A.1 Baran et al. achieved the total synthesis of dixiamycin B (1) for the first time in 2014 including a remarkable electrochemical method.5



Dixiamycin B    333

4.3.8 Demerits of Conventional Approach No conventional process is available for the total synthesis of dixiamycin B (1).5

4.3.9 Key Features of Total Synthesis Under Electrochemistry The pivotal step of the first total synthesis of dixiamycin B (1) includes a unique electrochemical oxidative dimerization method.5 The total synthesis of bioactive dixiamycin B (1) was performed through late-stage N–N bond generation from another natural product xiamycin A (3), which exhibits selective anti-HIV activity.3

4.3.10 Type of Reaction N–N bond formation under electrochemistry.5

4.3.11 Synthetic Strategy Under Electrochemistry Electrochemical oxidative dimerization method.5

4.3.12 Synthetic Route Baran et al. developed an electrochemical oxidative dimerization process for the total synthesis of dixiamycin B, a rare N−N-related dimeric natural product.5 The total synthesis was initiated from enantioenriched alcohol (2) to deliver xiamycin A (3) with substantial quantities over several steps involving Parikh−Doering oxidation, Wittig olefination, hydroboration/ Suzuki coupling, and Boc deprotection as vital steps. The investigators turned to electrochemistry to facilitate the targeted oxidative dimerization as traditional chemical oxidants provided unfruitful results. Oxidation methods were first tested on various simple carbazole derivatives to construct the N–N bond for the validation of the dimerization strategy; parent carbazole was subjected to yield dimer in about 63% yield through the N–N bond formation using electrochemical oxidation in DMF/MeOH

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Scheme 4.3.1.    The total synthesis of dixiamycin B using electrochemistry.

(19:1)–Et4NBr, carbon anode at a potential of +1.2 V vs Ag/AgCl for 18 h. These conditions could be employed in the key electrochemical reaction of xiamycin A (3) (Scheme 4.3.1). Thus, xiamycin A (3) underwent anodic oxidation at a slightly reduced potential (+1.15 V vs Ag/AgCl) for 4 h to furnish dixiamycin B (1) in 28% yield together with 17% bromoxiamycin and recovered xiamycin A (3). This method was a unique method of electrochemical dimerization for the synthesis of bioactive secondary metabolite and it was general for N−N dimerization of substituted carbazoles along with β-carbolines also.

References 1. Zhang Q, Mándi A, Li S et al. (2012) N–N-Coupled indolo-sesquiterpene atropo-diastereomers from a marine-derived actinomycete. Eur J Org Chem 2012: 5256−5262. 2. Corsello MA, Kim J, Garg NK. (2017) Indole diterpenoid natural products as the inspiration for new synthetic methods and strategies. Chem Sci 8: 5836–5844. 3. Meng Z, Yu H, Li L et al. (2015) Total synthesis and antiviral activity of indolosesquiterpenoids from the xiamycin and oridamycin families. Nat Commun 6: 6096. 4. Xu Z, Baunach M, Ding L et al. (2012) Bacterial synthesis of diverse indole terpene alkaloids by an unparalleled cyclization sequence. Angew Chem Int Ed 51: 10293–10297. 5. Rosen BR, Werner EW, O’Brien AG et al. (2014) Total synthesis of dixiamycin B by electrochemical oxidation. J Am Chem Soc 136: 5571−5574.

Chapter 4

Furofuran Lignans 4.4.1 Natural Source Liriodendron tulipifera L. (Yangambin, 1),1 Sesamum indicum L. (Sesamin, 2),2,3 and Araucaria angustifolia (Eudesmine, 3).4

4.4.2 Structure

4.4.3 Systematic Name (1S,3aR,4S,6aR)-1,4-bis(3,4,5-trimethoxyphenyl)tetrahydro-1H,3Hfuro[3,4-c]furan (1). (1S,3aR,4S,6aR)-1,4-bis(benzo[d][1,3]dioxol-5-yl)tetrahydro-1H,3Hfuro[3,4-c]furan (2). (1S,3aR,4S,6aR)-1,4-bis(3,4-dimethoxyphenyl)tetrahydro-1H,3Hfuro[3,4-c]furan (3). 335

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4.4.4 Structural Features Structurally, furofuran lignans such as yangambin (1), sesamin (2), and eudesmin (3) contain a substituted 3,7-dioxabicyclo[3,3,0]octane skeleton. Yangambin (1), sesamin (2), and eudesmin (3) comprise four contiguous stereogenic centers, two of which are situated at the pseudobenzylic position and the other two situated at the ring junctions.1–3

4.4.5 Class of Compounds Lignans.1–3

4.4.6 Pharmaceutical Potential Yangambin (1), sesamin (2), and eudesmin (3) are pharmacologically active furofuran lignans. Yangambin (1) shows antiallergic, analgesic properties, protective activities against cardiovascular collapse and apoptosis induction, and protective properties against cardio­ vascular collapse and anaphylactic shock. It also exhibits selective inhibition against platelet-activating factors.5–7 Sesamin (2) displays anticancer,8,9 antihypertensive,10,11 and antioxidant activities.12 Lignan eudesmin (3) exhibits antioxidant13,14 and neuritogenic15 properties. It also displays selective inhibition against platelet-activating factor16 and T-cell proliferation.17

4.4.7 Conventional Approach Furofuran lignans constitute one of the main subclasses of the lignan family of secondary metabolites; they consist of a wide variety of structures because of various configurations and different linkage patterns, and they display a broad range of biological properties.5–18 Furofuran lignans are found in plentiful plants.19,20 However, the enantioselective total synthesis of furofuran lignans is comparatively underdeveloped despite more than 100 furofuran lignans being isolated.21 Takano et al. achieved the asymmetric total synthesis of various furofuran lignans for the first time from diethyl L-tartrate as the starting material in 1988.22 Although various methodologies were documented for the enantioselective synthesis of furofuran molecules of natural origins, most



Furofuran Lignans    337

of them rely on protocols of chiral pool or chiral auxiliary-induced asymmetric synthesis.23 Kan et al. developed the asymmetric total synthesis of various furofuran lignans involving an organocatalytic asymmetric aldol transformation as a leading step.24 More recently, Zhang and co-workers accomplished a practical and efficient protocol for tetrahydrofurans with three stereocenters via Pd-catalyzed asymmetric allylic cycloaddition.25

4.4.8 Demerits of Conventional Approach Conventional approaches proceed through longer-step transformations such that Takano et al. methodology needs more than 15 steps.22 Although several biological activities have been studied to date, various furofuran lignans have never been biologically examined, and the mode of action and the structure–activity relationship remain intangible.25 The yield of lignans through the conventional approach was low such that Watanabe et al. applied Yuzikhin’s condition26 (PbO2, TFA, and CH2Cl2) for an asymmetric oxidative dimerization of 3,4,5-trimethoxycinnamic acid derivative, but the yield of furofuran lignans was relatively low (yangambin needs five steps, 30% yield, and caruilignan A needs six steps, 30% yield).27 Moreover, the other substrates bearing fewer oxygen atoms on the benzene ring delivered a trace amount of the desired bislactones.28

4.4.9 Key Features of Total Synthesis Under Electrochemistry The key step for the syntheses of lignans yangambin (1), sesamin (2), and eudesmin (3) consists of a novel electrochemical methodology for the asymmetric oxidative dimerization of cinnamic acid analogs.28

4.4.10 Type of Reaction C–C bond formation under electrochemistry.28

4.4.11 Synthetic Strategy Under Electrochemistry Asymmetric oxidative dimerization.28

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4.4.12 Synthetic Route Watanabe and co-workers demonstrated the asymmetric oxidative dimerization of cinnamic acid derivatives by a novel electrochemical protocol; three natural bioactive lignans yangambin (1), sesamin (2), and eudesmin (3) were synthesized by this electrochemical methodology with high enantiomeric excess in 2016.28 Initially, electrolysis substrates (6a–d) were prepared from cinnamic acid derivatives (4a–d) through a condensation reaction of L-proline with t-butyl ester in the presence of the HOBt and DCC in THF and subsequent treatment with TFA. Carboxylic acids (6a–d) underwent oxidative dimerization to afford key intermediate bislactones (7a–d) under Ronlan’s conditions.29 This crucial step was carried out in the presence of the n-Bu4NBF4, CH2Cl2/TFA (5:1) using Pt anode and Pt cathode to create C–C bonds under constant current (Scheme 4.4.1). The yield of the 7c and 7d was low (8–10% and 85–87% ee for 7c) because of the decomposition of the starting materials (6c and 6d).28 Bislactones (7a–c) provided compounds (8a–c) on reduction with Ca(BH4)2. Finally, the targeted natural lignans yangambin (1), sesamin (2), and eudesmin (3) were obtained from (8a–c) in the presence of the methanesulfonyl chloride.

Scheme 4.4.1.  Syntheses of yangambin (1), sesamin (2), and eudesmin (3) using electrochemistry.



Furofuran Lignans    339

References   1. Dickey EE. (1958) Liriodendrin, a new lignan diglucoside from the inner bark of yellow poplar (Liriodendron tulipifera L.). J Org Chem 23: 179–184.   2. Budowski P, Markley KS. (1951) The chemical and physiological properties of sesame oil. Chem Rev, 48: 125–151.   3. Michailidis D, Angelis A, Aligiannis N et al. (2019) Recovery of sesamin, sesamolin, and minor lignans from sesame oil using solid support-free liquid–liquid extraction and chromatography techniques and evaluation of their enzymatic inhibition properties. Front Pharmacol 10: Article 723.  4. Dryselius E, Lindberg B. (1956) Pinoresinol and its dimethyl ether from Araucaria angustifolia. Acta Chem Scand 10: 445–446.   5. Castro-Faria-Neto HC, Bozza PT, Cruz HN et al. (1995) Yangambin: A new naturally-occurring platelet-activating factor receptor antagonist: Binding and in vitro functional studies. Planta Med 61: 101–105.   6. Marques RCP, de Medeiros SRB, Dias CS et al. (2003) Evaluation of the mutagenic potential of yangambin and of the hydroalcoholic extract of Ocotea duckei by the Ames test. Mutat Res 536: 117–120.  7. Hausott B, Greger H, Marian B. (2003) Naturally occurring lignans efficiently induce apoptosis in colorectal tumor cells. J Cancer Res Clin Oncol 129: 569–576.   8. Hirose N, Doi F, Ueki T et al. (1992) Suppressive effect of sesamin against 7,12-dimethylbenz[a]-anthracene induced rat mammary carcinogenesis. Anticancer Res 12: 1259–1265.   9. Hibasami H, Fujikawa T, Takeda H et al. (2000) Induction of apoptosis by Acanthopanax senticosus HARMS and its component, sesamin in human stomach cancer KATO III cells. Oncol Rep 7: 1213–1219. 10. Matsumura Y, Kita S, Morimoto S et al. (1995) Antihypertensive effect of sesamin. I. Protection against deoxycorticosterone acetate-saltinduced hypertension and cardiovascular hypertrophy. Biol Pharm Bull 18: 1016–1019. 11. Matsumura Y, Kita S, Tanida Y et al. (1998) Antihypertensive effect of sesamin. III. Protection against development and maintenance of hypertension in stroke-prone spontaneously hypertensive rats. Biol Pharm Bull 21: 469–473. 12. Nakano D, Itoh C, Takaoka M et al. (2002) Antihypertensive effect of ­sesamin. IV. Inhibition of vascular superoxide production by sesamin. Biol Pharm Bull 25: 1247–1249. 13. Mbaze LM, Lado JA, Wansi JD et al. (2009) Oxidative burst inhibitory and cytotoxic amides and lignans from the stem bark of Fagara heitzii (Rutaceae). Phytochemistry 70: 1442–1447. 14. Lee J, Lee D, Jang DS et al. (2007) Two new stereoisomers of tetrahydrofuranoid lignans from the flower buds of Magnolia fargesii. Chem Pharm Bull 55: 137–139.

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15. Yang YJ, Park JI, Lee H et al. (2006) Effects of (+)-eudesmin from the stem bark of Magnolia kobus DC. var. borealis Sarg. on neurite outgrowth in PC12 cells. Arch Pharm Res 29: 1114–1118. 16. Pan JX, Hensens OD, Zink DH et al. (1987) Lignans with platelet activating factor antagonist activity from magnolia biondii. Phytochemistry 26: 1377–1379. 17. Cho JY, Yoo ES, Baik KU et al. (1999) Eudesmin inhibits tumor necrosis factor-α production and T cell proliferation. Arch Pharm Res 22: 348–353. 18. Xu W-H, Zhao P, Wang M et al. (2019) Naturally occurring furofuran lignans: Structural diversity and biological activities. Nat Prod Res 33: 1357–1373. 19. Zhang J, Chen J, Liang Z et al. (2014) New lignans and their biological activities. Chem Biodivers 11: 1–54. 20. Ward RS. (1999) Lignans, neolignans and related compounds. Nat Prod Rep 16: 75–96. 21. Mori N. (2018) Synthetic studies on optically active furofuran and diarylbutane lignans. Biosci Biotech Biochem 82: 1–8. 22. Takano S, Ohkawa T, Tamori S et al. (1988) Enantio-controlled route to the furfuran lignans: The total synthesis of (–)-sesamolin, (–)-sesamin, and (–)-ocuminatolide. J Chem Soc Chem Commun: 1988: 189–191. 23. Syed MK, Murray C, Casey M. (2014) Stereoselective synthesis of lignans of three structural types from a common intermediate, enantioselective synthesis of (+)-yangambin. Eur J Org Chem: 2014: 5549–5556. 24. Kobayashi M, Ueno H, Yoshida N et al. (2019) Diastereodivergent and regiodivergent total synthesis of princepin and isoprincepin in both (7″R,8″R) and (7″S,8″S) isomers. J Org Chem 84: 14227–14240. 25. Zhao C, Khan I, Zhang YJ. (2020) Enantioselective total synthesis of furofuran lignans via Pd-catalyzed asymmetric allylic cycloadditon of vinylethylene carbonates with 2-nitroacrylates. Chem Commun 56: 12431–12434. 26. Yuzikhin OS, Vasil’ev AV, Rudenko AP. (2000) Oxidation of aromatic compounds: VIII. Oxidative dehydrodimerization of cinnamic acid derivatives in the system CF3COOH-CH2Cl2-PbO2. Russ J Org Chem 36: 1743–1754. 27. Mori N, Watanabe H, Kitahara T. (2006) Simple and efficient asymmetric synthesis of furofuran lignans yangambin and caruilignan A. Synthesis 400–404. 28. Mori N, Furuta A, Watanabe H (2016) Electrochemical asymmetric dimerization of cinnamic acid derivatives and application to the enantioselective syntheses of furofuran lignans. Tetrahedron 72: 8393–8399. 29. Ronlan A, Bechgaard K, Parker VD. (1973) Electrochemistry in media of intermediate acidity. Part VI. Coupling reactions of simple aryl ethers. Acta Chem Scand 27: 2375–2382.

Chapter 5

(–)-Heptemerone B and (–)-Guanacastepene E 4.5.1 Natural Source Coprinus heptemerus [family: Psathyrellaceae, heptemerone B (1)]1,2 and endophytic fungus CR115 growing on the branches of Daphnopsis americana [family: Thymelaeaceae, guanacastepene E (2)].3

4.5.2 Structure

4.5.3 Systematic Name (1S,2S,3aR,3bS,6R,8aS,10aS)-1-isopropyl-8a,10a-dimethyl-3-oxo2,3,3a,3b,5,6,7,8,8a,9,10,10a-dodecahydro-1H-azuleno[4,5,6-cd] isobenzofuran-2,6-diyl diacetate (1).

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4.5.4 Structure

4.5.5 Systematic Name (1S,2S,3aR,3bS,6R,8aS,10aS)-6-hydroxy-1-isopropyl-8a,10a-dimethyl-3oxo-2,3,3a,3b,5,6,7,8,8a,9,10,10a-dodecahydro-1H-azuleno[4,5,6-cd] isobenzofuran-2-yl acetate (2).

4.5.6 Structural Features The neodolastane diterpenoids heptemerones and guanacastepenes share a tricyclic neodolastane carbon skeleton which includes fused five-, seven-, and six-membered rings (tricyclic C5–C7–C6 core). It was classified by two angular methyl groups in a 1,4 relationship at C8 and C11, together with an additional isopropyl substituent at C12.1–4

4.5.7 Class of Compounds Diterpenes.1–4

4.5.8 Pharmaceutical Potential Neodolastanes heptemerones C, D, and G were bacteriostatic against Gram-positive bacteria Micrococcus luteus, Bacillus brevis, Corynebacterium insidiosum, and Bacillus subtilis as well as Gramnegative bacteria Pseudomonas fluorescens at 20 μg/mL concentration.2 It was evident that the most active compound of the family is heptemerone G (MIC in the range of 1 μg/mL), which was the same range as guanacastepene A. It has been examined that α,β-carbonyl compounds (aldehyde and ketone) are likely the active pharmacophores responsible for antibiotic properties. The antibacterial activities were negligible in an



(–)-Heptemerone B and (–)-Guanacastepene E    343

hour when heptemerone G was treated with cysteine (1 equiv). Heptemerone A, C, and G exhibited attractive cytotoxic activities; heptemerone G was the most active against Mono-Mac-6 with an IC50 value as low as 2.8 μM.2 Guanacastepene A displayed antibiotic activity against antibioticresistant Gram-positive bacteria. It exhibited antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VREF); 7–10 mm and 17 mm zones of growth inhibition were noticed, when agar plates streaked with MRSA were treated with 50μg of guanacastepene A or 30 μg of vancomycin, respectively.3–5 This diterpene also showed moderate activity against a panel of Gram-positive along with Gram-negative bacteria and Candida albicans. Guanacastepene A showed haemolytic property against human red blood cells, very likely by non-specific membrane lysis.5

4.5.9 Conventional Approach Heptemerones A–G were isolated from a fungus, Coprinus heptemerus, in 2005.1 Diterpene heptemerone B (1) was originated as a colorless oil that bears the molecular formula C24H34O6. It comprises three carbonyl groups as one ketone together with two acetoxy groups, as well as one carbon– carbon double bond; its unsaturation index is 8. Trauner and co-workers achieved the first total synthesis of heptemerone B (1), and its selective saponification provided guanacastepene E (2).6 The founding member of the family is guanacastepene A, which was isolated from a Daphnopsis americana tree found in the Guanacaste region of Costa Rica4; guanacastepenes B–O were originated from neutralized cultures of CR115 grown in potato dextrose broth in 2001.3 Liu et al. isolated guanacastepene E (2) and a novel diterpenoid named 2,15-epoxy-5,13dihydroxyneodolast-3-en-14-one from cultures of the basidiomycete Trametes corrugate in 2009.7 Sorensen et al. reported efficient, enantioselective syntheses of both natural (+)- and unnatural (–)-guanacastepene E for the first time as well as formal total syntheses of (+)- and (–)-guanacastepene A from (S)-(+)-carvone as a chiral pool starting material.8 An asymmetric total synthesis of guanacastepene E comprises three key reactions: an effective p-allyl Stille cross-coupling and an intramolecular enone-olefin [2+2] photocycloaddition together with a stereoelectronically managed reductive fragmentation of a conjugated cyclobutyl ketone.

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4.5.10 Demerits of Conventional Approach Sorensen et al. developed the first total synthesis of guanacastepene E (2) involving [2+2]-cycloaddition as a leading step.8 However, it was not free from a few demerits. The authors prepared important organoselenide as a mixture of diastereoisomers from ketone in the presence of the SmI2 and hexamethylphosphoramide in exposure to THF and phenyl selenium bromide. However, the yield of the organoselenide was comparatively low (50%).8 Moreover, the key acetate ester was produced from unstable hydroxy ketone using a highly corrosive chemical acetic anhydride through acetylation of the hydroxyl group.

4.5.11 Key Features of Total Synthesis Under Electrochemistry The stereoselective and convergent total synthesis of the (–)-heptemerone B and (–)-guanacastepene E include the application of electrochemistry for the construction of the central seven-membered ring as modern technology. Besides, total syntheses of bioactive diterpenes comprise an intramolecular Heck reaction to build one quaternary stereocenter and organocuprate chemistry for the creation of the other; interestingly, the five-membered ring was constructed through ring-closing metathesis.6

4.5.12 Type of Reaction C–C bond formation under electrochemistry.6

4.5.13 Synthetic Strategy Under Electrochemistry Electrochemical oxidation.6

4.5.14 Synthetic Route Trauner et al. described the total synthesis of the (–)-heptemerone B (1) and (–)-guanacastepene E (2) involving uncommon electrochemical oxidation as a green methodology.6 The concise and convergent total synthesis was started with known compound 3,4-diodofuran (3) to deliver



(–)-Heptemerone B and (–)-Guanacastepene E    345

silyl enol ether (4) over several steps involving the Dess–Martin periodinane condition, a diastereoselective Heck cyclization, regioselective deprotonation followed by silylation as leading steps. Next, the concept of electrochemistry was applied as a green process to construct a central seven-membered ring from silyl enol ether (4) under the conditions established by Moeller.9,10 In this crucial step, silyl enol ether (4) underwent anodic oxidation in the presence of the 2,6-lutidine, 0.1 M LiClO4, 20% CH3OH in DCM and RVC anode (0.9 mA) to afford tetracycle (8) in 81% yield as a single isomer (Scheme 4.5.1). The desired (–)-heptemerone B (1) was obtained from tetracycle (8) over several steps and selective saponification of (1) furnished guanacastepene E (2) in the presence of K2CO3 in methanol. The total synthesis was completed through the longest linear sequence which includes 17 (18) steps.6

Scheme 4.5.1.  Total synthesis of (–)-heptemerone B and (–)-guanacastepene E using electrochemistry.

