Recent Applications of Selected Name Reactions in the Total Synthesis of Alkaloids 0128240210, 9780128240212

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Recent Applications of Selected Name Reactions in the Total Synthesis of Alkaloids

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Recent Applications of Selected Name Reactions in the Total Synthesis of Alkaloids

Majid M. Heravi

Department of Chemistry, School of Sciences, Alzahra University, Vanak, Tehran, Iran

Vahideh Zadsirjan Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran, Iran

Elsevier Radarweg 29, PO Box 211, 1000 AE Amsterdam, Netherlands The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States Copyright Ó 2021 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-824021-2 For information on all Elsevier publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Susan Dennis Acquisitions Editor: Emily McCloskey Editorial Project Manager: Megan Ashdown Production Project Manager: Paul Prasad Chandramohan Cover Designer: Greg Harris Typeset by TNQ Technologies

Dedication To my granddaughter Teeda on the occasion of her sixth birthday.

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Contents Acknowledgments

1.

Applications of selected name reactions in total synthesis of alkaloids 1.

2.

1 7

Introduction Mechanism Applications of DielseAlder cycloaddition reaction in total synthesis of alkaloids References

11 13 14 48

Recent advances in applications of FriedeleCrafts reactions in total synthesis of alkaloids 1. 2.

4.

Introduction References

Applications of DielseAlder cycloaddition reaction in total synthesis of alkaloids 1. 2. 3.

3.

ix

Introduction Applications of FriedeleCrafts in total synthesis of alkaloids 2.1 Intermolecular FriedeleCrafts alkylation reactions 2.2 Intramolecular FriedeleCrafts alkylation reaction 2.3 FriedeleCrafts acylation reaction References

59 62 62 79 93 96

Recent advances in applications of Heck reaction in the total synthesis of alkaloids 1.

Introduction 1.1 Mechanism of Heck reaction 2. Applications of Heck reaction in total synthesis of alkaloids References

107 109 110 140

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viii Contents

5.

Recent advances in applications of Mannich reaction in total synthesis of alkaloids 1.

Introduction 1.1 Mechanism of the Mannich reaction 1.2 Asymmetric Mannich reactions 2. Applications of the Mannich reaction in total synthesis of alkaloids References

6.

194 220

Introduction Application of PicteteSpengler reaction in the total synthesis of alkaloids References

227 229 280

Introduction Mechanism Applications of the Sonogashira reaction in the total synthesis of alkaloids References

295 296 297 316

Recent advances in applications of Suzuki reaction in the total synthesis of alkaloids 1. 2. 3.

Index

191 192

Applications of the Sonogashira reaction in the total synthesis of alkaloids 1. 2. 3.

9.

Introduction Mechanism of the PausoneKhand reaction Applications of the PausoneKhand reaction in the total synthesis of alkaloids References

Applications of PicteteSpengler reaction in the total synthesis of alkaloids 1. 2.

8.

158 182

Applications of PausoneKhand reaction in the total synthesis of alkaloids 1. 2. 3.

7.

153 154 155

Introduction Reaction mechanism Applications of Suzuki reaction in total synthesis of alkaloids References

325 327 329 369 383

Acknowledgments Writing a book is harder than I thought it would be but more satisfying and gratifying than I ever could have imagined. This book would not have been possible without the endeavors and efforts of my coauthor, Dr. Vahideh Zadsirjan, to whom I am properly thankful. My thanks also extend to Miss Leila Mohammadi for helping me prepare Chapter 6, and to Miss Nazgol Zahedi, who helped design the cover page. Although this period of my life was filled with many ups and downs due to the breakout of the pandemic COVID-19, I am thankful to those who have always been able to turn to in these dark and desperate years. They sustained me in ways I never knew I needed. Finally, I appreciate the financial support of the Iran Science Elites Foundation, and my coauthor appreciates the support and encouragement received from the Alzahra University Research Council. Majid M Heravi May 2021

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Chapter 1

Applications of selected name reactions in total synthesis of alkaloids Chapter outline 1. Introduction

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References

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1. Introduction Chemistry is a fundamental, vital, and dominant science primarily oriented toward making discoveries to meet the world’s continuous and growing demand for new chemical objects. Pioneering solutions in all types of disciplines related to chemistry require thoughtful elegance in preparing new molecules with specific properties that satisfy general concerns and are also important and groundbreaking. Indeed, organic chemistry is the fundamental science lying between pharmacology and biology. In fact, its subdiscipline, so-called organic synthesis, is the state of the art in science for constructing structurally simple and complex substances whose primary element is carbon. Organic molecules contain both carbon and hydrogen. Although many organic chemicals also contain other elements, the carbonehydrogen bond is what defines them as organic. Organic synthesis derives its importance and supremacy from its aptitude and capability to analyze and synthesize molecules from atoms and other more and less complex molecules. Practical organic chemistry is paramount to our welfare, safety, and prosperity because it produces precious chemicals, molecules, objects, and materials that are often vital to our health and fitness or that may benefit literally all aspects of our daily lives. General expertise resulting from organic synthesis has inspired a host of discoveries that have provided welfare to all of society, comprising beneficial products ranging from unique, exclusive materials such as pharmaceuticals, dyes, cosmetics, and agricultural substances to diagnostics and high-technology chemicals used in computers, cell phones, and spacecraft. Nevertheless, the synthesis of new chemical materials Recent Applications of Selected Name Reactions in the Total Synthesis of Alkaloids https://doi.org/10.1016/B978-0-12-824021-2.00005-4 Copyright © 2021 Elsevier Inc. All rights reserved.

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2 Applications of Name Reactions in Total Synthesis of Alkaloids

requires not only the accurate and exact design and preparation of structural space but also economic feasibility for large-scale production; all of these pose serious challenges to the synthetic development community. Thus, in addition to the question of whether a design is possible, nowadays it is also important to know how to conduct a synthesis to achieve a low cost while complying with the principles defined for green chemistry [1]. The finest, leading, and most important subdivision in organic synthesis is total synthesis, the endeavor of synthesizing molecules that have been isolated and fully characterized from natural sources in the laboratory. In another words, total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially available precursors. It usually refers to a process not involving the aid of biological processes, thus distinguishing it from semisynthesis. Nowadays, the total synthesis of complex natural products remains among the most exciting and dynamic areas of chemical research. Undoubtedly, the capability and talent of humankind to duplicate or reproduce the molecules of living beings and generate other molecules exactly like them is an extraordinary and revolutionary development in the social and scientific history of humankind. The total synthesis of natural or designed complex bioactive molecules in several laboratories worldwide and their impact on chemistry, biology, and medicine over the last 5 decades as a result of scientific discoveries and their applications have revolutionized the art of organic synthesis vividly and historically. Its birth traces back to 1828, when Friedrich Wo¨hler (1800e1882), a German chemist, synthesized urea, which is renowned as a typical example of a compound, a so-called natural product, from the living world. He was known for his work in inorganic chemistry as the first scientist to isolate the chemical elements beryllium and yttrium in pure metallic form. He began his higher education at Marburg University in 1820 [2]. Urea and similar molecules were commonly known as natural products, a term regularly denoting secondary metabolites. As mentioned above, the first natural product synthesized in the laboratory was urea. This important discovery, albeit unanticipated, showed that in addition to the occurrence of compounds naturally, humans could build these molecules of living nature in the laboratory without the aid of vital force, living creatures, or their organs. This important miracle resulted in the collapse of vitalism and the acceptance of the phenomenon of isomerism, and this revolution in science led to an understanding and appreciation of organic synthesis. The achievement of the synthesis of urea by Wo¨hler was followed by the total synthesis of acetic acid, a natural product containing two carbon atoms (as opposed to urea’s one), by German chemist Hermann Kolbe in 1845. After that, the playing field of chemical synthesis experienced startling growth, which inspired the power to construct progressively complex and diverse molecular architectures. The artistic nature of total synthesis provided the opportunity for this discipline to be called a fine art in addition to a particular science.

Applications of selected name reactions in total synthesis Chapter | 1

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Due to extraordinary growth in the quality and quantity of different methodologies in the art of organic synthesis, especially the so-called name reactions nowadays, synthetic organic chemists have the power to replicate some of the most fascinating and interesting molecules of living nature in the laboratory and apply their developed synthetic protocols and technologies to construct a plethora of them, which are useful or even vital in large scale and have allowed the chemical industries to flourish. Some of these molecules assist and expedite biology and medicine, as they have often been beneficial as biological tools and drug candidates for clinical development. Moreover, by engaging stylish and elegant catalytic reactions and properly designed synthetic pathways, organic synthetic chemists provide not only naturally occurring compounds and their analogs but also numerous other organic compounds for applications in various spaces and ranges of science and technology that are useful to our daily lives. Total synthesis is a discipline frequently encompassing not only the dominions of technology but also the plants kingdom. It is state-of-the-art because in its practice, it stimulates the supreme potential for originality and thought. Creativity in total synthesis encompasses both the sighting and development of powerful reactions and the creation of synthetic approaches for building well-defined complex target molecules, natural or unnatural. While investigation in the former zoned synthetic methodologydfuels and permits trainings in the latter, i.e., target synthesis, the latter arena is a challenging field for the former. Combining the two parts delivers thrilling efforts that derive from anticipation, experience, and monitoring. Persistent total synthesis especially provides the most serious examination of chemical reactions, known and novel, titled and unnamed, while its overall influence and competence delivers a measure of its condition at any specified time. The relationship of total synthesis and its tools, chemical reactions, is a captivating topic regardless of whether it is read, written, or experienced. Currently, the organic chemist faces the challenge of navigating the vast body of literature that is generated daily. Papers and review articles are full of scientific terminology comprising reports of methods, reactions, and processes distinct by the names of the inventors or by a well-acknowledged phrase. A name reaction is a chemical reaction named after its discoverers or developers. Well-known examples include Kolbe’s reaction, in which phenol with sodium hydroxide gives the sodium phenoxide ion, which with carbon dioxide in acidic medium results in hydroxybenzoic acid (salicylic acid) [3], the Clemmensen reduction, in which the carbonyl group of aldehydes and ketones is reduced to the CH2 group on treatment with zinc amalgam and concentrated hydrochloric acid [4], and the WolffeKishner reduction, in which the carbonyl group of aldehydes and ketones is reduced to the CH2 group on treatment with hydrazine followed by heating with sodium or potassium hydroxide in a highboiling solvent such as ethylene glycol [5].

4 Applications of Name Reactions in Total Synthesis of Alkaloids

Other well-known reactions are the Grignard reaction [6], Wittig reaction [7], Claisen condensation [8], DielseAlder reaction [9], and FriedeleCrafts alkylation and acylation reactions [10]. Several published books have been completely dedicated to name reactions [11e13]. More importantly, the Merck Index, which is a chemical encyclopedia, includes a specific supplement of name reactions. As organic chemistry advanced and became established during the 20th century, chemists started connecting and communicating synthetically valuable, useful, and convenient reactions with the names of their discoverers or developers. On many occasions, the name is simply a reminder; in some cases, the person whose name is associated with the reaction was not the first to discover the reaction but instead managed to popularize it. In other words, some reactions were not really explored by their namesakes. Examples include the Aldol reaction [14] and Aldol condensation [15], Pummerer rearrangement, Pinnick oxidation, and Birch reduction [16]. Even though systematic methods for identification of reactions based on the reaction mechanism or overall transformation exist (such as the IUPAC Nomenclature for Transformations), the more expressive names are frequently awkward or not detailed enough, and thus discoverer names are habitually applied more on the basis of well-organized and efficient communication [17]. The use of “name reactions” plays an important role in organic chemistry. Knowing these name reactions and being indulgent of their scientific content is indispensable for enthusiastic and dedicated graduate students and devoted practical organic chemists [18,19]. Natural products are molecules produced naturally by any organism, including primary and secondary metabolites. They comprise an immense range of molecules, including very small molecules, such as urea, and complex constructions, such as paclitaxel [20]. The comprehensive definition of a natural product is anything produced by life that involves biotic substances such as wood, silk, biobased materialsdfor example, bioplastics, corn, and starch, bodily fluids such as milk, and plant exudatesdand other natural materials once found in living organisms, for example, soil and coal. A more constrictive description of a natural product is any organic compound generated by a living organism and found in nature [21,22]. The term natural product has also been extended for commercial purposes to denote cosmetics, dietary supplements, and foods produced from natural sources without supplementary artificial components. Within the realm of organic chemistry, the description of a naturally occurring compound is usually limited to organic compounds isolated from nature that are shaped by primary or secondary metabolism [23], while in the arena of medicinal chemistry, the meaning is frequently further constrained to only secondary metabolites [24]. Secondary metabolites are not truly indispensable for survival yet deliver organisms that give them an evolutionary lead [25]. Numerous secondary metabolites are cytotoxic and have been designated

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and optimized through evolution for use as “chemical warfare” agents against quarry, pillagers, and opposing organisms [26]. Although much attention has been paid to natural sources and resulted in the isolation of bioactive components as potential lead compounds in drug discovery or for commercial purposes [27] approved by the US Food and Drug Administration, drug development from nature has received diminished interest from pharmaceutical firms in the 21st century partly because of variable and undependable access and sources, intellectual property, charge and turnover worries, cycle and seasonal or environmental changeability of composition, and harm to sources due to rising loss rates [27]. Natural products chemistry is a distinct area of chemical research which is also important in the history of chemistry. As a matter of fact the sourcing of substances in early preclinical drug discovery research, started by the understanding of traditional medicine and ethno pharmacology/ Naturally occurring compounds have high structural diversity and exceptional pharmacological or biological properties due to natural selection and evolutionary processes that have formed their functions over hundreds of thousands of years. In fact, the structural diversity of natural products far exceeds the abilities of the synthetic community in the laboratory. The impact of total synthesis has also prompted discoveries in biology and medicine. Traditional medicine refers to health performance, methods, information, and principles incorporating plant-, animal-, and mineral-based medicines, mystical therapies, manual techniques, and exercises applied singularly or in combination to treat, diagnose, prevent, and cure illnesses or maintain wellbeing. In the written record, the study of herbs begins 5000 years ago with the ancient Sumerians, who described well-established medicinal uses for plants. In ancient Egyptian medicine, the Ebers Papyrus from ca. 1552 BCE records a list of folk remedies and magical medical practices. The development of experimental methods for practical chemistry and the discoveries of natural products such as urea, quinine, morphine, and strychnine in the late 18th and early 19th centuries arranged the fundamentals that provided the motivation for the development of total synthesis [28]. In fact, natural products played a decisive role in the emergence and advancement of organic synthesis from its birth to the present day. Thus, from the early days of elemental analysis and now the full characterization of natural products, these products have captivated and challenged organic chemists, initially with their structural identification and then with their total synthesis. By the beginning of the twentieth century, chemists had synthesized several natural and designed complex alkaloids, including cocaine, caffeine, nicotine, theobromine atropine, tubocurarine mescaline, serotonin, and dopamine [29]. The latter half of the twentieth century propelled striking advances in the area of synthetic methodology that drove the art of organic synthesis to higher

6 Applications of Name Reactions in Total Synthesis of Alkaloids

stages of sophistication, pragmatism, and competence. These new methodologies eased the discovery research, product development, and industrial production of pharmaceuticals and other fine chemicals that have enhanced daily life. Prior to the nineteenth century, all compounds purified from plantsdsuch as tartaric acid, oxalic acid, and tannins-exhibited acidic properties. Nevertheless, an alkaline material called potash was extracted from burnt wood and later found to encompass basic compounds of pharmacological interest. In 1806, Friedrich Wilhelm Sertu¨rner isolated, for the first time, a pure compound that showed the same pharmacological sleep-inducing properties of the crude opium extract from which this compound was isolated. In 1819, Meissner found that all these compounds displayed alkaline properties and thus proposed naming them alkaloids [30]. Any of a class of natural products containing organic nitrogen bases is called an “alkaloid.” Alkaloids have diverse and important physiological activities in humans and other animals. Well-known alkaloids comprise notorious morphine, strychnine, quinine, ephedrine, and nicotine (Fig. 1.1). Alkaloids are found primarily in plants and are particularly communal in certain families of flowering plants. Indeed, as many as one-quarter of higher plants are estimated to contain alkaloids, and several thousand different types have been recognized. Generally, a given species contains only a few kinds of alkaloids, although both the opium poppy (Papaver somniferum) and the ergot fungus (Claviceps) contain about 30 different types. In fact, alkaloids include a massive class of approximately 12,000 natural products [31]. The principal requirement for classification as an alkaloid is the presence of a basic nitrogen atom at any position in the molecule that does not involve nitrogen in an amide or peptide bond. Alkaloid-containing plants have been used by humans since ancient times for therapeutic and recreational purposes. For example, medicinal plants have been known in Mesopotamia from about 2000 BCE. The Odyssey, one of two major ancient Greek epic poems attributed to Homer (the presumed author of the Iliad and the Odyssey) denoted that a gift given to Helen by the Egyptian queen, a drug causing unconsciousness and oblivion, contained opium. A Chinese book on houseplants written in the 1st to 3rd centuries BCE declared

FIGURE 1.1 Pharmacologically important alkaloids discovered early in the history of alkaloids. Morphine, strychnine, quinine, and caffeine are shown.

Applications of selected name reactions in total synthesis Chapter | 1

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the medical use of ephedra and opium poppies. In addition, coca leaves have been used by South American Indians since ancient times. Most classes of natural products are composed of similar chemical structures in which the same starting materials come together in related biosynthetic pathways but can be implicated and realized from remarkably extensive descriptions. Thus, the alkaloids shape a group of structurally diverse and biogenically independent and dissimilar molecules, and no biochemical standard as an outstandingly clear or typical example is applied throughout alkaloid biosynthesis [32]. In fact, the biosynthetic routes of alkaloids are as diverse as the chemical structures found within this important class of natural products. Alkaloids are the oldest effectively employed drugs throughout the historical treatment of several diseases [33]. Alkaloids can be classified in terms of their chemical structures, biological activities, routes of biosynthesis, and incidence into heterocyclic and nonheterocyclic alkaloids, sometimes called protoalkaloids or biological amines. They are derived biosynthetically from corresponding amino acids and are frequently generated by a decarboxylation process. To date, six main groups of alkaloids have been documented depending on the amino acid of origin. These are the derivatives of L-ornithine, L-lysine, L-tyrosine/L-phenylalanine, L-histidine, L-tryptophan, and glycine/aspartic acid [34]. This group contains the most diverse and pharmacologically active plant-derived alkaloids, which are recognized as showing diverse biological activities even at very low doses [35]. In continuation of our interest in the applications of name reactions such as the Aldol reaction, Mannich reaction, Wittig reaction (chapter), DielseAlder reaction, Pechmann reaction, BischlereNapieralski reaction, and PaaleKnorr synthesis in the synthesis of heterocycles and total synthesis of natural products [36e55], in this book, we try to underscore the applications of selected name reactions in the total synthesis of alkaloids, especially those showing diverse biological activities. Due to the large number of references in retained names and their applications in the total synthesis of natural products, we limit this book to recent advances in applications of selected name reactions in the total synthesis of one of the most important, widespread, and prevalent families of natural products that show diverse biological properties, the so-called “alkaloids.”

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[3]

(a) P. Anastas, N. Eghbali, Chem. Soc. Rev. 39 (2010) 301; (b) S.L. Tang, R.L. Smith, M. Poliakoff, Green Chem. 7 (2005) 761. (a) M.E. Weeks, The Discovery of the Elements, P. A. Easton: J. Chem. Educ, sixth ed., 1956, 910 pp.; (b) J.R. Partington, History of Chemistry, Martino Publishing., 1998, pp. 320e326. R. Manuja, S. Sachdeva, A. Jain, J. Chaudhary, Int. J. Pharmaceut. Sci. Rev. Res. 22 (2013) 109.

8 Applications of Name Reactions in Total Synthesis of Alkaloids [4] (a) E. Clemmensen, Chem. Ber. 46 (1913) 1837; (b) E. Clemmensen, Chem. Ber. 47 (1914) 51; (c) E. Clemmensen, Chem. Ber. 47 (1914) 681. [5] (a) N. Kishner, J. Russ. Phys. Chem. Soc. 43 (1911) 582; (b) L. Wolff, Justus Liebigs Ann. Chem. 394 (1912) 86. [6] M.B. Smith, J. March, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, sixth ed., Wiley-Interscience, New York, 2007. [7] (a) A. Maercker, Org. React. 14 (2004) 270; (b) A. Maercker, Org. React. 14 (1965) 270; (c) W. Carruthers, Some Modern Methods of Organic Synthesis, Cambridge University Press, Cambridge, UK, 1971, pp. 81e90; (d) R.W. Hoffmann, Angew. Chem. Int. Ed. 40 (2001) 1411. [8] (a) F.A. Carey, Organic Chemistry, sixth ed., McGraw-Hill, New York, NY, 2006; (b) L. Claisen, A. Claparede, Ber. Dtsch. Chem. Ges. 14 (1881) 2460; (c) L. Claisen, Ber. Dtsch. Chem. Ges. 20 (1887) 655; (d) C.R. Hauser, B.E. Hudson Jr., Org. React. 1 (1942) 266. [9] (a) A. Whiting, C.M. Windsor, Tetrahedron 54 (1998) 6035; (b) M.C. Kloetzel, Org. React. 4 (1948) 1; (c) H.L. Holmes, Org. React. 4 (1948) 60. [10] (a) C. Friedel, J.M. Crafts, Compt. Rend. 84 (1877) 1392; (b) C.C. Price, Org. React. 3 (1946) 1; (c) J.K. Groves, Chem. Soc. Rev. 1 (1972) 73; (d) S.C. Eyley, Compr. Org. Synth. 2 (1991) 707; (e) H. Heaney, Compr. Org. Synth. 2 (1991) 733. [11] A. Hassner, C. Stumer, Organic Syntheses Based on Name Reactions, vol. 22, Elsevier, 2002. [12] J. Jack, A. Li, Name Reactions: A Collection of Detailed Reaction Mechanisms, Springer, 2003. [13] B.P. Mundy, M.G. Ellerd, F.G. Favaloro Jr., Name Reactions and Reagents in Organic Synthesis, Wiley, 2005. [14] (a) L.G. Wade, Organic Chemistry, sixth ed., Prentice Hall, Upper Saddle River, New Jersey, 2005, pp. 1056e1066; (b) M.B. Smith, J. March, Advanced Organic Chemistry, fifth ed., Wiley Interscience, New York, 2001, pp. 1218e1223; (c) R. Mahrwald, Modern Aldol Reactions, Volumes 1 and 2, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2004, pp. 1218e1223. [15] F.A. Carey, R.J. Sundberg, Advanced Organic Chemistry: Part B: Reaction and Synthesis, Springer Science & Business Media, 2007. [16] (a) P.W. Rabideau, Z. Marcinow, Org. React. 42 (1992) 1; (b) L.N. Mander, Compr. Org. Synth. 8 (1991) 489. [17] J.F. Bunnett, Organic Name Reactions. A Contribution to the Terminology of Organic Chemistry, Biochemistry, and Theoretical Organic Chemistry, Helmut Krauch and Werner Kunz. Translated from the second revised German edition by John M. Harkin. Wiley, New York, (1964), 1965. [18] H. Wang, Comprehensive Organic Name Reactions, Wiley, 2010, pp. 515e520. [19] E.J. Corey, Name Reactions for Carbocyclic Ring Formations, vol. 5, John Wiley & Sons, 2010. [20] K.C. Nicolaou, C.R. Hale, C. Nilewski, Chem. Rec. 12 (2012) 407.