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References   1. Valdivia C, Kettering M, Anke H et al. (2005) Diterpenoids from Coprinus heptemerus. Tetrahedron 61: 9527–9532.   2. Kettering M, Valdivia C, Sterner O et al. (2005) Heptemerones A-G, seven novel diterpenoids from Coprinus heptemerus: Producing organism, fermentation, isolation and biological activities. J Antibiot 58: 390–396.  3. Brady SF, Bondi SM, Clardy J. (2001) The guanacastepenes: A highly diverse family of secondary metabolites produced by an endophytic fungus. J Am Chem Soc 123: 9900–9901.  4. Brady SF, Singh MP, Janso JE et al. (2000) Guanacastepene, a fungalderived diterpene antibiotic with a new carbon skeleton. J Am Chem Soc 122: 2116–2117.   5. Singh MP, Janso JE, Luckman SW et al. (2000) Biological activity of guanacastepene, a novel diterpenoid antibiotic produced by an unidentified fungus CR115. J Antibiot 53: 256–261.   6. Miller AK, Hughes CC, Kennedy-Smith JJ et al. (2006) Total synthesis of (−)-heptemerone B and (-)-guanacastepene E. J Am Chem Soc 128: 17057–17062.   7. Liu R, Liu J-K. (2009) A new neodolastane diterpene from cultures of the basidiomycete Trametes corrugate. Heterocycles 78: 2565–2570.   8. Shipe WD, Sorensen EJ. (2006) Convergent, enantioselective syntheses of guanacastepenes A and E featuring a selective cyclobutane fragmentation. J Am Chem Soc 128: 7025–7035.  9. Mihelcic J, Moeller KD. (2004) Oxidative cyclizations: The asymmetric synthesis of (−)-alliacol A. J Am Chem Soc 126: 9106–9111. 10. Mihelcic J, Moeller KD. (2003) Anodic cyclization reactions: The total synthesis of alliacol A. J Am Chem Soc 125: 36–37.

Chapter 6

(+)-N-Methylanisomycin 4.6.1 Natural Source Various species of Streptomyces (S. griseolous and S. roseochromogens; family: Streptomycetaceae)1 and Streptomyces sp. SA3079 and No. 638.2 (anisomycin).2,3

4.6.2 Structure

4.6.3 Systematic Name (2R,3S,4S)-4-hydroxy-2-(4-methoxybenzyl)pyrrolidin-3-yl acetate (2). (2S,3R,4R)-4-hydroxy-2-(4-methoxybenzyl)pyrrolidin-3-yl acetate (3).

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4.6.4 Structural Features Structurally, an iminosugar anisomycin comprises a pyrrolidine ring bearing a hydroxyl group, an acetoxy group, and a benzene ring with a methoxy group.1–3 The absolute stereochemistry of the natural antibiotic (–)-anisomycin is 2R,3S,4S, confirmed by X-ray crystallographic analysis.4

4.6.5 Class of Compounds Antibiotic.1–3

4.6.6 Pharmaceutical Potential The antibiotic (–)-anisomycin displays selective and potent activities against pathogenic protozoa and various fungi strains.5 It was applied clinically for the therapy of trichomonas vaginitis and amebic dysentery.6 It shows antitumor together with antiviral properties because of apoptotic action, including on mammalian cell lines in the nanomolar region.3,7,8 Currently, it has been observed that many derivatives of anisomycin displayed robust glycosidase inhibitory activity against α-rhamnosidase and certain other glycosidases.9

4.6.7 Conventional Approach The bacterial antibiotic anisomycin was originated from Streptomyces griseolus; it is a strong and reversible inhibitor of protein synthesis.1 The structural features include a characteristic trans-diol, one being acetylated. Hence, synthetic chemists are attracted to developing various approaches for synthesizing anisomycin and its analogs.10–14 However, Shaw et al. developed the concise and effective synthetic protocol for the total synthesis of unnatural (+)-anisomycin from the cheap carbohydrate D-glucose as a starting material with an overall yield of 23% in 2016.15

4.6.8 Demerits of Conventional Approach Conventional methods possess a few disadvantages such as poor stereoselectivity, harsh conditions, and overall low yield due to long

(+)-N-Methylanisomycin    349

reaction routes, together with inadequate protection groups in the late stages.15

4.6.9 Key Features of Total Synthesis Under Electrochemistry The pivotal step of the first total synthesis of (+)-N-methylanisomycin (2) comprises the regio- and stereo-selective cyclization of (E)- and (Z)-δalkenylamines by anodic oxidation of their lithium amides for the formation of the key intermediate substituted pyrrolidine.16

4.6.10 Type of Reaction C–N bond formation under electrochemistry.16

4.6.11 Synthetic Strategy Under Electrochemistry Regio- and stereo-selective cyclization of alkenylamines by anodic oxidation.16

4.6.12 Synthetic Route Suginome and co-workers developed an asymmetric total synthesis of (+)-N-methylanisomycin (1) utilizing an oxidative anodic cyclization of δ-alkenylamine from L-diethyl tartrate (4) as a starting material.16 Electrolysis substrates (5a/5b) were synthesized from L-diethyl tartrate (4) over several steps, including Swern oxidation and Wittig reaction as leading steps. Next, (E)-δ-alkenylamine (5a) was reacted with butyllithium at –78 °C; subsequently, anodic oxidation of the resulting lithium amide provided the key intermediate pyrrolidine (6) as a single stereoisomer in 53% yield. The crucial step of anodic oxidation occurred to generate a new C–N bond in the presence of the 0.25 M LiClO4–THF/HMPA at –10 °C and electrolyzed at a constant current (17.5 mA/cm2, 1.2 F/mol of (5a)) (Scheme 4.6.1). Similarly, (Z)-δ-alkenylamine (5b) was transformed into methylpyrrolidine (6). Finally, pyrrolidine (6) was effective to provide the targeted (+)-N-methylanisomycin (1) over several steps. Thus, the total synthesis of (1) was completed in 15 steps with an overall

350  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Scheme 4.6.1.    Total synthesis of (+)-N-methylanisomycin using electrochemistry.

isolated yield of 14% including regio- and stereo-selective cyclization by anodic oxidation as a central step.

References   1. Sobin BA, Tanner FW Jr. (1954) Anisomycin, a new anti-protozoan antibiotic. J Am Chem Soc 76: 4053.   2. Ishida S, Yamada O, Futatsuya F et al. (1975) In Proceedings of the First Intersectional Congress of IAMS, vol. 3. Hasegawa T (Ed.). Science Council of Japan, Tokyo, 641.  3. Hosoya Y, Kameyama T, Naganawa H et al. (1993) Anisomycin and new congeners active against human tumor cell lines. J Antibiot 46: 1300–1302.   4. Schaefer JP, Wheatley PJ. (1968) Structure of anisomycin. J Org Chem 33: 166–169.  5. Jimenez A, Vazquez D. (1979) In Antibiotics. Hahn FE (Ed.). Springer, Berlin, 1–19.   6. Korzybski T, Kowszyk-Gmdifer Z, Kurytowicz W. (1978) Antibiotics, vol. 1. American Society of Microbiolgy, Washington, DC, 343–346.  7. Quintana VM, Selisko B, Brunetti JE et al. (2020) Antiviral activity of the natural alkaloid anisomycin against dengue and Zika viruses. Antiviral Res. 176: 104749.  8. Schwardt O (1999) Stereoselective synthesis and biological evaluation of anisomycin and 2-substituted analogues. Synthesis, 1999(S1): 1473–1490.

(+)-N-Methylanisomycin    351

  9. Kim JH, Curtis-Long MJ, Woo DS et al. (2005) α-Rhamnosidase inhibitory activities of polyhydroxylated pyrrolidine. Bioorg Med Chem Lett 15: 4282–4285. 10. Zeng J, Zhang Q, Zhang HK et al. (2013) Practical synthesis of trans-­ dihydroxybutyrolactols as chiral C4 building blocks and their application to the synthesis of polyhydroxylated alkaloids. RSC Adv 3: 20298. 11. Li J, Feng YH, Li XB et al. (2012) Concise synthesis of (−)-anisomycin. Chin Chem Lett 23: 647–649. 12. Joo J-E, Lee K-Y, Pham V-T et al. (2007) Application of Pd(0)-catalyzed intramolecular oxazine formation to the efficient total synthesis of (−)-anisomycin. Org Lett 9: 3627–3630. 13. Kim JH, Curtis-Long MJ, Seo WD et al. (2005) Stereodivergent syntheses of anisomycin derivatives from d-tyrosine. J Org Chem 70: 4082–4087. 14. Detz RJ, Abiri Z, Griel RL et al. (2011) Enantioselective copper-catalysed propargylic substitution: Synthetic scope study and application in formal total syntheses of (+)-anisomycin and (−)-cytoxazone. Chem Eur J 17: 5921–5930. 15. Ajay S, Saidhareddy P, Shaw AK. (2016) Stereoselective total synthesis of unnatural (+)-anisomycin. Synthesis 48: 1191–1196. 16. Tokuda M, Fujita H, Miyamoto T et al. (1993) New total synthesis of (+)-N-methylanisomycin by anodic cyclization of δ-alkenylamine. Tetrahedron 49: 2413–2426.

Chapter 7

Pyrrolophenanthridone Alkaloids 4.7.1 Natural Source Crinum bulbispermum Milne [family: Amaryllidaceae, pratorinine (1), pratorimine (2), hippacine (3)]1–5 and Haemanthus kalbreyeri [family: Amaryllidaceae, kalbretorine (4)].6

4.7.2 Structure

4.7.3 Systematic Name 10-hydroxy-9-methoxy-7H-pyrrolo[3,2,1-de]phenanthridin-7-one (1). 9-hydroxy-10-methoxy-7H-pyrrolo[3,2,1-de]phenanthridin-7-one (2). 9,10-dihydroxy-7H-pyrrolo[3,2,1-de]phenanthridin-7-one (3). 8-hydroxy-7H-[1,3]dioxolo[4,5-j]pyrrolo[3,2,1-de]phenanthridin-7one (4).

353

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4.7.4 Structural Features Pyrrolophenanthridone alkaloids include a heteropolycyclic skeleton bearing indole together with N-benzoyl moieties. A phenanthridone alkaloid kalbretorine (4) contains a lactam carbonyl, methylene­ dioxy functions, and a hydroxyl group peri to a carbonyl function.6 Phenanthridone alkaloids pratorinine (1) and pratorimine (2) comprise one hydroxyl group and one methoxy group, whereas hippacine (3) possesses two hydroxyl groups.1–5

4.7.5 Class of Compounds Alkaloids.1–6

4.7.6 Pharmaceutical Potential Lycorine-type alkaloid pratorinine (1) was tested on human leukemic Molt 4 cells and it was observed that (1) displays cytotoxic activity toward T-cell leukemia.3 Pratorimine (2) shows cytotoxicity against Meth-A (mouse sarcoma) and LLC (Lewis lung carcinoma) tumor cell lines with ED50 = 4.1 µg/mL and >10 µg/mL, respectively.4 Phenanthridone alkaloid kalbretorine (4) potently inhibited the growth and viability of S-180 tumor cells; in doses of 20 µg and above, it provided largely proliferation of the splenic lymphocytes in healthy adult male mice.6

4.7.7 Conventional Approach Ghosal et al. isolated bioactive alkaloid kalbretorine (4) bearing molecular formula C16H19NO4 (mp 245–248 °C) as a straw-colored solid soluble in alkali provided a reddish ferric test for chelated phenols.6 Miki et al. reported the application of a halodecarboxylation taking advantage of PhI(OAc)2/LiX system and the subsequent reduction as the vital step for the efficient synthesis of cytotoxic kalbretorine (4) and its derivatives.7 Kerr et al. demonstrated a suitable, one-pot, domino sp2–sp3 amidation for the construction of indolines as well as indoles from o-triflyloxyphenethyl carbonates.8 This sequence comprises, as the discrete components, a palladium-catalyzed amidation of the aryl triflate subsequent by a unique substitution of an aliphatic carbonate. The advantage of the method is



Pyrrolophenanthridone Alkaloids    355

illustrated by the two- or three-step rapid syntheses of the secondary metabolites anhydrolycorinone, pratosine, oxoassoanine, and hippadine.

4.7.8 Demerits of Conventional Approach Ghosal et al. achieved the first synthesis of alkaloid kalbretorine (4). However, the yield was low.6 Meyers and co-workers developed an elegant synthesis of this bioactive natural kalbretorine from starting material N-benzyl-7-bromoindoline, yet the yield was still insufficient.9 O-(Methoxyaryl) oxazoline was prepared from fluorooxazoline through an intermediate by butyllithium, a toxic, flammable liquid and vapor.9

4.7.9 Key Features of Total Synthesis Under Electrochemistry The key step of total syntheses of pyrrolophenanthridone alkaloids comprises electrochemical intramolecular C(sp2)–H cross-coupling, which was accomplished by the construction of an influential electrophilic radical cation intermediate in the MeNO2–HFIP–LiClO4 system and dehydrogenative indole synthesis.10

4.7.10 Type of Reaction C–C bond formation under electrochemistry.10

4.7.11 Synthetic Strategy Under Electrochemistry Electrochemical intramolecular cross-coupling reaction.10

4.7.12 Synthetic Route Recently, Chiba et al. accomplished a metal-free total synthesis of pyrrolophenanthridone alkaloids utilizing anodic oxidation of the same electron-rich indoline moiety as the leading steps.10 In the case of the total synthesis of natural products and drug discovery, a common strategy is an aryl–aryl cross-coupling.11 Palladium-assisted cross-coupling is employed frequently in the area of medicinal chemistry.12 However, alternative

356  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

methodologies are needed as Pd catalysts are costly and cytotoxic. Hence, the investigators applied electrochemical intramolecular C(sp2)–H crosscoupling as green technology and dehydrogenative indole synthesis to synthesize naturally occurring alkaloids such as kalbretorine (4), pratorinine (1), pratorimine (2), hippacine (3), hippadine (16), pratosine (15), oxoassoanine (13), and anhydrolycorinone (14) elegantly. The authors started the total synthesis of promising alkaloid kalbretorine (4) from 2,3,4-trimethoxybenzoyl indoline (6) (Scheme 4.7.1). Triethyl orthoformate, TsOH, in toluene was used for the regioselective protection of the trihydroxy benzoyl group of (7), after the complete demethylation of (6). Kalbretorine precursor was constructed through O-methylation, and deprotection, together with methylene protection. The targeted kalbretorine (4) was synthesized after final demethylation in a total of nine steps from indoline (5). Seven natural alkaloids were synthesized through metal-free electrochemical intramolecular cross-coupling reactions as a green technique by applying the MeNO2–HFIP–LiClO4 system as a powerful enhancer for radical cation reactivity (Scheme 4.7.2).10

Scheme 4.7.1.    Total synthesis of kalbretorine using electrochemistry.



Pyrrolophenanthridone Alkaloids    357

partial demethylation using Aq. piperidine

Scheme 4.7.2.  Total syntheses of pratorinine, pratorimine, and hippacine using electrochemistry.

References   1. Ghosal S, Rao PH, Jaiswal DK et al. (1981) Alkaloids of Crinum pratense. Phytochemistry 20: 2003−2007.  2. Ghosal S, Saini KS, Frahm AW. (1983) Alkaloids of Crinum latifolium. Phytochemistry 22: 2305−2309.

358  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

  3. Abd el Hafiz M, Ramadan MA, Jung ML et al. (1991) Cytotoxic activity of Amaryllidaceae alkaloids from Crinum augustum and Crinum bulbispermum. Planta Med 57: 437−439.   4. Min BS, Gao JJ, Nakamura N et al. (2001) Cytotoxic alkaloids and a flavan from the bulbs of Crinum asiaticum var. Chem Pharm Bull 49: 1217−1219.  5. Ramadan MA, Kamel MS, Ohtani K et al. (2000) Minor phenolics from Crinum bulbispermum bulbs. Phytochemistry 54: 891−896.  6. Ghosal S, Lochan R, Kumar AY et al. (1985) Alkaloids of Haemanthus kalbreyeri. Phytochemistry 24: 1825–1828.   7. Yasuyoshi M, Hideaki U, Masashi D et al. (2012) Synthesis of pyrrolophenanthridone alkaloid kalbretorine from indolecarboxylic acids via hypervalent iodine(III) mediated halodecarboxylation and reduction. Tetrahedron Lett 53: 1924–1927.   8. Ganton MD, Kerr MA. (2005) A domino amidation route to indolines and indoles: Rapid syntheses of anhydrolycorinone, hippadine, oxoassoanine, and pratosine. Org Lett 7: 4777−4779.   9. Hutchings RH, Meyers AI. (1996) An oxazoline-mediated synthesis of the pyrrolophenanthridine alkaloids and some novel derivatives. J Org Chem 61: 1004–1013. 10. Okamoto K, Chiba K. (2020) Electrochemical total synthesis of pyrrolophenanthridone alkaloids: Controlling the anodically initiated electron transfer process. Org Lett 22: 3613–3617. 11. Nicolaou KC, Bulger PG, Sarlah D. (2005) Palladium-catalyzed cross-coupling reactions in total synthesis. Angew Chem Int Ed 44: 4442−4489. 12. Cooper TWJ, Campbell IB, Macdonald SJF. (2010) Factors determining the selection of organic reactions by medicinal chemists and the use of these reactions in arrays (small focused libraries). Angew Chem Int Ed 49: 8082−8091.

Chapter 8

8,9-Seco-ent-kaurane 4.8.1 Natural Source Rabdosia shikokiana var. occidentalis, Rabdosia umbrosa var. hakusanensis (Kudo) Hara, and Rabdosia shikokiana, Rabdosia plant (family: Lamiaceae or Labiatae).1–3

4.8.2 Structure

4.8.3 Systematic Name (3S,4aR,10R,13aR,Z)-6-hydroxy-4,4,13a-trimethyl-9-methylene-8,13dioxo-1,2,3,4,4a,5,6,8,9,10,11,12,13,13a-tetradecahydro-7,10-(metheno) benzo[11]annulen-3-yl acetate (1). (3S,4aR,10R,13aR,Z)-6-methoxy-4,4,13a-trimethyl-9-methylene-8,13dioxo-1,2,3,4,4a,5,6,8,9,10,11,12,13,13a-tetradecahydro-7,10-(metheno) benzo[11]annulen-3-yl acetate (2). (2S,5aR,8S,9aR,11aR)-11-hydroxy-5a,9,9-trimethyl-13-methylene-5,12dioxododecahydro-3H-2,11a-ethanobenzo[5,6]cyclodeca[1,2-b]oxiren8-yl acetate (3). 359

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(2S,5aR,8S,9aR,11aR)-11-methoxy-5a,9,9-trimethyl-13-methylene-5,12dioxododecahydro-3H-2,11a-ethanobenzo[5,6]cyclodeca[1,2-b]oxiren8-yl acetate (4). (3S,4aR,10R,13aR,E)-8-hydroxy-4,4,13a-trimethyl-9-methylene-13-oxo2,3,4,4a,5,8,9,10,11,12,13,13a-dodecahydro-1H-7,10-methano­benzo[11] annulen-3-yl acetate (5).