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Nature Publishing Group, All natural, Nat. Chem. Biol. 3 (2007) 351. G. Samuelson, Drugs of Natural Origin: A Textbook of Pharmacognosy, Taylor & Francis Ltd, 1999. J.R. Hanson, Natural Products: The Secondary Metabolite, Royal Society of Chemistry, Cambridge, 2003. D.A. Williams, T.L. Lemke, Chapter 1: Natural products, in: Foye’s Principles of Medicinal Chemistry, fifth ed., Lippincott Williams Wilkins, Philadelphia, 2002, p. 25. R.A. Maplestone, M.J. Stone, D.H. Williams, Gene 115 (1992) 151. P. Hunter, EMBO Rep. 9 (2008) 838. J.W. Li, J.C. Vederas, Science 325 (2009) 161. K.C. Nicolaou, Angew. Chem. Int. Ed. 52 (2013) 131. (a) J. Kurek, Introductory chapter: alkaloids-their importance in nature and for human life, in: Alkaloids-Their Importance in Nature and Human Life, IntechOpen, 2019; (b) G.A. Cordell, Introduction to Alkaloids: A Biogenetic Approach, Wiley., New York, 1981, p. 619. M. Hesse, Alkaloids, Nature’s Curse or Blessing Wiley-VCH, Weinheim, 2002. J. Ziegler, P.J. Facchini, Annu. Rev. Plant Biol. 59 (2008) 735. E. Ravin˜a, The Evolution of Drug Discovery: From Traditional Medicines to Modern Drugs, John Wiley & Sons, 2011. M. Wink, A short history of alkaloids, in: M.F. Roberts, M. Wink (Eds.), Alkaloids. Biochemistry, Ecology, and Medicinal Applications, Plenum Press, New York-London, 1998, pp. 11e44. T. Aniszewski, Alkaloids Secrets of Life. Alkaloid Chemistry, Biological Significance, Applications and Ecological Role, vol. 56, 710, Elsevier B.V., The Netherlands, 2007, p. 1829. H. Hata, J. Parasitol. (1994) 518. M.M. Heravi, E. Hashemi, N. Nazari, Mol. Divers. 18 (2014) 441. M.M. Heravi, P. Hajiabbasi, Monatsh. Chem. 143 (2012) 1575. M.M. Heravi, A. Fazeli, Heterocycles 81 (2010) 1979. M.M. Heravi, E. Hashemi, Monatsh. Chem. 143 (2012) 861. M.M. Heravi, E. Hashemi, F. Azimian, Tetrahedron 70 (2014) 7. M.M. Heravi, E. Hashemi, N. Ghobadi, Curr. Org. Chem. 17 (2013) 2192. M.M. Heravi, E. Hashemi, Tetrahedron 68 (2012) 9145. M.M. Heravi, A. Bakhtiari, Z. Faghihi, Curr. Org. Synth. 11 (2014) 787. M.M. Heravi, S. Asadi, B.M. Lashkariani, Mol. Divers. 17 (2013) 389. M.M. Heravi, V. Zadsirjan, Tetrahedron: Asymmetry 24 (2013) 1149. M.M. Heravi, T. Ahmadi, M. Ghavidel, B. Heidari, H. Hamidi, RSC Adv. 5 (2015) 101999. M.M. Heravi, M. Ghanbarian, V. Zadsirjan, B.A. Jani, Monatsh. Chem. (2019) 1. M.M. Heravi, S. Khaghaninejad, M. Mostofi, Adv. Heterocycl. Chem. 112 (2014) 1. M.M. Heravi, S. Khaghaninejad, N. Nazari, Adv. Heterocycl. Chem. 112 (2014) 183. S. Khaghaninejad, M.M. Heravi, Adv. Heterocycl. Chem. 111 (2014) 95. M.M. Heravi, T. Alishiri, Adv. Heterocycl. Chem. 113 (2014) 1. M.M. Heravi, V. Zadsirjan, K. Kafshdarzadeh, Z. Amiri, Asian J. Org. Chem. 9 (2020) 1999. A. Nazari, M.M. Heravi, V. Zadsirjan, J. Organomet. Chem. (2020) 121629. M.M. Heravi, V. Zadsirjan, M. Daraie, M. Ghanbarian, Chemistry 5 (2020) 9654. M.M. Heravi, V. Zadsirjan, H. Hamidi, M. Daraie, T. Momeni, Recent applications of the Wittig reaction in alkaloid synthesis, in: The Alkaloids: Chemistry and Biology, vol. 84, Academic Press, 2020, pp. 201e334.

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Chapter 2

Applications of DielseAlder cycloaddition reaction in total synthesis of alkaloids Chapter outline 1. Introduction 2. Mechanism

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3. Applications of DielseAlder cycloaddition reaction in total synthesis of alkaloids References

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1. Introduction Organic synthesis is the state of the art for the planned construction of organic compounds and is recognized as one of the most important branches of organic chemistry. Several areas of research are found within the general field of organic synthesis, such as total synthesis, semisynthesis, and methodology. Ranging from apparently simple to potentially Nobel-winning transformations, synthetic approaches should possess several properties that all organic chemists hope for in their contemplated synthetic approaches. It is hoped that an approach is highly effective, facile, powerful, atom-economical, and extremely selective. It must be possible to use the method under secured mild reaction conditions, and of course, it must comply with green chemistry principles [1]. On the other hand, cycloaddition reactions are certainly the organic reactions closest to the brain and heart of virtually every synthetic organic chemist [2,3]. One of the most compatible reactions having the just-mentioned qualities is undoubtedly the DielseAlder (DA) reaction, which is also a cycloaddition reaction and was developed for the construction of highly functionalized sixmembered rings. The most conversant cycloaddition reaction is the DA cycloaddition reaction (explicitly, a [4 þ 2] cycloaddition) between a conjugated diene and a substituted alkene, frequently called as a dienophile, to construct a substituted cyclohexene system (Scheme 2.1). It was first explored by two German chemists, Otto Diels and Kurt Alder, in 1928. The importance Recent Applications of Selected Name Reactions in the Total Synthesis of Alkaloids https://doi.org/10.1016/B978-0-12-824021-2.00004-2 Copyright © 2021 Elsevier Inc. All rights reserved.

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12 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 2.1 DielseAlder cycloaddition reactions.

of the DA cycloaddition reaction is indicated by the two chemists’ introduction in 1950 as the joint Nobel Prize laureates in chemistry [4]. In our time, the DA reaction is one of the most common and elegant strategies for the construction of six-membered ring systems [5e9]. The diene component of the DA reaction can be either open-chain or cyclic and can bear various substituents. However, the diene should be able to exist in the s-cis conformation, because this is the only conformer that can partake as a partner for the dienophile in the reaction. Although substituted butadienes are stereotypically more stable in the s-trans conformation, in most cases the energy difference is small (w2e5 kcal/mol). A particularly reactive diene is 1methoxy-3-trimethylsiloxy-1,3-butadiene, well known as Danishefsky’s diene [10]. It has specific synthetic applications because it provides an a,be unsaturated cyclohexenone system when the 1-methoxy substituent after deprotection of the enol silyl ether is removed. Two derivatives of Danishefsky’s diene, namely the 1,3-alkoxy-1-trimethylsiloxy-1,3-butadienes (Brassard dienes) [11] and 1-dialkylamino-3-trimethylsiloxy-1,3-butadienes (Rawal dienes) [12], are also synthetically useful (Fig. 2.1). In a normal-incident DA reaction, the dienophile has an electronwithdrawing group in conjugation with the alkene; in an inverse-demand situation, the dienophile is conjugated with an electron-donating group [13]. Dienophiles can be selected to involve a “protected functionality." The dienophile can be more effectively subjected to a DA reaction with a diene hosting such functionality onto the product. In that way, several desirable functionalities can be introduced to DA adducts. Notably, the finished product cannot be prepared in a single DA step because equivalent dienophile is either unreactive or unreachable [13].

FIGURE 2.1 General form of Danishefsky, Brassard, and Rawal dienes.

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2. Mechanism DA reaction is a classical model of a concerted pericyclic reaction [14]. It is assumed to take place via a single, cyclic transition state [15] without any detectable intermediate created during the reaction proceeding to completion. Thus, the DA reaction is controlled by orbital symmetry deliberationsdit is classified as a [p4sþp2s] cycloaddition, showing that it proceeds via the superficial/superficial interaction of a 4p electron system (the diene structure) with a 2p electron system (the dienophile structure), an interaction that results in a transition state without an additional orbital symmetry-enforced energetic barrier and permits the DA reaction to occur easily (Scheme 2.2) [10]. When heteroatoms are included in the bond-forming step, the DA reaction is called a hetero-DielseAlder (HDA) reaction. The normal-electron-demand DA reaction is controlled by the energy gap separating the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO) between an electron-deficient dienophile and an electron-rich diene. By contrast, the inverse electron-demand DA reaction is subjugated by the LUMOeHOMO interaction between an electron-deficient diene and an electron-rich dienophile (Scheme 2.3) [16]. In addition to HAD, there is another variant of the DA reaction, the intramolecular [4 þ 2] cycloaddition reaction (IMDA) [17]. These DA reactions can create four new chiral centers. Therefore, asymmetric DA (ADA) and asymmetric hetero DA (AHDA) reactions are thought of as the most powerful tools for constructing optically active six-membered homocycles and heterocycles, respectively. These asymmetric variants of DA reactions have extensive and useful applications in the organic synthesis and synthesis of optically active products and show a wide range of biological potencies. The paramount importance of ADA and AHDA reactions has recognized especially in the total synthesis of naturally occurring compounds, virtually all of which bear at least one chiral center and are mostly isolated from natural sources as a single stereoisomer [18]. DA reactions comprise at least one heteroatom, irrespective of the kind, and are collectively called HDA reactions. For instance, a carbonyl group can successfully react with dienes to afford dihydropyran rings, a reaction known as the oxo-DielseAlder reaction. Alternatively, imines can be used either as the dienophile or at various sites in the diene to generate various N-heterocyclic compounds via the aza-Diels-Alder reaction. Asymmetric aza-Diels-Alder reactions are frequently used as a commanding protocol to synthesize the optically active nitrogen-containing

SCHEME 2.2 Suggested mechanism for the DielseAlder reaction.

14 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 2.3 Classification of DielseAlder reactions: EDG, electron-donating group; EWG, electron-withdrawing group; HOMO, highest occupied molecular orbital; LUMO, lowest unoccupied molecular orbital.

heterocycles prevalent in natural products [17a,18c,19]. Due to the importance and usefulness of DA reactions [20e25], we recently published on the applications of DielseAlder (i.e., IMDA) reactions in the total synthesis of natural products [26e28], thus indicating the importance of various DA reactions in the art of organic synthesis. In continuing our interest, in this chapter we underscore the most recent applications of DA reactions in the total synthesis of one the most important, widespread, and prevalent families of natural products that show diverse biological properties, the so-called “alkaloids.”

3. Applications of DielseAlder cycloaddition reaction in total synthesis of alkaloids Aspidosperma alkaloids are a subset of the naturally occurring monoterpenoid indole alkaloids derived from the fusion of tryptamine and a terpene unit, which show diverse biologically activities. Aspidosperma alkaloids have a stereochemically rich pentacyclic core in common and replete with functional groups and stereogenic centers. Their complex and interesting structural features have provided a challenging arena for new strategies and have thus generated considerable interest from the synthetic community. Members of this class include minovine [29], ()-aspidospermine and (þ)-spegazzinine [30], (þ)-N-methylaspidospermidine, ()-vindorosine and kopsinine (21) [31]. In this regard, much effort has been made for the divergent total synthesis of their members, their unique common, pentacyclic intermediate 11 and other key strategic bonds [32], in a single step. ()-Kopsinine (21), having the

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common structural features of a member of the Aspidosperma alkaloids, was initially isolated from Kopsia longiflora Merr [33]. Boger and co-workers achieved the total synthesis of ()-kopsinine (21) and its unnatural enantiomer and disclosed their strategic pathway in 2015 [34]. It involved a late-stage SmI2-assisted transannular free radical conjugate addition reaction for the construction of the bicyclo[2.2.2] octane core via strategic C21eC2 bond formation. Key to the protocol was installation of the underlying skeleton by an intramolecular [4 þ 2]/[3 þ 2] cycloaddition cascade of a 1,3,4-oxadiazole to create the required precursor C21 functionalized pentacyclic ring system 11 in a single step, in which the C3 methyl ester found in the natural product served as a building block of a key 1,3,4oxadiazole substituent, motivating it to partake in the initiating DA reaction and stabilizing the intermediate 1,3-dipoles. In this strategy [35,36], the oxido bridge in 11 was initially cleaved upon treatment with NaCNBH3 (20% HOAc/ i-PrOH) to deliver the corresponding alcohol 12 as a sole diastereomer rising from hydride reduction of an intermediate N-acyliminium ion entirely from the less hindered convex face. Compound 12 as a pure diastereomer, following the Chugaev elimination procedure [37], was first transformed to the respective Cbz (N-carboxybenzyl) carbamate 14 as a mixture of diastereomers via the free indoline 13. This carbamate 14 was separated via semipreparative Daicel CHIRALCEL OD column chromatography to give a mixture of (þ)-14 and ent-()-14. The required natural enantiomer (þ)-14 was separated from the aforementioned mixture using a semipreparative column, and its structure was established by single-crystal X-ray diffraction. The natural enantiomer (þ)-14 following the Chugaev elimination procedure [37] was converted into methyl dithiocarbonate (þ)-15 in excellent yield in the presence of NaH, CS2 in tetrahydrofuran (THF), followed by reaction of the resultant with MeI. Xanthate (þ)-15, was then subjected to smooth elimination under mild thermal conditions and delivered ()-16 in good yield. Silyl ether motif of ()-16 was cleaved using Bu4NF in THF followed by treatment of the resulting primary alcohol ()-17 by CH3SO2Cl in THF and then treatment with NaI, delivering the primary iodide ()-18. Upon treatment of ()-18 with SmI2 in 10:1 THF/ hexamethylphosphoramide, compound ()-19 was obtained with excellent yield but contaminated by a detectable quantity of the C3 diastereomer (99%. (R)-94 was subjected to diastereoselective intramolecular DA reaction under already secured optimal reaction conditions (heating in toluene at 140  C in a sealed tube in the presence of 1 equiv. of dibutylhydroxytoluene) to obtain tricyclic endo adducts 95 and 96 in 62% and 16% yields, respectively. The stereochemistry of 95 was established on the basis of its NOE correlation from the proton at C-2 to the proton at C-21, and the absolute configuration of diastereomer 96 was assigned by single-crystal X-ray crystallographic analysis. The diastereoselectivity in IMDA employing (R)-94 can be explicated as follows. The steric repulsion between the atomic bulky groups on C-2 and a proton on C-5 results in the shift of equilibrium leading to the chief construction of required adduct 95. Next, p-nitrobenzoate moiety in 95 was removed using K2CO3 in MeOH to obtain alcohol 97 in almost quantitative yield that upon oxidation employing AZADOL and iodobenzene diacetate delivered ketone 98 in high yield [109]. The latter was reacted with phenylhydrazine (99) in the presence of a catalytic amount of cyanuric chloride (100) [110] to give hydrazone amide 101 in respectable yield. At this stage, the configuration of 101 was assigned as 16S,21R by X-ray crystallographic data analysis. Selective reduction of amide 101 using alane delivered the secondary amine that was protected with a benzyl group in order to avoid its reaction with the ester group in the acidic condition, thus forming a suitable precursor for the Fischer indole synthesis in high yield. Heating of 103 (99% ee) in the presence of ZnCl2 in refluxing AcOH [111] resulted in a [3.3]-sigmatropic rearrangement to afford 104 in high yield and excellent ee (97%). Lastly, upon treatment of the latter with AlCl3 in anisole [112], the Na-Bn group, was cleaved to furnish the desired alkaloid andranginine (105). For characterization of the structure of this synthetic sample, its UV, 1H NMR, 13C NMR, and mass spectra were obtained in combination with its chromatographic behavior and were compared with those of the natural sample isolated from K. arborea [100] and found to be in full agreement. However, the optical rotation of the synthetic sample 105 with the assigned configuration as the 16S,21R was dextrorotatory, opposite that of natural 105, and its absolute values of specific rotation [[a]D 19 þ 96.1 (c 0.15, CHCl3)] were quite different at [[a]D 20e24.3 (c 0.1, CHCl3)], and their absolute values of specific rotation were very different from those reported for the sample isolated from natural source: [[a]D 19 þ 96.1 (c 0.15, CHCl3)]. In conclusion, the natural andranginine (105) isolated from K. arborea contained the ()-enantiomer predominantly and existed as a scalable mixture [113] [(16R,21S)/(16S,21R) ¼ in an approximately 62:38 ratio (Scheme 2.12). The ergot alkaloids are mycotoxins produced by several species of fungi in the genus. Cycloclavine (117) is an ergot alkaloid, an important group of natural products having a fused indole core in common. Members of this

Applications of DielseAlder cycloaddition reaction Chapter | 2

SCHEME 2.12 Total synthesis of (þ)-andranginine (105).

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30 Applications of Name Reactions in Total Synthesis of Alkaloids

family have long assisted as a motivation for drug design and discovery [114]. It was first isolated in 1969 from seeds of the African morning glory shrub Ipomoea vatke and later from Aspergillus japonicus, a species of filamentous fungus [115,116]. In primary biological screening, it showed promising insecticidal and antiparasitic activities [117]. During the past 3 decades, much effort has been made in the structural elucidation and biogenetic origin of ergot alkaloids [114]. The exceptional structural features of cycloclavine (117), containing pyrrolidine-fused cyclopropane as well as three sequential chiral centers at carbons at C(5), C(8), and C(10), in which two of them all-carbon quaternary, along with divers’ biological activities, have caught the eyes of synthetic chemists as an interesting target. The first total synthesis of ()-cycloclavine was achieved in 2008 by Sza´ntay [118]. After that ,several other accomplishments in the total synthesis of cycloclavine (117) as racemat have been reported by Wipf et al. in 2011 [119], Cao and co-workers [120], and the Brewer research group, who developed a new strategy for the formal total synthesis of ()-cycloclavine in 2014 [121]. However, no asymmetric total synthesis of cycloclavine had yet been achieved. The first asymmetric total synthesis of cycloclavine (117) was achieved by Wipf and co-workers, who reported the concise (8-step) asymmetric synthesis of ()-cycloclavine [122]. Notably, the same research group in 2018 extended this strategy toward its enantiomer (þ)-cycloclavine and revealed the biological characterization of the binding profile of both enantiomers on 16 brain receptors [123]. To reach this objective and launch a concise pathway to either enantiomer as well as related compounds, these authors first revised their previous achievement in which they had synthesized to racemic cycloclavine in 14 step with a 1.2% overall yield. Armed with this previous experience, they contemplated a rationalized asymmetric total synthesis of the unnatural enantiomer ()-cycloclavine (117) and accomplished the first asymmetric synthesis of total synthesis of ()-cycloclavine (117) in eight steps and a 7.1% overall yield. In their design, key features involved the first catalytic asymmetric cyclopropanation of allene catalyzed by the dirhodium catalyst Rh2(S-TBPTTL)4, the enone 1,2-addition of a new 2,2,6,6-tetramethyl-1piperidinyloxy (TEMPO) carbamate methyl carbanion, and intramolecular strain-promoted IMDA methylenecyclopropane (providing a crucial tricyclic enone intermediate in entantiopure form). The total synthesis started with allene (106) as an ideal atom-economical precursor to MCPs. Allene (106) was reacted with cyclopropanation 108 in the presence of dirhodium complex 107 [124] as the catalyst to give MCPs. In fact, complex 107 [124] was found to be the most promising catalyst for this enantioselective conversion in terms of providing the best e.r. at low temperature. When the feasibility of the first vital reaction was confirmed, allene (106) was found to be a suitable compound for cyclopropanation 108 in the presence of dirhodium complex 107 [124] which had already been selected as the catalyst of choice to give the enantiomerically

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pure 109 in high yield on a gram scale. Next, the vinylogous amide 110 was deprotonated using n-BuLi at 78  C in THF and then reacted with activated ester 109 to provide amide 111. Notably, the E/Z ratio of 110 was found to be unimportant because both starting isomers gave the E alkene product 111, possibly due to fast isomerization of the enamine upon deprotonation and privileged trapping of the E enamide. Amide 111 was analyzed using chiral supercritical fluid chromatography and disclosed an e.r. of 87:13 that had been affected the enantiomeric enrichment gained in the prior cyclopropanation step. Then, treatment of amide 111 with NaHMDS caused enolization to the corresponding enolate, which was trapped in situ with TBSCl to afford the highly reactive amino silyloxy diene 112. This diene was subjected to an antiselective intramolecular [4 þ 2] cycloaddition with the unresolved methylenecyclopropane under MWI at 95  C. The obtained crude enol ether was directly submitted to TBAF cleavage to deliver separable diastereomers of ketone 113 in 4.8:1 d.r. at C(5). The relative configuration at the newly constructed ring junction in the major diastereomer was determined as trans using a combination of interpretation of NMR data and X-ray analysis. Then, a Pd(DMSO)2(TFA)2-catalyzed straight dehydrogenation of ketone 113 was accomplished to provide less-substituted enone 114 (ee 99%) as sole regioisomer and as a crystalline solid through a modified methodology first developed by Diao et al. [125] for the aerobic dehydrogenation of ketones. Then, the ultimate challenge of this strategy involved the introduction of the indole core circumvented by IMDA reaction [126e129]. Boc-carbamate-stabilized furfurylamine methyllithium addition on enone 114 suffers stereo- and chemoselectivity problems. The problem actually arose from the competitive lactam addition with ketone addition. The problem was evaded by development of a new TEMPO carbamate that resulted in a more thermodynamically stable and chemoselective furyl lithium species 115. This reagent underwent 1,2-addition to enone 114 at low temperature in ether to give the tertiary allylic alcohol 116 as a separable 1.5:1 mixture of diastereomers at C(3). The relative configuration of the major diastereomer was determined through 1D NOE/2D ROESY correlations combined with X-ray data analysis. Next, alcohol 116 was submitted to the IMDA reaction in toluene at 135  C, followed by reduction of the lactam moiety with LiAlH4 to furnish the desired unnatural alkaloid ()-cycloclavine [()-117] in moderate yield. In the late stage, the IMDA reaction involved cyclization/aromatization sequence was accompanied by concurrent thermolysis [130] of the TEMPO carbamate protecting group to deliver the desired protective-group-free indole (Scheme 2.13). The marine alkaloids ()-lepadins AeC belonging to the cis-decahydroquinoline alkaloids have been isolated along with five others from different marine sources, namely from a specimen of Didemnum sp. collected in the Bahamas including the tunicate Clavelina lepadiformis [131]. The structures of ()-lepadins AeC were assigned by an integrated analysis of MS, IR, and 1 H, 13C, and 2D NMR spectra. The structural elucidation for these lepadin

32 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 2.13 Total synthesis of ()-cycloclavine (117).

alkaloids confirmed that all have a common structural backbone of a cisdecahydroquinoline ring involving a C-2 methyl group, a C-3 oxygenated (hydroxy or acyloxy) group, and a C-5 eight-carbon side chain. The absolute configuration of lepadin was solved by interpretation of NOE measurements and excitation coupled circular dichroism of the corresponding N-p-bromobenzoyl derivative. Lepadins A and B exhibited substantial in vitro cytotoxicity toward several human cancer cell lines [131b]. The biological potencies and outstanding structural features of these lepadin alkaloids have received much attention from the synthetic community. In addition, their natural scarceness has created several problems for further screening for biological evaluation. Thus, their total synthesis has stirred up the interest of synthetic organic chemists [132] and resulted in many attempts by several research groups that have resulted in many smart strategies toward ()-lepadins AeC. Consequently, the efforts made by several research groups, led by Toyooka [133], Kibayashi [134], Ma [135], and Amat [136], were successful and resulted in accomplishment of the total synthesis of these interesting targets. Furthermore, a racemic formal synthesis of lepadin B and a synthesis of (þ)-lepadin B were also achieved by Zard [137] and Charette and co-workers [138], respectively. Despite these successful attempts, due to their exceptional biological potencies and unified and challenging structural characteristics, the

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total synthesis of different lepadin alkaloids is still in much demand for finding novel pathways to develop more brief and efficient synthesis of these targets. Among the intensive and decided research groups, Chen and co-workers, armed with the experience of using diverse chiral dienophile-induced DA reactions for the asymmetric synthesis of other natural products [139], designed several elegant, brief, and effective pathways to ()-lepadins AeC with practically one of them achieved. Chen et al. in 2017 accomplished a novel concise and convenient approach to ()-lepadins AeC [140]. Their strategy was designed based on a stereoselective DA reaction using a chiral dienophile as a substrate. Their smart plan was also adaptable to the synthesis of ()-lepadin B from 5-deoxy-D-ribose in 13 steps with 14.8% overall yield. This approach provided the cis-decahydroquinoline core bearing five stereogenic centers, which were generated rapidly via stereoselective cycloaddition followed by five-step, one-pot hydrogenation-cyclization resulting in successful total synthesis of ()-lepadins AeC. Notably, the strategy was designed so that chiral oxygenated chain in dienophile 120 not only induced auspicious stereoinduction in the cycloaddition to create the three desired stereogenic centers on the six-membered ring but also was reasonably appropriate for the ensuing construction of the substituted piperidine ring. The cleavage of the chiral moiety in compression with previously reported dienophiles [139], dienophile 120, was accompanied with higher atom economy after the cycloaddition. In accordance with planning, commercially available 5-deoxy-D-ribose was readily transformed to the known but key intermediate 134 in 10 steps, from which ()-lepadins B, A, and C were synthesized in three to four steps. The notable merit for this elegant design was its usefulness for gaining access to other related cis-decahydroquinoline alkaloids with a trans C-5 substituent moiety. This elegant strategy started from commercially available 5-deoxy-D-ribose (118), which upon treatment with (carboethoxymethylene) triphenylphosphorane, afforded the required target E-conjugated ester 119 with excellent stereoselectivity. Triol 119 was then converted to the another required copartner, dienophile 120, in decent yield in a one-pot fashion consisting of DDQ as selective oxidant for oxidation of allyl alcohol with subsequent addition of 2,2-dimethoxypropane. Having chiral enone 120 available in hand, it was reacted as a dienophile with benzyl trans-1,3butadiene-1-carbamate (121) as a diene under the key DA reaction conditions [141]. This mixture was heated in toluene at 80  C, which pleasantly provided a mixture involving the two anticipated cycloaddition adducts 122 (76% yield) and 123 (12% yield). The relative configuration of the trisubstituted cyclohexene moiety in the cycloadducts was assigned by NMR spectroscopic data analysis. In the 1H NMR spectrum of the chief isomer 122, the large H-2 coupling constant (dd, J ¼ 12.0, 4.0 Hz) at 3.67 ppm specified its axial orientation in the half chair conformation. Its small J value (4.0 Hz) ensuing from the axial-pseudo-equatorial coupling of H-2 with H-1 designated that the substituted cyclohexene 122 had a 1,2-cis relationship. Similarly,

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coupling constant H NMR data analysis showed the minor isomer 123 had the 1,2-cis and 2,3-trans geometry on its trisubstituted cyclohexene core. Seemingly, two cycloadducts 122 and 123 are both generated via the endo transition state relative to the ketocarbonyl moiety in dienophile 120, albeit with opposite facial selectivity. In addition, it can be presumed that the preferably controlled stereochemistry of 120 in the related DA reactions is similar to that of the known dienophile 124, which has been employed in the synthesis of infectocaryone to provide cycloadduct intermediate 126 [139a]. Therefore, the absolute configuration of chief isomer 122 was determined as (1R, 2S, 3R) on the basis of comparison with the trisubstituted cyclohexene 126, and it was consequently approved by the conversion of 122 into the natural products. As a result, all stereochemistry of intermediate 127 were consistent with that of ()-lepadins AeC. Then, deoxygenation of ketone 127 was attempted to provide methylene product. All efforts using the conventional methods for this deoxygenation such as CagliotieWolffeKishner reduction [142], thioacetalbased reduction [143], YamamuraeClemmensen reduction [144], and its Arimoto variant [145], were all found to be unsuccessful. Thus, an alternative route to complete the subsequent synthesis was required. Upon hydrolysis of the isopropylidene group of 129 in AcOH/H2O at 70  C, triol 130 was obtained in which its less steric hydroxyl group was selectively oxidized with TEMPO to give methyl ketone 131. The latter was directly transformed to trisubstituted olefin 132 as a sole stereoisomer via a sequential diacetylation/ b-elimination to give a,b-unsaturated ketone 132. The latter was then subjected to an operationally facile hydrogenation in which five successive conversions including saturation of the di- and trisubstituted olefins, elimination of the N-Cbz group, intramolecular cyclic imine generation, and stereoselective reduction of the imine intermediate took place cleanly to deliver two cis-2,6-substituted piperidines, 133a and 133b, as a pair of epimers at the acetoxy positions (d.r. ¼ 3.5:1). The major isomer 133a was then subjected to N-Boc protection and O-debenzylation to deliver the known required intermediate (þ)-134 through Amat’s synthesis of ()-lepadins AeC [136]. Upon oxidation of the latter, aldehyde 135 was obtained. Then, the octadienyl side chain associated with deacetylation was installed to the latter via already known strategies such as the HornerWadsworthEmmons reaction [136] or alkenyl iodide-based Suzuki coupling to furnish 136 as the well-recognized common precursor of ()-lepadins A and B [134b,135,136]. In the meantime, minor isomer 133b was submitted to similar operations to give 137 as the respective C-3 epimer of 136. Inversion of the C-3 stereogenic center in 137 via the oxidation/reduction strategy also gave the desired target 136. An ultimate cleavage of the N-Boc group in 136 provided ()-lepadin B (Scheme 2.14). In addition, this work also constitutes a formal total synthesis of ()-lepadin C, because decahydroquinoline intermediate 134 may be transformed to the alkaloid in four steps following the Amat [136] and Ma [135] procedures.

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SCHEME 2.14

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Total synthesis of ()-Lepadins AC.

Securinega is a genus of plants in the family Phyllanthaceae first described as a genus in 1789. As presently conceived, the genus is native to Madagascar and the Mascarene Islands in the Indian Ocean. The Securinega alkaloids are classified in a family of bridged tetracyclic natural products occurring in the plants of Securinega, Phyllanthus, Flueggea, and other genera in the Euphorbiaceae family [146]. Securinega alkaloids are extensively distributed in southern China, isolated from Flueggea virosa, and have been used for a long time as traditional medication in the treatment of eczema, allergic dermatitis, and scald [147]. Two new alkaloids, virosaines A (157) and B, were isolated as pseudoenantiomers from the twigs and leaves of Flueggea virosa, and their structures were fully characterized by Zhao and co-workers in 2012. Neither virosaine A nor B showed cytotoxic activity against selected cancer cell lines [148]. Among these alkaloids, virosaines A (157) and B have been isolated and their structures characterized to show they contain the pentacyclic caged structures common in the Securinega alkaloids [148]. Only the caged pentacyclic backbone present in virosaine A (157) has been attractive enough to make it an interesting target in the synthetic community. Their unique

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SCHEME 2.14 cont’d

birdcage shape, with unprecedented skeletal structures containing polyfunctionalized features and an unusual tetracyclic core incorporating a trihydro-1,2-oxazine ring, has made them attractive targets for total synthesis. However, to date, only a few successful total syntheses of virosaine A (157) have been reported, one involving the generation of a tetracyclic intermediate via an intramolecular aza-Michael addition, generation of an N-hydroxypyrrolidine through a Cope elimination, and an intramolecular [1,3]-dipolar cycloaddition to generate a complex 7-oxa-1-azabicyclo[3.2.1]octane ring system [149]. The only total synthesis of virosaine B so far reported was by Yang, Li et al. in 2013 [150].

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Gleason and co-workers accomplished the total synthesis of ()-virosaine A (157) in 10 steps and in 9% overall yield [151]. It involved a one-pot sequential DA cycloaddition/organolithium addition and an intramolecular epoxide-opening/nitrone [3 þ 2] cycloaddition as vital steps. Accordingly, oxazaborolidinone-prompted cycloaddition of 2-bromoacrolein (142) to furan (141) generated the intermediate oxabicycle 144 [4d,152]. Notably, the latter was found to be not sufficiently stable to be isolated [152] and thus was trapped in situ by an addition of organolithium 145 to obtain 146 in high yield, 2.7:1 d.r. and 83% ee [153]. Recrystallization of the diasteromers of 146, delightfully, provided alcohol 146 in >20:1 d.r. and >99% ee. The abovementioned one-pot process assembled all but two carbons of the final desired target. The latter, upon acid-catalyzed dioxolane cleavage, provided lactol 147 that was subsequently condensed with TBSONH2 to deliver O-silyl oxime 148 in excellent yield over two steps. The latter, in the presence of NaH, was smoothly converted to the corresponding epoxide 149 in virtually quantitative yield. Having the required epoxide 149 in hand, it was subjected to a sequential cascade opening/nitrone cycloaddition using acetic acid as solvent in one-pot fashion to provide 151 in excellent 92% yield from 149. In conclusion, by taking advantage of benefits the above-mentioned cascade process, the challenging core of virosaine A (157) was provided in just five steps from commercially available starting materials. Sequential cascade reaction of 151 with diimidazole in toluene and then with n-BuNH2 in CHCl3 led to the formation of 152, which was lithiated selectively at C14 using 2.2 equivalents of s-BuLi (sec-butyllithium) followed by quenching of the formed lithiated species with Br2 to give alkyl bromide 153 exclusively in respectable yield. Radical allylation of alkyl bromide 153 using allyl tributyl tin under Keck’s reaction conditions cleanly resulted in the corresponding allylated carbamate 154 in high yield [154]. The carbamate in the latter was removed by LiAlH4 to deliver the corresponding alcohol 155 in excellent yield without any simultaneous NeO bond cleavage. The latter was subjected to ozonolysis to give a lactol that upon instant oxidation using DMP afforded lactone 156. In the final step, the latter was exposed to activated neutral Al2O3 to furnish the desired alkaloid, ()-virosaine A (157) in respectable yield (Scheme 2.15). Lundurines, grandilodines, and lapidilectines belong to Kopsia alkaloids. Owing to their structural features and fascinating biological activities [155], this class of natural alkaloids has grabbed the attention of the synthetic community. As a result, several research groups have attempted the chemical synthesis of this class of natural alkaloids, and noteworthy progress have been made. The efforts of the groups of Pearson [155a,b], Nishida [98c,f,155c,d], Qin [155e,f], and Echavarren [98b] have resulted in the sophisticated total synthesis of lundurines, grandilodine C, and lapidilectine B. The prominent structural features of these complicated synthetic targets involve the indoline core with fused cyclopropyl and g-lactone, respectively. In contrast, lapidilectam and grandilodine B (173) isolated from the genus Kopsia [156] have

38 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 2.15 Total synthesis of ()-virosaine A (157).

the opened-type architecture bearing two methyl esters at C7 and C16. The opened-type Kopsia alkaloid grandilodine B contains four stereogenic centers, three of them quaternary, making it a challenging and stimulating synthetic target for Zu and co-workers, who accomplished its first total synthesis and revealed their results in 2017; it has received much attention from the synthetic community [157]. In their strategy, the opened-type Kopsia alkaloid grandilodine B (173) contained the polycyclic ring system and four stereogenic centers, three of them quaternary; the polycyclic ring system of the A ring was directly constructed, and C16 was assembled via DA reaction and the C7 quaternary carbon center established by diastereoselective cyanation of tertiary alcohol; the B ring was constructed via a facial- and regioselective nitrone 1,3dipolar cycloaddition, while the C ring was built up through a late-stage SN2

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39

alkylation. The total synthesis of grandilodine B (173) started with the construction of the A ring and induction of C16 stereocenter planned by conducting the DA reaction [158]. To the purpose, the required dienophile 159 was provided as a mixture of E/Z isomers (4:5) via the reaction of commercially accessible ethyl glyoxylate with indoxyl 158. The DA reaction of 159 as dienophile with its partner, diene 160, proceeded cleanly, delivering spirocycle 161 as the major epimer (C16 a/b ¼ 4:1) in excellent yield. This observed C16 a/b selectivity of the reaction was assumed to be due to the equilibrium between the E/Z isomers of 159, in which the Z isomer reacted faster. The A ring of the target was constructed, and the C16 a-ester of grandilodine B (173) was installed to provide the required compound in enough amount (in multigram scale). This is an example of the power and brevity of DA reaction in solving different synthetic problems. Deprotection of 161 using TBAF and ketal formation delivered ketone 162, which subjected to diastereoselective 1,2addition with allyl Grignard reagent to afford the tertiary alcohol 163. Now, introduction of the all-carbon C7 quaternary center with inversion of configuration of the tertiary alcohol involved another key reaction. A nitrile group is known as an appropriate carbanion equivalent, as it shows reactivity in the cyanation of tertiary alcohols [159] and can be used as a replacement to a methyl ester. Conversion of 163 to 164 was catalyzed by metal Lewis acid, InBr3 166, albeit a substantial quantity of undesired products were formed by elimination of the alcohol and by CN-promoted ketal opening. Pleasantly, following the procedure developed by Kim et al. for the cyanation of secondary alcohols [159b], when B(C6F5)3 was used as the catalyst, 164 was obtained in good yield and with excellent diastereoselectivity. After the C7 quaternary carbon was set up, alkene 164 with the right configuration was subjected to oxidative cleavage with subsequent of reduction using NaBH4, resulting in the formation of the corresponding primary alcohol 165, which was further transformed into ketone 166 through the removal of the ketal and protection of the primary alcohol. After construction of ring A along with introduction the all-carbon C7 quaternary center via DA reaction, construction of the B ring of grandilodine B (173) was contemplated. To achieve such task, 1,3-dipolar cycloaddition of nitron was considered as the key approach [160], because this reaction has previously been employed in the total synthesis of natural products [161]. In the total synthesis of grandilodine B (173), the correct stereochemistry at C14 and C20 was the key concern and thus must be controlled. To do so, substrate 166 was selected as substrate and decorated with a bulky TIPS-protecting group at the top face. Then, this TIPS-protected ketone 166 was reacted with benzylhydroxylamine to give the suitable nitrone as a precursor for the 1,3-dipolar cycloaddition, which upon generation was directly reacted with methyl acrylate to deliver isoxazolidine 167 as a mixture of two isomers (C14). Pleasantly and as anticipated, the reaction proceeded smoothly to completion with excellent facial selectivity and regioselectivity. Consequently, sequential cleavage of the NeO bond/debenzylation and amide

40 Applications of Name Reactions in Total Synthesis of Alkaloids

formation occurred under Pd-catalyzed hydrogenation [162] to afford spirolactam 168. In this way, the B ring of grandilodine B was successfully installed by a two-step reaction. The TIPS group of 168 was removed with subsequent mesylation of both alcohols to deliver the key intermediate 169 as the precursor for the construction of the C ring of grandilodine B (173) via SN2 alkylation. However, the conversion of 169 to 170 was perplexing, seemingly due to the poor nucleophilicity of the amide-NH. Extensive attempts were made to secure the optimal reaction conditions for the formation of the C ring via SN2 alkylation of the amide-NH. At last, the transformation of 169 to 170 was successfully accomplished, albeit in moderate yield, by using Cs2CO3 as the base and toluene as the nonpolar solvent. Subsequently, the mesylate moiety in 170 was eliminated using PhSeNa in THF./EtOH and then H2O2, DCM to deliver alkene 171. In a two-step approach, alkene 171 was first converted into the corresponding amide using K2CO3 and H2O2 [163] and then directly converted to the corresponding methyl ester 172 using Meerwein’s reagent [164]. As a final point, the latter was subjected to ester exchange with MeOH to furnish the desired alkaloid grandilodine B (173) in satisfactory yield. This synthetic sample was fully characterized, and its characterization data were compared with those of the authentic sample isolated from mature and found to be identical (Scheme 2.16) [156b]. Catharanthine 190 is a terpene indole alkaloid originated by the medicinal plant Catharanthus roseus and Tabernaemontana divaricata. Although it is believed to be derived from strictosidine, the exact mechanism is still unknown. Catharanthine is a precursor to clinical anticancer and antitumor natural products of the vinblastine and vincristine [165] formed by dimerization of catharanthine with vindoline. Catharanthine itself is an inhibitor of tubulin self-assembly into microtubules, although not so potent as vinblastine or vincristine. It showed antitumorigenic effect as well as inhibited cAMP phosphodiesterase activity. It also can distress cold-induced pain signals in mammals as a potent TRPM8 antagonist [99g]. Due to its interesting biological activity and structural complexity, containing a pentacyclic scaffold as well as bearing three stereogenic centers and a quaternary carbon, it has received attention from the synthetic community. Its low natural abundance is another motivation for synthetic organic chemists to consider it an attractive target and thus, several attempts toward its total synthesis have been made [166], resulting in successful racemic synthesis by Bu¨chi [166a,167,168], Raucher [166h], Sundberg [166l], and Fukuyama [166m], while intramolecular examples have been achieved by Kuehne [166i] and Oguri [169a]. Despite these achievements, the asymmetric total synthesis of 190 has remained subtle. After Bu¨chi’s seminal synthetic effort [166a], most recent endeavors had been directed toward asymmetric total synthesis of 190 [169]. In 2018, Kim and co-workers had a breakthrough by achieving an asymmetric route to substituted isoquinuclidines, present in catharanthine (190), using a

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41

SCHEME 2.16 Total synthesis of grandilodine B (173).

“ketene equivalent” approach. Their strategy involved an organocatalyzed DA reaction and Ru(Bipy)3Cl2$(H2O)6 catalyzed photoredox cleavage [170]. Encouraged by this achievement, they attempted asymmetric total synthesis of catharanthine (190). Relying on the experiences attained from investigation of the retrosynthetic pathway, acrolein was used as a ketene equivalent in a reaction with diene chloride 175 provided from partial reduction of pyridine using NaBH4 followed by reaction with benzoyl chloride. Thus, a Nakanotype DA reaction between 175 and acrolein in the presence of 176 as catalyst gave 178 in high yield on decagram scale [171] in 97: 3 er (HPLC). The

42 Applications of Name Reactions in Total Synthesis of Alkaloids

crude 1H NMR spectroscopy indicates that the reaction mixture contained 98: 2 dr. The yield of the DA step is comparable to analogous enantioselective dihydropyridine DA reactions used in total synthesis [138,172,173]. Delightfully, the crucial transformation of aldehyde 178 into ketone 179 was accomplished employing a Ru(Bipy)3Cl2$(H2O)6 photoredox catalyzed cleavage with molecular oxygen in high yield and on a gram scale [174]. The ketone 179 was protected with 1,3-propanediol in the presence of p-TsOH to afford 1,3-dioxane ketal 181 in almost quantitative yield. The latter as a crude was coupled to 3-indole acetic acid in the presence of EDC, afforded amide 184 in satisfactory yield over two steps. Amide 184 was treated with stoichiometric (MeCN)2PdCl2 and AgBF4 in MeCN delivered 185 in good yield [175]. The deprotection of 185 took place sluggishly (over 1 week) in the presence of p-TsOH in acetone/H2O affording 186 in high yield. Worthy to mention, the elegant access to 186 was achieved in only eight steps from pyridine compared well with the previously reported strategy by Doris et al. [169b] to prepare 186 in 16 steps from N-CBz-serine. Reaction of 186 with ethynyl magnesium bromide in THF gave 188 with a >19:1 d.r. (crude 1H NMR). The latter upon hydrogenation of 188 in the presence of PtO2 in MeOH delivered 189 in high yield over two steps. Compound 189 was transformed to the desired alkaloid, catharanthine (190) in acceptable overall yield in six steps involving already known and reported procedures [166a] and constituted the asymmetric formal total synthesis of catharanthine (190) (Scheme 2.17). Lycoposerramine-R (208) is a novel skeletal type of Lycopodium alkaloid initially isolated in 2009 by Takayama et al. [176]. It is a tetracyclic compound bearing a cis-hydrindane group fused to a 2-pyridone moiety. It also has a piperidine ring, fused to the cis-hydrindane, sharing a quaternary carbon at C12. These interesting structural features make it a good candidate for synthetic investigation. Four total synthetic pathways have been accomplished and disclosed, so far [177]. In this context, in 2018, Yokoshima and co-workers disclosed their achievements and their route for the total synthesis of lycoposerramine-R (208). Their synthetic strategy involved a ClaiseneIreland rearrangement for the assemblage of a two-carbon segment and an HDA reaction for the construction of a cyclic enol ether that upon the reaction with an ethynyl group built a cis-hydrindane core bearing a quaternary carbon. The pathway was completed by the synthesis of 2-pyridone utilizing 2-(phenylsulfinyl)acetamide. In this pathway, an Au-catalyzed cyclization between an ethynyl group as well as a cyclic enol ether motif is generated via an HDA reaction of an enone [178]. The synthetic strategy started with the easily accessible enone 191 [179], which was subjected to a MoritaeBaylise Hillman reaction in an aqueous cationic micellar solution to give the hydroxy ketone 192 [180]; upon acetylation, this delivered acetate 193. After protection of the ketone moiety in the latter, the resultant silyl enolate 194 was subjected to a ClaiseneIreland rearrangement [181]. NaHMDS and TMSCl in THF

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43

SCHEME 2.17 Formal synthesis of catharanthine (190).

afforded the corresponding carboxylic acid 195. The latter upon esterification using (diazomethyl) (trimethyl) silane, delivered methyl ester 196 in moderate yield over three steps. The silyl group in 196 was removed, employing TBAF and AcOH liberating the relatively active enone 197, which directly reacted with butyl vinyl ether in the presence of a catalytic quantity of Yb(fod)3 to give the cyclic enol ether 199 in excellent yield [182,183]. In addition to the attachment of a two-carbon unit, this HDA reaction caused both protection and regioselective activation of the ketone group in its enol ether form. Upon reduction of ester moiety in 199 using DIBAL, aldehyde 200 was obtained, which was reacted with propargyl magnesium bromide, resulting in the introduction of an ethynyl group to deliver the corresponding propargyl alcohol 201. The latter was subjected to cyclization reaction using (Ph3P)AuCl and AgSbF6 in MeOH to deliver compound 202 in satisfactory yields. It is assumed that the cyclization occurred between the ethynyl group and the enol ether moiety of 201 in a 5-exo-dig fashion leading to the construction of pyran

44 Applications of Name Reactions in Total Synthesis of Alkaloids

ring, which was cleaved to form a dimethyl acetal moiety in the expected product 202. The latter upon acidic hydrolysis of its dimethyl acetal gave aldehyde 203, which underwent reductive amination with benzylamine to afford tricyclic compound 204 [177a]. Dess-Martin oxidation of the latter generated enone 205, which was transformed into 2-pyridone 207 following the procedure reported previously [184], in which 2-(phenylsulfinyl) acetamide (206) initially was added (conjugate addition) to the enone moiety followed by cyclization and removal of sulfoxide under acidic conditions. To complete the total synthesis, the benzyl group on the nitrogen atom of 207 was removed via standard hydrogenolysis to furnish the desired lycoposerramine-R (208) (Scheme 2.18). The Ericaceae are a family of flowering plants commonly recognized as the heath or heather family and have been used for a long time in traditional herbal folk medicines to treat various diseases due to their curative properties. The family is large and found most commonly in acidic and infertile growing conditions. There are 4250 identified species, and over 150 grayanane

SCHEME 2.18 Total synthesis of lycoposerramine-R (208).