4.8.4 Structural Features The 8,9-seco-ent-kaurane diterpenoids comprise an extraordinary cyclohexyl-fused bicyclo[7.2.1]dodecane skeleton bearing 5−7 stereogenic centers. Diterpenoids (−)-shikoccin, (−)-epoxyshikoccin, (+)-O-methyle­ poxyshikoccin, (−)-O-methylshikoccin, and (+)-rabdohakusin were supposed to be biogenetically derived from (−)-shikoccidin (12) having a bicyclo[3.2.1]octane core.1–3

4.8.5 Class of Compounds Diterpenoids.1–3

4.8.6 Pharmaceutical Potential Shikoccin (1) exhibited antitumor activity against P388 lymphocytic leukemia in mice [dose 60-7.5, evaluation T/C (%) 124-107].4 Shikoccin (1), (−)-O-methylshikoccin (2), epoxyshikoccin (3), and O-methyle­ poxyshikoccin (4) showed potent inhibitory effects against HeLa with IC50 values of 0.08, 0.30, 0.25, and 0.13 mg/mL, respectively.5 Moreover, these diterpenoids show potent cytotoxicity against KB, FM 3A/B cells, Ehrlich ascites, and Walker intramuscular carcinomas.4–6

4.8.7 Conventional Approach The total syntheses of 8,9-seco-ent-kauranoids remain attractive yet challenging targets for synthetic investigation because of their intriguing structures and interesting biological properties. However, Paquette et al. developed the only total synthesis of (−)-O-methylshikoccin and

8,9-Seco-ent-kaurane    361

(+)-O-methylepoxyshikoccin to date.7 The key step of the strategy includes oxy-Cope rearrangement of a spirocyclopentenol. The same authors also accomplished the practical route for the total synthesis of (–)-O-methylshikoccin and (+)-O-methylepoxyshikoccin involving a [3,3]-sigmatropic rearrangement of spirocyclic intermediates. The overall yield of enantiopure O-methylshikoccin was nearly 8% from the Wieland–Miescher ketone, and this approach also permits convenient access to naturally occurring epoxide.8

4.8.8 Demerits of Conventional Approach O-Methylshikoccin was prepared from alkene using 2,3-dichloro-5,6dicyano-1,4-benzoquinone (DDQ), a toxic compound with LD50 (lethal dose, 50%) of 82 mg/kg,3 and it liberates toxic HCN upon exposure to H2O. This crucial step also possesses a highly corrosive reagent acetic anhydride for acetylation.7 The yield of the alcohol was low (14%), and the kinetic instability of this alcohol delivered O-methyl derivative under strongly basic conditions.8

4.8.9 Key Features of Total Synthesis Under Electrochemistry The pivotal step of the asymmetric total syntheses of five 8,9-secoent-kauranoids includes an electrochemical ODI–[5+2] cascade reaction. Variously functionalized bicyclo[3.2.1]octadienone was constructed from sensitive ethynylphenol by the anodic oxidation under mild electrochemical conditions. Concise total syntheses also comprise a [2,3]-sigmatropic rearrangement and a directed retro-aldol/aldol process.9

4.8.10 Type of Reaction C–C bond formation under electrochemistry.9

4.8.11 Synthetic Strategy Under Electrochemistry Electrochemical oxidative dearomatization-induced-[5+2] cascade reaction.9

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4.8.12 Synthetic Route More recently, Ding et al. conducted the asymmetric total syntheses of five 8,9-seco-ent-kauranoids in a concise and efficient way involving the electrochemical oxidative dearomatization-induced (ODI)-[5+2] cascade reaction.9 The authors initiated the total synthesis with the practical preparation of sensitive ethynylphenol (8). Commercially available epoxide (−)-(6) (98% ee) provided ester (7) through the sequence of Eschenmoser−Tanabe fragmentation along with oxidative esterification over three steps in 51% yield. Ester (7) underwent photo-Fries rearrangement in THF10 and then stereoselective ketone reduction by LiBH4 at room temperature for 30 min to generate ethynylphenol (8) and its C7-epimer on a decagram scale in 85% yield (4:1 d.r.). The anodic oxidation of (8) took place in the presence of the electrolyte nBu4NBF4 and an additive in MeCN at room temperature for 10 h to afford the desired bicyclo[3.2.1]octadienone (9) (0.82 g, 65%) and tricycle (10) (98 mg, 9%) (Scheme 4.8.1). The key intermediate (9) was

Scheme 4.8.1.  Total electrochemistry.

syntheses

of

8,9-seco-ent-kaurane

diterpenoids

using

8,9-Seco-ent-kaurane    363

effective in producing sulfone (11) over several steps. Diterpenoids (−)-shikoccin, (−)-epoxyshikoccin, (+)-O-methylepoxyshikoccin, (−)-Omethylshikoccin, and (+)-rabdohakusin were obtained from sulfone (11) finally.

References  1. Fujita E, Ito N, Uchida I et al. (1979) Structures of shikoccin, a unique 8,9-seco-ent-kaurene diterpenoid, and shikoccidin (X-ray crystallography), a new penta-oxygenated ent-kaurene diterpenoid. J Chem Soc Chem Commun 18: 806–807.  2. Kubo I, Matsumoto T, Asaka Y et al. (1984) Structure of rabdohakusin. Chem Lett 13: 1613.   3. Node M, Ito N, Fuji K et al. (1982) Three new 8, 9-seco-ent-kaurane diterpenoids from Rabdosia shikokiana (Labiatae). Chem Pharm Bull 30: 2639–2640.   4. Nagao Y, Ito N, Kohno T et al. (1982) Antitumor activity of Rabdosia and Teucrium diterpenoids against P 388 lymphocytic leukemia in mice. Chem Pharm Bull 30: 727–729.   5. Fuji K, Node M, Ito N et al. (1985) Terpenoids. L. Antitumor activity of diterpenoids from Rabdosia shikokiana var. occidentalis. Chem Pharm Bull 33: 1038–1042.   6. Fuji K, Xu H-J, Tatsumi H et al. (1991) Design and synthesis of antitumor compounds based on the cytotoxic diterpenoids from the genus Rabdosia. Chem Pharm Bull 39: 685–689.   7. Paquette LA, Backhaus D, Braun R. (1996) Direct asymmetric entry into the cytotoxic 8,9-secokaurene diterpenoids. Total synthesis of (−)-Omethylshikoccin and (+)-O-(methylepoxy)shikoccin. J Am Chem Soc 118: 11990–11991.   8. Paquette LA, Backhaus D, Braun R et al. (1997) First synthesis of cytotoxic 8,9-secokaurene diterpenoids. An enantioselective route to (−)-Omethylshikoccin and (+)-O-methylepoxyshikoccin. J Am Chem Soc 119: 9662–9671.  9. Wang B, Liu Z, Tong Z et al. (2021) Asymmetric total syntheses of 8,9-­seco-ent-kaurane diterpenoids enabled by an electrochemical ODI-[5+2] cascade. Angew Chem Int Ed 60: 14892–14896. 10. Mag TM, Martin HJ, Mulzer J. (2009) Total synthesis of the antibiotic kendomycin by macrocyclization using photo-Fries rearrangement and ringclosing metathesis. Angew Chem Int Ed 48: 6032–6036.

Chapter 9

Teleocidins B-1–B-4 4.9.1 Natural Source Streptomyces mecliocidius (family: Streptomycetaceae).1–3

4.9.2 Structure

4.9.3 Systematic Name (4S,7S)-4-(hydroxymethyl)-7,10-diisopropyl-8,10,13-trimethyl-13-vinyl1,3,4,5,7,8,10,11,12,13-decahydro-6H-benzo[g][1,4]diazonino[7,6,5-cd] indol-6-one. 365

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4.9.4 Structural Features The unique structure of the natural product teleocidin B comprises indolactam and cyclic terpenoid. Structurally, a terpenoid indole alkaloid includes an amino group at the 4-position along with a modified mono terpenyl moiety at the 6,7-positions of the indole core.4 Teleocidins B-1, B-2, B-3, and B-4 contain four stereogenic centers, of which two possess all-carbon quaternary stereogenic centers located at the pseudobenzylic positions.1–3

4.9.5 Class of Compounds Alkaloids.1–3

4.9.6 Pharmaceutical Potential Teleocidin B is one of the most influential tumor promoters, and it is a potent protein kinase C (PKC) activator; the toxic substance teleocidin displayed a specific toxic action toward Japanese killifish and mice.1–3 It has been observed that in rodent cell cultures, teleocidin B and dihydroteleocidin B have effects similar to those of 12-O-tetradecanoylphorbol-13-acetate. Teleocidin inhibits the binding of phorbol esters to cell-surface receptors at nanomolar concentrations. Teleocidins show strong PKC activation, similar to phorbol and associated secondary metabolites.5

4.9.7 Conventional Approach A natural product teleocidin B included four diastereomeric compounds, such as teleocidins B-1 to B-4. Terpenoid indole alkaloids teleocidin B are linked to other secondary metabolites, such as lyngbyatoxin A (aka teleocidin A-1) and (–)-indolactam V.6 However, structurally, teleocidin B are more complex as they comprise two quaternary carbon centers inserted within a six-membered cyclic skeleton. The unparalleled structure of teleocidin B and its powerful biological activity have drawn keen interest from chemists and biologists. Thus, many studies on teleocidins have been developed over the years. Nakatsuka et al. described total



Teleocidins B-1–B-4    367

syntheses of (+)-teleocidin B-3 and B-4 for the first time by applying various functionalizing transformations from indole as a starting material.6 The same authors started from methyl indole-3-carboxylate to synthesize indole derivatives by applying intramolecular cyclization together with oxidative cleavage of the C–N bond at l-position.7 Eigenbrott and co-workers synthesized a simplified teleocidin analog from dinitrotoluene through indole with activity comparable to other familiar tumor promoters.8 Sames et al. prepared the core of teleocidin B4 from tertbutyl derivative. The pivotal steps are two C–H bond functionalization cycles, alkenylation, and oxidative carbonylation of two methyl groups.9 Tanner and co-workers employed the Claisen rearrangement to construct the precursor of triflate; the intramolecular Heck reaction was assisted only by bidentate phosphine ligands in yielding the product of a 5-endotrig cyclization predominantly.10

4.9.8 Demerits of Conventional Approach Two conventional syntheses suffer from a few demerits, such as they need 17–28 steps and poor stereocontrol in synthesis.11 Conventional syntheses proceed without stereocontrol at three out of the four chiral centers. Moreover, a pale-yellow corrosive liquid was used to prepare selenide from primary alcohol.6 A corrosive chemical ethyl chloroformate was employed to construct the ethyl carbamate from the monoamine through a protection reaction; protection should be avoided in view of sustainable chemistry.8

4.9.9 Key Features of Total Synthesis Under Electrochemistry The total synthesis of teleocidins includes electrochemical amination to form the secondary amine as a green approach. Cu-mediated tryptophol construction, a marvelous base-induced macrolactamization, and a Sigman−Heck reaction were also pivotal steps in this 11-step synthesis.11

4.9.10 Type of Reaction C–N bond formation under electrochemistry.11

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4.9.11 Synthetic Strategy Under Electrochemistry Electrochemical amination.11

4.9.12 Synthetic Route Baran and co-workers demonstrated a stereocontrolled synthesis of the teleocidins B-1, B-2, B-3, and B-4 by applying electrochemical amination as a crucial step.11 The total synthesis started from commercially available 4-bromoindole (5) to produce 4-bromo N-acetylindole (6) through acetylation. Next, an electrochemical (e) approach for amination occurred between compound (6) and L-valine methyl ester (7) in the presence of the NiBr2·glyme, LiBr, a suitable ligand, and DBU as a base in DMA at room temperature for 7 h to furnish secondary amine (8) in 51% yield (>1 g every 7 h) (Scheme 4.9.1). Herein, electrochemistry plays a crucial role in constructing the C–N bond by employing a commercial potentiostat on a ca. 400 mg scale. Secondary amine (8) was very efficient in delivering the desired products teleocidins B-1–B-4 over several steps. Thus, the 11-step total synthesis of teleocidins was finished through a unified and modular approach.

Scheme 4.9.1.    Total synthesis of teleocidins B-1–B-4 using electrochemistry.



Teleocidins B-1–B-4    369

References   1. Takashima M, Sakai H. (1960) A new toxic substance, teleocidin, produced by Streptomyces. Part I. Production, isolation and chemical studies. Bull Agric Chem Soc Jpn 24: 647–651.   2. Takashima M, Sakai H. (1960) A new toxic substance, teleocidin, produced by Streptomyces. Part II. Biological studies of teleocidin. Bull Agric Chem Soc Jpn 24: 652–655.   3. Takashima M, Sakai H, Mori R et al. (1962) A new toxic substance, teleocidin, produced by Streptomyces. Part IV. Degradative studies of hydroteleocidin B and teleocidic anhydride. Agric Biol Chem 26: 669–678.  4. Hitotsuyanagi Y, Fujiki H, Suganuma M et al. (1984) Isolation and structure elucidation of teleocidin B-1, B-2, B-3, and B-4. Chem Pharm Bull 32: 4233–4236.   5. Umezawa K, Weinstein IB, Horowitz A et al. (1981) Similarity of teleocidin B and phorbol ester tumour promoters in effects on membrane receptors. Nature 290: 411–413.   6. Nakatsuka S, Masuda T, Goto T. (1987) Total syntheses of (±)-teleocidin B-3 and B-4. Tetrahedron Lett. 28: 3671–3674.   7. Nakatsuka S, Masuda T, Goto T. (1986) Synthetic studies on teleocidin II. Synthesis of indole derivatives containing the same substituent to teleocidin bat 6- and 7-positions of indole nucleus. Tetrahedron Lett. 27: 6245–6248.   8. Webb II RR, Venuti MC, Eigenbrott C. (1991) Synthesis of a tetramethyl analogue of teleocidin. J Org Chem 56: 4706–4713.   9. Dangel BD, Godula K, Youn SW et al. (2002) C–C bond formation via C–H bond activation: Synthesis of the core of teleocidin B4. J Am Chem Soc 124: 11856–11857. 10. Vital P, Norrby P, Tanner D. (2006) An intramolecular Heck reaction that prefers a 5-endo- to a 6-exo-trig cyclization pathway. Synlett 2006: 3140–3144. 11. Nakamura H, Yasui K, Kanda Y et al. (2019) 11-Step total synthesis of teleocidins B-1−B-4. J Am Chem Soc 141: 1494−1497.

Chapter 10

Thebaine 4.10.1 Natural Source Papaver bracteatum Lindl. (family: Papaveraceae).1,2

4.10.2 Structure

4.10.3 Systematic Name (4R,7aR,12bS)-7,9-dimethoxy-3-methyl-2,3,4,7a-tetrahydro-1H-4,12methanobenzofuro[3,2-e]isoquinoline.

4.10.4 Structural Features An opiate alkaloid thebaine (1) bears chemical similarities with morphinan alkaloids, such as morphine and codeine. Thebaine (1) comprises a basic phenanthrene skeleton having a bridging piperidine ring; it includes two methoxy groups at 3-position (A ring) and 6-position (C ring) and a crucial N atom at 17-position (D ring) as well as a furan ring.2 371

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4.10.5 Class of Compounds Alkaloid.1,2

4.10.6 Pharmaceutical Potential The opium alkaloid thebaine comprises various medicinal and industrial values. It has been observed that subcutaneous LD50 (lethal dose) of the phenanthrene alkaloid thebaine (1) in mice was 31 mg/kg, and its intraperitoneal LD50 was 20 mg/kg. Note that other authors examined an LD50 value of 42 mg/kg in mice.3 The toxic effects of alkaloid thebaine are higher than morphine; as a narcotic, it is more efficient than morphine, but the analgesic effects of opioid analgesic morphine are higher.4 Electrophysiologically, the spasmolytic activity of thebaine was similar to that of bitter, crystalline alkaloid strychnine, but it differed from morphinan alkaloids morphine and codeine.3 Various studies have been carried out to examine the physical dependency linked to thebaine, most of which have suggested that thebaine does not induce serious physical dependence as morphine.5 Biosynthetically, a minor opium alkaloid thebaine (1) is the biosynthetic progenitor of morphine and codeine.6,7 It is an appropriate precursor for the industrial semisynthetic production of suitable pharmaceuticals, such as buprenorphine, oxycodone, and naloxone.6,7 A thebaine derivative buprenorphine is significantly more potent than morphine; as an analgesic, it is a partial µ agonist that is 25–50 times more powerful than morphine as an analgesic. Another analgesic, thebaine derivative oxycodone, is applied to manage moderate to severe pain.

4.10.7 Conventional Approach Sharghi et al. observed vast areas which were covered with Papaver bracteatum Lindl. in the Alborz mountains in the north of Iran. The authors obtained 2.6 g of pure thebaine (1) (26% of dry latex); this alkaloid (melting point 193 °C) was identified by infrared absorption and proton magnetic resonance spectra.1 Various methods are available for the synthesis of thebaine (1).8–12 Dihydrocodeinone was transformed to the desired thebaine (1) in four steps with a 27% yield.8,9 In another method, direct methyl enol ether construction took place from codeinone; it claims

Thebaine    373

a 27% yield of the natural alkaloid (1).10 Schwartz et al. also reported a methodology involving the oxidative coupling of a reticuline derivative as a leading step; the overall yield in total synthesis of dl-thebaine remains in the 1–2% range.11 Rapoport et al. described the practical synthesis of thebaine together with oripavine from codeine and morphine, respectively, involving the formation of codeine methyl ether as a leading step.12

4.10.8 Demerits of Conventional Approach Conventional approaches include several traditional oxidants, such as MnO2–silica, K3Fe(CN)6, Ag2CO3–celite, or VOCl3.13–16 However, all methodologies suffered from relatively low yields or the generation of unwanted regioisomers. Most of the conventional approaches were not able to include green reagents and sustainable technologies.

4.10.9 Key Features of Total Synthesis Under Electrochemistry The biomimetic and electrochemical synthesis of (±)-thebaine along with its natural (–)-enantiomer (1) comprises a regio- as well as diastereoselective, anodic, intramolecular coupling of 3′,4′,5′-trioxygenated laudanosine derivatives. The electrolytic transformation was carried out using a simple undivided constant current setup.17

4.10.10 Type of Reaction C–C bond formation under electrochemistry.17

4.10.11 Synthetic Strategy Under Electrochemistry A regioselective and diastereoselective anodic coupling.17

4.10.12 Synthetic Route Opatz et al. developed total syntheses of racemic thebaine and (–)-thebaine in 2018 using electrochemistry as a sustainable technique.17 The biomimetic

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total synthesis of thebaine was based on the regio- and diastereo-selective, anodic coupling of 3′,4′,5′-trioxygenated laudanosine derivatives. The authors commenced the total synthesis of thebaine from homo­ veratrylamine (2) and methyl gallate (3); this methodology is based upon cheap and naturally occurring starting materials. Homoveratrylamine (2) was converted to building block α-aminonitrile (4) over four steps in 86% yield and methyl gallate (3) was transformed to another building block benzyl bromide (5) over seven steps in 45% yield. Next, the 1-benzyltetrahydroisoquinoline framework was constructed from these two building blocks through the deprotonationalkylation-reduction sequence affording racemic (6). After establishing the exact protecting groups, the trioxygenated laudanosine derivative (±)-(7) underwent the anodic coupling to produce morphinandienone (±)-(8) using an undivided cell, Pt electrodes, MeCN, and HBF4 at constant current conditions (Scheme 4.10.1). (±)-Thebaine was obtained from morphinandienone (±)-(8) over several steps finally.17 The investigators also achieved the enantioselective synthesis of natural (–)-thebaine from homoveratrylamine (2) and methyl gallate (3); compound (2) was transformed to α-aminonitrile (9) over three steps in 90% yield. Compound R-(10) was obtained by the reaction between

Scheme 4.10.1.    Total synthesis of (±)-thebaine using electrochemistry.

Thebaine    375

Scheme 4.10.2.    Total synthesis of (–)-thebaine using electrochemistry.

α-aminonitrile (9) and benzyl bromide (5). R-(11) was subjected to the anodic coupling to produce (+)-(12a) under similar conditions (Scheme 4.10.2). (+)-(12a) was very effective in delivering the targeted (–)-thebaine over several steps successfully.17 The semisynthetic opioid oxycodone (14-hydroxy-7,8-dihydro­ codeinone) is obtained from naturally occurring thebaine; it is commercially manufactured on a multiton scale.18,19 Oxycodone is applied as a powerful analgesic, e.g., for pain management in cancer patients, and it includes a significantly better oral bioavailability compared to morphine.20 A study disclosed that noroxycodone is the urinary metabolite of strong opioid agonist oxycodone (13) in rabbits.21 The same investigators synthesized (−)-oxycodone (13) based on the regio- and diastereo-selective construction of a 4a−2′-coupled morphinandienone using a combination of electrochemistry and substrate design in 2019.22 Laudanosine derivative R-(11) was derived from the same methyl gallate (3) and vanillin through homoveratrylamine (naturally occurring and cheap starting materials) by applying for a

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Scheme 4.10.3.    Total synthesis of (−)-oxycodone using electrochemistry.

Noyori asymmetric transfer hydrogenation.23 R-(11) was subjected to anodic coupling to generate morphinandienone (+)-(12a) using the undivided cell, BDD (boron-doped diamond) anode, Pt cathode, MeCN, and HBF4 at constant current electrolysis (Scheme 4.10.3). The total synthesis of a (−)-oxycodone (13) was finished from the same intermediate morphinandienone (+)-(12a) over several steps involving a [4+2] cycloaddition with photogenerated singlet oxygen.

References  1. Sharghi N, Lalezari I. (1967) Papaver bracteatum Lindl., a highly rich source of thebaine. Nature 213: 1244.   2. Carlin MG, Dean JR, Ames JM. (2020) Opium alkaloids in harvested and thermally processed poppy seeds. Front Chem 8: Article 737.   3. Corrado AP, Longo VG. (1961) An electrophysiological analysis of the convulsant action of morphine, codeine and thebaine. Arch Int Pharmacodyn Ther 132: 255–269.   4. Preininger V. (1972) The pharmacology and toxicology of the alkaloids from the plants of the family Papaveraceae. Acta Univ Palacki Olomuc Fac Med 61: 213–254.  5. Navarro G, Richardson R, Zuban AT. (1976) Propranolol and morphine. Psychopharmacol 51: 39–42.  6. Millgate AG, Pogson BJ, Wilson IW et al. (2004) Analgesia: Morphinepathway block in top1 poppies. Nature 431: 413–414.   7. Biancofiore G. (2006) Oxycodone controlled release in cancer pain management. Ther Clin Risk Manag 2: 229–234.   8. Rapoport H, Lovell CH, Reist HR et al. (1967) The synthesis of thebaine and northebaine from codeinone dimethyl ketal. J Am Chem Soc 89: 1942–1947.