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diterpenoids have been isolated from this genus [185]. One of the most wellknown and economically important members of the Ericaceae is Rhododendron. Rhodomolleins XX (230) and XXII (231), two congeners of the grayanoid family, were isolated from Rhododendron molle G. Don (Ericaceae) [186]. Biosynthetically, these molecules are presumed to create from a common entkaurane scaffold that involves a characteristic bicyclo-[3.2.1]octane (C/D) ring system [187]. These discrete features make grayanoids striking targets for synthetic investigations [188]. Nevertheless, only two total syntheses have been reported, apparently due to the contests in the construction of their polyfunctionalized tetracyclic framework. Matsumoto and co-workers achieved and reported total synthesis of grayanotoxin II based on a key biomimetic photo-santonin rearrangement in 39 steps [188a,b], and Shirahama et al. accomplished an asymmetric total synthesis of ()-grayanotoxin III in 38 steps in 1994 [188c]. Ding and co-workers accomplished the first total synthesis of rhodomolleins XX and XXII in 23 and 22 steps and disclosed their results in 2019 [189]. Their strategy comprised a Ti(III)-assisted reductive epoxide-opening/ Beck witheDowd rearrangement process that capably installed the bicyclo [3.2.1]octane scaffold of highly oxidized grayanane diterpenoids as well as incorporation of a Cu(tbs)2-catalyzed intramolecular cyclopropanation, a diastereoselective oxidative dearomatization induced DA cycloaddition and a MeReO3-catalyzed Rubottom oxidation. Although this strategy has permitted the first total synthesis of rhodomolleins XX and XXII in 23 and 22 steps, respectively, it can be adapted to the total synthesis of other members of other grayanoids as well as other related diterpenoids and alkaloids and permit further evaluation of their biological activities. This approach started with construction of the ketoepoxide 220. The 1,2-addition of Grignard reagent 209, provided in four steps from commercially accessible, 3-hydroxy-2methoxybenzaldehyde [190] to 3-methylbut-2-enal gave alcohol 210 in high yield. The latter was subjected to a Claisen rearrangement with n-butyl vinyl ether [191] with subsequent Roskamp homologation of the resultant aldehyde in the presence of catalytic amount of SnCl2 and ethyl diazoacetate to deliver b-keto ester 211 in good yield over two steps. Different metal catalysts for the intramolecular cyclopropanation for the construction of the A ring, Cu(tbs)2 (212), (5 mol%) [192], was selected as the catalyst of choice to promote the conversation of 211 to the anticipated [5.3]-fused bicycle 213 in high yield over two steps. Ring-opening of the cyclopropane in 213 accompanied by acetal protection of the ketone upon exposure to TMSOTf/(CH2OTMS)2, provided 214 in satisfactory yield. A substrate-controlled epoxidation of the D6,7 olefin 214 gave the b-isomer as sole compound, which upon further hydrogenative ring-opening of the generated epoxide at the benzylic position gave 215 in respectable yield over two steps. The latter upon, a tandem b-keto phosphonate formation/HornereWadswortheEmmons olefination in the presence of excess LDA delivered enone 216 in high yield. Desilylation of 216

46 Applications of Name Reactions in Total Synthesis of Alkaloids

generated intermediate vinylphenol 217, which then subjected to an IMDA cycloaddition catalyzed by PhI(OAc)2 in MeOH, to afford a 2.8:1 mixture of 218 a and 218b (ORTEP drawing) in excellent combined yield [193]. Compound 218a was subjected to SmI2-catalyzed reductive demethoxylation to afford 219, in which upon the epoxidation of the D13,14 olefin proceeded from the rounded face of the bicyclo[2.2.2]octane scaffold gave the desired 220 as a single diastereomer in high yield over two steps. Having 220 in hand, sequential reductive epoxide-opening/BeckwitheDowd rearrangement reaction was planned. This plan was successfully implemented in the presence of catalytic amount of Cp2TiCl2, Mn, and 2,4,6-collidine$HCl in DCE to obtain the desired bicyclo[3.2.1]octane 222 in satisfactory yield on gram scale along with the generation of undesired but separable 221 in poor yield. The structure of 222 was established by X-ray crystallographic analysis of its corresponding diacetate 223 (ORTEP drawing). It should be mentioned that using nonpolar solvent was found crucial to the success of the above tandem reaction as well as the role played by free alcohol at C6 of 220 in the regioselective control of the reductive epoxide-opening step. With gram scale of 222 in hand, it was subjected to regioselective methylenation on its ketone moiety at its C16 using the Petasis reagent, followed by deacetylation in one-pot fashion to provide enol 224 in good yield (ORTEP drawing). Treatment of the latter with PhSeCl and pyridine, although proceeding slowly, but concurrent elimination of the resultant selenide occurred to forge the desired D1,5 double bond, delivering 225 in excellent yield. This result showed the participation of an exclusive a-facial selenation [194], which have been supported by the fact that addition of unnecessary oxidants (m-CPBA, H2O2, NaIO4, etc.) to make the elimination faster via a selenoxide intermediate resulted in messy reaction mixtures. As anticipated, Mukaiyama hydration of the more reactive D15,16 olefin took place from the convex face of the bicyclo[3.2.1]octane scaffold affording triol 226 in good yield as a single diastereomer. After cautious protection of the ketone at C2 as a silyl dienol ether (227), the Grignard addition to the C10 ketone, which was apparently directed by the pseudo-axial C6eOH, afforded 228 as the exclusively detectable isomer. The latter without being isolated, was further converted into the desired alkaloid rhodomollein XXII (231) under an acidmediated desilylation in satisfactory yield over two steps. On the other hand, the a-hydroxylation at C3 of 31 seemed being challenging. Although Rubottom oxidation using DMDO showed an acceptable diastereoselectivity (2.5:1 at C3), the chemical yield was unacceptable. (ca. 20%). Using other oxidants such as m-CPBA, Davis’ oxaziridine, and Cu/TBHP, although increased the yield but resulted in desilylation of the enol ether, and the dihydroxylation of 228 to give 229 and its C3 epimer in high yield but as a mixture in 4:1 ratio. Pleasantly, by using the catalytic amount of MeReO3, H2O2, and pyridine [195], 229 was provided in excellent d.r. (>20:1). The latter was then deprotected in the presence of PPTS to furnish the desired

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alkaloid rhodomollein XX (230) in satisfactory yield over three steps. 1H and 13 C NMR spectra recorded from synthetic samples of 230 and 231 were compared with those of authentic samples isolated from natural sources that were found to be in full agreements (Scheme 2.19) [196].

SCHEME 2.19

Late-stage synthesis of rhodomolleins XX (230) and XXII (231).

48 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 2.19 cont’d

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50 Applications of Name Reactions in Total Synthesis of Alkaloids [25] [26] [27] [28] [29] [30] [31] [32] [33]

[34] [35] [36] [37] [38] [39]

[40] [41] [42] [43]

[44]

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Chapter 3

Recent advances in applications of FriedeleCrafts reactions in total synthesis of alkaloids Chapter outline 1. Introduction 2. Applications of FriedeleCrafts in total synthesis of alkaloids 2.1 Intermolecular FriedeleCrafts alkylation reactions

59 62 62

2.2 Intramolecular FriedeleCrafts alkylation reaction 2.3 FriedeleCrafts acylation reaction References

79 93 96

1. Introduction FriedeleCrafts (FC) reactions in organic chemistry refer to two main reaction typesdalkylation and acylation. FC reactions are frequently employed to attach substituents to an aromatic ring [1]. Historically, Charles Friedel and James Mason Crafts successfully obtained amylbenzene in 1887 when they treated amyl chloride with aluminum chloride (AlCl3) in benzene (Scheme 3.1) [1]. Both FC reaction types are classified as electrophilic aromatic substitution [2e5]. FC alkylation consists of the alkylation of an aromatic ring with an alkyl halide catalyzed by strong Lewis acids such as AlCl3, ferric chloride, or other MXn reagents [6]. A general mechanism for FC alkylation using tertiary alkyl halides has been suggested, as depicted in Scheme 3.2 [7]. Naturally, as is the case for other important organic reactions that have been modified during the

SCHEME 3.1 Aluminum chloride (AlCl3)-mediated reaction between amyl chloride and benzene as originally developed by Friedel and Crafts in 1887. Recent Applications of Selected Name Reactions in the Total Synthesis of Alkaloids https://doi.org/10.1016/B978-0-12-824021-2.00009-1 Copyright © 2021 Elsevier Inc. All rights reserved.

59

60 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 3.2 A suggested mechanism for the FriedeleCrafts alkylation reaction.

intervening years, FC reactions have witnessed several modifications since their development, especially the utilization of other Lewis acids as catalysts instead of the commonly used AlCl3. In this regard, other Lewis acids such as BF3, BeCl2, TiCl4, SbCl5, Sc(OTf)3, Mo(CO)6, and SnCl4 have been successfully used as catalysts in several FC alkylation reactions. Moreover, strong Brønsted acids involving hydrofluoric acid, sulfuric acid, or superacids such as HF.SbF5 and HSO3F.SbF5 have also been fruitfully examined as catalysts and have shown dramatic acceleration in this transformation; of course, each possesses showed its merits and drawbacks. One major and well-realized drawback in FC reactions is the requirement for stoichiometric or superstoichiometric amounts of a Lewis or Brønsted acid. From a green chemistry point of view, utilizing toxic alkyl halides as starting materials inevitably leads to the formation of vast quantities of side products as salts. Thus, the further development of FC reactions that can be performed effectively under a process that is both environmentally benign and cost-effective is still much in demand. In this regard, the replacement of alkyl chlorides with other less toxic alkylating reagents such as alcohols was a major improvement in FC alkylation reaction. Delightfully, several nontoxic alcohols and many activated double bonds have been successfully used instead of alkyl halides. In such reactions, the use of alcohols results in only water as the side product, whereas the use of compounds bearing activated double bonds, such as styrenes, is anticipated to have no side products [8]. Such improvements have made FC alkylation reaction a method of choice for the alkylation of arenes and heteroarenes in both academia and chemical industries [9]. In addition, the FC acylation reaction is used for the acylation of aromatic rings catalyzed by the same Lewis acid, such as AlCl3. The most common acylating agents used in FC acylation reactions are various acyl chlorides and also acid anhydrides (Scheme 3.3) [10]. It is worth mentioning that the product of an FC acylation reaction is a ketone that upon creation forms a relatively stable complex with Lewis acids such as AlCl3. The formation of this complex is typically irreversible under reaction conditions, and thus for efficient FC acylation, a stoichiometric amount or more of the Lewis acids should generally be used, which is dissimilar to the case with FC alkylation, in which Lewis acids are used in

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61

SCHEME 3.3 A typical FriedeleCrafts acylation reaction.

catalytic amounts because they are continuously regenerated. However, other reaction conditions for FC acylation are similar to those of FC alkylation, and other attributes of FC acylation give it greater merit than FC alkylation. The product of FC acylation is a ketone that contains a carbonyl group and is electron-withdrawing; thus, the ketone product is always less reactive than the original molecule, and therefore undesired multiple acylations do not take place. More importantly, in the FC alkylation reaction, a carbocation is generated as a reactive intermediate that can be subjected to rearrangements, which is a common phenomenon in carbocation chemistry, while in FC acylation, a generated acylium ion is stabilized by resonance in which one of the resonance forms bears a positive charge on the oxygen (Scheme 3.4). The sustainability of the FC acylation reaction depends greatly on the stability of the reagent used. Among acyl halides, formyl chloride is too unstable to be isolated. Thus, in the synthesis of benzaldehyde through FC acylation, the required formyl chloride should be generated in situ. In such cases, the GattermanneKoch reaction is a good alternative. It involves the reaction of benzene and carbon monoxide (CO) in the presence of a mixture of AlCl3, cuprous chloride, and HCl as a catalytic system under high pressure [11]. A reasonable mechanism for FC acylation has been proposed as depicted in Scheme 3.4. Initially, an acylium center is generated. The reaction is completed by deprotonation of the arenium ion using AlCl-4 that is regenerated from AlCl3. However, dissimilar to the case of a strictly catalytic alkylation reaction, the ketone product obtained is usually of moderate yield. Notably, the

SCHEME 3.4 Suggested probable mechanism for FriedeleCrafts acylation reaction.

62 Applications of Name Reactions in Total Synthesis of Alkaloids

Lewis base generated during this reaction reacts with a strong Lewis acid such as AlCl3 to form a complex. Noticeably, the formation of this complex is usually irreversible under reaction conditions. Therefore, a stoichiometric amount of AlCl3 is required. Upon aqueous workup, this formed complex is destroyed to produce the desired ketone. As an example, in the typical synthesis of deoxybenzoin, 1.1 equivalents of AlCl3 are required with respect to the limiting reagent, phenylacetyl chloride [12]. It is worth mentioning that in certain cases, especially when an activated benzene ring is used, FC acylation can be successfully performed in the presence of a catalytic quantity of a milder Lewis acid (e.g. Zn(II) salts) or a Brønsted acid catalyst using anhydride or even carboxylic acid as the acylation agent. Applications of FC reactions (alkylation and acylation) in organic synthesis have been widely studied and reported [6,12e16]. Moreover, the application of FC reactions in the total synthesis of natural products and complex molecules showing diverse biological activities, and the application of intermolecular and intramolecular FC reactions in the total synthesis of natural products, have been reviewed by our group [17]. Due to the importance and usefulness of FC reactions in the art of organic synthesis, in this chapter, we try to underscore the applications of FC reactions in the total synthesis of one the most important, widespread, and prevalent families of natural products showing diverse biological properties, the so-called “alkaloids.”

2. Applications of FriedeleCrafts in total synthesis of alkaloids 2.1 Intermolecular FriedeleCrafts alkylation reactions Epipolythiodiketopiperazine alkaloids exemplify a structurally interesting and biologically potent class of secondary fungal metabolites [18,19]. Among them, (þ)-luteoalbusin A (20) and (þ)-luteoalbusin B (21) have exhibited interesting biological activities. In 2012, Wang et al. isolated [20] (þ)-luteoalbusin A (20) and (þ)-luteoalbusin B (21) from the marine fungi Acrostalagmus luteoalbus [20]. Such naturally occurring compounds comprise a C3-(30 -indolyl) substituent and an epipolythiodiketopiperazine (ETP) substructure bearing a di- or trisulfide bridge with a diketopiperazine self-possessed of tryptophan and serine. Movassaghi and coworkers accomplished and reported the brief total synthesis of (þ)-luteoalbusins A (20) and B (21) and reported this achievement in 2015. This strategy comprises the FC reaction, C3-indole addition to a cyclotryptophan-derived diketopiperazine, a late-stage diketopiperazine dihydroxylation, and a C11-sulfidation sequence [21]. This total synthesis commenced with the Ag-mediated FC reaction of already known diketopiperazine (þ)-13 [20], which upon reaction with indole derivative 12 in the presence of silver(I) hexafluoroantimonate and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) in CH2Cl2 gave the expected

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C3-indolylhexacycle (þ)-14 in good yield. The latter was then transformed to the required key indoline (þ)-15. Subsequent reaction of 15 with triphenylmethanesulfenyl chloride (TrSCl) and Et3N provided the anticipated mixed disulfide ()-16 in virtually quantitative yield [22]. Upon activation of the C15 isobutyrate group of the latter followed by cyclization of the disulfide with concurrent elimination of the triphenylmethyl cation, catalyzed by BF.3OEt2 in CH2Cl2, (þ)-luteoalbusin A acetate (18) was obtained in excellent yield. Unveiling of the C17 alcohol from acetate (þ)-18 was accomplished by trimethyltin hydroxide [23] in toluene at 90  C to give the desired natural product, (þ)-luteoalbusin A (20) in good yield. Notably, all physical and spectral data collected and recorded for the synthesized (þ)-luteoalbusin A (20) were in agreement with those obtained for the authentic sample isolated from the natural source [20]. The total synthesis of (þ)-luteoalbusin B (21) was also achieved by utilization of the vital intermediate thioisobutyrate (þ)-15. The required mixed trisulfide (þ)-17 was provided in satisfactory yield upon sequential treatment of thioisobutyrate (þ)-15 with hydrazine followed by the addition of chloro(triphenylmethyl)disulfane (TrSSCl) in the presence of Et3N as described above [22]. In situ acylation of the N1 indoline nitrogen of trisulfide (þ)-17 using (CF3CO)2O and DTBMP in CH3CN with subsequent addition of hafnium trifluoromethanesulfonate gave the required precursor epitrithiodiketopiperazine (þ)-19 in excellent yield, albeit as a 1.6:1 mixture of epitrisulfide conformers (Scheme 3.5). Sequential C17-deacylation of corresponding luteoalbusin B (þ)-19 through mild methanolysis in the presence of Otera’s catalyst [24] with subsequent N1-deacylation by hydrazinolysis [22] furnished the desired natural product (þ)-luteoalbusin B (21) in good yield as a 4:1 mixture of epitrisulfide conformers. All physical and spectroscopic data for the synthetic sample of (þ)-luteoalbusin B (21) were in accord with those of the authentic compound reported by Wang and co-workers [20]. Tropical endophytic fungi were found to be ironic and dependable sources of a broad range of bioactive compounds [25]. In 2013, Cubilla-Rios and coworkers isolated ()-mycoleptodiscin A (34) from the endophytic fungus Mycoleptodiscus sp [26]. It contained a sesquiterpenoid scaffold linked to the C-3 and C-4 positions of the indole group. 4,5 Mycoleptodiscin B was found to inhibit cell growth of four cancer cell lines, whereas the biological potency of mycoleptodiscin A (34) is not yet broadly known, probably due to its natural source insufficiency. In this regard, in 2016, Dethe and co-workers demonstrated a biomimetic total synthesis of ()-mycoleptodiscin A (34) commencing with a chiral key intermediate provided by FC alkylation of 7methoxyindole and an enantiopure primary allylic alcohol [27]. Interestingly, this intramolecular FC reaction at C-4 of the indole derivative could be used in the total synthesis of other C-4-substituted indole alkaloids, which are prevalent in other natural products. 1,7-Methoxyindole (28) and alcohol (þ)-27 were found to be appropriate precursors for the inter- and

64 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 3.5 Total synthesis of (þ)-luteoalbusins A (20) and B (21).

intramolecular FC reaction as a key step in the biomimetic total synthesis of ()-mycoleptodiscin A (34). 1,7-Methoxyindole (28) was commercially available or easily accessible, whereas alcohol 27 was synthesized in six steps from WielandeMiescher ketone derivative 22 [28]. Thus, total synthesis of ()-mycoleptodiscin A (34) was started by the intermolecular FC reaction of 1,7-methoxyindole (28) and allylic alcohol 27 in the presence of BF3$OEt2 in CH2Cl2 to give 3-alkylated indole 29 in high yield. Next, after four steps, compound 29 was converted into 7-hydroxyindole derivative 33. Pleasantly for the oxidation, the radical oxidant Fre´my’s salt [29] was successfully used instead of the alternative, IBX, to afford the desired natural product mycoleptodiscin A (34) with higher yield (Scheme 3.6). The physical and spectral data of the synthetic sample were in complete agreement with those of the authentic sample isolated from the natural source [26]. (þ)-Haplophytine (46) is classified as a dimeric indole alkaloid [30] and was initially isolated in 1952 from the dried leaves of the shrub Haplophyton

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SCHEME 3.6 Total synthesis of ()-mycoleptodiscin A (34).

cimicidum grown in Central America by Snyder and coworkers [31]. Leaves of the plant have been used as an insecticide since ancient times, and Alam et al. found that (þ)-haplophytine (46) exhibited inhibition toward acetylcholinesterase [32]. From a structural point of view, (þ)-haplophytine (46) contains a diazabicyclo[3.3.1]nonane scaffold in the left unit, while the right unit has an aspidosperma one. This fascinating structure has stimulated synthetic organic chemists to strive for its total synthesis [33]. The first total synthesis of (þ)-haplophytine (46) was achieved and reported in 2009 by Tokuyama and co-workers [34] and was followed instantly by the further endeavors of Nicolaou and coworkers [35]. Following that, Tokuyama and coworkers in 2016 reported the total synthesis of (þ)-haplophytine with direct coupling and latestage oxidative rearrangement as key steps. This synthetic approach comprised the direct coupling of the two units via - an AgNTf2-catalyzed FC reaction, building of the diazabicyclo[3.3.1]nonane scaffold via late-stage chemoselective aerobic oxidation of the 1,2-diaminoethene group, trailed by a

66 Applications of Name Reactions in Total Synthesis of Alkaloids

sequential semipinacol-type rearrangement [36]. The total synthesis started from aspidosperma compound 35 [37] that was initially reduced under Luche reaction conditions [38] to provide a secondary amine, which upon allylation afforded compound 36. The precursor for the preparation of the left unit, iodoindolenine (39), was easily synthesized from indole 37 [34] by its transformation to chiral and pure optically active tetrahydro-b-carboline 38 followed by treatment of the resultant with NIS. Next, in a crucial step, the direct coupling of 36 and 39 via the AgNTf2-catalyzed FC reaction provided a separable mixture of dimeric compounds, cis-40 and trans-41 (ca. 2.4:1) in a good combined yield. After separation of cis-40 as key intermediate, it was converted into compound 45 in five steps. Ultimately, upon sequential removal of the tosyl group of 45/saponification of the methyl ester and oxidative formation of the lactone ring [39], the desired alkaloid (þ)-haplophytine (46) was obtained in satisfactory yield (Scheme 3.7). Che and coworkers initially isolated (þ)-asperazine (56) along with (þ)-pestalazine A (54) and the C3sp3N10 linked (þ)-pestalazine B in 2008 from the plant pathogenic fungus Pestalotiopsis theae [40]. Fascinatingly, in a second examination of extracts from Aspergillus niger, the same research group also successfully extracted N10 -linked isomer of (þ)-asperazine (56) and congener of iso-pestalazine A (65) and (þ)-pestalazine A 66 [40]. In general, alkaloids containing hexahydropyrroloindole scaffold are structurally interesting and show biologically diverse activities [41]. The dimeric diketopiperazine incorporation of these metabolites is supplied with the sort of molecular complexity that frequently results in the development of new synthetic strategies [42]. Indisputably, one of the utmost challenges for synthetic organic chemists is developing effective entree for the introduction of the quaternary chiral centers with the desired configurations via stereoselective CeC bond formation. The alkaloids containing heterodimeric diketopiperazines with an exceptional quaternary C33spC80 2sp join, as the prototypical targets have also grabbed the attention of synthetic community. In this regard, the total synthesis of (þ)-asperazine (56) [43] and its very recently isolated congeners (þ)-iso-pestalazine A (65) and (þ)-pestalazine A (66), which contain the heterodimeric diketopiperazine framework with an exceptional quaternary C33spC80 2sp join, has generated much interest in the synthetic community. While exceptional developments have been accomplished in the synthesis of C3-aryl pyrroloindolines [44e46], the introduction of the C3quaternary chiral center in the synthesis of diketopiperazines has been largely overlooked. Gratefully, Overman’s sophisticated total synthesis of (þ)-asperazine (56) [47] established an initial introduction of the C3quaternary chiral center via an intramolecular Heck reaction [48] with subsequent formation of the diketopiperazines. This achievement seems to be a prospect for the future and the only key answer to the total synthesis of alkaloid (þ)-asperazine (56).

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SCHEME 3.7 Bioinspired total synthesis of (þ)-haplophytine (46).

67

68 Applications of Name Reactions in Total Synthesis of Alkaloids

In the total synthesis of the (þ) naseseazine B alkaloid (51), the desired C3arene connectivity was tenable by placement of an N1-protected C3substituted indole ()-47 with potent p-nucleophilicity at its C60 /C70 positions [49]. Fashionable C70 FC regioselection for compound ()-50 was guaranteed by the use of trifluoroborate ()-48, whose anionic directing group could ease fitted ion pairing with the C3-derived cation from bromide (þ)-49. Finally, compound 50, upon catalytic hydrogenation, was converted to the desired (þ) naseseazine B alkaloid (51) [50] in good yield (Scheme 3.8) [49,52]. Armed with this experience, Movassaghi and co-workers accomplished the total synthesis of alkaloids (þ)-asperazine (56), (þ)-iso-pestalazine A (65), and (þ)-pestalazine A (66) and revealed their results in 2016 [51]. Their strategy involved a late-stage C3eC80 FC reaction of polycyclic diketopiperazines to secure the challenging formation of the C3sp3C80 sp2 linkage [49]. The elegant and integrated total synthesis of alkaloids (þ)-asperazine (56), (þ)-iso-pestalazine A (65) and (þ)-pestalazine A (66) was completed in 11 steps starting from market purchasable N-Boc-L-tryptophan methyl ester with 6.8%, 8.0%, and 4.8% overall yields. A vital step of this approach was a novel developed regioselective reductive ring opening reaction that allowed the transposition of a more p-nucleophilic and regioselective indoline onto the final late step, leading to diverse installation. Such an approach was a gift to the researchers, with the greatest tractability in rapid regaining of C3eC80 bound structural alternatives of these kinds of fascinating natural products for future research.

SCHEME 3.8 Concise total synthesis of naseseazine B (51).

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The simplest approach to total synthesis of alkaloid (þ)-56 started from trifluoroborate (þ)-52a, which was reacted with bromide (þ)-53a in the presence of AgSbF6, DTBMP, and 18-crown- 6 in Et2NO2 under FC reaction conditions as a vital step to afford compound 54a in moderate yield. The latter was transformed to indoline (þ)-55 after several steps, and in turn indoline was converted into the desired alkaloid, (þ)-asperazine (56), in two steps including treatment with trifluoroacetic acid (TFA) in CH2Cl2 and further interaction with TFA in CH2Cl2/n-BuOH as a solvent system under pressure at 120  C (Scheme 3.9) [51]. Although this total synthesis of alkaloid (þ)-56 [47] was a great accomplishment, it more importantly resulted in the development of a methodology for the fruitful introduction of the C3-quaternary chiral center to the synthesis of the diketopiperazines present in several other alkaloids. An alternative total synthesis of (þ)-asperazine (56) was also achieved starting with initial attempts to obtain tetracyclic bromide (þ)-53a via diastereoselective bromocyclization of indole (þ)-57a [53] using N-bromosuccinimide (NBS), BF3$OEt2 in MeCN, at 0  C to obtain the versatile bromides (þ)-53a and (þ)-53b on a gram scale. With enough bromide (þ)-53a and (þ)-53b in hand, it was converted to the corresponding C6chlorinated tetracycles (þ)-58a and (þ)-58b. First, 53a was treated with Nchlorosuccinimide (NCS), TFA in MeCN, at 23  C and then (þ)-53b in chlorosuccinimide (NCS), TiCl4, in MeCN to afford the corresponding

SCHEME 3.9 Total synthesis of (þ)-asperazine (56).

70 Applications of Name Reactions in Total Synthesis of Alkaloids

C6-chlorinated tetracycles (þ)-58a and (þ)-58b, respectively. Silver(I) (AgSbF6)-promoted C3 bromide ionization in EtNO2 converted indolines (þ)-58a and (þ)-58b to the corresponding hydrates (þ)-59a and (þ)-59b, respectively, with satisfactory yields. Then, hydrates (þ)-59a and (þ)-59b were converted into their silyl ethers (þ)-60a and (þ)-60b on multigram scale, respectively. The silyl ethers (þ)-60a and (þ)-60b under mild Pd-catalyzed carboxybenzyl removal [54] in the presence of Pd(OAc)2, Et3SiH, NEt3 in CH2Cl2 as solvent afforded the required indolines (þ)-61a and (þ)-61b, respectively. Notably, no trace of dehalogenated product was observed. Next, in a vital step, (þ)-61a and (þ)-58a were reacted under a silver-promoted FC reaction (AgSbF,6 DTBMP, EtNO,2 23  C) to afford bisindoline (þ)-62a. Decisive HMBC and NOESY correlations obtained from two-dimensional NMR analysis supported the previously structural elucidation of bis-indoline (þ)-62a [51]. Substrate (þ)-62a (MsOH, Et3SiH, CH2Cl2, 23  C) gave the corresponding silyl ether (þ)-63a in satisfactory yield [55]. Silyl cleavage proceeded smoothly, scrutinizing various conditions. The highest yield (67%) was obtained using a combination of triethylsilane with methanesulfonic acid to afford the expected desilylated compound (56). The product was identified as (þ)-asperazine (56) by comparison of its spectral data and optical rotation with those of the authentic sample of Overman’s synthetic (þ)-asperazine [47] and the isolated metabolite [43] (Scheme 3.10). Total synthesis of (þ)-pestalazine A (65) was also achieved by using D-leucine counterpart (þ)-61b instead of indoline (þ)-61a and reacting it with bromide (þ)-58a in nitroethane under the same Ag-mediated conditions via an FC reaction to produce the respective bis-chlorinated dimer (þ)-62b in moderate yield. The latter was then hydrodehalogenated to give silyl ether (þ)-63b in high yield, which subsequently was desilylated using tetrabutylammonium fluoride and also proceeded smoothly to give alcohol (þ)-64b in high yield. The latter was subjected to an already secured optimal reductionring opening strategy using methanesulfonic acid and triethylsilane, TBAF, THF, 23  C, 1 h and MsOH, Et3SiH, CH2Cl2, 23  C, 4 h to furnish the desired alkaloid indole (þ)-65 in good yield. Significantly, indole (þ)-65 came to be considered (þ)-iso-pestalazine A, showing an optical rotation of þ99 degrees (c 0.17, MeOH) compared with Che’s value of þ203 degrees (c 0.10, MeOH) [40] for natural (þ)-pestalazine A. This auspicious discovery resulted in an ideal podium to reveal the power of the modular FC reaction to CeC bond formation (Scheme 3.10) [51]. The total synthesis of (þ)-pestalazine A (66) started with an FC reaction. The required FC components indoline (þ)-61a and bromide (þ)-58b, already in hand, were subjected to FC reaction conditions (in the presence of AgAbF6, DTBMP in Et2NO2) to obtain dimer (þ)-62c in moderate yield. Then, upon related carboxybenzyl hydrogenolysis and bis-dechlorination of dimeric substrate (þ)-62c followed by desilylation of ether, (þ)-63c was obtained in high yield, which was converted to 64c upon treatment with TASF in DMF, in

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SCHEME 3.10 Total synthesis of (þ)-asperazine (56) and (þ)-iso-pestalazine A (65).

respectable yield. The alcohol (þ)-64c, upon reduction and ring-opening, furnished indole (þ)-66 in high yield (Scheme 3.11) [51]. Delightfully, all physical and spectral data of synthetic (þ)-66 were in complete accord with

72 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 3.11 Total synthesis of (þ)-pestalazine A (66).

those of the sample isolated and reported by Che et al. for (þ)-pestalazine A, and thus confirmed the correct structure of (þ)-66. In addition, the optical rotation for (þ)-66 was þ211 degrees (c 0.13, MeOH), which was in accord with the reported value for the sample isolated from the natural source [40]. In the late 1920s, Henry et al. first classified “akuamma” in proceeding to name a series of novel alkaloids isolated from Picralima nitida (akuamma trees) [56]. The naturally occurring akuammiline compounds, classified as a family of alkaloids, have attracted much interest from synthetic organic chemists [57]. Akuammiline-containing herbs have been used as folk medication by native societies of Southeast Asia and West Africa for the treatment of respiratory diseases, chronic pain, and malaria [58]. Recent investigations on akuammilines have disclosed a broad range of biological potencies. They have been found to have antibacterial, antiinflammatory, and anticancer properties and thus have received considerable global attention from synthetic organic and medicinal chemists. (þ)-Strictamine (83) is classified as an akuammiline-type compound; it was initially isolated by Schnoes and coworkers in 1966 [59] and showed NF-kB inhibition [60]. From a structural point of view, it is categorized by a highly crowded methanoquinolizidine cage bearing four surrounded chiral centers. These structural shapes have made this distinctive molecule a striking objective among the synthetic community, and much effort has been made toward its total synthesis [61]. So far, 14 members of the akuammiline alkaloid family have been synthesized by several research groups [62,63]. Three recognized total syntheses of strictamine (83) have been reported by Fujii/Ohno [63S], Gaich [63t,u], and Snyder [63v]. Markedly,

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among all these total syntheses, the only enantioselective strategy accomplished and revealed was by Garg [63q] and Snyder coworkers [63v]. Total synthesis of strictamine (83) was achieved and reported by Qin and coworkers in 2016. It involved FC cyclization as a vital step to construct the D-ring and the critical C7 all-carbon quaternary carbon center as well as an aza-1,6-conjugate addition to install the 2-azabicyclo[3.3.1]nonane system [64]. This group accomplished and reported an effective stereoselective total synthesis (þ)-strictamine commenced from readily available 67 that was transformed to tetracycle 75. Based on work by Bach and coworkers [65], the latter was then subjected to a Pd(II)-mediated regioselective FC reaction [65] at the C-2 position of the indole proceeding smoothly in the presence of bromide 68 to furnish the key intermediate tryptophan derivative 67. The latter was then transformed to compound 75 after several steps. Having compound 75 available in multigram quantities, it was converted to compound 82 as an important synthetic intermediate after several steps, including removal of the N4-Boc group in 80 employing CF3COOH in CH2Cl2 [63r], which was introduced by Zhu and coworkers as an intermediate in total synthesis of racemic strictamine [63r]. At last, 82 in optically pure form was transformed to the desired target, (þ)-strictamine (83). The NMR spectral data for compound 82 were compared with those reported in the literature and found to be identical [63reu]. Thus, by successful synthesis of enantiomerically pure 82, a novel asymmetric total synthesis of (þ)-strictamine (83) was accomplished (Scheme 3.12). Hexahydropyrroloindole alkaloids demonstrate structural assortment and a broad array of biological potencies and thus have attracted much interest from synthetic organic chemists [66]. This subfamily of alkaloids includes compounds such as T988s [67], (þ)-gliocladine C [68], (þ)-bionectin A [69], and (þ)-leptosin D [70], which were verified to be gifted as lead compounds for several new antitumor agents [68,69,71]. In 2017, Tokuyama et al. accomplished and reported the total synthesis of (þ)-T988 B and C in 19 and 18 steps in a 20.2% overall yield. In this strategy, the indole unit was brought together regioselectively at the sterically hindered C10b position via asymmetric bromocyclization followed by AgNTf2-catalyzed FC reaction. The dithiodioxopiperazine unit was effectively built through radical-promoted CeH brominationedehydrobromination protocol of the dioxopiperazine ring in one-pot fashion [72]. The total synthesis of (þ)-T988 B (99) and C (98) started with condensation of L-tryptophan methyl ester hydrochloride (84) and D-serine derivative 85 [73] followed by TBS protection of the resulting primary alcohol and Boc protection of the indole NH to obtain compound 87, which in turn was transformed to dioxopiperazine 88 through elimination of the benzyloxycarbonyl moiety and treatment with base. The latter then underwent bromocyclization upon treatment with NBS in toluene or CH2Cl2 according to Sodeoka’s procedure to obtain a mixture of the desired bromopyrroloindoline

74 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 3.12 Formal total synthesis of (þ)-strictamine (83).

89 and its undesired diastereomer 90 as a by-product [74]. Having desired substrate 89 available, it was reacted with indole in the presence of AgNTf2 in CH2Cl2 at 0  C under FC reaction conditions to obtain the desired coupling product 91 in moderate yield along with a tiny quantity of inseparable respective regioisomers to variation of the indole position (5- or 6-position of the indole). Having established an easy and stereoselective installation of the chief scaffold of T988s via diastereoselective bromocyclization and highly effective AgNTf2-catalyzed coupling of bromopyrroloindoline with indole via FC reaction, compound 89 was transformed to diacetate 97 after several steps. The total syntheses of (þ)-T988 B (99) and C (98) were completed via

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decisive construction of epidithiodioxopiperazine relying on Overman’s strategy [75]. Compound 97 was treated with hydrogen sulfide in the presence of BF3$OEt2, assisting in the elimination of TBS and two Boc protecting groups and formation of dithiol through the generation of an N-acyliminium ion, followed by exposure of the resulting dithiol to iodine to generate epidithiodioxopiperazine derivative, which upon methanolysis catalyzed by La(OTf)3 in MeOH, provided the desired target, (þ)-T988 C (98). In addition, upon treatment of the latter with NaBH4 and reacting the resultant with methyl iodide [76], another desired natural product, (þ)-T988 B (99), was obtained (Scheme 3.13). The alkaloids, comprising [2,3-b]indole diketopiperazine (DKP) derivatives, are a huge and assorted class of tryptophan isolated from natural sources [66]. They all contain indole moiety at the C-3 position. Due to their interesting molecular structures and biological potencies as anticancer, antiviral, and antibacterial agents, they have been viewed with considerable fascination [77e79]. Among them, gliocladin C (109) especially has stirred up the interest of synthetic organic chemists. It was initially isolated by Usami et al. in 2004 and showed cytotoxic properties in P388 lymphocytic leukemia cells in vitro [80,81]. Although the core skeletal in gliocladin C (109) is conjoint to other DKP alkaloids, it exceptionally comprises a trioxopiperazine group uncommon in other alkaloids of this class. Total synthesis of gliocladin C (109) was achieved by Martin and coworkers and reported in 2017 [82]. This exceptional protocol involved a unique nucleophilic addition of a diketopiperazine as an isatin derivative with subsequent crucial FC alkylation of the resultant tertiary alcohol with indole to provide the strategic quaternary center. Chemoselective oxindole reduction and cyclization gave hexahydropyrrolo [2,3-b]indole diketopiperazine as a key intermediate that was easily transformed into ()-gliocladin C, ()-T988C, and ()-gliocladine C, concluding in the shortest pathway to such alkaloids that has been achieved to date, needing only eight steps and giving an 18.2% overall yield from market purchasable 100. In addition, Overman et al. have attractively demonstrated that gliocladin C can be employed as a vital intermediate in the synthesis of many related ETP alkaloids, including T988 C (98) and gliocladine C (109) [67,75]. Total synthesis of ()-gliocladin C (109) was started from market purchasable or readily available oxazolidine 100, which reacted with isobutylchloroformate to form a mixed anhydride that was in situ reacted with serine methyl ester hydrochloride 101 in the presence of N-methyl morpholine to give the already known dipeptide derivative 102 in good yield in one-pot fashion. The latter, upon catalytic reduction and hydrogenolysis (H2, 10% Pd/C) in the presence of HCl with subsequent treatment with NH4OH, gave the desired DKP 103 in high yield. Having 103 available, it was converted to 105. Generation of the quaternary center required trapping of the stabilized carbocation intermediate created from ionization of the tertiary alcohol group in

76 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 3.13 Total synthesis of (þ)-T988 C (98) and (þ)-T988 B (99).

105 with indole as a p-nucleophile [83]. Thus, the O-silylated derivative of 105 was subjected to facile ionization and reaction with indole via FC reaction catalyzed by TMSOTf furnished 106 as a sole diastereomer in high yield [66]. Upon treatment of the latter with BF3$OEt2 and subsequent addition of

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AlH3$NEtMe,2 compound 107 was obtained, which in turn was transformed as allyl scavenger 108 in excellent yield. Ultimately, cleavage of the exocyclic methylene group in the latter gave the desired natural product ()-gliocladin C (109) in moderate yield. Alternatively, 108 was dihydroxylated under Upjohnlike conditions with subsequent oxidative cleavage of the resultant vicinal diol in the presence of Pb(OAc)4 in pyridine to furnish ()-gliocladin C (109) in better yield over two steps (Scheme 3.14) [84]. It is worth mentioning that 108 is an appropriate intermediate in the total synthesis of many other naturally occurring ETP compounds. For instance, treatment of 108 with Boc anhydride mediated by DMAP gave 110 in virtually quantitative yield, which was then converted to another desired natural product, alkaloid ()-T988 C (98), in six steps (Scheme 3.15) [82].

SCHEME 3.14

Total synthesis of ()-gliocladin C (109).

SCHEME 3.15 Total synthesis of ()-T988 C (98).

78 Applications of Name Reactions in Total Synthesis of Alkaloids

In addition, intermediate 108 was hydrated at the less substituted enamide following Mukaiyama reaction conditions [85] to give 111 in high yield as a mixture (w1:1) of diastereomers. Upon silylation followed by global Boc protection, the latter was converted to 112 as a mixture (w3:2) of diastereomers in good yield. The latter was transformed by Overman et al. to the desired natural product ()-gliocladine C (109) over four steps (Scheme 3.16) [75]. Marine algae are microorganisms that function as rich sources of bioactive compounds, having various backbones in their structures and showing diverse biological potencies. They contain a class of meroterpenoids, a fused polycyclic diterpene along with an aromatic ring, in their structures. The marine brown algae, Stypopodium zonale, have plentifully originated in the Western Caribbean Sea. In 1971, Gonzalez and coworkers isolated taondiol from marine alga Taonia atomaria, which was found to be optically pure ()-taondiol [86]. In 1980, Fenical and coworkers isolated taondiol from S. zonale that was found to be (þ)-taondiol 129, an optical antipode of that formerly reported by the Gonzalez et al. [87a]. Thus, it was assumed that both enantiomers ()-taondiol and (þ)-taondiol can be provided (isolated) from different sources of marine algae. It was found that in addition to the common scaffolds that are present in substances isolated from different marine algae, both taondiol have an uncommon spiro-o-benzoquinonefuran scaffold. In 1973, Kitahara and coworkers achieved and reported the biomimetic total synthesis of DL-taondiol as racemat via acid-mediated polyene cyclization of epoxide of the geranyl derivative of toluquinol [88]. In 2018, Dethe and coworkers achieved and reported the first asymmetric total synthesis of (þ)-taondiol (129), a pentacyclic marine meroterpenoid, in 14 steps as the longest linear sequence, with a 3.1% overall yield. The same group has determined the absolute configuration of (þ)taondiol (129). The noteworthy features in the synthetic pathway are a polyfunctionalized tricyclic diterpenoid

SCHEME 3.16 Total synthesis of ()-gliocladine C (109).

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core, Robinson-type annulation, a stylish hydrogen transfer olefin reduction, and Lewis acid-catalyzed FC alkylation via one-pot manner for the CeC and CeO bond formations [89]. This supreme total synthesis of (þ)-taondiol (129) started from synthesis of the polycyclic diterpene moiety 121 as a primary target. To this end, the ketone 113 was first selectively protected by ethylene glycol, and the protected ketone was subjected to Robinson-type annulation to furnish tricyclic diterpene 114 over two steps. Then, the latter was transformed to tricyclic alcohol 121 (as an appropriate precursor for FC reaction) in gram scale after eight steps, involving different functional group transformations and protectione deprotection processes. Furthermore, the multistep synthesis of 124 as another suitable counterpart for FC reaction was contemplated and executed. It was started by VilsmeiereHaack reaction on trimethoxybenzene 122, which provided the trimethoxy benzaldehyde 123 in high yield. Then, selective demethylation of 123 was conducted in the presence of AlCl3 with subsequent reduction of the aldehyde group using NaCNBH3 to give 124 in satisfactory yield over two steps. As hypothesized, the FC reaction of hydroxyquinol 124 with already provided diterpenoid 121 in the presence of BF3$OEt2 gave a pentacyclic meroterpenoid core 125 directly via sequential CeC and CeO bond formations in good yield. After four steps, the latter was converted into demethylated product 128. In conclusion, upon hydrogenolysis using H2 and Pd(OH)2, the latter afforded the desired alkaloid, (þ)-taondiol (129), in acceptable yield over two steps. The physical and spectral data of (129) were found to be in agreement with those previously reported for the authentic compound isolated from the natural source (Scheme 3.17) [87,88aec].

2.2 Intramolecular FriedeleCrafts alkylation reaction Despite their addiction influence, natural opium alkaloids such as notorious ()-morphine and ()-codeine are two enormously imperative analgesics in clinical use [90]. Some atypical benzomorphans [91e94], as morphine analogues, have been synthesized through structural modifications. Such uncharacteristic benzomorphans significantly abridge the addiction consequence, whereas their high power and related pharmacokinetic possessions are preserved [95]. In this respect, the function of pentazocine as a prescribed drug is an exceptional example [91]. Furthermore, ()-pentazocine is 20 times more effective than its (þ)-enantiomer. Nevertheless, few stereoselective synthetic pathways for these molecules are accessible, and providing them in an optically pure form is limited to resolution of the respective racemat [92], chiral-auxiliary-induced stereoselective synthesis [93], and Pd-catalyzed stereoselective allylic alkylation [94]. An effective total synthesis of ()-9epi-pentazocine, a diastereoisomer of ()-pentazocine, from D-tyrosine [96] and also a recognized synthesis of (þ)- and ()-aphanorphine from (2S,4R)-4hydroxyproline have been accomplished and reported [97].

80 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 3.17 Total synthesis of (þ)-taondiol (129).

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In 2016, Zhang et al. achieved an effective stereoselective total synthesis of ()-pentazocine (139) and ()-metazocine (141) in nine steps and with 24% overall yields starting from the easily accessible D-tyrosine derivative 130. It features a ring-closing metathesis reaction for the construction of the C ring and an intramolecular FC reaction for the installation of the B ring [98]. The strategy described above was found applicable to stereoselective synthesis of a wide variety of optically pure benzomorphan analogues and thus has simplified their total synthesis, providing these clinically significant compounds in prerequisite quantities for biological and medicinal chemistry screening. As depicted in Scheme 3.18, the total synthesis of ()-pentazocine (139) started from D-tyrosine derivative 130, which was easily accessible from natural D-tyrosine via five steps in high overall yield [96]. Having 130 in hand, it was converted to tetrasubstituted alkene 136 after several steps. Then, tetrasubstituted alkene 136 was subjected to desulfonation and N-benzylation in the presence of Na/C10H8 in DME followed by treatment of the resultant with BnBr, K2CO3 as base in DMF as solvent at 70  C to provide 137 in high yield over two steps. In a key step, the latter was subjected to regio- and stereoselective intramolecular FC cyclization in refluxing HBr to furnish tricycle 138 in satisfactory yield. Remarkably, in this vital step, two new chiral centers were created with excellent stereocontrol in accord with the previously

SCHEME 3.18 Synthesis of ()-pentazocine (139).

82 Applications of Name Reactions in Total Synthesis of Alkaloids

reported results [96,99]. Furthermore, the relative stereochemistry in 138 was unambiguously established by an NOE analysis. Having compound 138 in hand, total synthesis of the target was almost completed. Catalyzed debenzylation of 138 with subsequent N-prenylation furnished the desired natural product ()-pentazocine (139) in high overall yield over two steps. Metazocine is an opioid analgesic related to ()-pentazocine (139), showing remarkable analgesic effects [100]. The total synthesis of ()-metazocine (141) is outlined as depicted in Scheme 3.19. Compound 136 was subjected to desulfonylation followed by reductive amination to furnish methylated amine 140 as a vital intermediate [101]. Basically, under the same reaction conditions as for the preparation of compound 137 above, compound 140 underwent a highly enantioselective intramolecular FC reaction with simultaneous O-demethylation to furnish the desirable alkaloid ()-metazocine (141) in high yield [93,94]. Palmanine (149) was initially isolated from the extract of Berberis empetrifolia Lam [102] and Berberis darwinii Hook [103] by Valencia and coworkers in 1982 and 1984. From a structural point of view, it involved isoindolobenzazepine core. Despite showing feeble biological potencies due to its unique and interesting structure, it has attracted much attention from the organic synthetic community. In 2017, Kim et al. accomplished and reported the first brief total synthesis of palmanine (149) as racemat involving azepine ring construction via an applied FC reaction [104]. Accordingly, the total synthesis was started from market purchasable 3,4-dimethoxyphenethylamine 142, which was converted to 144 in high yield upon treatment with t-butyl bromoacetate. The latter was converted to 147 as an appropriate precursor for FC reaction. Thus, the latter was subjected to intramolecular Pd-catalyzed FC reaction in the presence of bis-(diphenylphosphino) dinaphthalene to furnish 148 in moderate yield. Lastly, the total synthesis of palmanine (149) as the desired target was completed upon oxidation of the latter with (1S)-(10camphorsulfonyl)oxaziridine in excellent yield [105]. It should be mentioned that oxidation of 148 did not give the optically pure natural product (149), apparently due to poor facial selectivity or rapid racemization (Scheme 3.20) [104]. Fargesine (160), an indole N-oxide alkaloid, was isolated from the root and stem of Evodia fargesii Dode in 2006 by Zhu research group. The fruits of E. fargesii Dode have been used for some time in traditional medicine as an

SCHEME 3.19 Total synthesis of ()-metazocine (141).