Thebaine    377

 9. Eppenberger U, Warren ME, Rapoport H. (1968) Stereochemie der Umwandlung von Dihydrothebain in Thebain Synthese von markierten Thebainen. Helv Chim Acta 51: 381. 10. Seki I. (1970) Studies on the morphine alkaloids and its related compounds. XVII. One-step preparations of enol ether and pyrrolidinyl dienamine of normorphinone derivatives. Chem Pharm Bull 18: 671–676. 11. Schwartz MA, Mami IS. (1975) Biogenetically patterned synthesis of the morphine alkaloids. J Am Chem Soc 97: 1239–1240. 12. Barber RB, Rapoport H. (1975) Synthesis of thebaine and oripavine from codeine and morphine. J Med Chem 18: 1074–1077. 13. Blasko G, Dornyei G, Barczai-Beke M et al. (1984) Studies aimed at the synthesis of morphine. 7. Biomimetic total synthesis of (±)-pallidine. J Org Chem 49: 1439–1441. 14. Cava MP, Buck KT. (1969) Some synthetic studies in the isoquinoline series. Tetrahedron 25: 2795–2805. 15. Stuart KL. (1971) Morphinandienone alkaloids. Chem Rev 71: 47–72. 16. Franck B, Dunkelmann G, Lubs HJ. (1967) Synthesis of a morphinan derivative by oxidative ring closure. Angew Chem Int Ed 6: 1075–1076. 17. Lipp A, Ferenc D, Gütz C et al. (2018) A regio- and diastereoselective anodic aryl-aryl-coupling in the biomimetic total synthesis of (–)-thebaine. Angew Chem Int Ed 57: 11055–11059. 18. Hudlicky T. (2015) Recent advances in process development for opiatederived pharmaceutical agents. Can J Chem 93: 492. 19. Berenyi S, Csutoras C, Sipos A. (2009) Recent developments in the chemistry of thebaine and its transformation products as pharmacological targets. Curr Med Chem 16: 3215–3242. 20. Riley J, Eisenberg E, Müller-Schwefe G et al. (2008) Oxycodone: A review of its use in the management of pain. Curr Med Res Opin 24: 175–192. 21. Pöyhiä R, Vainio A, Kalso E. (1993) A review of oxycodone’s clinical pharmacokinetics and pharmacodynamics. J Pain Symptom Manage 8: 63–70. 22. Lipp A, Selt M, Ferenc D et al. (2019) Total synthesis of (−)-oxycodone via anodic aryl−aryl coupling. Org Lett 21: 1828–1831. 23. Uematsu N, Fujii A, Hashiguchi S et al. (1996) Asymmetric transfer hydrogenation of imines. J Am Chem Soc 118: 4916–4917.

Part 5

Flow Chemistry in Total Synthesis of Bioactive Natural Products: An Efficient and Modern Synthetic Tool

Chapter 1

Coronaridine 5.1.1 Natural Source Tabernaemontana heyneana Wall1,2 and Vinca rosea3 (family: Apocynaceae).

5.1.2 Structure

5.1.3 Systematic Name Methyl 7-ethyl-7,8,9,10,12,13-hexahydro-5H-6,9-methanopyrido[1′,2′: 1,2]azepino[4,5-b]indole-6(6aH)-carboxylate.

5.1.4 Structural Features Pentacyclic iboga-type alkaloid coronaridine (1) contains a bicycloazaoctane system; the carbocyclic six-membered ring moiety generated by C(14), C(15), C(20), C(21), C(16), and C(17) of the bicycloazaoctane system takes place in the twist conformation. The 18-carbomethoxyibogamine (1) comprises indole core, ester functionality, and ethyl group.3 381

382  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

5.1.5 Class of Compounds Alkaloid.1–3

5.1.6 Pharmaceutical Potential Alkaloid coronaridine (1) showed antifertility properties.2 Coronaridine (1) displayed TCF/β-catenin inhibitory activities with an IC50 value of 5.8 µM.4

5.1.7 Conventional Approach Gata et al. reported the total synthesis of racemic coronaridine (1) from 7-oxo-18-tosyloxyibogamine; the synthesis of racemic coronaridine consists of the construction of lactam nitrile, carbinolamine, cyanoenamine, 18-cyanoibogamine, and carboxylic acid.5

5.1.8 Demerits of Conventional Approach The conventional approach was not free from the angle of green chemistry. The intermediate lactam nitrile was prepared from 7-oxo18-tosyloxyibogamine using KCN; it releases HCN gas, a very toxic chemical asphyxiant.5

5.1.9 Key Features of Total Synthesis Under Flow Chemistry The basic feature of the semisynthesis of natural alkaloid coronaridine (1) comprises the transformation of the amine (+)-catharanthine into the (+)-coronaridine by applying visible-light photoredox catalysis in flow.6

5.1.10 Type of Reaction C–C bond formation under flow chemistry.6

5.1.11 Synthetic Strategy Under Flow Chemistry Fragmentation reaction.6

Coronaridine    383

5.1.12 Synthetic Route Stephenson et al. developed the synthesis of the bioactive alkaloid (+)-coronaridine (1) along with (−)-pseudovincadifformine (2) and (−)-pseudotabersonine (3), by the combination of flow chemistry and visible-light photochemistry in 2014 as these green modern technologies provide a great opportunity to enhance the overall efficiency of total synthesis further.6 The investigators started syntheses of natural products

Scheme 5.1.1.  Syntheses of (+)-coronaridine, (−)-pseudovincadifformine, and (−)pseudotabersonine using flow chemistry.

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from (+)-catharanthine (4) to deliver the cyanated fragmentation product (5) in the presence of the photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 and TMSCN (trimethylsilyl cyanide) through a visible-light-assisted transformation in 93% yield after 3 h in batch mode (Scheme 5.1.1). The same transformation was carried out in a flow photochemical reactor with the intention to reduce reaction time, enhance scalability, and permit for the safe, controlled formation of very poisonous HCN (prussic acid).7 This fragmentation transformation was finished with a residence time of only 2 min in a 96% yield. Next, hydrogenation of the fragmentation product (5) was carried out to afford 6 with high diastereoselectivity. Finally, compound (6) was subjected to the aminonitrile rearrangement conditions to furnish the desired product (+)-coronaridine (1) as the sole product in 48% yield over two steps; it is the highest yielding synthesis of coronaridine from catharanthine.8 (−)-Pseudovincadifformine (2) and (−)-pseudotabersonine (3) were synthesized from the key fragmentation product (5) successfully.6

References 1. Govindachari TR, Joshi BS, Saksenas AK et al. (1966) Correlation of heyneanine with ibogamine. Chem Commun (London) 1966: 97a. 2. Meyer WE, Coppola JA, Goldman L. (1973) Alkaloid studies VIII: Isolation and characterization of alkaloids of Tabernaemontana heyneana Wall and antifertility properties of coronaridine. J Pharm Sci 62: 1199–1201. 3. Taeye LD, Bruyn AD, Pauw CD et al. (1981) Alkaloids of Vinca rosea L isolation and identification of coronaridine. Bull Soc Chim Belg 90: 83–87. 4. Ohishi K, Toume K, Arai MA et al. (2015) Coronaridine, an iboga type ­alkaloid from Tabernaemontana divaricata, inhibits the Wnt signaling pathway by decreasing β-catenin mRNA expression. Bioorg Med Chem Lett 25: 3937–3940. 5. Hirai S, Kawata K, Nagata W. (1968) Total synthesis of (±)-coronaridine and an improved synthesis of (±)-ibogamine. Chem Commun (London) 1968: 1016–1017. 6. Beatty JW, Stephenson CRJ. (2014) Synthesis of (−)-pseudotabersonine, (−)-pseudovincadifformine, and (+)-coronaridine enabled by photoredox catalysis in flow. J Am Chem Soc 136: 10270–10273. 7. Tucker JW, Zhang Y, Jamison TF et al. (2012) Visible-light photoredox catalysis in flow. Angew Chem Int Ed 51: 4144–4147. 8. Gorman M, Neuss N, Cone NJ. (1965) Vinca alkaloids. XVII. Chemistry of catharanthine. J Am Chem Soc 87: 93–99.

Chapter 2

Dictyodendrin B 5.2.1 Natural Source Dictyodendrilla verongiformis (family: Dictyodendrillidae).1

5.2.2 Structure

5.2.3 Systematic Name Sodium 5-hydroxy-2-(4-hydroxybenzoyl)-3-(4-hydroxyphenethyl)-1,4bis(4-hydroxyphenyl)-3,6-dihydropyrrolo[2,3-c]carbazol-7-yl sulfate.

385

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5.2.4 Structural Features A marine indole alkaloid dictyodendrin B (1) contains a highly substituted unique pyrrolo[2,3-c]carbazole scaffold and bears one sulfate group in the periphery.1 The complex poly(hetero)aromatic architecture of dictyodendrins also consists of three or four p-hydroxybenzene groups.1

5.2.5 Class of Compounds Alkaloid.1

5.2.6 Pharmaceutical Potential A scarce alkaloid dictyodendrin B (1) displayed promising telom­ erase inhibitory activity.1 Five alkaloids dictyodendrins A–E inhibited telomerase entirely at 50 µg/mL concentration.

5.2.7 Conventional Approach In 2003, Fusetani et al. isolated telomerase inhibitors, five novel indole alkaloids dictyodendrins A–E, from the Japanese marine sponge Dictyodendrilla verongiformis.1 Natural bioactive dictyodendrin B (1) was obtained as a yellowish amorphous solid bearing the molecular formula C41H29N2O10SNa lower than another alkaloid dictyodendrin A by elements of C2H4O. Secondary metabolites dictyodendrins A–E display inhibitory activity against telomerase, making them potential lead molecules as anticancer agents.1 In 2016, Ready and co-workers reported that dictyodendrins F, H, and I show cytotoxicity against various human cancer cell lines.2 In addition, they display inhibitory activity towards β-site amyloid-cleaving enzyme 1 (BACE1); dictyodendrins F, H, and I are also recognized as potential lead compounds for the therapy of Alzheimer’s disease.3 The highly substituted pyrrolo[2,3-c]carbazole scaffold and intriguing biological activities of dictyodendrins have attracted much interest from the organic synthetic and biological community. So, various total syntheses of dictyodendrins have been reported to date. Fürstner and co-workers achieved the first total synthesis of a scarce marine alkaloid dictyodendrin B (1) involving the reductive cyclization of ketoamide to indole as a vital step assisted



Dictyodendrin B    387

by low-valent titanium.5 Photochemical 6π-electrocyclization, regioselective bromi­nation of the pyrrolocarbazole, and deprotection of all lateral methyl ether groups were also central steps of this concise synthesis. The same investigators also developed the first total syntheses of the marine quinoid dictyodendrin C, its extreme labile quinomethide analog dictyodendrin E, together with the acylated congener alkaloid dictyodendrin B (1).6 The key step of flexible syntheses comprises the construction of the densely functionalized pyrrolo[2,3-c]carbazole in multigram quantities with magnificent overall yield acting as a common intermediate. Jia et al. achieved the total synthesis of dictyodendrins B and E involving a palladium-catalyzed Larock indole synthesis along with a palladiumassisted one-pot consecutive Buchwald−Hartwig amination/C−H activation transformation as central steps through the highly convergent strategy in 2013.7 Ready et al. described a compact total synthesis of dictyodendrin F together with the total syntheses of dictyodendrins H and I for the first time in six steps. Aryl ynol ethers were applied as the crucial building blocks to install aryl and heteroaryl rings in the dictyodendrins.2 In 2020, Ohno et al. described total syntheses of dictyodendrins A–F based on the goldcatalyzed annulation of azido-diynes along with N-Boc pyrrole for the formation of the pyrrolo[2,3-c]carbazole skeleton. The investigators also evaluated the biological activities of the synthesized dictyodendrin analogs; the cytotoxicity of newly synthesized dictyodendrin analogs was assessed toward HCT116 cells at 30 µM by applying the colorimetric MTS assay.8

5.2.8 Demerits of Conventional Approach Most traditional syntheses employed strategies based on installing the necessary substituents before forming the pyrrolo[2,3-c]carbazole core. So, modern research demands more diversity and novelty for these telomerase inhibitors dictyodendrins A–E.8 Besides, the conventional approach was not free from the angle of green chemistry as various syntheses include toxic chemicals.

5.2.9 Key Features of Total Synthesis Under Flow Chemistry The basic feature of the total synthesis of dictyodendrin B (1) involves a late-stage implementation of a carbazole ring closure through flow

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chemistry, the formation of a number of catalytic C–H functionalization processes along with highly selective electrophilic aromatic substitutions carried out in complex environments.9

5.2.10 Type of Reaction C–N bond formation under flow chemistry.9

5.2.11 Synthetic Strategy under Flow Chemistry C–H amination.9

Scheme 5.2.1.    Synthesis of dictyodendrin B using flow chemistry.



Dictyodendrin B    389

5.2.12 Synthetic Route Gaunt et al. executed the total synthesis of bioactive natural product dictyodendrin B (1) from readily available 4-bromoindole (2) through a sequential C–H functionalization strategy in 2015.9 The heteroaromatic starting material (2) was very efficient to produce azide (3) over several steps. Next, a carbazole ring closure of (3) occurred to provide a key carbazole (5) in 62% yield without chromatography by the C–H amination process presumably through the formation of nitrene intermediate (4) using flow chemistry (Scheme 5.2.1). The azide (3) was placed in super-heated dioxane at 180 °C in a continuous-flow process as a crucial step, processing over one gram of the important azide (3) in 30 min. Finally, natural indole alkaloid dictyodendrin B (1) was synthesized from carbazole (5) via sulfonylation/global deprotection; the total synthesis was finished including six direct functionalizations around the heteroarene scaffold as part of a gram-scale plan towards the secondary metabolite.9

References 1. Warabi K, Matsunaga S, van Soest RWM et al. (2003) Dictyodendrins A-E, the first telomerase-inhibitory marine natural products from the sponge Dictyodendrilla verongiformis. J Org Chem 68: 2765–2770. 2. Zhang W, Ready JM. (2016) A concise total synthesis of dictyodendrins F, H, and I using aryl ynol ethers as key building blocks. J Am Chem Soc 138: 10684–10692. 3. Zhang H, Conte MM, Khalil Z et al. (2012) New dictyodendrins as BACE inhibitors from a southern Australian marine sponge, Ianthella sp. RSC Adv 2: 4209–4214. 4. Zhang W, Ready JM. (2017) Total synthesis of the dictyodendrins as an arena to highlight emerging synthetic technologies. Nat Prod Rep 34: 1010–1034. 5. Fürstner A, Domostoj MM, Scheiper B. (2005) Total synthesis of dictyodendrin B. J Am Chem Soc 127: 11620–11621. 6. Fürstner A, Domostoj MM, Scheiper B. (2006) Total syntheses of the telomerase inhibitors dictyodendrin B, C, and E. J Am Chem Soc 128: 8087–8094. 7. Liang J, Hu W, Tao P et al. (2013) Total synthesis of dictyodendrins B and E. J Org Chem 78: 5810–5815.

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8. Matsuoka J, Inuki S, Matsuda Y et al. (2020) Total synthesis of dictyodendrins A–F by the gold-catalyzed cascade cyclization of conjugated diyne with pyrrole. Chem Eur J 26: 11150–11157. 9. Pitts AK, O’Hara F, Snell RH et al. (2015) A concise and scalable strategy for the total synthesis of dictyodendrin B based on sequential C–H functionalization. Angew Chem Int Ed 54: 5451–5455.

Chapter 3

Goniofufurone 5.3.1 Natural Source Goniothalamus giganteus Hook. f., Thomas (family: Annonaceae).1

5.3.2 Structure

5.3.3 Systematic Name (3aR,5R,6S,6aR)-6-hydroxy-5-((R)-hydroxy(phenyl)methyl)tetrahydro­ furo[3,2-b]furan-2(3H)-one.

5.3.4 Structural Features The skeleton of goniofufurone (1) contains a five-membered lactone ring in which the carbonyl peak of a saturated γ-lactone appears at 1755 cm–1 (IR spectrum).1 This styryl-lactone also includes a [3.3.0]furofuranone scaffold, a monosubstituted phenyl group, and two hydroxy group moieties.1,2 391

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5.3.5 Class of Compounds Styryl-lactone.1

5.3.6 Pharmaceutical Potential The styryl-lactone goniofufurone (1) with an unusual natural skeleton exhibited selective but moderate cytotoxic activity against A-549 (human lung carcinoma) with ED50 = 4.76 µg/mL and moderate toxicity to the brine shrimp.1 7-O-Methyl derivatives of goniofu­ furone and 7-epi-(+)-goniofufurone showed 1177- and 451-fold better potencies compared to the leads goniofufurone and 7-epigoniofufurone; structure–activity relationship (SAR) discloses that the insertion of a methoxy group at the C-7 position may enhance the antiproliferative effects of the analogs.3

5.3.7 Conventional Approach In 2019, the concise synthesis of bioactive furanofurone compound (+)-goniofufurone (1) was accomplished by Chen et al. from the known D-glucono-δ-lactone derivative containing an acid-assisted cascade cyclization for the formation of the furanofurone bicyclic skeleton in onepot.4 Popsavin and co-workers achieved syntheses of 15 novel analogs of goniofufurone and 7-epi-goniofufurone carrying a halogen or azido functionality at the C-7 position in 2017.5 Shaw et al. demonstrated the stereoselective total synthesis of natural (+)-goniofufurone (1) based on stereochemically different furanoid glycal vital building blocks obtained from readily available sugars in diversity-oriented synthesis (DOS).6 Mallesham and co-workers conducted the total syntheses of (+)-goniofufurone and (+)-dicinnamoyl goniofufurone from diacetone D-glucose through a “chiron approach”.7 Prasad et al. described a practical, effective enantiospecific synthesis of natural styryl-lactones goniofufurone and 7-epi-goniofufurone in high overall yields from a common chiral building block obtained from D-(–)-tartaric acid based on the utility of a masked tetrol, including an alkene tether along with four contiguous hydroxy groups.8

Goniofufurone    393

5.3.8 Demerits of Conventional Approach Although the Paternò–Büchi reaction (an excited state of carbonyl compounds and an alkene) provided the oxetane successfully through a [2+2] photocycloaddition specifically, this reaction has some significant limitations; it frequently furnishes the most direct as well as the economic route to this type of four-membered heterocycle.9 The conventional batch irradiation provided a 2:1 inseparable mixture of the desired oxetane with a good yield. However, the conversion was slow and needed running at fairly high dilution. Hence, meaningful scale-up in batch was comparatively restricted. So, the total synthesis of (+)-goniofufurone (1) requires a Paternò–Büchi reaction utilizing flow chemistry because FEP continuous flow reactors can be effective in the scale-up of organic photochemistry, mainly in the case of high dilution transformations where the large volumes of solvent are not agreeable with fixed volume batch reactors.10

5.3.9 Key Features of Total Synthesis Under Flow Chemistry The main features of the total synthesis of (+)-goniofufurone (1) comprise the construction of the oxetane through a photochemical Paternò−Büchi reaction. The batch limitations of this vital step were overcome by the application of a three-layer FEP flow photoreactor permitting the preparation of >40 g of intermediates in a single run in 97% yield. The insertion of the lactone ring was accomplished as another key step through the unique Wacker-style oxidation of an enol-ether bond for the first time (a study over 20 oxidants).10

5.3.10 Types of Reactions C–O and C–C bond formations under flow chemistry.10

5.3.11 Synthetic Strategy Under Flow Chemistry Paternò–Büchi [2+2] photocycloaddition.10

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5.3.12 Synthetic Route Booker-Milburn et al. conducted a short and scalable synthesis of natural cytotoxic (+)-goniofufurone (1) from the enantiopure enol ether in just five steps with 11.5% overall yield involving a short flow-photochemistry as a remarkable step in 2016.10 The synthesis started from a commercially available and low-cost sugar derivative D-isosorbide (2) to afford the bicyclic enol ether (3) in a two-step sequence to follow the method of Berini and Deniau with 78% overall yield (50 g batches).11 Next, enol ether (3) underwent a photochemical Paternò−Büchi reaction to deliver the oxetane (5) through flow chemistry as a green technique (Scheme 5.3.1). A 2:1 inseparable mixture of the targeted oxetane (5) and a structural regioisomer (4) were obtained by the irradiation of bicyclic enol ether (3) with benzaldehyde (1.4 equiv) in MeCN (0.03 M) in a batch immersion well (400 mL) using a 400-W medium-pressure lamp. The batch irradiation provided a good overall yield (93%) but the transformation was slow and needed running at a fairly high dilution. However, this crucial step was carried out by the three-layer FEP flow reactor in conjunction with a 400-W medium-pressure lamp (1 mL/min, 70 min residence time) and it generated over 40 g of the 4/5 mixture (97% isolated yield) in a single 83 h run. The synthesis of bioactive

Scheme 5.3.1.    Total synthesis of (+)-goniofufurone using flow chemistry.

Goniofufurone    395

styryl-lactone (+)-goniofufurone (1) was completed from the 4/5 mixture over four steps successfully.10

References  1. Fang X-p, Anderson JE, Chang C-j et al. (1990) Novel bioactive styryllactones: Goniofufurone, goniopypyrone, and 8-acetylgoniotriol from Goniofha/ arnus giganteus (Annonaceae). X-Ray molecular structure of goniofufurone and of goniopypyrone. J Chem Soc Perkin Trans 1: 1655–1661.   2. Tuchinda P, Munyoo B, Pohmakotr M et al. (2006) Cytotoxic styryl-lactones from the leaves and twigs of Polyalthia crassa. J Nat Prod 69: 1728−1733.   3. Francuz J, Popsavin M, Djokić S et al. (2018) Novel O-methyl goniofufurone and 7-epi-goniofufurone derivatives: Synthesis, in vitro cytotoxicity and SAR analysis. Med Chem Commun 9: 2017–2027.   4. Zhang Y, Liu X, Shui F et al. (2019) A concise synthesis of (+)-goniofufurone, (+)-7-epi-goniofufurone, (+)-crassalactones B and C. Tetrahedron Lett 60: 1784–1787.  5. Francuz J, Kovacevic I, Popsavin M et al. (2017) Design, synthesis and in vitro antitumour activity of new goniofufurone and 7-epi-goniofufurone mimics with halogen or azido groups at the C-7 position. Eur J Med Chem 128: 13–24.  6. Pal P, Shaw AK. (2011) Stereoselective total syntheses of (+)-exo- and (-)-exo-brevicomins, (+)-endo- and (-)-endo-brevicomins, (+)- and (-)-cardio­ butanolides, (+)-goniofufurone. Tetrahedron 67: 4036–4047.   7. Sharma GVM, Mallesham S. (2010) Stereoselective total synthesis of styryllactones: (+)-crassalactones B and C, (+)-howiionol A, (+)-tricinnamate, (+)-goniofufurone, and (+)-dicinnamoyl goniofufurone. Tetrahedron: Asymmetry 21: 2646–2658.   8. Prasad KR, Gholap SL. (2008) Stereoselective total synthesis of bioactive styryllactones (+)-goniofufurone, (+)7-epi-goniofufurone, (+)-goniopypyrone, (+)-goniotriol, (+)-altholactone, and (-)-etharvensin. J Org Chem 73: 2–11.   9. Burkhard JA, Wuitschik G, Rogers-Evans M et al. (2010) Oxetanes as versatile elements in drug discovery and synthesis. Angew Chem Int Ed 49: 9052−9067. 10. Ralph M, Ng S, Booker-Milburn KI. (2016) Short flow-photochemistry enabled synthesis of the cytotoxic lactone (+)-goniofufurone. Org Lett 18: 968–971. 11. Berini C, Lavergne A, Molinier V et al. (2013) Iodoetherification of isosor­ bide-derived glycals: Access to a variety of O-alkyl or O-aryl isosorbide derivatives. Eur J Org Chem 2013: 1937−1949.

Chapter 4

Grossamide 5.4.1 Natural Source Capsicum annuum var. grossum (bell pepper) (family: Solanaceae or nightshade).1

5.4.2 Structure

Grossamide (1)

5.4.3 Systematic Name (2R,3R)-2-(4-hydroxy-3-methoxyphenyl)-N-(4-hydroxyphenethyl)-5-((E)-3((4-hydroxyphenethyl)amino)-3-oxoprop-1-en-1-yl)-7-methoxy-2,3dihydrobenzofuran-3-carboxamide.

5.4.4 Structural Features The product of oxidative coupling with two molecules of feruloyl tyramine in vivo is considered a phenolic amide grossamide (1).1 397

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Structurally, natural bioactive grossamide (1) comprises dihydrobenzofuran moiety having two asymmetric carbons and this neolignane (1) also contains phenolic hydroxyl groups, two methoxyls, and two amide linkages at side chains of dihydrobenzofuran core.1,2

5.4.5 Class of Compounds Neolignan.1

5.4.6 Pharmaceutical Potential A representative lignanamide grossamide (1) displayed potential antiinflammatory activity on LPS-induced NO production in RAW 264.7 macrophages with IC50 value of 26.0 ± 3.8 (μM).3 Natural neolignan grossamide (1) also showed antineuroinflammatory activity in BV2 microglia cells by suppressing the TLR4-mediated NF-κB pathway.4 In 2021, it has been observed that N-trans-grossamide (IC50 value of 1.948 ± 0.381 μM) showed better anti-inflammatory activities compared to cis-grossamide (IC50 value of 4.405 ± 0.249 μM).5

5.4.7 Conventional Approach In 1981, a research team led by Sadao Sakamura reported the isolation of a novel lignan amide grossamide as colorless crystals.1 The same investigators also determined the relative configuration of grossamide in 1983. It has been observed that lignanamide grossamide shows no specific rotation in the range of 435–700 nm on ORD, so it is a racemate although it consists of two asymmetric carbons in the dihydrobenzofuran moiety.2 The first enantioselective total synthesis of grossamide (1) was developed by Ley et al. using a continuous fully automated flow process in 2006.6

5.4.8 Demerits of Conventional Approach No conventional approach is available in the literature to date.6

Grossamide    399

5.4.9 Key Features of Total Synthesis Under Flow Chemistry The remarkable feature of the synthesis of grossamide (1) itself was synthesized by an enzyme-assisted oxidative dimerization of one of these amides, tyramide.6 The functionalization of a prepacked column of PS-HOBt (polymer-supported HOBt) as the activated ester was accomplished by eluting the column with a solution of ferulic acid and PyBrOP along with DIPEA (Hünig’s base) in dimethylformamide.

5.4.10 Types of Reactions C–N, C–O, and C–C bond formations under flow chemistry.6

5.4.11 Synthetic Strategy Under Flow Chemistry Enzyme-mediated oxidative dimerization.6

5.4.12 Synthetic Route The multistep synthesis of the grossamide (1), a novel lignan amide, comprises the first reported synthesis of a secondary metabolite by a continuous flow process.6 It still stands out against current success in this field. This synthesis consists of automated computer control, prepacked polymer-assisted reagent, or scavenger cartridges. It sums up just the synthesis of one secondary metabolite, and the ideas strongly established the principles of a machine-aided protocol for complex compound assembly under continuous flow chemistry conditions. It represents a landmark in this field. To start the synthesis, ferulic acid was installed into polymer-assisted hydroxybenzotriazole (PS-HOBt). It provided the corresponding active ester by utilizing DIPEA and bromo­ tripyrrolidinophosphonium hexafluorophosphate (PyBrOP). A small focussed library of amides could be synthesized. Natural product grossamide (1) itself was synthesized in high yield by an enzyme-assisted oxidative dimerization of one of these amides, tyramide (a fourth column packed with an immobilized peroxidase enzyme) (Scheme 5.4.1). It needed passage through a final column, including a silica gel aided

400  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Scheme 5.4.1.    Synthesis of neolignan grossamide using flow chemistry.

Horseradish Peroxidase in amalgamation with a buffered (sodium dihydrogen phosphate buffer, pH 4.5) hydrogen peroxide–urea complex in acetone–water (1:4).6

References 1. Yoshihara T, Yamaguchi K, Takamatsu S et al. (1981) A new lignan amide, grossamide, from bell pepper (Capsicum annuum var. grossum). Agric Biol Chem 45: 2593–2598. 2. Yoshihara T, Yamaguchi K, Takamatsu S et al. (1983) The relative configuration of grossamide and hordatines. Agric Biol Chem 47: 217–220. 3. Sun J, Gu YF, Su XQ et al. (2014) Anti-inflammatory lignanamides from the roots of Solanum melongena L. Fitoterapia 98: 110–116. 4. Luo Q, Yan X, Bobrovskaya L et al. (2017) Anti-neuroinflammatory effects of grossamide from hemp seed via suppression of TLR-4-mediated NF-κB signaling pathways in lipopolysaccharide-stimulated BV2 microglia cells. Mol Cell Biochem 428: 129–137. 5. Zhuang X-C, Zhang Y-L, Chen G-L et al. (2021) Identification of anti-inflammatory and anti-proliferative neolignanamides from Warburgia ugandensis

Grossamide    401

employing multi-target affinity ultrafiltration and LC-MS. Pharmaceuticals 14: 313. 6. Baxendale IR, Griffiths-Jones CM, Ley SV et al. (2006) Preparation of the neolignan natural product grossamide by a continuous flow process. Synlett 2006: 427–430.

Chapter 5

Hennoxazole A 5.5.1 Natural Source A species of the genus Polyfibrospongia sponge (family: Thorectidae).1

5.5.2 Structure

5.5.3 Systematic Name (2R,4R,6R)-6-((R)-2-(2′-((S,3E,6Z,9E)-6,8-dimethylundeca-3,6,9-trien1-yl)-[2,4′-bioxazol]-4-yl)-2-methoxyethyl)-2-methoxy-2-methyltetra­ hydro-2H-pyran-4-ol.

5.5.4 Structural Features Structurally, natural hennoxazoles include an unusual 2,4-linked bisoxazole ring system at their molecular scaffold.1 Structurally interesting secondary metabolites also contain the non-conjugated triene side chain bearing a

403

404  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

trisubstituted Z-double bond, a remote stereogenic center, and the functionalized pyranyl ring.1,2

5.5.5 Class of Compounds Alkaloid.1,2

5.5.6 Pharmaceutical Potential Hennoxazole A (1) exhibited antiviral activity against herpes simplex type 1 (IC50 0.6 µg/mL) and peripheral analgesic property comparable with that of indomethacin.1

5.5.7 Conventional Approach Scheuer et al. isolated hennoxazole A (1) from a sponge Polyfibrospongia sp. (phylum Porifera) off the coast of Miyako Island in Okinawa, Japan, as a light yellow oil carrying a molecular formula C29H42N2O6 in 1991.1,2 The original structure elucidation work confirmed the correct atomic connectivity and the allotment of relative stereochemistry about the C2–C6 pyran ring was safe. However, the stereochemical details remain ambiguous; the relative stereochemistry and the absolute configuration of the distant C8 and C22 stereogenic centers were unrevealed. Wipf et al. reported the total synthesis and structure elucidation of hennoxazole A (1) for the first time; this pioneering synthetic work disclosed the total synthesis of the unnatural antipode of hennoxazole A, which was able to solve the stereochemical puzzle.2 The basic features of this synthesis comprise the combination of pyran and triene segments through a highly convergent strategy, the application of the m-xylene as a pyran synthon, and the substitution of a sterically hindered allylic ester at C(22).2 Williams et al. carried out an enantio-controlled total synthesis of (–)-hennoxazole A (1) by a convergent approach. The basic features of this synthesis consist of asymmetric allylations, effective oxazole formations, and novel use of the Terashima reduction.3 Yokokawa and co-workers achieved an effective strategy for the synthesis of the structurally and biologically interesting marine secondary metabolite hennoxazole A. The remarkable features of this convergent route involve



Hennoxazole A    405

Mukaiyama aldol reaction for the construction of the functionalized tetrahydropyran fragment, Wacker oxidation, and chelation-controlled 1,3-syn reduction.4 Smith et al. demonstrated an enantioselective total synthesis of (–)-hennoxazole A (1) from serine methyl ester in 17 steps, the longest linear sequence, through a convergent asymmetric route.5 The direct stereo-controlled insertion of the C8-methyl ether and the quick functionalization of thiazolidinethione derivatives are central steps of this synthesis. The total synthesis of natural product (–)-hennoxazole A was executed by the same investigator in 14 steps from readily available 4-methyloxazole-2-carboxylic acid involving pyran/bisoxazole fragment synthesis, and a [2,3]-Wittig–Still rearrangement for effective insertion of the trisubstituted Z-double bond as vital steps.6

5.5.8 Demerits of Conventional Approach The landmark synthesis by Wipf et al. needs more steps; it goes ahead in a 28-step longest linear sequence from mercaptoimidazole.2 The remarkable fact of this synthesis is that hennoxazole A and its C22 epimer are chromatographically and spectroscopically identical except by optical rotation. Hence, any other planned syntheses would need the insertion of C22 with ideal stereochemical fidelity, as separation would not be feasible at the end of the synthesis.6

5.5.9 Key Features of Total Synthesis Under Flow Chemistry The remarkable features of the total synthesis of (–)-hennoxazole A comprise the preparation of aldehyde (13), the core fragment of the natural product from 5-pentenoic acid involving flow chemistry methods. A highly stereo-controlled 1,5-anti aldol coupling and a stereoselective gold-assisted alkoxycyclization process together with a cross-metathesis are also three key reactions of this synthesis.7

5.5.10 Types of Reactions C–C, O–H, and C=C bond formations under flow chemistry.7

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Scheme 5.5.1.    Total synthesis of (–)-hennoxazole A using flow chemistry.



Hennoxazole A    407

5.5.11 Synthetic Strategy Under Flow Chemistry Coupling, cyclodehydration, saponification, etc.7

5.5.12 Synthetic Route Ley et al. conducted the total synthesis of antiviral marine natural product (–)-hennoxazole A (1) utilizing integrated batch and flow chemistry methods in 16-step longest linear sequence with 2.8% overall yield.7 The batch preparation of important ketone (4) was started from commercially available (R)-epichlorohydrin (2) with the lithium anion derived from dithiane (3). Next, the flow-chemistry methods were selected to prepare the key bisoxazole core (13). Initially, 5-pentenoic acid (5) underwent the straightforward coupling with carbonyldiimidazole (6) and (±)-serine methyl ester (7) using triethylamine followed by the cyclodehydration in the presence of the diethylaminosulfur trifluoride and CaCO3/ SiO2 scavenger provided the corresponding oxazoline (8) in 86% yield (Scheme 5.5.1). Oxazole derivative (9) was obtained in excellent yield from the intermediate (8) on oxidation using bromochloroform, DBU in MeCN; it was subjected to saponification to furnish the corresponding acid (10) in 93% yield in the presence of the aqueous NaOH. This precursor (10) was transformed into the targeted bisoxazole ester (12) in a notable yield (90%) utilizing the oxazole-forming process on multigram scales (>5 g). Finally, a batch reduction of (12) was carried out in the presence of the DIBAL-H to deliver aldehyde (13), the core fragment of the natural product. The targeted diol (14) was synthesized by the 1,5-anti aldol reaction between ketone (4) and aldehyde (13) in the presence of the (–)-Ipc2BCl along with an in situ reduction of the boron intermediate. The diol (14) as a single diastereomer was very effective to provide the natural product (–)-hennoxazole A (1) identical to an authentic sample.7

References 1. Ichiba T, Yoshida WY, Scheuer PJ et al. (1991) Hennoxazoles: Bioactive bisoxazoles from a marine sponge. J Am Chem Soc 113: 3173–3174. 2. Wipf P, Lim S. (1995) Total synthesis of the enantiomer of the antiviral marine natural product hennoxazole A. J Am Chem Soc 117: 558–559. 3. Williams DR, Brooks DA, Berliner MA. (1999) Total synthesis of (−)-­ hennoxazole A. J Am Chem Soc 121: 4924–4925.

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4. Yokokawa F, Asano T, Shioiri T. (2001) Total synthesis of (2)-hennoxazole A. Tetrahedron 57: 6311–6327. 5. Smith TE, Kuo W-H, Bock VD et al. (2007) Total synthesis of (−)-hennoxazole A. Org Lett 9: 1153–1155. 6. Smith TE, Kuo W-H, Balskus EP et al. (2008) Total synthesis of (−)-hennoxazole A. J Org Chem 73: 142–150. 7. Fernández A, Levine Z, Baumann M et al. (2013) Synthesis of (–)-hennoxazole A: Integrating batch and flow chemistry methods. Synlett 24: 514–518.

Chapter 6

Massarinolin A 5.6.1 Natural Source Massarina tunicata Shearer & Fallah (family: Lophiostomataceae).1,2

5.6.2 Structure

5.6.3 Systematic Name (2′R,3′S,6R)-3′-hydroxy-4″-methyl-2-methylene-3′H,5′H,5″H-dispiro [bicyclo[3.1.1]heptane-6,4′-furan-2′,2″-furan]-5″-one.

5.6.4 Structural Features A sesquiterpene massarinolin A (1) contains a remarkably complex ring skeleton bearing an unusual tetracyclic ring system.1 In its interesting structure, it includes an oxaspiro[3.4]octane comprising an all-carbon quaternary center and a strained bicyclo[3.1.1]heptane together with oxaspirolactone (an acid-labile dioxaspiro[4.4]nonane) are packed.1,2 409

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5.6.5 Class of Compounds Bergamotane sesquiterpene.1

5.6.6 Pharmaceutical Potential A natural sesquiterpene massarinolin A (1) is active against Bacillus subtilis (ATCC 6051), providing a zone of inhibition of 17 mm at 200 µg/ disk.1 It is also active against Staphylococcus aureus (ATCC 29213), affording a 10-mm zone of inhibition.1

5.6.7 Conventional Approach A bioactive natural product massarinolin A (1) was isolated from liquid cultures of the aquatic fungus Massarina tunicate.1 Shearer et al. also isolated metabolites massarinolins B and C from the same source, and massarinolins A–C are the first compounds to be reported from any member of the genus Massarina.1 As a sesquiterpene with only 15 carbon atoms, fungal metabolite massarinolin A (1) features rare ring systems with the molecular formula C15H18O4, suggesting seven degrees of unsaturation. Bermejo and co-workers accomplished the total synthesis of (+)-massarinolin B and (+)-4-epi-massarinolin B from the allylic lactone involving the Nozaki–Hiyama–Kishi reaction as a central step.2 The Cr(II)- and Ni(II)-assisted important coupling of various chiral aldehydes with (E)-β-iodomethacrylates took place to produce the corresponding γ-hydroxy-α,β-unsaturated esters. Recently, Freis et al. reported the total synthesis of (+)-massarinolin A involving Prins reaction and oxidative furan cyclization as key steps.3

5.6.8 Demerits of Conventional Approach The total synthesis of (+)-massarinolin B and (+)-4-epi-massarinolin B with moderate yields was achieved by Bermejo et al. comprising the preparation of an advanced intermediate.2 Dai et al. developed the first and enantioselective total synthesis of massarinolin A including the photochemical Wolff rearrangement through flow chemistry as a green technique.4 This step was performed at a small scale, but the batch



Massarinolin A    411

transformation was very difficult to scale up to at least gram scale as it would need a vast quartz reaction flask as well as a big photoreactor.4

5.6.9 Key Features of Total Synthesis Under Flow Chemistry The divergent approach features for the first enantioselective total syntheses of massarinolin A (1), purpurolides B, D, and E, along with 2,3-deoxypurpurolide C consists of a scalable flow photochemical Wolff rearrangement to construct the crucial bicyclo[3.1.1]heptane, an enantioselective organocatalyzed Diels–Alder reaction, and a late-stage allylic C–H.4

5.6.10 Type of Reaction C–O bond formation under flow chemistry.4

5.6.11 Synthetic Strategy Under Flow Chemistry Photochemical Wolff rearrangement.4

5.6.12 Synthetic Route In 2021, Dai and co-workers described the first enantioselective total syntheses of a bioactive bergamotane sesquiterpene massarinolin A, purpurolides B, D, and E, and 2,3-deoxypurpurolide C through the divergent approach including a flow photochemical Wolff rearrangement as a key step.4 The investigators commenced the total synthesis by preparing carboxylic acid (6) from (–)-limonene oxide (2) through the reported four-step sequence;5 the preparation of carboxylic acid (6) via the four-step sequence worked smoothly with a high yield but with only about 43% ee. So, the authors planned to develop a novel enantioselective approach to yield the carboxylic acid (6) with better ee; in this approach, an organocatalyzed Diels–Alder reaction took place between diene (3) and dienophile (4) in the presence of the chiral amine catalyst to afford aldehyde (5) (84% yield

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Scheme 5.6.1.  Total syntheses of massarinolin A, purpurolides B, D, and E, and 2,3-deoxypurpurolide C using flow chemistry.



Massarinolin A    413

and 89% ee) initially.6 It also included Corey–Fuchs homologation and the Brown hydroboration–oxidation for the preparation of important carboxylic acid (6) as vital steps. Interestingly, each step of the new enantioselective approach can be performed at the gram scale (89% ee and 66% overall yield). Next, an α-diazoketone (7) was prepared from carboxylic acid (6) over three steps to explore the Wolff rearrangement by flow chemistry for the proposed ring contraction.7 In this crucial step, the α-diazoketone (7) underwent flow photochemical Wolff rearrangement in the presence of the methanol and triethyl amine at 23 °C using UV light to furnish important intermediate (8) in 65% yield on a large scale (Scheme 5.6.1).8 A separable 1:1 mixture of 9a and 9b was obtained in 72% yield from intermediate (8) for the proposed divergent synthesis. Compound (9a) was converted to a separable mixture of 10a and 10b (d.r. = 1:1.8) in a 99% yield. Finally, compound (10a) provided the revised structure of massarinolin A (1b), and compound (10b) delivered the proposed structure of massarinolin A (1a) over two steps. This synthesis also led to the structural revision of bioactive massarinolin A. Bergamotane sesquiterpenes purpurolides B, D, and E and 2,3-deoxypurpurolide C were also synthesized from compound (9b).4

References 1. Oh H, Gloer JB, Shearer CA. (1999) Massarinolins A-C: New bioactive sesquiterpenoids from the aquatic fungus Massarina tunicate. J Nat Prod 62: 497–501. 2. Lopez MR, Bermejo FA. (2006) Total synthesis of (D)-massarinolin B and (D)-4-epi-massarinolin B, fungal metabolites from Massarina tunicate. Tetrahedron 62: 8095–8102. 3. Carreira EM, Freis M. (2021) Total synthesis of (+)-massarinolin A. Synfacts 17: 1307. 4. Dai M, Wang Y-C, Cui C. (2021) Flow chemistry-enabled divergent and ­enantioselective total syntheses of massarinolin A, purpurolides B, D, E, 2,3-deoxypurpurolide C, and structural revision of massarinolin A. Angew Chem Int Ed 60: 24828–24832. 5. Ota K, Hamamoto Y, Eda W et al. (2016) Amitorines A and B, nitrogenous diterpene metabolites of Theonella swinhoei: Isolation, structure elucidation, and asymmetric synthesis. J Nat Prod 79: 996–1004.