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SCHEME 3.20 Total synthesis of (149) through FriedeleCrafts cyclization.

analgesic against bellyache and to dismiss cough after measles. Fargesine (160) contains an N-oxide-tethered 7-membered ring bridging at the C3- and C4-positions of the indole [106]. The unique structure of fargesine (160) has drawn enormous attention from the synthetic organic community. Jia et al. achieved and published the first total synthesis of fargesine (160) [107]. Total synthesis of fargesine (160) was also accomplished and reported by Nemoto et al. in 2017 [108]. This research group described the total synthesis of fargesine in 11 steps with 10.1% overall yield from compound 150. This approach relied on the Pd-catalyzed intramolecular FC type CeH couplingeallylic amination tandem to build the 3,4-fused tricyclic indole scaffold [109]. The total synthesis started from easily accessible monoprotected 1,4-butyn-diol 150 [110]. The latter, upon reaction with N-(tertbutoxycarbonyl)-p-toluenesulfonamide in the presence of PPh3 and diethyl azodicarboxylate (DEAD), furnished the respective propargylamine derivative, which upon reaction with 20 equivalents of TFA (CF3COOH) afforded compound 151 in high yield. The latter was then coupled with the easily accessible benzyl alcohol derivative 152 [111] in the presence of PPh3/DEAD to obtain compound 153 in good yield. Upon reduction of the nitro group in 153 using zinc powder, the resulting amine was protected with a tosyl group to afford 154. Then, in a crucial step, the latter was subjected to Pt-catalyzed intramolecular FC-type CeH couplingeallylic amination tandem reaction to obtain the key intermediate, the 3,4-fused tricyclic indole framework in which the tandem cyclization proceeded smoothly to afford the respective 3-alkylidene indoline derivative 155. The latter was next isomerized into the 3,4-fused tricyclic indole derivative 156 in good yield upon treatment with 30

84 Applications of Name Reactions in Total Synthesis of Alkaloids

equivalents of TFA. The key intermediate 156 available in hand was converted to compound 159 in several steps. At the end, selective oxidation of the tertamine moiety in 159 by using m-CPBA in DMF at room temperature gave the desired alkaloid fargesine (160) in 51% yield (Scheme 3.21). Stemonaceae plants are ironic sources of bioactive natural products, especially alkaloids. They have extensively been recommended by Japanese and Chinese medicos as customary medicines as antitussive. Currently, over 150 kinds of alkaloids have been isolated and characterized [112]. They are classified into eight different groups, most of them contain a pyrrolo[1,2-a] azepine nucleus as core structure. Some of them, such as bisdehydroneostemoninine (172) and bisdehydrostemoninine (179) contain an oxaspirolactone moiety. Despite the recent interest in the total synthesis of Stemona alkaloids [113], literature survey revealed only a few reports. The first total synthesis of Stemona alkaloids (172) and (179) as racemat have been accomplished in 2018 by Dai and co-workers [114]. The synthetic approach involved a Pd-promoted carbonylative spirolactonization of hydroxycyclopropanol 169 leading to facile construction of the oxaspirolactone core and a Lewis acid-catalyzed tandem FC cyclization and lactonization of 165 to build the 5-7-5 tricyclic core of the desired targets (172) and (179).

SCHEME 3.21 Total synthesis of fargesine (160).

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Accordingly, this pathway started from the reaction of market purchasable 161 and 162, which were easily resulted in the pyrrole derivative 163 through a modified Clauson-Kaas reaction [115] and Weinreb amide formation. The latter was reacted with vinyl Grignard reagent via nucleophilic addition with subsequent reduction of the resulting enone using NaBH4 to afford allylic alcohol 164. The latter was then converted into tricyclic lactone 166 via a twostep bypass involving cross-metathesis of 164 and methyl acrylate with Grubbs second-generation catalyst, which gave a,b-unsaturated ester 165. The latter key step was subjected to tandem FC cyclization and lactonization catalyzed by boron trifluoride etherate to construct the azepine ring along with the fused g-butyrolactone ring [116] to give the 2.6:1 separable mixture of diastereomers favored of the desired product 166 with a trans-ring junction. The latter, after several steps, was transformed to compound 171 bearing an exomethylene group. The latter was then subjected to Ru3(CO)12-promoted isomerization of the exo-methylene to an endocyclic double bond to give the desired alkaloid, bisdehydroneostemoninine (172) as racemat form in good overall yield after purification by column chromatography [117]. The structure of bisdehydroneostemoninine (172) was unambiguously established by X-ray crystallography. The structure of synthetic bisdehydrostemoninine (179) was also confirmed, unequivocally, by X-ray crystallography (Scheme 3.22). The Stemona alkaloids create a family of naturally occurring compounds involving a pyrrolo[1,2-a]azepine core, which in turn are classified into eight diverse groups [118]. Several members of this family were found to be ironic sources of different naturally occurring compounds with diverse biological potencies, such as anthelmintic, antitussive, antitumor, and insecticidal influences [119e122]. In 2006, bisdehydroneostemoninine (172), as typical of the stemoamide group, was initially isolated from the roots of Stemona tuberosa by Lin et al. [123]. The total synthesis of bisdehydrostemoninine and bisdehydroneostemoninine as racemat were accomplished employing Pdmediated carbonylative spirolactonization as the vital step [124]. Ma et al. accomplished the formal asymmetric total synthesis of bisdehydroneostemoninine using L-glutamic acid as the chiral pool and reported their results in 2019. In this strategy, the vital steps involved the ring opening the chiral epoxide, regioselective and enantioselectively using dimethylsulfonium methylide and FC cyclization with subsequent lactonization to furnish the 5-75 tricyclic core of the desired Stemona alkaloids [125]. Notably, this synthetic pathway offered a breakthrough to screen the biological activities of optically pure bisdehydroneostemoninine. The synthesis started from L-glutamic acid 181 as the chiral pool. The latter, upon treatment with HBr, NaNO2, and KBr, was transformed to the respective bromide 182 with retention of configuration via a diazonium salt-mediated double-inversion approach. Then, upon reduction of two carboxylic acid moieties of 182 using borane, the diol 183 was obtained. The latter was transformed to the a b-unsaturated ester 190 after several steps. In a key step, the latter was converted to the azepine ring as well

86 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 3.22 (179).

Total synthesis of bisdehydroneostemoninine (172) and bisdehydrostemoninine

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as the transfused g-butyrolactone ring 191 in enantiomerically pure form via a boron trifluoride etherate catalyzed domino FC cyclization and lactonization in one-pot fashion. The latter, as the key intermediate, was transformed into the desired natural product, bisdehydroneostemoninine alkaloid (172), in good yield (Scheme 3.23). Proaporphine alkaloids are well-known intermediates in the biogenetic route of aporphines. They have a skeletal structure demonstrated by stepharine and featuring a tetracyclic system involving tetrahydroisoquinoline and spirocyclohexadienone moieties [126]. In 1985, Shamma et al. isolated the proaporphine ()-misramine from the Egyptian Roemeria hybrida and R. dodecandra (Papaveraceae) [127]. Relying on spectral data, ()-misramine (217) was proved to bear an exceptional pentacyclic scaffold with four chiral centers involving an all-carbon quaternary center. Even though the biological potency of 217 has not been properly established, it is assumed to show biological activity in the range of pain control because its structure is analogous to that of opioids such as the notoriously famous morphine. The first total synthesis of ()-misramine (217) was accomplished and reported in 2018 by

SCHEME 3.23 Synthesis of bisdehydroneostemoninine (172).

88 Applications of Name Reactions in Total Synthesis of Alkaloids

Yoshida et al. in 24 steps with 2.0% overall yield [128]. The synthetic approach was based on an asymmetric intramolecular FC 1,4-addition in the presence of a chiral organocatalyst to build a spiroindane scaffold bearing an all-carbon quaternary stereogenic center and a double-reductive amination of the keto-aldehyde to construct a piperidine ring at the end of the total synthesis. This approach is started from market purchasable 2,4,6-tribromoanisole 192 that is initially converted to resorcinol derivative 193 following a known procedure [129]. After more than seven steps, the latter was converted to cyclohexenone-resorcinol, an appropriate substrate for the intramolecular FCtype 1,4-addition. To provide the S configuration of the spiro-carbon epicinchonine, amine 200 was employed as a catalyst in the intramolecular FC-type 1,4-addition to furnish the spiroindane 201. With enantioenriched spiroindane 201 in hand, it was converted to O-TBS misramine 216 [130] as a single diastereomer after several steps. Ultimately, upon removal of the TBS group from 216, ()-misramine (217) was obtained. The physical and spectral data for this synthetic sample were in agreement with those of authentic compound, isolated from natural source [127]. The C-6a stereochemistry in synthetic sample 217 was established by an NOE experiment, where irradiation of H-6a led to a 2.1% increase in the H-8eq signal similar to that of the natural product (Scheme 3.24) [127]. Cephalotaxus alkaloids have been attractive synthetic targets for several years due to their fascinating structural features and biological potencies [131e133]. They contain an azaspiranic tetracyclic scaffold involving a benzazepine moiety and a 1-azaspiro[4.4]nonane segment. An archetypal member of this family, ()-cephalotaxine (227), was initially isolated in 1963 by Paudler and co-workers from Cephalotaxus harringtonii [134]. Cephalezomine A has a drupacine-type backbone and the same oxygenated side chain as homoharringtonine [135]. The structure of cephalezomine G was first suggested as the a,a-syn-diol 227 [136]. It should be noted that compound 227 was prepared before the isolation and structural elucidation of cephalezomine G from nature [137]. Cephalezomine G (227) was found to have four adjoining chiral centers in the cyclopentane D ring, one of which is a quaternary carbon atom having a nitrogen substituent. The selective assemblage of these chiral centers has been a chief synthetic contest, particularly in view of the sterically burdened nature of the D ring. Furthermore, effective installation of the surrounded azaspirocycle moiety was found to be challenging. The first asymmetric synthesis and configurational elucidation of ()-cephalezomine G was accomplished by Kim et al. and reported in 2019 [138]. The highly functionalized Ca-substituted proline derivative was provided from D-proline as the sole chiral source through a C / N / C chirality transfer approach consisting of a stereoselective N-allylation and [2,3]-Stevens rearrangement. The azaspiranic tetracyclic scaffold was built employing ring-closing metathesis and the FC reaction. In this strategy, adjoining OH groups were assembled in the latter steps of the total synthesis.

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SCHEME 3.24 Total synthesis of ()-misramine (217).

The total synthesis commenced from the easily accessible (E)-cinnamyl alcohol 218 [139] bearing a 3,4-diacetoxy group. Upon bromination, the latter was converted to cinnamyl bromide 219 as the chief product. The latter was

90 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 3.24 cont’d

transformed in several steps to compound 223, which in turn, after five steps, furnished cis-diol 224 as the sole detected diastereomer. To the latter, a twocarbon unit was assembled in two steps by elimination of the benzyl-type N-substituent with subsequent reductive amination with 2,2dimethoxyacetaldehyde (225) to furnish acetal 226. In a key step, the latter was subjected to FC reaction using an excess of methanesulfonic acid in which a CeC bond was formed, leading to the generation of the respective enamine intermediate, which upon direct reduction using a borane tert-butylamine complex in a one-pot fashion gave the originally proposed structure of natural product cephalezomine G (227) in satisfactory yield [140]. It is worth noting that the 1H NMR spectrum of the synthesized compound 227 in CD3OD did not match that of the authentic sample isolated from the natural source. This was justified by considering that the TFA used as an HPLC eluent during the isolation of natural products [140] had an effect on spectrum data recorded for the sample, with naturally occurring cephalezomine G showing signals of the TFA salt. Comparison of the 1H NMR spectrum of TFA salt 2270 with that recorded in CD3OD disclosed diminutive agreement. The authors were pleased to claim that the 1H and 13C NMR spectra of their synthesized 227 recorded in CDCl3 were in good accord with those already reported for the a,a-syndiol 227 (Scheme 3.25) [137]. It was presumed that Ishibashi et al. suggested that the correct or even definite structure for cephalezomine G is 2a,3b-anti-diol 236 [141]. For assemblage of the antistereochemistry of the C-2 and C-3 chiral centers, several trans-dihydroxylation reactions were first endeavored for the azaspiranic substrate. The attempted Prevost-type reactions were unproductive. Challenges for the epoxidation and ring opening of the epoxide also provided ineffective evidence. Efforts to influence inversion of configuration of the C-3 hydroxyl groups in 224 and 227 via a sequential reaction of C-2 hydroxyl group protection followed by SN2 type displacement at C-3 with nucleophiles were also met with disappointment. These failures could be ascribed to the steric congestion around the cyclopentene ring that avoids facile access of

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SCHEME 3.25 Total synthesis of the originally suggested structure of cephalezomine G (227).

external nucleophiles from the b-face. To circumvent the steric hindrance problematic, the nitrogen atom on the b-face was employed to deliver an oxygen nucleophile to the C-3 position in an intramolecular manner, and thus the N-Boc group as an internal nucleophile was chosen. Replacement of the benzyl-type N-substituent in 224 with a Boc group was accomplished via hydrogenolysis in the presence of Boc2O to obtain 228. Monoprotection of a less hindered C-2 hydroxyl group in diol 228 was accomplished with TBSOTf at low temperature to afford 229 as a major product with an isomeric ratio of 5:1. Intramolecular nucleophilic substitution of the C-3 hydroxyl group was achieved upon treatment of 229 with diethylaminosulfur trifluoride to provide the seven-membered cyclic carbamate 230 [142] upon cleavage of the cyclic carbamate group of 230 by the effect of phenyl lithium to afford amino alcohol 231. Under several conventional strategies in the presence of KOH/EtOH and HCl, the desired target was not obtained [143]. Notably, in the original total synthesis of cephalezomine G (227), an external two-carbon source was introduced through reductive amination with 225 to obtain compound 232. Dissimilarly to the aforementioned case, the acid-catalyzed FC reaction of 232 provided benzyl ether 233 with simultaneous deprotection of the TBS group.

92 Applications of Name Reactions in Total Synthesis of Alkaloids

It can be assumed that compound 233 may result from capture of the oxonium intermediate by the C-3 hydroxyl group. Attempts for reduction at the benzylic position of 233 were unsuccessful, possibly due to the incomplete orbital overlap between the CeO s-bond and the p-system of benzene. Therefore, the C-3 hydroxyl group was protected as a pivalate 234 to avoid its participation in the FC reaction. Sequential one-pot FC reaction/reduction afforded benzazepine 235, which upon deprotection of the pivaloyl group in 235 using LiAlH4 lastly resulted in compound 236. The 1H NMR spectra of synthetic 236 were not in agreement with those of the natural product. Nevertheless, spectroscopic data for its TFA salt 2360 were in accord with those obtained and reported for the natural product. The optical rotation sign and value obtained for 2360 {[a] D 20 ¼ 46.9 (c 1.8, MeOH), lit [136]. [a]D ¼ 48 (c 1.8, MeOH)} were also in good accordance, which established the absolute configuration of natural ()-cephalezomine G unambiguously as 2S,3S,4S,5S (Scheme 3.26). In 1992, Smitka and co-workers isolated and reported [144a], 18 members of ambiguine indole alkaloids from blue-green algae. These secondary metabolites showed a wide variety of biological potencies such as antimycotic, antifungal, and antibiotic activities [144a,c,e,f,145] similar to those of good medical treatment agents such as streptomycin, puromycin, and amphotericin [144c]. Ambiguines have the core structure of hapalindoles, but in contrast have a prenyl moiety at the C-2 position of the indole ring. Commonly, as set up in 13 members of the group, the prenyl moiety joins the indole C-2 position and the distal

SCHEME 3.26 Completion of the total synthesis of cephalezomine G (236).

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cyclohexane ring to construct a seven-membered ring (249). Due to these fascinating structural features and appropriate biological potencies, ambiguines have attracted continued attention from synthetic organic chemists for more than two decades [146]. A brief total synthesis of ()-ambiguine P (249) was achieved and reported by Rawal et al. in 2019 via a [4 þ 3] cycloaddition reactionstimulated approach and an FC reaction to install the pentacyclic ambiguine scaffold as well as introduction of the tertiary hydroxy group using an NBScatalyzed sequential brominationenucleophilic substitution [147]. It is worth mentioning that during preparation of this achievement for publication, Sarpong et al. reported their step-forward synthesis of (249) [148]. The total synthesis of ()-ambiguine P (249) was started from the easily accessible ketone 237, which was converted into the desired siloxydiene 240 via four steps. The latter was converted to tetracycle 242 as an appropriate precursor for FC reaction. Next, upon treatment of 242 with BF3$OEt2 and MeOH, the ambiguine scaffold was provided through intramolecular FC reaction to afford pentacycle 243 in good yield. The latter was converted to diene 248 after five steps, which upon treatment with NBS afforded a product wherein the C-15 hydrogen had been replaced with a hydroxyl group. When this reaction was conducted in the presence of water [149], compound 248 was simply converted to the C-15 hydroxylated product, isolated as a mixture of diastereomers (2.0:1) in which pure ()-ambiguine P (249) was separated out from the mixture in moderate yield (Scheme 3.27).

2.3 FriedeleCrafts acylation reaction Azepine and azocine are seven- and eight-membered ring systems, respectively. They contain a nitrogen atom and form a significant family of organic molecules exhibiting fascinating conformational structure and a broad assortment of biological potencies [150]. For instance, isoindolobenzapine alkaloids such as chilenine, lennoxamine, and deoxychilenine that have been isolated from genus Berberis are well recognized for their biological potencies toward lung, colon, and prostate cancers [151]. Magallanesine (256a), a tetracyclic fused-ring system, is the first isoindolobenzazocine class of alkaloid isolated from B. darwinii [152]. In 1981, Shamma and coworkers accomplished [153] the total synthesis of magallanesine (256a) before its isolation from the plant B. darwinii. Then, after its isolation, Danishefsky and coworkers [154] accomplished the first total synthesis of (256a) using intramolecular aldol condensation in six steps with a 56% overall yield. Then, Kurihara and co-workers [155a,b] accomplished the total synthesis of (256a). In 2015, Kim and coworkers accomplished the total synthesis of (256a) [156]. In 2018, Tilve and coworkers accomplished and reported the total synthesis of (256a) employing a novel three-step synthetic pathway to build an azocine ring system employing anion chemistry and intramolecular FC reaction of an ester. This strategy permits the construction of azocine ring analogues with satisfactory overall yields [157].

94 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 3.27 Total synthesis of ()-ambiguine P (249).

Accordingly, this strategy commenced from the reaction of ethyl 6(chloromethyl)-2,3-dimethoxybenzoate 251a and 2 equivalents of market purchasable 2-(3,4-dimethoxyphenyl)ethan-1-amine 250b in THF to furnish isoindolinone 252b by sequential cascade alkylation-amidation in one-pot fashion [161]. The latter was deprotonated in the presence of NaHMDS followed by alkylation using ethyl bromoacetate 255a to obtain the key intermediate, ethyl ester 253b [158]. Only a few reports are available in which esters are used as acylating agents [159]. Then, 253b was subjected to intramolecular FC acylation in the presence of P2O5/methanesulfonic acid (Eaton’s reagent) as a key step to afford tetrahydro benzoazocine 254b in only moderate yield. At the final step, the latter was converted to magallanesine analogue 256b by dehydrogenation with DDQ (Scheme 3.28) [156].

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SCHEME 3.28 Total synthesis of magallanesine analogue 256b.

After successful synthesis of magallanesine 256b, the total synthesis of its analogue 256a was contemplated and executed by this group in 2018 [157]. The synthetic pathway started with the reaction of 2-(benzo[d] [1,3]dioxol-5yl)ethan-1-amine 250a [160] with 251a in THF under reflux condition to afford the isoindolinone derivative 252a. Upon alkylation of intermediate 252a using tert-butyl bromoacetate 255c, the corresponding ester 253a was obtained in high yield. The ester 253a was next submitted to the Eaton’s reagent (P2O5 in CH2Cl2) to afford compound 254a via intermolecular FC reaction. Upon dehydrogenation using DDQ, 254a was converted to a compound, and its spectral data matched with the spectral data reported in the literature for magallanesine 256a [154,155b] (Scheme 3.29).

SCHEME 3.29 Synthesis of magallanesine (256a) and its analogues.

96 Applications of Name Reactions in Total Synthesis of Alkaloids

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Chapter 4

Recent advances in applications of Heck reaction in the total synthesis of alkaloids Chapter outline 1. Introduction 107 1.1 Mechanism of Heck reaction 109

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1. Introduction The “Heck reaction” (also called the MizorokieHeck reaction) is the chemical reaction of an unsaturated halide (triflate) with an activated alkene in the presence of a base and a palladium (Pd) species as catalyst to generate a substituted alkene. One of the benefits of the Heck reaction is its outstanding trans-selectivity. The Heck reaction is a Pd-catalyzed carbonecarbon crosscoupling reaction that takes place between aryl halides or vinyl halides and activated alkenes in the presence of a base. Recent developments in catalysts and reaction conditions have resulted in a much broader range of donors and acceptors that are amenable to the Heck reaction [1]. Historically, this reaction was named after Tsutomu Mizoroki and Richard F. Heck, who independently explored such a CeC bond formation in the late 1960s and early 1970s. Heck was working at the Delaware chemical firm Hercules and had long been interested in transition-metal chemistry, an interest that was uncommon at the time. In 1968, he published a paper on a new carbonecarbon bond formation catalyzed by Pd that coupled aromatic rings and alkenes [2]. It was an exciting advance for Pd chemistry, which was just starting its advance. However, the reaction had a few drawbacks. For one thing, it required a full equivalent of a Pd salt, which was costly, and it worked best only with aromatic rings substituted with tin or toxic mercury. Interestingly, half a world Recent Applications of Selected Name Reactions in the Total Synthesis of Alkaloids https://doi.org/10.1016/B978-0-12-824021-2.00006-6 Copyright © 2021 Elsevier Inc. All rights reserved.

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away at Tokyo Institute of Technology, Tsutomu Mizoroki, a young associate professor who was also engaged in discovering transition-metal chemistry, followed up on Heck’s work, reporting a reaction involving the coupling of alkenes with iodine-substituted aromatic rings via a recyclable Pd catalyst in the absence of tin or toxic mercury [3]. This first example of the process, which nowadays is primarily called the Heck reaction, was reported in 1972 as independent research [4]. This reaction was the first example of a carbonecarbon bond-forming reaction that followed a Pd(0)/Pd(II) catalytic cycle, which is the same catalytic cycle seen in other Pd(0)-catalyzed cross-coupling reactions. In fact, the Heck reaction is a way to obtain substitute alkenes with exceptional trans-selectivity. The Heck reaction is used widely in the synthesis of several useful organic compounds in the agrochemical, fine chemicals, pharmaceutical, and other industries. It has attracted much interest from the synthetic community due to its high efficiency and simplicity. Heck methodology is also attractive from a synthetic point of view because of its high chemoselectivity, mild reaction conditions, low toxicity, and low reagent cost, especially if the Pd-based catalyst can be recycled (Scheme 4.1) [5]. The Heck reaction is also defined as a vinylation or arylation of olefins in which large varieties of olefin derivatives such as acrylates, styrenes, or intramolecular double bonds can be used. Although the original and main essential catalyst in the Heck reaction is Pd, modifications have occurred over the years, and various Pd forms, such as Pd-immobilized [6,7] and Pd nanoparticle-based [8] catalysts, are being investigated as effective and recyclable catalysts. In addition, a wide variety of metals and a vast range of ligands have been investigated in the Heck reaction. Significant progress for the preparation and characterization of a variety of ligands and catalysts has been made for avoiding protection and deprotection procedures in multistep synthetic pathways, thus permitting such routes to be conducted in fewer steps [9,10]. Palladium is usually the preferred metal, as it tolerates a wide variety of functional groups and has a remarkable ability to assemble CeC bonds effectively among appropriately functionalized substrates. Like most Pd-based methodologies, the Heck reaction proceeds with stereo- and regioselectivity to provide the desired products in excellent yield. Generally, less crowded structures are preferred during the Heck reaction, which often favors a trans-product. Few suggested mechanisms are plausible to support the regioselectivity [11e13] and stereoselectivity of the Heck reaction [14,15].

SCHEME 4.1 The Heck reaction.

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In addition, the literature survey discloses many articles claiming that the Heck reaction has been successfully performed in the absence of one of the components (other than substrates)-for example, a reaction that is ligand-free [16e18] or solvent-free [19,20]. Recent papers have also designated how to recover the used catalyst, especially when it is used in an aqueous medium or neat water [21], which implies a potential green strategy with the Heck reaction [22e24]. Several suggestive and authoritative reviews have covered various aspects and issues of the Heck reaction as well as related topics for further reading [25e37]. They describe applications and mechanisms in the search for high turnover numbers, asymmetric synthesis, separation techniques, etc. In addition to these useful reviews, a couple manuscripts offer general overviews of the body of research on the Heck reaction; these overviews cover some research that is comprehensive and other research that is not so evocative [5]. In fact, the Heck reaction is currently and broadly demarcated as the Pd(0)mediated coupling of an aryl or vinyl halide or triflate with an alkene. Although for several years the synthetic applications of this transformation had been largely unappreciated, nowadays the applications of this powerful tool in the total synthesis of natural products, especially alkaloids, has grown dramatically [38]. The innovation and development of its asymmetric variation have been stimulated over the past 2 decades by the necessity in the art of organic synthesis for the generation of tertiary and quaternary stereogenic centers by CeC bond formation. In addition, the catalytic asymmetric variation of the Heck reaction has emerged as a dependable strategy for enantioselective CeC bond formation [39].

1.1 Mechanism of Heck reaction The common mechanism for the Heck reaction has been expansively recognized and accepted among organic chemical communities for many years; nevertheless, frequent recent, ongoing education has enlightened and refined the detailed mechanics of this important name reaction. Recent reviews on this subject offer a detailed debate over mechanistic studies of Heck cyclization [40]. As an example, a concise impression of the Heck reaction mechanism shall now be provided. A plausible mechanism for the Heck reaction of aryl halides or perfluorosulfonates is depicted in Scheme 4.2. It begins with the oxidative addition of a Pd(0) catalyst to generate an o´-arylpalladium(II) complex. The order of reactivity for this oxidative addition stage, and classically for the overall reaction, is X ¼ I > OTf > Br >> Cl [41]. Coordination of an alkene with Pd followed by CeC bond formation via syn addition generates an o-alkylpalladium(II) intermediate that was readily subjected to a-hydride elimination to discharge the alkene as the expected product. In this reasonable mechanistic pathway, the presence of a base is a prerequisite for transformation of the

110 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 4.2 Suggested probable mechanism for Heck reaction.

hydridopalladium(II) complex to the active Pd(0) catalyst to sufficiently complete the catalytic cycle. Although the mechanism illustrated in Scheme 4.2 offers an all-purpose explanation of the obligatory steps for catalytic olefination, many investigations of this important name reaction have proposed that this “textbook” diagram is an enormous generalization of the elimination. The applications of Heck reactions in the art of organic synthesis have been widely studied and published [5,14,24,42e44]. Due to our interest in the Heck reaction [45e54], we reviewed the applications of Heck reactions in the synthesis of heterocyclic compounds in 2010 [55] and updated that review in 2018 [56].We have also reviewed the development of recent total synthesis of natural products based on the Heck reaction [57]. Because of the importance and usefulness of Heck reactions in the art of organic synthesis, we use this chapter to underscore recent applications of Heck reactions in the total synthesis of one of the most important, widespread, and prevalent classes of natural products to show diverse biological properties, the so-called “alkaloids.”

2. Applications of Heck reaction in total synthesis of alkaloids Alsmaphorazine alkaloids originally contain a hexacyclic core. Morita et al. in 2010 isolated two novel alkaloids, alsmaphorazines A and B, from Alstonia pneumatophora (Apocynaceae) collected in Malaysia. In the same paper, the same authors elucidated the structures of the aforementioned alkaloids [58]. The first total synthesis of alsmaphorazine B was accomplished in 15 steps and in 10.6% overall yield by Vanderwal and co-workers, who reported their results in 2015 [59]. Their strategy was based on the biosynthesis and total synthesis of ()-akuammicine (13). Several total syntheses of alkaloid ()-akuammicine (13) [60] have been achieved; among them, Andrade’s six-

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step synthesis is the shortest [61]. This strategy involved a cascade N-oxide fragmentation/hydroxylamine oxidation/intramolecular 1,3-dipolar cycloaddition sequence to effectively convert an oxidized congener of akuammicine into the complex hexacyclic architecture of the alsmaphorazine alkaloids. To accomplish this aim, Zincke aldehyde methodology was used to provide gram scale of ()-akuammicine (13) and was then extended to the total synthesis of alsmaphorazine B (14) by chemoselective oxidation of akuammicine leading to the key rearrangement. The synthesis of akuammicine (13) commenced with reductive amination of tryptamine using p-anisaldehyde to give secondary amine 8, which was in turn treated with potassium glutaconate salt 9 according to modification of the procedure previously reported by Marazano and co-workers [62] to furnish Zincke aldehyde 9 in high yield. The latter was subjected to an intramolecular cycloaddition reaction under basic conditions to furnish the corresponding tetracyclic enal 11 in high yield. The latter was then converted into 12 as an appropriate precursor for intramolecular Heck reaction at multi-gram scale. The latter in a key step was then subjected to intramolecular Heck reaction in the presence of Pd(OAc)2 as catalyst, PPh3 as ligand, and Et3N as base at 90  C to afford the desired racemic alkaloid, akuammicine (13), in nine steps with about 40% overall yield. As depicted in Scheme 4.3, having gram quantities of the racemic alkaloid ()-akuammicine (13), it was converted to the desired ()-alsmaphorazine B

SCHEME 4.3 Total synthesis of () akuammicine (13) and ()-alsmaphorazine B (14).

112 Applications of Name Reactions in Total Synthesis of Alkaloids

(14) in respectable yield by successive oxidations involving DesseMartin periodinane and BaeyereVilliger oxidations. The structure of this synthetic sample was determined by single-crystal X-ray diffraction, and comparison of its spectroscopic data with those of the authentic compound already reported by Morita [58] proved them to be identical. In 2002, Fong and co-workers isolated (þ)-decursivine (25), a tetracyclic scaffold indole alkaloid, from the leaves and stems of Rhaphidophora decursiva Schott (Araceae) [63]. It showed antimalarial potency. The unprecedented structure of this alkaloid includes trans-dihydrobenzofuran, an indole functionalized at the 3-, 4-, and 5-positions, and an eight-membered lactam that bridges the indole 3- and 4-positions. The exceptional molecular architecture along with diverse biological activity have made decursivine (25) an appealing target for organic synthetic chemists to attempt its total synthesis [64e69]. The first asymmetric synthesis of the natural indole alkaloid (þ)-decursivine was accomplished by Sun and co-workers, who revealed their results in 2011 [70]. The key step involved the PIFA-mediated intramolecular [3 þ 2] cycloaddition of 5-hydroxytryptophan with a substituted cinnamamide in a highly diastereoselective fashion. In the same year, the Mascal and Jia research groups independently reported a similar strategy for the advantageous synthesis of ()-decursivine via cascade sequences involving Witkop photocyclization [65,66a]. This cascade reaction was also employed in the asymmetric synthesis of (þ)- and ()-decursivine and a variety of decursivine analogues [66b]. Later, the overall synthetic efficiency of decursivine and its analogues was improved by the synthesis of benzofurans via a Pd-catalyzed CeH activation/oxidation tandem reaction [66c]. Jia and co-workers in 2015 accomplished a new synthetic pathway for the beneficial synthesis of ()-decursivine (25) and its analogues. It involved a sequential Pd(OAc)2-mediated Heck reaction/deprotection/oxidative cyclization cascade reaction. Other highlights of this strategy were a sequential Witkop photocyclization/elimination cascade reaction along with a Sm-promoted stereoselective reduction of benzofuran for the synthesis of 2-aryl-2,3-dihydrobenzo[b]furan. This novel synthetic approach for the asymmetric synthesis of ()-decursivine via two cascade sequences not only permitted the convenient synthesis of ()-decursivine in 10 steps and in 6.8% overall yield from 5-hydroxy-L-tryptophan methyl ester but also allowed the useful total synthesis of its analogues [71]. Accordingly, the total synthesis of ()-decursivine started with provision of the vital intermediate 20. Coupling of amine 15 with 2,2-dichloropropionic acid 16 gave cyclization precursor 17 in high yield. The protection of phenol 17 with TBS gave 18 in almost quantitative yield. The latter was then exposed to 254 nm UV in CH3CN, to give the required 19 in modest yield. Next, Boc-protection of the indole and amide nitrogen was conducted to give the desired key intermediate 20 in satisfactory yield. The latter was subjected to sequential CeH activation/ oxidation cascade reaction conditions for the synthesis of benzofuran, and only a trace amount of 22 was obtained [66c]. However, by removal of the TBS

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group from 20 using Pd(II), the phenol A was obtained, which in turn was subjected to intramolecular palladium(II)-catalyzed oxidative cyclization to give benzofuran 21. In fact, it was uncertain whether compound 22 was directly obtained from 20 via a sequential Heck reaction/deprotection/oxidative cyclization cascade reaction or from 21 by a Heck reaction. A controlled experiment was subsequently performed. Treatment of pure benzofuran 21 under secured optimal reaction conditions provided 22 in only 6% yield. Based on this result, it was proposed that 22 was chiefly generated from 20 via a sequential Heck reaction/deprotection/oxidative cyclization cascade reaction. Auspiciously, concurrent chemo- and stereoselective reduction of the furan double bond and deprotection of the amide Boc of 22 with Sm and I2 in methanol at ambient temperature delivered compound 23 as the sole product in high yield [66c,72]. Finally, deprotection of the Boc group at the indole nitrogen with TFA in dichloromethane afforded compound 24, which was easily transformed to ()-decursivine (25) via a sequential three-step reaction. In conclusion, total synthesis of ()-decursivine (25) was successfully achieved starting from 5-hydroxy-D-tryptophan methyl ester (Scheme 4.4).

SCHEME 4.4 Total synthesis of ()-decursivine (25).

114 Applications of Name Reactions in Total Synthesis of Alkaloids

The spiroindimicins are a family of unique alkaloids isolated from the deep-sea-derived marine actinomycete [73]. A PCR-based screening approach resulted in the identification of a deep-sea-derived Streptomyces sp. SCSIO 03032 capable of producing the new spiroindimicin bisindole alkaloids [74]. Structural elucidation of these compounds disclosed structurally unprecedented alkaloids that, by the presence of uncommon dichlorinated bisindole alkaloids, possessed an exceptional heteroaromatic [5,6] or [5,5] spiro-ringcontaining skeleton [75]. Biological screening exhibited moderate cytotoxicities against several cancer cell lines for 41. At first, the total synthesis of spiroindimicins B and C was accomplished by Sperry and co-worker in 2016 [76]. The structural elucidation of these synthetic compounds confirmed the exceptional heteroaromatic structure of these deep-sea-derived alkaloids. Spiroindimicin B (41) can be synthesized via methylation of spiroindimicin C (40), which in turn is synthesized by construction of the pyrrole ring from heteroannulation [77] of vinyl sulfone using methyl isocyanoacetate following the protocol developed by Magnus et al. [77a], which is mechanistically similar to the Scho¨llkopfeMagnuseBartoneZard (SMBZ) reaction [78]. Sperry and Blair accomplished the total synthesis of the first of two members of this family, ()-spiroindimicins B and C, and reported their outcomes in 2016 [76]. Their strategy involved assemblage of the spirocenter by employing an intramolecular Heck reaction, the instillation of a pentacyclic spirobisindole by Fischer indolization, and a late-stage SMBZ reaction for construction of the trisubstituted pyrrole. The total synthesis started with 28, the alkylation of iodoaniline 26 [79] with bromide 27 [80], and then proceeded smoothly via the SN2 reaction to afford compound 28 [81] as the required precursor of the Heck reaction. The latter was subjected to reductive Heck conditions in the presence of Pd(OAc)2, and then upon treatment of the resultant with HCO2Na (as the hydride source), gave spiroindolinyl pentanone ()-29. The latter was obtained as the result of a “normal” Heck reaction, rapid syn-b-hydride elimination [82,83] before reduction, and isomerization of the double bond resulting from reinsertion of the hydridopalladium species into the alkene with subsequent migration [84]. Captivatingly, addition of silver nitrate [85] to the reductive conditions increased the yield of ()-29. Next, the latter was easily hydrogenated to 30 in excellent yield using H2 (balloon) in the presence of Pd/C, EtOAc as solvent at ambient temperature. Having the important intermediate spiroindolinyl pentanone 30 available and in hand, the pathway was set for the crucial Fischer indolization. Reaction of the latter with 4-chlorophenylhydrazine in refluxing AcOH gave spirobisindole 32 in satisfactory yield, showing the perpetual value of this classic name reaction in the art of organic synthesis in the total synthesis of complex molecules and natural products [86]. N-protection of 32 afforded compound 33, which upon radical bromination with subsequent hydrolysis of the intermediate afforded alcohol 34 as a mixture of diastereomers, and subsequent oxidation gave ketone 35 in good yield over three steps started from 33.

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Ketone 35 was next reacted with 4-methylbenzenethiol in the presence of TiCl4 and Et3N at room temperature to afford the thioketal 36 in good yield, which was then subjected to oxidationeelimination [87] to afford a mixture of vinyl sulfone 38 and vinyl sulfoxide 37 (1.3:1). Compound 38 was then subjected to a crucial SMBZ reaction using methyl isocyanoacetate, which proceeded smoothly to furnish compound 39, securing complete construction of the heteroaromatic skeleton of [5,5]-spiroindimicin, and its structure was confirmed by single-crystal X-ray analysis. Cleavage of the protecting groups from 39 in the presence of sodium naphthalenide in THF followed by treatment of the resultant with AlCl3 in CH2Cl,2 at ambient temperature without other action allowed the desired natural product, spiroindimicin C ()-40, to be obtained in respectable yield. The latter, upon reductive amination using formaldehyde, NaBH3CN, AcOH in MeOH as solvent at room temperature, furnished another desired natural product, spiroindimicin B ()-41, in excellent yield (Scheme 4.5). The physical and spectroscopic data for the synthetic samples of spiroindimicins B (41) and C (40) were compared with those of authentic samples isolated from natural sources and found to be identical [75]. The alkaloids comprised in a carbazole nucleus are an unprecedented class of natural products. Due to their interesting structural features and broad range of biological potencies, they have received much attention from the synthetic community. Furthermore, carbazoles are vital structural segments of organic semiconductors, light-emitting diodes, etc. [88]. 1-Oxygenated prenyl carbazoles, as a chief subgroup of carbazoles, are potent and established antitumor agents. From this subgroup, clausamines F and E were isolated from Clausena anisata by Furukawa and co-workers in 2000 and showed inhibitory functions against EpsteineBarr virus. Clausamine E (47) exhibited exclusively cytotoxic activity against HL-60 [89]. In 2009, Furukawa and co-workers isolated two lactonic carbazole alkaloids, the so-called furanoclausamines A and B (45), from the stems of C. anisata [89]. The total syntheses of clausamine E (47) and furanoclausamine B (45) were achieved by Mal and co-workers in 2018. Their strategy involved Heck cross-coupling reaction and BreLi exchange as the key steps [90]. This total synthesis started with Boc-protected furoindolone 42, which reacted with methyl crotonate in the presence of LDA in THF to afford 1-hydroxycarbazole 43 in good yield. The latter, after several steps involving selective methylation, retro-Kolbe-Schmitt reaction [91] hydrolysis, bromination, and Pinnick oxidation, was converted to the corresponding acid 44, which was subsequently reacted with DBU/MeI in acetone to provide the respective methyl ester 46 [92]. The latter was used as an appropriate Heck cross-coupling reaction precursor [92] and was thus reacted with 3-methylbut-2-enal in the presence of Pd(OAc)2, TBAB, PPh3, and K2CO3 in DMF at 120  C to give the desired alkaloid, clausamine E (47), in good yield [93]. In this way, the first total synthesis of clausamine E (47) was accomplished in 11 steps from readily available furoindolone 42. Upon treatment of acid 44 with n-Bu2Mg and

116 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 4.5 Total synthesis of spiroindimicins B (41) and C (40).

n-BuLi [94], with subsequent reaction of the resultant with 3-methyl-but-2enal in THF at 20  C, the other desired alkaloid, furanoclausamine B (45), was obtained in satisfactory yield. In summary, the Heck reaction of 46 gave the desired target alkaloid clausamine E (47). The BreLi exchange of 44 with subsequent reaction with 3-methyl-but-2-enal provided the other desired natural product, furanoclausamine B (45) (Scheme 4.6). Indolosesquiterpenoids have attracted extraordinary attention from both chemical and biological points of view [95e101]. Because of the small number of members of these alkaloids isolated from natural sources for systematic evaluations of biological activities, their total synthesis in the

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SCHEME 4.6 Total synthesis of clausamine E (47).

laboratory was envisioned [102e108]. Hertweck [109e112] and Zhang [113e115] independently isolated xiamycin A (53) from Streptomyces species. It was found that the antibiotics oridamycins A and B isolated from natural sources have a similar backbone to that of xiamycin A (53), although they are dissimilar at quaternary C16 owing to their opposite stereochemistry [116]. Many congeners of 53, such as dixiamycin C, oxiamycin, and indosespene, have also been isolated from the same species and fully characterized [111e115]. They were also recognized as the biosynthetic precursors. Considerable effort has been made toward revealing the biogenesis of this class of natural products, including elucidation of the relevant gene clusters and enzymes [111e114]. Chemical syntheses of these compounds [107,108] were contemplated that could help in further understanding of the biosynthetic relationships within this indolosesquiterpenoid family as well as discovery of the unknown biological activities of the other members. In 2014, Baran and co-workers [107] accomplished and reported the first total synthesis of xiamycin A and dixiamycin B. The total synthesis of xiamycin A, oridamycins A and B, dixiamycin C, and indosespene, all isolated from Streptomyces, were achieved and reported in 2015 by Meng et al. [117]. For this purpose, the authors exploited two parallel protocols to install the carbazole core, (a) by sequential 6p-electrocyclization/aromatization and (b) via indole C2eH bond activation/Heck annulation sequence. The total synthesis of xiamycin A (53) using protocol (a) began with already known optically active epoxide 48 [118], which was converted into compound 49 in good overall yield via a two-step

118 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 4.7 Total synthesis of xiamycin A (53).

sequential 2-azaadamantane N-oxyl oxidation [119,120]/esterification. The latter was transformed to compound 50 after several steps involving Cuerva and Oltra cyclization [121e124], Grignard addition, and electrocyclization followed by aromatization and conventional protectionedeprotection as key steps. The compound 50, upon desulfonylation, gave compound 52, which upon TMSE deprotection furnished the desired alkaloid xiamycin A (53) in satisfactory overall yield. The structure of this alkaloid was established unambiguously by X-ray crystallographic analysis (Scheme 4.7). Next, total synthesis of xiamycin A (53) was attempted via protocol (b), involving the CeH bond activation/Heck annulation sequence as a vital step. The second approach to xiamycin A (53) rewarded the strategy of indole C2eH activation/Heck-type annulation. This approach started from compound 49, which was reacted with N-Boc-3-(tributylstannyl)indole 54 [125] via a Stille coupling cross-coupling reaction [126] followed by deprotection of Boc [127] to give polyfunctionalized required precursor 55 in good overall yield. The latter was then subjected to a Ti(III)-catalyzed radical cyclization to give decalin 56 as a sole diastereomer in good yield [122]. The latter, in the presence of Pd(OAc)2 and p-benzoquinone in a mixture of AcOH/toluene as solvent at 50  C via a developed oxidative/Heck aromatization sequence, gave compound 58, which upon treatment with TASF gave a mixture of indosespene (57) and the desired target xiamycin A (53), respectively (Scheme 4.8). The structure of 57 was also confirmed unambiguously by X-ray crystallographic analysis. The above protocol was also employed in the total synthesis of oridamycins A (64) and B (67) using oxidative/Heck annulation sequence as a vital step. This protocol started with 3-geranyl indole 59, and upon N-sulfonylation [128] using PhSO2Cl in NaOH followed by allylic oxidation using SeO2, tBuOOH provided alcohol 60 in high overall yield. The latter was transformed to decalin 61 via a two-step reaction. The configuration of its C16 was confirmed unambiguously by X-ray crystallographic analysis,. Decalin 61 was then subjected to desulfonylation followed by oxidative/Heck annulation (vide

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SCHEME 4.8 Total synthesis of xiamycin A (53).

supra) to provide carbazole 62, which in turn underwent a sequential two-step reaction involving the reduction of ketone 62 and TMSE deprotection to provide the desired alkaloid ()-oridamycin A (64). For the synthesis of ()-oridamycin B (67), carbazole 62 was condensed with NH2OMe followed by Boc-protection to give the precursor for oxidation, and in the presence of Pd(OAc)2, PhI(OAc)2 in a mixture of Ac2O/AcOH at 110  C, furnished acetate 65. The latter was subjected to deprotection of the oxime, acetyl, and Boc groups under acidic conditions with subsequent reduction of the unprotected carbonyl group to give the intermediate 66 in good overall yield. Finally, by removal of TMSE group in 66 in the presence of TASF in DMF (50  C, 2 h, 91%), the desired alkaloid ()-oridamycin B (67) was obtained in high yield (Scheme 4.9). The flinderole AeC alkaloids remarkably function as selective inhibitory agents against Dd2 (chloroquine-resistant) P. falciparum. Worthy of mention is that the flinderole AeC alkaloids are rapid-functioning and at present are the drugs of choice for the treatment of malaria through a different mechanism of action that is better than chloroquine and related drugs for intrusion of the parasitic hemoglobin [129]. Malaria is still a life-threatening and mostly communal infectious disease in tropical and subtropical areas of the world [130]. In 2009, Avery et al. isolated flinderoles AeC from the plant genus Flindersia along with the previously other known natural products borrerine, borreverine, isoborreverine, and dimethylisoborreverine [131]. The structural elucidation of flinderoles AeC showed that all the aforementioned isolated products as well as desmethylflinderole C have a pyrrolo[1,2-a]indoles scaffold in common. Their high antimalarial potencies with other interesting biological activities have made them imperative synthetic targets within the synthetic community. Since isolating them for further biological screening in

120 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 4.9 Total synthesis of oridamycins A (64) and B (67).

enough quantity from natural sources was found disappointing, it was highly desirable to develop a concise and effective synthetic pathway [132]. Along these lines, a couple sophisticated strategies for the total synthesis of flinderole alkaloids, which provide them in higher amounts for wider biological evaluation, have been acknowledged in the chemical literature [132]. Pandey and co-workers in 2016 reported a concise and swift divergent protocol for the preparation of the pyrrolo[1,2-a]indoles scaffold and its application in the total synthesis of flinderoles A (72), B (73), and C (74) and desmethylflinderole C (75) [133]. This strategy employed optimized intermolecular Heck coupling and InCl3-catalyzed stereo- and regioselective [3 þ 2] annulation reactions as the crucial steps. The preparation of flinderole scaffold started with easily accessible bromo compound 68 [134], which initially underwent a vital intermolecular Heck coupling reaction with market purchasable 2-methyl-3-buten-2-ol in the presence of Pd(OAc)2 as catalyst, tri-(o-tolyl)phosphine as ligand, and, Et3N as base in CH3CN as solvent in a sealed tube at 100  C (under pressure) to give the corresponding alcohol 69 as an isolable product in satisfactory yield [24]. Then the latter was subjected to a [3 þ 2] annulation reaction catalyzed by InCl3 [135] in toluene to give flinderole scaffolds 70 and 71 in high yield, and in an isolable 3:2 diastereomeric ratio, by flash column chromatography. Next, the separated 70 in pure form

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underwent cleavage of the phthalimide group upon treatment with hydrazine monohydrate to give a bis-amine intermediate that was subsequently subjected to reductive amination with formaldehyde in the presence of Na(CN)BH3/ MeOH at 0  C to ambient temperature to afford the desired alkaloid, flinderole A (72), in excellent yield (Scheme 4.10). Interestingly, when the bis-amine intermediate 70 was subjected to reductive amination using formaldehyde in the presence of Na(CN)BH3/acetonitrile and acetic acid at 0  C to room temperature, the other desired target, flinderole B (73), was obtained in high yield. As depicted in Scheme 4.11, flinderole C (74) and desmethylflinderole C (75) were provided from the bis-amine intermediate derived from compound 71 following an analogous series of procedures. The physical properties and spectroscopic data of flinderoles AeC (72, 73, 74) and desmethylflinderole C (75) were in full accord with the data given in the chemical literature [132]. The ergot alkaloids are a significant group of indole-derived mycotoxins showing robust and diverse biological potencies such as ergotism, a severe disease caused by chronic ingestion of toxic food-contaminated fungal secondary metabolites [136]. Cycloclavine (88) is placed in the subclass of clavine-type ergot alkaloids. Initially, in 1969, cycloclavine (88) was isolated by Hofmann and co-workers from seeds of Ipomoea hildebrandtii Vatke. The same authors fully characterized its structure. They also determined its absolute configuration as 5R,8S,10S and reported it in the same paper [137]. Cycloclavine (88) was found to have an exceptional pentacyclic framework involving a 3-azabicyclo[3.1.0]hexane substructure. In 2016, Opatz and coworkers reported a brief (in just eight linear steps) and convergent pathway to the racemic alkaloid cycloclavine (88) [138]. It comprised two sequential coupling reactions, one involving selective alkylation of a dienolate and a Heck reaction as the crucial step. This total synthesis was started with commercially available allylamine (76) to afford compound 77 upon N-formylation using neat ethyl formate, which in turn was treated with LiALH4 with subsequent reaction of the reduced compound with methacryloyl chloride 78 to give methacryloyl amide 79. Consequently, ring-closing metathesis (RCM) of the latter in the presence of catalyst 80 (catMETium RF1) [139] furnished pyrrolinone 81 as a key building block in good yield over three steps. On the other hand, another crucial building block, 3-(bromomethyl)indole 83, was provided using market-purchasable or easily accessible 4-bromoindole (82) over four steps in high overall yield [140,141]. Reaction of 83 with deprotonated pyrrolinone 81 resulted in an unexpectedly high selectivity for the desired lactam 84 as g-isomer. Then the latter, upon an intramolecular Heck cyclization (in the presence of Pd(OAc)2/Ph3P with Et3N and Ag2CO3 in toluene), afforded the tetracyclic lactam 86 in good yield. It is worth noting that the exomethylene isomer 85 was generated as the major product along with 86 when the intramolecular Heck cyclization was performed in the presence of Pd(OAc)2/Ph3P with Et3N in DMF or toluene. Finally, lactam 86,

SCHEME 4.10

Total synthesis of flinderoles A (72) and B (73).