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6. Ahrendt KA, Borths CJ, MacMillan DWC. (2000) New strategies for organic catalysis: The first highly enantioselective organocatalytic Diels−Alder reaction. J Am Chem Soc 122: 4243–4244. 7. Deng J, Li R, Luo Y et al. (2013) Divergent total synthesis of taiwaniaquinones A and F and taiwaniaquinols B and D. Org Lett 15: 2022–2025. 8. Fuse S, Otake Y, Nakamura H. (2017) Integrated micro-flow synthesis based on photochemical Wolff rearrangement. Eur J Org Chem 44: 6466–6473.

Chapter 7

Nazlinine 5.7.1 Natural Source Nitraria schoberi L. (family: Zygophyllaceae).1

5.7.2 Structure

5.7.3 Systematic Name 4-(2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)butan-1-amine.

5.7.4 Structural Features The comparatively simple structure of alkaloid nazlinine (1) comprises a 2,3-disubstituted indole system; it contains tetrahydro-β-carboline or tryptoline with an aliphatic side chain bearing a primary amine group.1

5.7.5 Class of Compounds Alkaloid.1

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5.7.6 Pharmaceutical Potential Tricyclic indole alkaloid nazlinine (1) exhibits serotonergic activity.1 The chemical messenger is serotonin that’s believed to perform as a mood stabilizer. The study reveals that serotonin levels can have an effect on mood and behavior. Natural nazlinin contracted coeliac along with mesenteric arteries. ED50 (median effective dose) values for nazlinin were 111 ± 5 nmol (coeliac artery) and 70 ± 5 nmol (mesenteric artery).1

5.7.7 Conventional Approach The bioactive alkaloid nazlinine (1) was isolated1 from Nitraria schoberi whose structure was determined through a biomimetic synthesis from tryptamine and tetrahydropyridine.2 Two syntheses of β-carboline alkaloid nazlinine (1) are reported in the literature.2,3 Koomen et al. reported a one-step synthesis of natural nazlinine (1) by the reaction of likely biochemical precursors tryptamine and 2,3,4,5-tetrahydropyridine in the presence of the catalyst trifluoroacetic acid in water through a Pictet–Spengler reaction.2 This revised its structure. Lévy and co-workers developed an effective modification of the Pictet–Spengler reaction for the syntheses of nazlinine (1), indolo[2,3-a]quinolizidine, and elaeocarpidine.3 Initially, tryptamine reacted with glutaronitrile in acetic acid to furnish a nitrile, 1-(3-cyanopropyl)-tetrahydro-β-carboline together with indolo[2,3-a]quinolizidine via hydrogenation. Second, a reduction of nitrile occurred to provide racemic nazlinine (1) in the presence of the lithium aluminum hydride in a 79% yield.

5.7.8 Demerits of Conventional Approach Conventional approaches are not to the modular preparation of nazlinine and structural analogs.4 Moreover, Lévy et al. employed acute toxic glutaronitrile for the preparation of 1-(3-cyanopropyl)-tetrahydro-βcarboline.3

5.7.9 Key Features of Total Synthesis Under Flow Chemistry The key feature of an expedient synthesis of nazlinine (1) consists of flow electrochemistry to quickly prepare protected cyclic α-methoxyamines as

Nazlinine    417

a suitable synthetic technology through Shono oxidation. Microwaveassisted Pictet−Spengler reaction provided natural product nazlinine and related unnatural congeners.4

5.7.10 Type of Reaction C–O bond formation under flow chemistry.4

5.7.11 Synthetic Strategy Under Flow Chemistry Shono oxidation.4

5.7.12 Synthetic Route Ley and co-workers developed an expedient synthesis of the bioactive alkaloid nazlinine (1) using flow electrochemistry as a crucial step in 2014.4 At first, protected cyclic α-methoxyamines were synthesized from N-Boc-protected amines using a microfluidic electrolytic cell. Shono oxidation of N-Boc-protected amines (2, 4) took place in the presence of carbon anode, methanol solvent, and Et4N+BF4– electrolyte (20 mol%, substoichiometric loadings of electrolyte) to afford protected cyclic α-methoxyamines (3, 5) using a continuous flow electrochemical cell (flow rate = 120 mL/min c) (Scheme 5.7.1). The continuous flow conditions were employed to prepare α-methoxylation of a series of cyclic amines under optimization conditions, changing in ring size and protecting group. It has been observed that N-protected pyrrolidine, azepane, piperidine, and morpholine underwent Shono oxidation to furnish the corresponding products (3, 5) in high yields and purity through

Scheme 5.7.1.    Synthesis of natural nazlinine using flow electrochemistry.

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Scheme 5.7.2.    Synthesis of related unnatural congener using flow electrochemistry.

Scheme 5.7.3.  Shono oxidation of N-protected cyclic amines in the microfluidic electrolytic cell and related unnatural congeners.

flow electrochemistry. Next, this intermediate (3) underwent a microwave‐ assisted Pictet–Spengler reaction with tryptamine (6) in the presence of the camphor sulfonic acid in water at 130 °C to provide a natural alkaloid nazlinine (1) in 87% yield. A small library of unnatural analogs could be synthesized through a two-step process involving flow electrochemistry as an enabling technology (Schemes 5.7.2 and 5.7.3).

References 1. Ustünes L, Ozer A. (1991) Chemical characterization and pharmacological activity of nazlinin, a novel indole alkaloid from Nitraria schoberi. J Nat Prod 54: 959–966.

Nazlinine    419

2. Wanner MJ, Velzel AW, Koomen G-J. (1993) Biomimetic synthesis of nazlinin: A structural revision. Chem Soc Chem Comm 1993: 174−175. 3. Diker K, Biach KE, de Maindreville MD et al. (1997) Reductive PictetSpengler cyclization of nitriles in the presence of tryptamine: Synthesis of indolo[2,3-a]quinolizidine, nazlinine, and elaeocarpidine. J Nat Prod 60: 791−793. 4. Kabeshov MA, Musio B, Murray PRD et al. (2014) Expedient preparation of nazlinine and a small library of indole alkaloids using flow electrochemistry as an enabling technology. Org Lett 16: 4618–4621.

Chapter 8

Neomarchantin A 5.8.1 Natural Source Schistochila glaucescens (family: Schistochilaceae).1–3

5.8.2 Structure

5.8.3 Systematic Name 2,7-Dioxa-1,8(1,3),3,6(1,4)-tetrabenzenacyclodecaphane-12,64-diol.

5.8.4 Structural Features The ring B of all the natural bis(bibenzyls) is invariably paradisubstituted except isoplagiochin which is the main feature common to all bis(bibenzyls). Besides, the ethano bridge in ring A of natural 421

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bis(bibenzyls) is in a position meta to the ether oxygen along with rings C and D which are oxygenated and situated in a position meta to the ethano bridges.4 Natural neomarchantin A (1) is a member of the marchantin subclass of macrocyclic bisbibenzyls bearing two biaryl ether subunits (two para- and two meta-substituted benzene rings) and two phenolic –OH groups in a rigidified structure.

5.8.5 Class of Compounds Macrocyclic bisbibenzyl.1

5.8.6 Pharmaceutical Potential Bisbibenzyls neomarchantins A (1) and B showed cytotoxicity against P388 leukaemia cells with IC50s 8–18 µg/mL.1 Secondary metabolite neomarchantin A (1) is a member of the marchantin subclass which constitutes the most often occurring skeletal type of macrocyclic bisbibenzyls.4 Marchantins showed several biological activities including cytotoxicity, antioxidant, antibacterial, and antimycotic effects.5–8 It has been also investigated that the marchantins include activity against influenza A (both H3N2 and H1N1) along with influenza B viruses.9

5.8.7 Conventional Approach Screening of an extract of the New Zealand liverwort Schistochila glaucescens displayed activity against P388 mouse leukaemia cells.1 Bioactivity-directed isolation led to bisbibenzyls neomarchantins A and B and marchantin C along with a novel sesquiterpene lactone glaucescenolide.1 Kodama et al. reported the total synthesis of a cytotoxic bis(bibenzyl) marchantin A in 12 steps successfully involving coupling of the acetonide of methyl gallate with para bromobenzaldehyde and an intramolecular Wadsworth–Emmons olefination as vital steps.10 The same investigators also accomplished total syntheses of marchantin A and riccardin B including the intramolecular Wadsworth–Emmons olefination of the phosphonates for the formation of new macrocyclic bis(bibenzy1) frameworks as a central step.11 In 2011, Speicher and co-workers developed the efficient total synthesis of the subtype of bis(bibenzylic)



Neomarchantin A    423

molecules with two biarylether connections, and methylated derivatives marchantin O and P were prepared first by modification of the arene subunits.12

5.8.8 Demerits of Conventional Approach From the angle of sustainable chemistry, traditional syntheses of marchantins were not free of a few demerits because conventional approaches include the application of harmful thionyl bromide and triethyl phosphite, producing toxic fumes, for the construction of key intermediate phosphonate.10 Moreover, a conventional batch reactor needs more time (17 h) to build an important biaryl ether intermediate compared to a green flow reactor (10 min).13

5.8.9 Key Features of Total Synthesis Under Flow Chemistry The remarkable feature of the total synthesis of neomarchantin A (1) includes the flow reactor for C−O and C−C bond formations with a dramatic improvement in reaction time (10 min vs 17 h) compared to the batch reactor. It also involves a key catalytic macrocyclic olefin metathesis reaction for the synthesis of a macrocyclic bisbibenzyl natural product by applying continuous flow methods for the first time as green techniques.13

5.8.10 Types of Reactions C–O and C–C bond formations under flow chemistry.13

5.8.11 Synthetic Strategy Under Flow Chemistry Cham−Evans−Lam coupling, SNAr reaction, and olefin metathesis.13

5.8.12 Synthetic Route Collins and co-workers demonstrated the total synthesis of natural macrocycle neomarchantin A (1) involving continuous flow techniques as

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(a)

and (b)

Scheme 5.8.1.    Synthesis of neomarchantin A using continuous flow techniques.



Neomarchantin A    425

key steps in 2017.13 The synthesis was initiated with the preparation of central biaryl ether intermediate (4) using Ullmann coupling protocols (Batch) or Cu-catalyzed Chan−Evans−Lam couplings (continuous flow). The synthesis of the key biaryl ether unit (4) was first examined by applying the Ullmann coupling. However, the yield was disappointing (yield 26%, pyridine, 25 mol% CuO, 19 h)13; the reaction provided a similar yield of 33% under the continuous flow/Chan–Evans–Lam conditions by the coupling of phenol (2) and boronic acid (3). Hence, an alternative approach was investigated for the preparation of biaryl ether intermediate (4) to improve yield with a shorter reaction time. For this purpose, the coupling of phenol (2) occurred with aryl fluoride (5) to furnish the desired biaryl ether unit (4) in 86% yield in the presence of the K2CO3 in DMSO at 130 °C for 12 min under continuous flow conditions (SNAr reaction) (Scheme 5.8.1). The bis-styrenyl intermediate (6) was obtained from ether unit (4) over several steps. Next, the synthesis of the macrocyclic core of natural neomarchantin A (1) was performed in a continuous flow using a tube-in-tube reactor via olefin metathesis.14 The cyclization of the bis-styrenyl intermediate (6) took place to afford the targeted 20-membered ring (7) using a more active catalyst (5 mol%) in toluene at 110 °C in 49% yield with a 10 min residence time. C−C bond construction through the key macrocyclization event proceeded in similar yields in batch and in a continuous flow, while the flow method provided a dramatic betterment in reaction time (10 min vs 17 h). The completion of the synthesis was accomplished through the hydrogenolysis of the diene (6) and subsequent deprotection of the methyl ether to deliver macrocyclic bisbibenzyl neomarchantin A (1), whose spectral analyses matched those in the literature.1–3

References   1. Scher JM, Burgess EJ, Lorimerb SD et al. (2002) A cytotoxic sesquiterpene and unprecedented sesquiterpenebisbibenzyl compounds from the liverwort Schistochila glaucescens. Tetrahedron 58: 7875–7882.   2. Niu C, Qu J-B, Lou H-X. (2006) Antifungal bis[bibenzyls] from the Chinese liverwort Marchantia polymorpha L. Chem Biodivers 3: 34–40.   3. Tori M, Masuya T, Asakawa Y. (1990) New macrocyclic bisbibenzyls from the liverwort Schistochila glaucescens. J Chem Res (S) 1990: 36.   4. KeserG GM, Nogradi M. (1995) The chemistry of macrocyclic bis(bibenzyls). Nat Prod Rep 12: 69–75.

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  5. Shen J, Li G, Liu Q et al. (2010) Marchantin C: A potential anti-invasion agent in glioma cells. Cancer Biol Ther 9: 33−39.   6. Asakawa Y, Toyota M, Taira Z et al. (1983) Riccardin A and riccardin B, two novel cyclic bis(bibenzyls) possessing cytotoxicity from the liverwort Riccardia multifida (L.) S. Gray. J Org Chem 48: 2164−2167.   7. Hsiao G, Teng C-M, Wu C-L et al. (1996) Marchantin H as a natural antioxidant and free radical scavenger. Arch Biochem Biophys 334: 18−26.   8. Schwartner C, Michel C, Stettmaier K et al. (1996) Marchantins and related polyphenols from liverwort: Physico-chemical studies of their radical-­ scavenging properties. Free Radical Biol Med 20: 237−244.  9. Iwai Y, Murakami K, Gomi Y et al. (2011) Anti-influenza activity of ­marchantins, macrocyclic bisbibenzyls contained in liverworts. PLoS One 6: e19825. 10. Kodama M, Shiobara Y, Matsumura K et al. (1985) Total synthesis of marchantin A, a novel cytotoxic bis(bibenzyl) isolated from liverworts. ­ Tetrahedron Lett 26: 877–880. 11. Kodama M, Shiobara Y, Sumitomo H et al. (1988) Total syntheses of marchantin A and riccardin B, cytotoxic bis(bibenzyls) from liverworts. J Org Chem 53: 72–77. 12. Speicher A, Holz J, Hoffmann A. (2011) Syntheses of marchantins C, O and P as promising highly bioactive compounds. Nat Prod Commun 6: 393–402. 13. Morin É, Raymond M, Dubart A et al. (2017) Total synthesis of neomarchantin A: Key bond constructions performed using continuous flow methods. Org Lett 19: 2889−2892. 14. Brzozowski M, O’Brien M, Ley SV et al. (2015) Flow chemistry: Intelligent processing of gas–liquid transformations using a tube-in-tube reactor. Acc Chem Res 48: 349−362.

Chapter 9

Spirodienal A 5.9.1 Natural Source Sorangium cellulosum KM0141 (family: Polyangiaceae).1

5.9.2 Structure

5.9.3 Systematic Name (2E,4Z,6S,7S,8S)-7-hydroxy-8-((2S,3S,5S,6R,8R,9R,10R)-5-hydroxy-8((2R,3S,4S,E)-3-hydroxy-4,6-dimethyloct-6-en-2-yl)-10-methoxy-3,9dimethyl-1,7-dioxaspiro[5.5]undecan-2-yl)-6-methylnona-2,4-dienal.

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5.9.4 Structural Features Spiroketal spirodienal A (1) contains 1,7-dioxaspiro[5,5]undecan-5-ol and a conjugated dienone system with an interesting aldehyde group at the side chain. Spirodienal A (1) comprises the diene with (Z) configuration of the Δ4,5 double bond and (E) configuration of Δ2,3 double bond.1 It also consists of three hydroxy groups and one methoxy with a 6,6-spiroketal moiety; the structure of the spirodienal A (1) is very similar to spirangien A.1–3

5.9.5 Class of Compounds Polyketides.1,3,7

5.9.6 Pharmaceutical Potential Spiroketal spirodienal A (1) displayed moderate antifungal activity against Botrytis cinerea (inhibition zone at a concentration of 10 µg/8 mm disk: 12 mm), Trichophyton mentagrophyte (10 mm), Botryosphaeria dithidea (12 mm), and Sclerotinia sclerotiorum (10 mm).1 Spirodienal B showed potent cytotoxicity against human tumor cells with IC50 values ranging from 0.02 to 875.9 nM. The activity of spirodienal B was higher than 4000 times stronger compared to doxorubicin as a reference in terms of IC50, against human tumor cells, such as HCT-15.4 Spirodienal C exhibited moderate antifungal activity against Botrytis cinerea, Sclerotinia sclerotiorum, Botryosphaeria dithidea, and Trichophyton mentagrophyte.5

5.9.7 Conventional Approach Optically active spirodienal A (1) was isolated from the myxobacterium Sorangium cellulosum KM0141 as colorless oil having molecular formula C32H54O7 by combined HRESIMS and 13C NMR spectrometry, named spirodienal (1).1 It indicated six degrees of unsaturation from the molecular formula. Ahn et al. isolated cytotoxic spirodienal B from culture extracts of S. cellulosum in 2009 bearing molecular formula



Spirodienal A    429

C33H56O7.4 The same investigator also isolated spirodienal C (molecular formula C32H54O7) from myxobacterium Sorangium cellulosum bearing a specific rotation of +34.2°.5 Paterson et al. achieved the first total synthesis of cytotoxic (–)-spirangien A through a highly convergent and flexible synthetic protocol. The total synthesis of polyketide (–)-spirangien A includes the application of Stork–Wittig olefination along with Stille cross-coupling transformations to install the sensitive side chain, leading initially to the more stable methyl ester of spirangien A.6

5.9.8 Demerits of Conventional Approach No conventional approach is available for the total synthesis of spirodienal A (1).7

5.9.9 Key Features of Total Synthesis Under Flow Chemistry The key feature of the total synthesis of natural spirodienal A (1) consists of constructing a building block homoallylic alcohol; it was easily available in multigram quantities through a short flow sequence. Besides, the highlight of this study reveals the formation of the two complex coupling fragments, aldehyde and bis-alkyne, by the effective use of flow technologies. It is interesting to be noted that about 70% of the total synthesis steps were carried out by flow chemistry mode.7

5.9.10 Types of Reactions C–C and C–O bond formation and more under flow chemistry.7

5.9.11 Synthetic Strategy Under Flow Chemistry Wittig reaction, protecting group switch, reduction, crotylation, and more.7

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5.9.12 Synthetic Route In 2014, Ley et al. accomplished syntheses of natural bioactive spiroketal spirodienal A (1) for the first time and spirangien A methyl ester (2) using flow chemistry as major steps through a divergent and conceptually novel approach that integrates batch and flow chemistry.7 The authors initiated syntheses with 2,3-butane diacetal-protected aldehyde (3) to afford a key building block homoallylic alcohol (8) in multigram quantities through a short flow sequence. Initially, the starting material (3) reacted with ylide (4) to provide alkene (5) in 95% yield involving Wittig reaction, and then, hydrogenation of (5) delivered alkane (6) in above 99% yield (Scheme 5.9.1). Dioxolan compound (7) was obtained in excellent yield (above 99%) from an alkane (6) via protecting group switch; methyl ester (7) generated homoallylic alcohol (8) in 78% yield utilizing a telescoped reduction–crotylation protocol finally. All steps for the formation of an important building block (8) from the starting material (3) were performed through flow chemistry. Two state-of-the-art fragments aldehyde (20) and bis-alkyne (29) bearing the same three contiguous stereocenters were prepared from building block homoallylic alcohol (8). The syntheses of two complex coupling fragments aldehyde (20) and bis-alkyne (29) were started with a telescoped silylation–ozonolysis sequence from an olefin (8).

Scheme 5.9.1.    Synthesis of building block homoallylic alcohol using flow chemistry.



Spirodienal A    431

(iv)

Scheme 5.9.2.    Synthesis of the aldehyde fragment 20 using flow chemistry.

The preparation of former fragment aldehyde (20) was finished in 13 steps (9 in flow and 4 in batch) with 11.6% overall yield and later fragment bis-alkyne (29) was completed in 8 steps (7 in flow and 1 in batch) with 22% overall yield from key homoallylic alcohol (8) (Schemes 5.9.2

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Scheme 5.9.3.    Synthesis of the bis-alkyne 29 using flow chemistry.

and 5.9.3). The improvement of a number of novel protocols involving automated reagent addition, ozonolysis, silylations, olefinations, crotylations, and oxidations in flow is needed for completing these advanced two fragments’ syntheses. Traditional acid-catalyzed spiroketalization was employed for the preparation of the spiroketal



Spirodienal A    433

fragment in which the linear precursor was synthesized from an aldol reaction.8 Bis-alkyne (29) was coupled with an aldehyde (20) to produce the crucial spiroketal intermediate (30) in moderate yield over several steps including gold-catalyzed spiroketalization as a key step. The targeted natural product spirodienal A (1) was prepared from intermediate (30) in a three-step sequence involving a Sonogashira reaction, a mixedmetal cis-selective reduction, and allylic oxidation (Scheme 5.9.4). Finally, the synthesis of spirangien A methyl ester (2) was also finished

(vii) (viii) (ix) (x) (xi) (xii) (xiii)

Scheme 5.9.4.    Total syntheses of spirodienal A and spirangien A methyl ester using flow chemistry.

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from the key spiroketal intermediate (30), utilizing silyl protection of the hydroxy groups and subsequent iodination as major steps.

References 1. Ahn J-W. (2009) Spirodienal, a new spiroketal from Sorangium cellulosum. Bull Korean Chem Soc 30: 742–744. 2. Seto H, Otake N. (1982) The 13C-NMR spectra of polyether antibiotics and some empirical rules for structural studies of polyether antibiotics. Heterocycles 17: 555–580. 3. Niggemann J, Bedorf N, Florke U et al. (2005) Spirangien A and B, highly cytotoxic and antifungal spiroketals from the Myxobacterium Sorangium ­cellulosum: Isolation, structure elucidation and chemical modifications. Eur J Org Chem 2005(23): 5013–5018. doi.org/10.1002/ejoc.200500425. 4. Kwak JH, Ahn J-W. (2009) A new cytotoxic spiroketal from the Myxobacterium Sorangium cellulosum. Arch Pharm Res 32: 841–844. 5. Ahn J-W. (2009) Spirodienal C, a New spiroketal produced by Sorangium cellulosum (Myxobacteria). Bull Korean Chem Soc 30: 1218–1220. 6. Paterson I, Findlay AD, Noti C. (2008) Total synthesis of (−)-spirangien A and its methyl ester. Chem Commun 6408–6410. doi.org/10.1039/B816229H. 7. Newton S, Carter CF, Pearson CM et al. (2014) Accelerating spirocyclic poly­ ketide synthesis using flow chemistry. Angew Chem Int Ed 53: 4915–4920. 8. Battilocchio C, Baxendale IR, Biava M et al. (2012) A flow-based synthesis of 2-aminoadamantane-2-carboxylic acid. Org Process Res Dev 16: 798–810.

Chapter 10

Zephycarinatines 5.10.1 Natural Source Zephyranthes carinata (family: Amaryllidaceae).1

5.10.2 Structure

5.10.3 Systematic Name (3S,4aS,6aS,13bS)-7-isopentyl-3-methoxy-5-methyl-3,4,4a,5,6a,7-hexahydro[1,3]dioxolo[4,5-g]indolo[3,3a-c]isoquinoline-6,8-dione (1a). (3S,4aS,6aS,13bS)-3-methoxy-5,7-dimethyl-3,4,4a,5,6a,7-hexahydro[1,3]dioxolo[4,5-g]indolo[3,3a-c]isoquinoline-6,8-dione (1b).

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5.10.4 Structural Features Alkaloid zephycarinatines include a 6,6-spirocyclic core structure having multiple stereogenic centers.1 The skeleton of the plicamine-type alkaloids zephycarinatines C (1a) and D (1b) contains carbonyl, methylenedioxy functionalities bearing the 10bS absolute configurations based on the ECD spectra of zephycarinatines C (1a) and D (1b); they display positive Cotton effects at 208 and 225 nm suggesting their absolute configurations.1

5.10.5 Class of Compounds Plicamine-type alkaloids.1

5.10.6 Pharmaceutical Potential The inhibitory activities of natural alkaloid zephycarinatines C (1a) and D (1b) and their synthetic derivatives were evaluated on NO production by LPS-stimulated RAW264.7 cells. Zephycarinatines C and D did not display significant inhibitory activities at 30 µM. However, the synthetic derivative bearing a keto group exhibited moderate inhibitory activity against LPS-induced NO production; the synthetic cyclic product (5) showed dose-dependent inhibition of NO production with IC50 = 65.3 µM.2 As a structural analog, zephygranditines show cytotoxic activities against a variety of cancer cell lines and anti-inflammatory activities.3

5.10.7 Conventional Approach Zephycarinatines C (1a) and D (1b) were isolated from the whole plants of Zephyranthes carinata in 2017 as colorless, viscous liquids having their molecular formulas C23H28N2O5 and C19H21N2O5, respectively.1 Ohno et al. disclosed the first total synthesis of zephycarinatines C and D using flow chemistry.2

5.10.8 Demerits of Conventional Approach No conventional approach is available for the total synthesis of zephycarinatines C and D.2

Zephycarinatines    437

5.10.9 Key Features of Total Synthesis Under Flow Chemistry The basic features of the total synthesis of zephycarinatines C (1a) and D (1b) comprise the stereoselective reductive radical ipso-cyclization utilizing visible-light-assisted photoredox catalysis as well as a con­ tinuous flow reactor that permitted for efficient conversion.2

5.10.10 Type of Reaction C–C bond formation under flow chemistry.2

5.10.11 Synthetic Strategy Under Flow Chemistry Stereoselective radical ipso-cyclization.2

5.10.12 Synthetic Route In 2020, Ohno and co-workers accomplished the total synthesis of the plicamine-type alkaloids zephycarinatine C (1a) and D (1b) from carboxylic acid (2) through a non-biomimetic strategy involving flow chemistry for the development of scale-up synthesis.2 The starting material biphenyl carboxylic acid (2) was effective to furnish key precursor (3) over two steps; the relative configuration of important precursor (3) was established by X-ray crystallography. The oxazolidine substrate (3) provided the desired hemiaminal (4) bearing the potential to govern the chiral center at the α-position through the key radical ipsocyclization reaction. Treatment of the oxazolidine substrate (3) in MeCN with K2CO3 as a base in the presence of the photoredox catalyst [Ir{dF(CF3)ppy}2(dtbpy)]PF6 using two 40 W LED bulbs delivered the targeted spiro-compound (4) in 58% yield via a batch reactor (Scheme 5.10.1). This key reaction was also performed by a continuous flow reactor that allowed for effective transformation, mainly by enhancing the irradiation efficiency of the reaction mixture than batch processing (Scheme 5.10.1). The flow chemistry method produced the desired product (4) in 48% yield, but it needs a lower time than the batch chemistry method (24 h vs 4 h). The bioactive synthetic cyclic product (5)

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Scheme 5.10.1.    Total synthesis of zephycarinatines C and D using flow chemistry.

was obtained from spiro-compound (4) over two steps. Finally, the synthesis of the plicamine-type alkaloids zephycarinatines C (1a) and D (1b) was completed from the cyclic product (5) elegantly.

References 1. Zhan G, Zhou J, Liu J et al. (2017) Acetylcholinesterase inhibitory alkaloids from the whole plants of Zephyranthes carinata. J Nat Prod 80: 2462−2471. 2. Takeuchi H, Inuki S, Nakagawa K et al. (2020) Total synthesis of zephycarinatines via photocatalytic reductive radical ipso-cyclization. Angew Chem Int Ed 59: 21210–21215. 3. Wang HY, Qu SM, Wang Y et al. (2018) Cytotoxic and anti-inflammatory active plicamine alkaloids from Zephyranthes grandiflora. Fitoterapia 130: 163–168.

Index

A α-cleavage, 285 α-diazoketone, 413 α-methoxylation, 417 α-pyrone, 143–144 1,5-anti aldol coupling, 405 acetylcholinesterase (AChE) inhibitor, 30, 33 Achmatowicz rearrangement, 215 Actinoplanes deccanensis, 147–148 Actinopyga echinites, 129–130, 132 acyloin condensation, 58, 181 aeruginosin 298-A, 3, 5 aeruginosin 98-B, 3, 5 Alder-ene reaction, 31–32 alkaloid, 42, 192, 210 alkenylamines, 349 Alliacol A, 321–322 allylic alcohol, 216, 258, 266 allylic amination, 247 allylic oxidation, 433 Alzheimer’s disease, 30, 33, 256, 261, 386 Amanitaceae, 111 Amanita phalloides, 111–115 Amaryllidaceae, 29, 277 Amaryllidaceae alkaloid, 29

ambient temperature, 296, 327 ambiguine H, 209–212 (-)-ambiguine P, 117–120 amebic dysentery, 348 aminocyclitol, 175–178 aminonitrile rearrangement, 384 analgesic, 336, 372, 375 analgesic property, 404 Anion Relay Chemistry, 19, 22 anisomycin, 347, 348 (+)-anisomycin, 348 anodic coupling, 373–376 anodic cyclization reaction, 323–324, 346 anodic oxidation, 324, 327, 334, 345, 349–350, 355, 361–362 antiacetylcholinesterase activity, 84 antibacterial activity, 42, 124, 148, 157, 256, 288 antiviral activity, 91, 94, 186, 310, 334, 350, 404 antibiotic, 63, 123, 150, 166, 220, 306, 348 antibiotic CJ-16, 264, 123–127 antibody-drug conjugates (ADC), 115 anti-Bredt compound, 58 anticancer property, 278, 336 439

440  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

antidepressant, 170 antifeedant property, 284 antifertility properties, 382 antifungal activity, 130, 252, 428 anti-HIV activity, 273, 306, 310, 333 anti-HIV-1 activity, 78, 198 anti-inflammatory activity, 12, 192, 261, 296 antimicrobial activity, 118, 322 antimitotic activity, 46 antimitotic natural product, 105 antimycotic effects, 422 antineuroinflammatory activity, 398 antioxidant, 15, 335, 422, 426 anti-proliferative activity, 12, 14, 99, 104, 189 antitubercular activity, 142–143 antitumor, 104 antitumor activity, 70, 180, 360 antitumor antibiotics, 126 antitumor property, 288 antiviral, 404 Apocynaceae, 57, 61, 179, 183, 245, 381 Archangiaceae, 97 Archangium gephyra, 97 arene–epoxide, 279 argininol fragment, 5 aspergillide A, 213–217 Aspergillus ostianus, 213 Aspidosperma macrocarpon, 57, 179 Asteraceae, 35, 37, 40, 295 asymmetric allylations, 215, 404 asymmetric allylic alkylation, 6 asymmetric allylic cycloaddition, 337 asymmetric Diels–Alder cycloaddition, 84, 170, 257–258 asymmetric Heck transformation, 160 asymmetric Keck allylation, 20 asymmetric oxidative dimerization, 337–338 asymmetric Strecker synthesis, 46

atom economy, 53, 79 atom transfer radical addition, 216 atropisomeric indoloterpenoid, 332 aza-Cope/Mannich reaction, 227 aza-quaternary center, 227 azaspirolactam, 227 aza-Wittig thiazole ring closure, 65 B β-carbolines, 307, 334 β-selective glycosidation, 91–92 β-site amyloid-cleaving enzyme 1 (BACE1), 386 β-valienamine, 176 1,2-biradical, 317 1,4-biradical, 317 9-borabicyclo[3.3.1]nonane (BBN), 212 4-bromoindole, 212, 368, 389 Bacillus brevis, 342 Baeyer–Villiger oxidation, 13 Baker–Venkataraman rearrangement, 257 Barbier reaction, 73, 149 Barbier-type reaction, 72–73, 105–106 batch chemistry method, 437 batch reactor, 437 Bergamotane sesquiterpene, 410–411, 413 Bestmann ylide, 193–194 beta-amanitin, 113 bicyclic octapeptide α-amanitin, 111 bicycloazaoctane system, 381 bicyclo[3.1.1]heptane, 409, 411 bicyclo[3.3.1]-nonane core, 172 bicyclo[3.2.1]octadienone, 362 bioactive natural products, 7–8, 99, 101 bioactive polyketide, 73 Bionectriaceae, 239 Birch conditions, 178

Index    441

bis-alkyne, 430 Bischler–Napieralski reaction, 31 bislactones, 337–338 bisnaphthospiroketals, 288 bisnortriterpenoid, 198 bisoxazole ester, 407 bis-styrenyl intermediate, 425 blood–brain barrier (BBB), 30 blue LED light, 229, 316 brown hydroboration–oxidation, 413 Buchwald–Hartwig amination, 387 Bulbophyllum odoratissimum, 11 buprenorphine, 372 C 2-carboxy-6-hydroxyoctahydroindole (Choi) core, 4, 9 cagelike heptacyclic skeleton, 181 camphor sulfonic acid, 418 Candida albicans, 118, 210, 343 carbamate, 301, 328, 367 carbazole, 305–310, 332–334, 387, 389 carbazole nucleus, 305 Carreira strategy, 314 (R)-carvone, 310 (S′)-carvone, 119 (S′)-(+)-carvone, 343 cascade reaction, 53–54, 236, 361–362 Casuarinaceae, 89 Casuarina stricta, 89, 91 Catalpa speciosa, 283–284 (+)-catharanthine, 382, 384 C–C bond formation, 7, 37, 53, 72, 79, 86, 216, 221, 223, 241, 248, 266, 308, 323, 337, 344, 355, 361, 373, 382, 393, 399, 423, 437 C5-epi-isomer, 237 C7-epimer, 315 C–H activation, 20, 142, 199, 307, 387

Chalinidae, 41 Cham–Evans–Lam coupling, 423 C–H amination, 388–389 C(sp2)–H cross-coupling, 355 chemical messenger, 416 C(sp3)–H functionalization, 267–269, 316–317, 388 C–H hydroxylation, 280 chiral amine catalyst, 411 chiral cyclopropane, 193 chiral pool, 6, 142, 308, 337, 343 chiron approach, 30, 392 chloronitroso cycloaddition, 279 chlorophyll, 236 cholesterol biosynthesis, 316 Cinachyrella enigmatica, 17–18 cis-decalin, 254 cis-fused bicycle, 317 cis-fused cyclobutanone, 268, 316–317 cis-grossamide, 398 citraconic anhydride, 274 (+)-citronellal, 236 (R)-citronellal, 126 (S′)-(-)-citronellal, 234 Claisen rearrangement, 53, 170–171, 367 clasto-lactacystin, 265 C–N bond formation, 25–26, 114, 204, 211, 228, 327, 349, 367, 388 cobalt-mediated Nicholas alkylation, 119 C–O bond formation, 13, 92, 235, 258, 285, 289, 296, 316, 411, 417, 429 colon cancer cell lines, 70, 104 colorectal cancer (CRC) activity, 58, 180 convergent approach, 257, 404 Cope rearrangement, 142, 160 Coprinus heptemerus, 341, 343 Corey–Bakshi–Shibata (CBS), 137

442  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Corey–Fuchs homologation, 413 coronaridine, 381–384 cotton effects, 436 coupling constant, 272 coupling product, 243 coupling reaction, 30, 32, 113–114, 149, 177–178, 242–243, 274, 288, 355–356 crotylation, 142, 429–430, 432 C–S bond, 161 C–Sn bond formation, 105–106 Curtius rearrangement, 71, 227 cyanobacterial alkaloid, 118 cyclization reaction, 79, 187–188, 215, 323, 437 cycloaddition reaction, 31, 38–39, 118, 257, 281 [4+3] cycloaddition reaction, 118 cycloartane triterpenoid, 77, 198 cyclodehydration, 407 cyclopentadienylcobalt dicarbonyl [CpCo(CO)2], 199 cyclopropanation reaction, 7–9, 181–182 cyclotrimerization, 199 cytotoxic, 18–20, 46–48, 71–72, 98, 124, 176, 186, 202, 204, 214, 217, 240–242, 322, 326, 343, 354, 356, 392, 394, 422, 428–429, 436 cytotoxic activity, 176, 186, 354 cytotoxicity, 13, 36, 42, 70, 154, 215, 220, 234, 240, 278, 386–387, 427 cytotoxic peptide, 46, 202, 204, 326 cytotoxic properties, 47, 214 D 6-deoxygeigerin, 35–39 Danishefsky’s protocol, 212 DBU-assisted epoxide opening, 285 death-cap mushrooms, 111 decarboxylation reaction, 137

decarboxylative aldol condensation, 138 dehydrogenative indole synthesis, 355–356 dehydroprenylchalcone type, 256 deprotection protocol, 44 deprotection reaction, 20–21, 32, 59, 66, 100–101 desilylation, 173, 267 desilytion reaction, 172 Dess–Martin periodinane oxidation, 43, 265, 345 desulfonation reaction, 125, 161 desulfonylation reaction, 43 D-Hpla-D-Leu-L-Choi-Agma, 6 D-hydroxyphenyllactic (Hpla) subunits, 4, 7 diastereoselective Heck cyclization, 345 diastereoselectivity, 85–86, 138, 177, 322, 345, 384 Diazonidae, 325 DIBAL-H, 407 Dictyodendrilla verongiformi, 385–386 Dictyodendrillidae, 385 dictyodendrin B, 385–389 dicyclohexylammonium salt, 171 Dieckmann condensation, 227 Dieckmann cyclization, 235 Diels–Alder cycloaddition reaction, 31, 257 Diels–Alder/Schmidt reaction sequence, 85 digold photoredox, 249 dihomoallylalcohol, 8 dihydrobenzofuran moiety, 398 (+)-dihydropinidine, 24–26 dihydrostilbenes, 11–14 4,5-dihydroxyisoleucine (DHIL), 115 diketopiperazine intermediate, 241 dimethyldioxirane (DMDO), 265

Index    443

3-(4,5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT), 12 dioxolan compound, 430 1,3-dipolar cycloaddition, 136, 192–193, 226, 247 1,4-diradical, 268, 302 diterpene, 141–144, 342, 344 diterpenoid, 143, 153–156, 252, 332, 342–343, 360, 362–363 dixiamycin B, 307, 331–334 D-noviose, 148 double-allylation strategy, 37 D-quinovose (Qui), 130 drimentines, 219–223 D-xylose (Xyl) unit, 130 DZ-2384, 325–328 E 6π-electrocyclization/aromatization, 198, 306, 309 6-endo-dig carbocyclization, 171 5-endo-trig cyclization, 367 6-endo-trig cyclization, 54 6-exo-trig radical spirocyclization, 249 eastern hemisphere, 19, 78 ECD spectrum, 332 electrochemical amination, 367–368 electrochemical cell, 417 electrochemical oxidation, 307, 333, 344 electrochemical oxidative dimerization method, 333, 361–362 electrochemical protocol, 338 electrochemistry, 323–324, 327–328, 333–334, 337–338, 344–345, 349, 355, 361, 367–368, 373, 375, 416, 418 electrolysis substrate, 328, 338, 349 enamide photocyclization, 279

enantioselective, 30, 42–43, 53, 71, 84–86, 99, 112–113, 124–125, 138, 142, 149–150, 155, 162, 171, 173, 177, 199, 210, 214–215, 227, 240, 247, 252–253, 257–259, 265, 273, 288–293, 301, 307, 314, 336, 343, 374, 398, 405, 410–411, 413 enantioselective synthesis, 112, 138, 240, 288, 374 (-)-englerin A, 135–139 enigmazole A, 17–22 ent-kaurane diterpenoid, 153–154, 252, 360 enzyme-mediated oxidative dimerization, 399 (R)-epichlorohydrin, 301, 407 (S′)-epichlorohydrin, 25 (-)-epidihydropinidine, 23–27 equisetin, 235, 237 (+)-erogorgiaene, 141–145 Eschenmoser-Tanabe fragmentation, 362 Escherichia coli, 124, 210 ester hydrolysis reaction, 167 ethyl pyruvate, 167 eudesmin, 335–338 eugeniin, 90–91 Euphorbiaceae, 135, 191 Evans asymmetric aldol reaction, 273 Evans catalyst, 85 Evans’ oxazolidinone, 46 F [3.3.0]furofuranone scaffold, 391 fermentation process, 100 Ferrier carbocyclization, 177 ferulic acid, 399 feruloyl tyramine, 397 fidaxomicin, 147–151 Fischerella ambigua, 117–118 Fischerella sp., 209–210 Fletcher’s protocol, 254

444  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

flow chemistry, 7, 105, 113, 119, 177, 193, 379, 382–383, 387–389, 393–394, 399, 405–408, 410–413, 416–417, 423, 429, 430–434, 436–438 flow electrochemistry, 416–419 flow methods, 423 flow-photochemistry, 394 (-)-FR901483, 225–232 fragmentation cascade, 210, 212 fragmentation reaction, 382 Friedel–Crafts alkylation, 240 fungal metabolite, 234–236, 314, 316, 410 fungus CL39457, 123–124 furanofurone bicyclic skeleton, 392 (+)-fusarisetin A, 233–237 Fusarium sp. FN080326, 233–234, 237 G galanthamine, 29–32 Galanthus woronowi, 29 γ-amino butyric acid (GABA), 30 γ-hydrogens, 268 Garegg–Samuelsson reaction, 177 Geigeria aspera, 35–36, 39 geigerin, 35–39 geigerin acetate, 37 geminal difluoro analog, 231 Geum japonicum, 89 (-)-glaucocalyxin A, 153–156 Gliocladium roseum, 239–240 glycolic acid synthons, 315 glycosidase inhibitory activity, 348 gold-assisted alkoxycyclization, 405 gold-catalyzed cascade, 20 gold-catalyzed spiroketalization, 433 goniofufurone, 391 (+)-goniofufurone, 392–395 Goniothalamus giganteus, 391 Gorgoniidae, 141

green chemistry, 20, 72, 198, 215, 228, 265, 273, 289, 315, 322, 382, 387 green methodology, 38–39, 131, 229, 274, 344 green technique, 119, 155, 204, 276, 324, 327, 356, 394, 410 green tool, 7, 9, 44, 46, 52–53, 60, 73, 79, 101, 105, 113, 119, 125, 131, 137, 143, 154, 176–177, 181–182, 193–194, 198–199, 216, 221, 223, 248, 252, 273–274, 297 Grignard reagent, 20, 72, 106, 149, 198 grossamide, 397–400 growth inhibitory 50% (GI50), 18, 104, 202 Grubbs catalyst, 150 guanacastepene E, 341, 343–345 H 1-hydroxy-7-azabenzotriazole (HOAt), 205 haemolytic property, 343 (-)-halenaquinone, 159–162 half-maximal effective concentration (EC50), 78 haliclonin A, 41–44 halodecarboxylation, 354 hapalindole-related alkaloid, 117, 120 Hapalosiphonaceae, 209 harzianic acid, 165–168 Heck reaction, 137, 344, 367 Heck-type annulation/aromatization, 307 Hemiasterella minor, 45–49 Hemiasterellidae, 45 hemiasterlin, 45–49 hennoxazole A, 403–408 (-)-heptemerone B, 341–346 hetero-Diels–Alder, 19, 297

Index    445

hexafluoroacetylacetone [Cu(hfacac)2], 182 1H–1H COSY spectrum, 264 hippacine, 353–354, 356–357 histone deacetylase (HDAC) activity, 160 holostane, 130–131 Holothuriidae, 129 holothurin A2, 129–132 homoallylic alcohol, 429–431 homo-veratrylamine, 374 Horner–Emmons reaction, 192 Horner–Emmons–Wadsworth reaction, 324 Horner reaction, 13 Horner–Wadsworth–Emmons transformation, 167 horseradish peroxidase, 400 human cancer cell lines, 12–14, 220 human lung carcinoma, 392 Hünig’s base, 399 hybrid isoprenoid, 220–221, 223 hydroaminoalkylation method, 229 hydroazulenone, 38–39 hydroboration/Suzuki coupling, 333 hyperforin, 169–173 Hypericaceae, 169–173 Hypericum perforatum, 169–170 Hypocreaceae, 165, 225 I iboga-type alkaloid, 381 immunosuppressant property, 226 immunosuppressive activity, 154, 226 indolo-sesquiterpene, 332, 334 indotertine A, 219–223 influenza A viruses, 90, 422 influenza B viruses, 422 inhibitory concentration (IC50), 5, 24, 42, 58, 64, 71, 84, 90–91, 98, 104, 278, 288, 296, 300 inhibits acinar morphogenesis, 234

insecticide, 53 intermolecular C-H alkynylation, 266 intermolecular Diels–Alder reaction, 58, 143, 180 internal ketalization, 315 intramolecular Alder-ene (IMAE), 31 intramolecular aldol reaction, 227 intramolecular amidation, 241 intramolecular cross-coupling reaction, 355 intramolecular [3+2] cycloaddition, 59, 180 intramolecular [4+2]-cycloaddition, 85 intramolecular [4+3] cycloaddition, 136 intramolecular cyclopropanation, 58, 171, 181–182 intramolecular Diels–Alder reaction (IMDA), 58, 181, 155, 180, 234–235 intramolecular Friedel–Crafts transformation, 142 intramolecular Heck reaction, 344, 367 intramolecular Heck transformation, 280 intramolecular 1,5-hydrogen shift, 291 intramolecular Mitsunobu reaction, 187 intramolecular photoredox reaction, 290 intramolecular radical cyclization, 79 intramolecular Schmidt reaction, 227 Irciniidae, 69 Ir[dF(CF3)ppy]2(dtbbpy)PF6, 384 Ireland–Claisen rearrangement, 199 iridoid, 283–285 [Ir(ppy)2(dtbbpy) PF6], 223 isoharzianic acid, 166–168 isonitrile-promoted prenylation, 210

446  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

J Jungermannia atrobrunnea, 251–252 Jungermanniaceae, 251 (+)-jungermatrobrunin A, 251–254 K kalbretorine, 353–356 kalbretorine precursor, 356 KB nasopharyngeal carcinoma, 12 ketal Claisen rearrangement, 53 Khaya senegalensis, 51–52, 54 khayasin, 51–54 kirkamide, 175–178 kopsane alkaloids, 59–60 kopsanone, 57–60, 179–182 Kopsia, 58–59, 180–182, 245–247 Kopsia grandifoli, 245–246 kuwanon I, 256 kuwanon J, 256 L Labiatae, 153, 359 lactacystin, 263–268 Lamiaceae, 153 lanosterol, 131 laudanosine derivatives, 373–374 L-carvone, 79 LED irradiation, 216, 317 leishmanicidal activity, 192 Lemieux–Johnson oxidation, 43 lethal concentration 50 (LC50), 31, 70 lethal dose 50 (LD50), 214, 266, 361 leukamenin F, 153–156 leukemia cell line, 42, 70, 202 lignans, 336–338 Lipshutz’s micellar Negishi coupling, 215 lithiation/borylation methodology, 142 lithium bis(trimethylsilyl)amide (LiHMDS), 138, 162 Litsea verticillata, 271, 273, 276

litseaverticillol A, 274 litseaverticillol D, 272, 276 litseaverticillol E, 272, 276 longest linear sequence, 19, 47, 78–79, 132, 150, 167–168, 289, 345, 405, 407 Lophiostomataceae, 409 L-tert-leucine, 327–328 L-tyrosine, 5, 84, 229 luotonin A, 185–188 luotonins B and E, 186 Lycoris radia, 29, 277–278, 281 Lycoris radiata HERB, 278 lymphocytic leukemia cell (L1210), 214, 240 M 12-membered macrocycles, 325 12-membered macrolactone, 214 26-membered macrolide, 125 macrocyclic bisbibenzyl, 422–423 macrocyclic diamide alkaloid, 41 macrocyclic peptide, 326 macrocyclization, 66, 106, 150, 328, 425 macrolactone/thiolactone, 65 macrolide, 18–21, 104–105, 148–149, 214–215 macrolide antibiotic, 148 magic bullet, 46 Mannich-type process, 59 Marasmiaceae, 321 Marasmius alliaceus, 321–322 marine alkaloid, 211, 239–241, 386 marine antitumor agent, 69 marine macrolide, 18–20 marine metabolite, 18, 131 marine peptide, 47 marine products, 9 marine sediment, 64 marine sponge, 18, 21, 41–42, 69–70, 159–160, 201, 386

Index    447

Martin’s sulfurane, 310 Massarina tunicata, 409–411, 413 massarinolin A, 410 MCF-7 breast cancer cells, 98 mean growth inhibitory 50%, 18 median effective concentrations (EC50s), 36 median effective dose (ED50), 226, 314, 416 Meerwein-like reduction, 265 Meliaceae, 51 MeNO2–HFIP–LiClO4 system, 355–356 meroterpene, 170 methicillin-resistant Staphylococcus aureus (MRSA), 64, 91, 343 methylene blues, 274 methyl-N-acetyl-D-glucosamine, 177 mexicanolide, 52–55 Michael addition reaction, 86 Michael-type addition, 7 microbial product, 266 Microcystaceae, 3, 6 Microcystis aeruginos, 3, 5–6 Micromonosporaceae, 147, 299 microwave irradiation, 105, 113–114, 119–120, 125–126, 130–132, 137–138, 143–144, 149–150, 154–155, 161–162, 166–168, 171–172, 176–178, 181–182, 187–188, 193–194, 199, 203–205, 241, 248, 273–279 microwave precursor aldimine, 188 minimum inhibitory concentration (MIC), 24, 42 Mitsunobu conditions, 93 Mitsunobu cyclization, 186 Mn(OAc)3 mediated oxidative cyclization, 155 monoamine oxidase A (MAO-A), 58, 180

Moraxella catarrhalis 87A1055, 124 morphinandienone, 374–376 morphine, 371–373, 375 morphogenesis inhibitor, 234–235 Mother Nature, 30 Mukaiyama aldol adduct, 198, 240, 405 Mukaiyama aldol reaction, 240, 405 Mukaiyama hydration, 308 N naphtha[1,8-bc]furan core, 160, 162 Narasaka–Sharpless, 280 narcotic, 372 natural limonoid, 52–53 natural tripeptide, 46 n-butyllithium, 25, 216, 266, 273 Nectriaceae, 233, 239 Negishi-type coupling, 19 neodolastane diterpenoids, 342 neolignane, 398 neomarchantin A, 421–425 neurotrophic activity, 264 N–H bond formation, 31, 43, 59, 100 Nitraria schober, 415–416, 418 nitrene intermediate, 389 (+)-N-methylanisomycin, 347, 349 N-methylmorpholine-N-oxide (NMO), 281 N-methylpipecolic acid (Mep), 98 N-methyl-1,2,4-triazoline-3,5-dione (MTAD), 281 N–N bond formation, 333 non-biomimetic strategy, 437 non-polluting source, 66, 78, 113, 120, 130, 138 norbornanone skeleton, 285 noroxycodone, 375 Norrish-type cleavage, 210 Norrish type II reaction, 301–302 Norrish type I reaction, 285

448  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Norrish–Yang cyclization, 266, 268, 316 nortriterpenoid, 77–78, 198–200 nosiheptide, 63–67 noviolysation step, 149 Nozaki–Hiyama–Kishi reaction, 410 O O–H bond formation, 20, 47, 66 olefination and nitrile hydration, 119 O-methylshikoccin, 360–361 Orchidaceae, 11 organocascade catalysis, 58, 180 ortho-selective chlorination, 289 oxetane, 142, 393–394 oxidation reaction, 13–14, 19, 59, 324 oxidative anodic cyclization, 349 oxidative Bergman cyclization, 161–162 oxidative carbonylation, 367 oxidative cyclization, 30, 155, 161, 227, 296–297 oxidative decarboxylation, 308 oxidative dimerization, 333, 337–338, 399 oxindole, 240–241 oxycodone, 372, 375–376 oxy-Cope rearrangement, 142, 361 oxy-Michael addition, 199 oxy-Michael reaction, 215 ozonolysis, 125, 430, 432 P Parikh–Doering oxidation, 333 Paternò–Büchi reaction, 393–394 payload linkers, 115 Pd-mediated deracemization, 42 Peganum nigellastrum, 185 pentacyclic scaffold, 117, 305 peptide, 4–7, 46–49, 202–205 peptide-based macrocycle, 326

peroxide bridge, 254 pesticidal activities, 300 Petasis–Ferrier union/rearrangement, 19 pharmaceutical molecules, 8 pharmacokinetics, 326 phase-transfer catalyst, 186 phenanthrene skeleton, 371 phenanthridone alkaloid, 278, 280, 353–355 phenonium-type rearrangement, 47 phorbol ester, 366 phosphonate ester, 324 photo-assisted benzannulation, 308 photocatalyst, 237, 384 photochemical isomerization, 216 photochemical 6π-electrocyclization, 387 photochemical Wolff rearrangement, 410–411, 413 photocyclization, 279, 308, 310 photocyclization/desulfonylation, 310 photo-Fries rearrangement, 362 photogenerated singlet oxygen, 376 photoinduced oxidation, 274 photoredox cyclization, 248 photosensitizer, 236, 258, 274 photosubstrate, 290 Phyllanthus discoides, 191–192 Phyllanthus engleri, 135, 191–194 phyllantidine, 194 Picea engelmannii, 23 Pictet-Spengler reaction, 416–418 Pinaceae, 23 (-)-pinidinone, 24–27 Pinnick oxidation, 143, 307–308, 310 Pirrung–Heathcock antialdol conditions, 264 platelet-activating factor (PAF), 154, 336 plicamine-type alkaloids, 436–438 Polyangiaceae, 427

Index    449

polycyclic polyprenylated acylphloroglucinol (PPAP), 169–170 Polyfibrospongia sponge, 403 polyketide, 70, 72–73, 104, 159–162, 313–315, 428–429 polymer-assisted hydroxybenzotriazole, 399 polypeptidic antibiotic, 63–64 polyphenol, 90–91, 93, 256 positive Cotton effect, 332, 436 pratorimine, 353–354, 356–357 pratorinine, 354 prenyl chalcone, 258–259 proceranolide, 53–54 protection/deprotection, 248 proteolytic activity, 264 Psammocinia sp., 69 Psathyrellaceae, 341 pseudobenzylic positions, 366 pseudodisaccharide, 300 Pseudomonas fluorescens, 342 Pseudopterogorgia elisabethae, 141 pseudosugar, 299–300 (-)-pseudotabersonine, 383–384 (-)-pseudovincadifformine, 383–384 Psychotria kirki, 175–176 psymberin, 69–74 Pummerer rearrangement, 170 pyran synthon, 404 pyridinium chlorochromate (PCC), 248 (S′)-pyroglutaminol, 266 pyrrolizidinone skeleton, 124–125 pyrroloazocine, 246, 248 pyrrolo[2,3-c]carbazole scaffold, 386 pyrrolo[2,3-c]carbazole skeleton, 387 pyrroloindolines, 181, 241–242 pyrrolophenanthridone alkaloids, 353–356

R Rabdosia japonica, 153 radical 1,4-addition, 223 radical cascade reaction, 236 radical conjugate addition, 221–223 radical ipso-cyclization, 437 rapid ring-closing alkyne metathesis (RCAM), 20 reactive oxygen species (ROS), 236 reductive cyclization, 252, 386 regioselective Wacker–Tsuji oxidation, 25 reticulated vitreous carbon anode, 324 retro-Diels–Alder reaction, 37 retro-oxy-Michael, 214 Rhizopus sp. No. F-1360, 103 ring-closing alkyne metathesis (RCAM), 105 ring-closing metathesis (RCM), 19, 30, 150, 215, 247, 344 ROESY correlation, 78 Ronlan’s conditions, 338 Rosaceae, 89 rose bengal, 254, 258 RP9617, 63–67 Rubiaceae, 175 Ru(bpy)3Cl2·6H 2O, 258 S 1,3-syn reduction, 405 6,6-spirocyclic core, 436 8,9-seco-ent-kaurane, 359–363 8,9-seco-ent-kauranoids, 360, 362 saponification, 32, 47–48, 265, 343, 345, 407 Savige–Fontana methodology, 112 Schenck ene reaction, 252–253, 258 schilancitrilactone C, 77–80 Schisandraceae, 77, 197, 199 Schisandra lancifolia, 77–78 Schisandra rubriflora, 197–198

450  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Schistochila glaucescens, 421–422 ScIII-assisted regioselective ester hydrolysis, 65 scorzodihydrostilbenes B and D, 12 secondary allylic alcohol, 258 securinega, 192, 194 semisynthetic opioid, 375 semisynthetic production, 372 serotonergic activity, 416 serotonin levels, 416 sesamin, 335–338 sesquiterpene, 36–38, 136–137, 220, 272–274, 276, 284–285, 306–307, 321–324, 332, 410–411, 422 sesquiterpene lactone, 36 SGC-7901 gastric carcinoma, 12 sharpless asymmetric dihydroxylation, 315 sharpless asymmetric epoxidation, 71 Shiina conditions, 125 (-)-shikoccidin, 360 Shono oxidation, 417–418 Sigman-Heck reaction, 367 [3,3]-sigmatropic rearrangement, 20–21, 361 silylations, 432 simplex virus type 1 (HSV-1), 91 single-electron transfer (SET), 236, 290–291 singlet oxygen (1O2), 254, 274, 276, 376 Smalley’s method, 247 SNAr reaction, 423, 425 S–O bond-forming reaction, 131 Solanaceae, 397 solid-phase strategy, 204 Sonogashira coupling, 71 Sonogashira reaction, 433 Sorangium cellulosum, 427–429 specionin, 284–286 spirocycloheptadien, 301 spirocyclopentenol, 361

spirodienal A, 427–431, 433 spiroether structure, 289 spiroketal, 288–289, 428, 430, 432–434 spirolactam precursor, 228–229 spiroxins A–E, 288 squalene synthase, 314, 316 Staphylococcus aureus, 24, 64, 91, 124, 160, 343, 410 Staudinger-aza-Wittig condensation, 26 Staudinger ligation, 203 Stemona alkaloid, 84–85 Stemonaceae, 83–84 Stemona sessilifolia, 84 (-)-stenine, 83–87 stereoselective α-selenylation, 42 stereo selective epoxidation, 53, 176 Stille coupling, 150, 177, 279 Stille cross-coupling reaction, 177 Stork–Wittig olefination, 429 [5+1+2]-strategy, 112 Streptomyces actuosus 40037, 63 Streptomyces mecliocidius, 365 Streptomyces sp., 219–221, 263–264, 305–306, 331, 347 Streptomycetaceae, 63, 219, 263, 305, 331, 347, 365 strictinin, 89–94 structure-activity relationship (SAR), 99–100, 172–173, 337 styryl-lactone, 391–392, 395 substitution reaction, 25–26, 31 sulphonation, 131 superoxide anion generation, 296 sustainable chemistry, 73, 106, 326, 367, 423 sustainable technique, 327 sustainable technologies., 373 Suzuki coupling, 143, 148, 280–281, 333 Suzuki–Miyaura cross coupling, 288

Index    451

Swern oxidation, 73, 131, 176, 285, 349 Syzygium aromaticum, 89 T (+)-TAN1251C, 225, 227–231 tandem anodic coupling, 324 T-cell leukemia, 354 T-cell proliferation, 336 teleocidin B, 366–367 tellimagrandin II, 89–94 Terashima reduction, 404 terpenoid, 296 tert-butyldimethylsilyl chloride, 24 tertiary allylic alcohol, 258 Tetillidae, 17–18 tetrahydrocarbazolone, 182 tetramic acid, 166, 234–236 tetra-n-butylammonium fluoride (TBAF), 178, 288 tetranortriterpenoid, 52–53 tetrapeptides, 98 tetrapeptide formation, 204 thebaine, 371–376 thiopeptide antibiotics, 64 Thorectidae, 403 thymarnicol, 295–297 Thymelaeaceae, 341 topoisomerase I, 186 topoisomerase II, 186 trans-decalin, 234–235, 254, 305, 307–308 2,6-trans-tetrahydropyran core, 72 trehalase inhibitor, 300–302 trehazolin, 299–303 tributylstannyl-methanol (Bu3SnCH2OH), 178 trichloro ethyl ester (Tce ester), 66 Trichocomaceae, 213, 225 Trichoderma harzianum, 165–166 Trichophyton mentagrophyte, 428 trioxopiperazine fragment, 240

triterpene glycoside, 130, 132 tropylium cation, 37–38 tubulin inhibitor, 104 tubulysin U, 97–101 tubulysin V, 97, 99 tubuphenylalanine (Tup), 98–99 tubuvaline (Tuv), 98–99 U Uchiyama’s conditions, 281 Ullmann coupling, 425 ultrasonication, 9, 32, 39, 44, 48, 54, 60, 66, 73, 79, 93, 101 ultrasonic irradiation, 7–9, 13, 20, 25–27, 31–32, 37–38, 47–48, 52–53, 59, 66, 125, 177, 193 ultrasound irradiation, 14, 66, 101 ultrasound sonication, 14, 21, 43, 46, 60, 66, 73, 93, 101 Umpolung methodology, 323 unconventional activation technique, 26, 32, 48, 109, 132, 162, 168, 173 unconventional technique, 155 unnatural antipode, 289–290, 404 UV light, 268, 413 V vanillin, 375 Vilsmeier reaction, 13 Vinca rosea, 381 vinylmagnesium bromide, 314 violet LED, 317 visible-light irradiation, 210–211, 221–223, 228–229, 235–236, 241–242, 248, 252–253, 257–258, 266, 273–274, 276, 280–281, 285, 289–290, 296, 301, 308, 316 visible-light-mediated, 243 W Wacker oxidation, 234, 405 Wacker-style oxidation, 393

452  Modern Sustainable Techniques in Total Synthesis of Bioactive Natural Products

Wacker–Tsuji oxidation, 25–26 Wadsworth–Emmons olefination, 422 WF-1360F, 103–106 Wieland–Miescher ketone, 161, 307, 361 (8aR)-(-)-Wieland–Miescher ketone, 161 wild-type HSV-1, 91 Wittig–Horner reaction, 12–14 Wittig reaction, 24, 43, 349, 429–430 Wittig–Still rearrangement, 405 Wittig transformation, 19 X Xestospongia exigua, 159–160 xiamycin A, 305–307, 332–334

Y Yaku’amides A and B, 202–203 Yamada–Otani transformation, 161 Yamaguchi esterification, 149–150 Yamaguchi macrolactonization, 214 yangambin, 335–338 Yuzikhin’s condition, 337 Z zaragozic acid C, 313–318 zephycarinatines C and D, 436, 438 Zephyranthes carinata, 435–436 zwitterion, 290 Zygophyllaceae, 185, 415