122 Applications of Name Reactions in Total Synthesis of Alkaloids

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SCHEME 4.11 Total synthesis of flinderole C (74) and desmethylflinderole C (75).

upon a facile reduction using LiAlH4 was converted to amine 87, which was transformed to the desired alkaloid ()-cycloclavine (88) in satisfactory yield via cyclopropanation, as had been previously reported by Szantay and coworkers (Scheme 4.12) [142].

SCHEME 4.12 Total synthesis of ()-cycloclavine (88).

124 Applications of Name Reactions in Total Synthesis of Alkaloids

Cao and co-workers achieved the asymmetric total synthesis of (þ)-cycloclavine (88) in 13 steps with 2.0% overall yield and the total synthesis of (þ)-5-epi-cycloclavine (105) in 14 steps in 3.3% overall yield and reported their results in 2019 [143]. This short, effective, and asymmetric total synthesis of (þ)-cycloclavine (88) and (þ)-5-epi-cycloclavine (105) comprised a sequential addition of Grignard reagent to the C¼N bond formation/Heck reaction for the construction of the fused 656 ring systems, cyclopropanation, an ester aminolysis reaction, and an intramolecular [3 þ 2] cycloaddition/nitrogen extrusion as key steps. Accordingly, the asymmetric synthesis of (þ)-cycloclavine (88) started with the commercially available 4-bromoindole 89, which initially was converted to already reported Ellman (S)eN-tert-butanesulfinyl imine 90 (>99% ee) after five steps in 57% overall yield [144,145]. Then, the reaction of chiral imine 90 on gram scale with 2 equiv. of vinylmagnesium bromide in dichloromethane at 78  C gave a mixture of olefinic sulfenamides 91 and 92 with a diastereomeric ratio (d of 1.5:1) in 40% and 50% yields, respectively. After separation, pure compound 91, upon treatment with potassium bis(trimethylsilyl)amide with subsequent reaction with MeI, gave compound 93 as a suitable precursor for the Heck reaction in high overall yield over two steps. In a key step, the latter was subjected to a Heck reaction in the presence of Pd(OAc)2 as catalyst, Ph3P as ligand, and K2CO3 as base in refluxing CH3CN to give the required product 94 in moderate yield along with the 7-endo-trig cyclization product in better yield, which were separated by column chromatography [146,147]. After separation, compound 94 in pure form was transformed to compound 96 after three steps involving an important Rh-catalyzed conversion of compound 94 to compound 95. Compound 96, upon treatment with sodium naphthalenide in tetrahydrofuran at 78  C, resulted in the formation of compound 97 in virtually quantitative yield. In the final step, the latter was transformed into the desired alkaloid, (þ)-cycloclavine (88), via reduction following the already reported procedure by Wipf et al. [148]. The physical and spectroscopic data of this synthetic compound, (þ)-cycloclavine (88), were in complete accord with those of the authentic sample already reported by Wipf et al. [148,149] (Scheme 4.13). For the total synthesis of (þ)-5-epi-cycloclavine (105), the already separated monosubstituted olefin 98 in pure form was subjected to the Heck reaction using Pd(OAc)2/PPh3 and K2CO3 in refluxing MeCN, which afforded the products 99 and 100 in a 3:5 ratio and good combined yield. Compound 99 was converted to tosylhydrazone 102, which was in turn subjected to intramolecular formal [3 þ 2] cycloaddition [150] to provide ABCDE pentacyclic product 103 as a single isomer in good overall yield with a detected trace amount of pyrazoline 104. In the last stage, cleavage of two tosyl groups of 103 by treatment with sodium naphthalenide in THF followed by N-methylation of the deprotected compound furnished the desired alkaloid (þ)-5-epicycloclavine (105) in high yield and optically pure form (97% ee).

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SCHEME 4.13 Total asymmetric synthesis of (þ)-cycloclavine (88).

The spectroscopic data of this synthetic sample of (þ)-5-epi-cycloclavine (105) were in full agreement with those of the authentic sample of ()-5-epicycloclavine already reported by Wipf and co-workers [148]. In conclusion, the asymmetric synthesis of alkaloid (þ)-cycloclavine (88) in 13 steps with 2.0% overall yield and the total synthesis of (þ)-5-epi-cycloclavine (105) in 14 steps in 3.3% overall yield were accomplished with the Heck reaction as a crucial step (Scheme 4.14) [143]. Azepino[5,4,3-cd]indoles are an important alkaloid family and have been isolated from different natural sources. These alkaloids involving aurantioclavine (as a mixture of diastereomers) were isolated from the fungus Penicillium aurantiovirens [151]. Clavicipitic acid was isolated from the fungus Claviceps fusiformis [152], hyrtioreticulins C and D as diastereomeric alkaloids from the marine sponge Hyrtios reticulatus [153], and fargesine from the roots and stems of Evodia fargesii [154]. Furthermore, cimitrypazepine was isolated from the roots and rhizomes of black cohosh (Cimicifuga racemosa) [155]. Various synthetic approaches have been developed for the preparation of the azepino[5,4,3-cd]indole moiety, which are the most

126 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 4.14 Asymmetric synthesis of (þ)-5-epi-cycloclavine (105).

ubiquitous in these natural products and are obtainable from 3,4-disubstituted indoles for the assemblage of the azepine ring [155e160]. In fact, installation of both the pyrrole and azepine rings onto a functionalized benzene ring, although infrequent, is an important sequential bond formation [161e163] that offers a more flexible approach to various functionalized analogs compared with the use of a preinstalled indole ring as the starting material. Fargesine (118) is a tricyclic N-oxide alkaloid initially isolated from the roots and stems of E. fargesii in 2006 by Zhu and co-workers. The fruits of the E. fargesii have been used in Chinese traditional medicine as an analgesic and cough suppressant throughout history [154]. The first total synthesis of alkaloid fargesine (118) was achieved and reported in 2013 by Jia et al. [163]. On the other hand, the industrially related nonoxidized alkaloid, so-called cimitrypazepine 116, was later isolated from Black cohosh (C. racemosa), a flowering plant native to eastern North America [155]. Black cohosh has been used as folk medication by Native Americans for treatment of colds and rheumatism as well as for lessening menopause symptoms such as blazing, hot flashes, and night sweats. The first successful total synthesis of cimitrypazepine 116 was reported by Somei [164] and co-workers in 2001. It involved a PicteteSpengler type cyclization of N-methylserotonin and formaldehyde in which the key azepine ring was constructed.

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So¨derberg and co-workers in 2016 reported a concise synthetic pathway leading to the synthesis of the tricyclic alkaloids cimitrypazepine and fargesine. It involved an intramolecular Heck reaction and a Pd-catalyzed reductive N-heterocyclization for the construction of the pyrrole ring of the indole as vital steps [165]. Their strategy started with commercially available 4-hydroxy-2-iodo-1nitrobenzene, which was readily converted to 6-hydroxy-2-iodo-3nitrobenzaldehyde (106) following the already reported procedure [166]. Compound 106 was used for the synthesis of both cimitrypazepine 116 and fargesine (118) Reductive amination of 106 using 4-amino-1-butene and NaBH4 gave the required product 107. Both the hydroxy and the amino group in 107 were protected upon treatment with di-t-butyl dicarbonate ((Boc)2O) in the presence of 4-(N,N-dimethylamino)pyridine to provide the expected diprotected compound 108. Although compound 108 was planned as an appropriate precursor of the Heck reaction, it is worth noting that the Heck reaction of 108 was unpredictable, and varying ratios and yields of products were obtained from seemingly identical reaction conditions and concentrations. Compound 108 and the O-deprotected compound 109 were subjected to the intramolecular Heck reaction in the presence of (PdOAc)2, P(O-tol)3, Et3N at 120  C to give a mixture of products 110e113 in which the highest isolated yield of 110/111 was obtained in several attempts. Comparatively, cyclization of 109 was more consistent but afforded a slightly lower isolated yield of the 2-benzazepine product 111 (relative to 110 þ 111, 66%) and a slightly higher yield of 2-benzazocine 112. Pd-catalyzed reductive N-heterocyclization of 110 utilizing a bis(dibenzylideneacetone)palladium-1,3-bis(diphenylphosphino)propane-1,10phenanthroline catalyst system under the pressure of carbon monoxide (pCO ¼ 6 atm, 120  C) in DMF gave the di-N,O-protected azepino[5,4,3-cd] indole 114 along with the N-protected analog 115. When compound 111 was subjected to similar reaction conditions using the same reagents, compound 111 in a slightly lower isolated yield was obtained. The latter was treated with sodium bis(2-methoxyethoxy) aluminum hydride (Red-Al) in refluxing toluene, which resulted in the removal of both O-Boc and N-Boc groups along with reduction of a methyl group to give the desired alkaloid cimitrypazepine 116 in a respectable yield. On the other hand, reduction of 115 using Red-Al also gave alkaloid 116 in excellent isolated yield. All physical, spectroscopic, and analytical data of synthetic cimitrypazepine were in agreement with those of already reported values in the chemical literature that were isolated and synthesized by Nikolic and co-workers [155]. Alkaloid 116 was initially O-Boc-protected to afford 117 in excellent yield. Upon direct oxidation of 117 using m-CPBA and subsequent deprotection utilizing sodium hydroxide, another desirable alkaloid, fargesine 118, was obtained in a satisfactory yield (Scheme 4.15).

128 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 4.15 Total synthesis of fargesine (118).

Indole and substituted hydroindole derivatives are found in several naturally occurring compounds showing a broad range of biological potencies and are thus profoundly used in medicinal chemistry [167]. The alkaloid families integrating their heterocyclic systems are Erythrina and lycorane, which exhibit a broad scope of biological potencies [167e169]. Lycorane alkaloids have exhibited important antiproliferative potency in different cancer cell lines involving melanoma and multiple melanoma, leukemia, carcinoma, and lymphoma [170,171]. ()-g-Lycorane (127) was initially isolated from plants of the Amaryllidaceae family. It is a toxic crystalline alkaloid found in various Amaryllidaceae species, such as the cultivated bush lily (Clivia miniata), surprise lilies (Lycoris), and daffodils (Narcissus). It is highly poisonous or even lethal when swallowed in relatively high quantities. Lycorine is found in different species of Amaryllidaceae including the flowers and bulbs of daffodil, snowdrop (Galanthus) or spider lily (Lycoris). Lycorine is the most

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129

common alkaloid of Amaryllidaceae [172]. Total synthesis of ()-g-lycorane (127) was achieved by Hilton and co-workers, who reported their results in 2017 [173]. It was based on a crucial intramolecular acylal cyclization/Heck reaction sequence. Accordingly, it started from treatment of piperonylamine 119 with bromine in CH3COOH to afford 120 in high yield. The latter, as the free-base form, was condensed with cyclohexanone and diacetoxyacetyl chloride 122 to afford 123 in excellent yield (72%). The latter, as the cyclization precursor was treated with boron trifluoride diethyl etherate as per typical conditions, furnishing the bicyclic dihydroindolenone 124 in high yield. All attempts to synthesize lycorane from the bicyclic precursor 124 under radical conditions similar to those previously reported resulted in its degradation [174]. Thus, a Pd-catalyzed intramolecular Heck reaction with the conjugated amidic carbonyl was contemplated and executed [175]. Cyclization precursor 124 under Heck cyclization conditions using PdCl2, PPh3 under microwave irradiation (MWI) at 150  C gave 125 as the Heck cyclization product in respectable yield [175]. The conjugated double bonds in 125 were hydrogenated through utilization of an H-cube hydrogenation flow reactor. The latter was dissolved in a mixture of ethanol and ethyl acetate as solvent and in the presence of 10% Pd on charcoal as catalyst hydrogenated at 65  C and 60 bar pressure to afford the reduced product 126 in virtually quantitative yield. In the final step, the latter was reduced using lithium aluminum hydride following the procedure previously reported in the chemical literature to provide the desired alkaloid ()-g-lycorane (127) in satisfactory yield (Scheme 4.16) [174e].

SCHEME 4.16 Total synthesis of ()-g-lycorane (127).

130 Applications of Name Reactions in Total Synthesis of Alkaloids

The Erythrina alkaloids exhibit a wide scope of biological potencies and show pharmacological activities involving sedative, hypotensive, neuromuscular blocking, and CNS depressing. (þ)-3-Demethoxyerythratidinone (132) is one of the most important alkaloids of over 100 natural products generated by the Erythrina genus of flowering plants [176]. The genus Erythrina Mart. (Leguminosae, or Fabaceae) is collective in tropical and subtropical regions and also in varioius clement districts of the world [177e179]. The trees are planted as soil and watershed guardians, the leaves serve as high-quality food and as pet food as well as being extensively utilized in folk medicine in different parts of the world [180]. The erythrinan alkaloids involve a mediumsized group of naturally occurring products with a 1,2,3,4,5,6,8,9octahydroindolo[7a,1a] isoquinoline skeleton in common that are limited to the plant genera Erythrina (Fabaceae), Cocculus, Hyperbaena, and Pachygone (Menispermaceae). Demethoxyerythratidinone (132) has a tetracyclic tetrahydroisoquinoline core as the common structural feature of Erythrina alkaloids. The first total synthesis of demethoxyerythratidinone (132) was accomplished by Tsuda et al. and reported in 1984 [181]. A sophisticated and concise (six steps) total synthesis of ()-3-demethoxyerythratidinone was recently reported by Reisman et al. [182]. Booker-Milburn and co-workers achieved a brief (five-step) total synthesis of ()-3-demethoxyerythratidinone from a simple pyrrole derivative and reported their results in 2017 [183]. It comprised the preparation of gram quantities of a key tricyclic aziridine via an interesting photochemical cascade reaction and an unusual Heck cyclization while ligand control permitted effective formation of the desired alkaloids in respectable yield from the minor isomer present in an equilibrating mixture of labile enamines. This strategy started with pyrrole 128 that was irradiated (254 nm) to afford the key intermediate, the aziridine ()-129, in modest yield. Pleasantly, by using a three-lamp FEP-flow reactor, the yield of aziridine ()-129 was increased dramatically. The latter was converted into ()-130 in the presence of Pd2(dba)3, P(OPh)3, AcOH in CH2Cl2 at room temperature. Compound ()-130 was then transformed into enone ()-131 in two steps in good overall yield. Interestingly, when iodo-enone ()-131 was first treated with TFA in CH2Cl2 at room temperature and then Pd(OAc)2 (20 mol%) was added in accordance with the Orito procedure [184], not only ()-133 (56%) was obtained but also the desired alkaloid ()-132 was furnished in 28% isolated yield (Scheme 4.17). Akuammiline alkaloids are a family of biogenetically linked indole monoterpenoids chiefly isolated from Alstonia scholaris [185]. Scholarisine K (147) and alstolactine A (153) were first isolated from Alstonia scholaris leaves by Liu, Luo, and co-workers in 2014 and 2015, respectively [186,187]. The fascinating structures of scholarisine K and alstolactine A and a broad range of their biological properties have attracted much attention from the synthetic community. Thus, many protocols and methods have been developed

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131

SCHEME 4.17 Total synthesis of ()-3-demethoxyerythratidinone (132).

for their total synthesis, especially to construct their puzzling cagelike structures. The utmost of akuammiline alkaloids commonly contain indole polycyclic rings, a 1,3-bridged [3,3,1] bicycle, and all-carbon quaternary chiral centers on C-7. The first total synthesis of a member of Akuammiline alkaloids, namely vincorine, was accomplished and reported by Qin et al. [188]. The total synthesis of some members of akuammiline alkaloids have also been reported by several other research groups: Ma [189], MacMillan [190], Smith [191], Snyder [192], Garg [193], Zhu [194], Li [195], Zu [196], Yang [197], Fujii and Ohno [198], and Gaich [199]. Gao and co-workers achieved the total synthesis of scholarisine K (147) and alstolactine A (153) and reported their results in 2017 [200]. It involved RCM and an intramolecular Heck reaction for the assemblage of the 1,3-bridged [3,3,1] bicycle, an intramolecular alkylation with subsequent Fischer indolization to construct the fundamental skeleton of akuammilines, and bioinspired acid-catalyzed sequential epoxide ring-opening/lactonization to construct the second lactone ring of alstolactine A. Scholarisine K (147) was synthesized in 25 linear steps from commercially available starting materials. Accordingly, market-purchasable amino acid L-2allylglycine (>98% ee) was chosen as a suitable source of chirality for introducing the chiral amino moiety at C-3. Amino acid L-2-allylglycine was initially converted to aldehyde 134 without appreciable loss of ee and in gram scale via a modified sequential three-step reaction [201,202]. The latter was then transformed into 140 in several steps involving RCM [203] of 136 using Grubbs II catalyst, protection, and finally alkylation of 138 with allyl bromide 139 [204]. In a key reaction, a Pd(Ph3)4-catalyzed intramolecular Heck reaction performed in the presence of PMP in refluxing CH3CN 140 in which the C15eC20 bond formed, and then the o-nitrobenzenesulfonyl protecting group was replaced with Cbz to furnish a,b-unsaturated ester 141 in satisfactory yield over two steps. The latter was oxidized to conjugated ketone ester 142 (>98.4% ee) using Dess-Martin reagent. The latter was reduced using SmI2 to

132 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 4.18 Total synthesis of scholarisine K (147).

afford alcohol 144 in the presence of water (100 equiv.) in a respectable yield together with the isomer 143 (11% yield). After several steps, alcohol 144 was transformed to iodide 145 in good yield over eight steps involving various functional group transformations [195,205]. Iodide 145, upon trans-esterification and epoxide formation under basic conditions in MeOH, gave epoxide 146 in high yield. After two steps, which comprised the removal of N-Cbz under Pd(OH)2/C and reductive amination, the desired alkaloid scholarisine K (147) was obtained in good yield (Scheme 4.18). Pleasantly, this synthetic product gave 1H NMR, 13C NMR. Spectrometric and high-resolution mass spectrometric data as well as optical rotation results were identical to those of the sample obtained from natural source [201]. For the total synthesis of alstolactine A (153), which contains an additional lactone framework biogenetically derived from 147 via acid-promoted

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SCHEME 4.19

133

Total synthesis of alstolactine A (153).

lactonization was envisioned. Regrettably, exposing scholarisine K (147) to acidic conditions resulted in its decomposition. Thus, the already prepared epoxide 146 was treated with 3 M H2SO4 in acetone to give 148 in modest yield along with the elimination product 149 also in moderate yield. It was suggested initially that the epoxide is activated by protonic acid with subsequent intermolecular SN2 addition of water to generate intermediate 151, which then under acidic conditions afforded the cationic intermediate 152. Intramolecular lactonization created 148 (path A), and a second dehydration gave conjugated diene 149 (path B). Relying on similar conversions, the desired alkaloid alstolactine A (153) was obtained in high yield via replacement of the Cbz with a methyl group (Scheme 4.19) [201]. Tuberculosis (TB) is an infectious disease usually caused by Mycobacterium tuberculosis bacteria. TB generally affects the lungs but can also affect other parts of the body. The World Health Organization estimates that 10.4 million people were diagnosed with TB infection in 2016, of which 1.3 million died [206]. The classic symptoms of active TB are a chronic cough with bloodcontaining mucus, fever, night sweats, and weight loss. It was historically called consumption due to the weight loss. Infection of other organs can cause a wide range of symptoms [207]. TB is a treatable and preventable disease nowadays, but underdeveloped nations still suffer from TB because of limited resources and the ineffectiveness of first- and second-line anti-TB drugs [208]. Thus, discovery and development of safer, inexpensive, and more effectual

134 Applications of Name Reactions in Total Synthesis of Alkaloids

new compounds possessing anti-TB activity are still in much demand and are quite urgently needed. The pyrrole alkaloids exhibit a broad range of these biological activities [209]. Several compounds, such as denigrins AeC [210], solsodomine A [211], banegasine [212], and celastramycin A [213], that have shown anti-TB activity [214] are pyrrole alkaloids. Among them, denigrins A, B, and C are especially potent. They were initially isolated from the Indian marine sponge Dendrilla nigra [210]. Denigrin A (160) contains a 3,4-diarylpyrrole structure with C-3 and C-4 positions of the pyrrole engaged by p-hydroxyphenyl groups and C-2 and C-5 positions by imide carbonyls closely related to polycitrin A isolated from an ascidian Polycitor sp. [215], whereas denigrin B (166) contains an unusual, densely functionalized (Z)-benzylidene lactam group on one side of the 3,4-diarylpyrrole segment, indicative of the inhibition of DNA polymerase secondary metabolite dictyodendrin E [216]. Although the exact quantity of marine organisms utilized to isolate denigrins A and B was not reported [210], as with many other natural products, they suffer from having only a small and challenging number of naturally occurring specimens. Due to their interesting and unprecedented structural features along with established ant-TB activities, the total syntheses of denigrins A and B have received much attention from the synthetic chemist community. Torikai and co-workers accomplished the total synthesis of denigrins A (160) and B (166) from maleic anhydride in three and five steps with 62% and 31% overall yields, respectively, and revealed their results in 2018 [217]. In this strategy, Heck reaction, geometry-controlled vinylogous aldol condensation, and one-pot lactamization were the key steps. The total synthesis started with the 3,4-diaryl maleic anhydride 157 provided through Heck arylation of maleic anhydride using aryldiazonium tetrafluoroborate [218]. The best yield (69%) of coupled product 157 was achieved when the Heck reaction was performed in the presence of Pd(OAc)2 as catalyst and NaOAc as base in CH3CN as solvent. In this reaction, a column chromatography-separable 156 was also obtained. With compound 157 in gram scale in hand, it was reacted with 4-methoxyphenethylamine 158 in refluxing acetic acid to provide 159. At last, upon treatment of the latter with boron tribromide, the methyl groups of 159 were removed to furnish the desired target, denigrin A (160), in virtually quantitative yield (Scheme 4.20). The spectroscopic data of synthetic sample were in full agreement with those of sample, which were reported previously [210]. In the following, for the synthesis of denigrin B, the already prepared 157 via Heck reaction was treated with LiAlH4, which resulted in selective reduction of a carbonyl group [219] to give 3,4-diaryl butenolide 161 in high yield. Next, the latter was treated with 4-methoxyphenethylamine 158 in CH2Cl2 at ambient temperature to give the most probable intermediate 164, which upon refluxing in acetic acid furnished the desired benzylidenediarylpyrrole-2(5H)-one 6Z as a major product (165Z:165E ¼ 8:1, separable

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SCHEME 4.20

135

Total synthesis of denigrin A (160).

by silica gel column chromatography) in respectable yield in one-pot manner. The vinylogous aldol condensation [220] of 161 with 4-methoxybenzaldehyde 162 utilizing sodium carbonate in MeOH gave the desired Z-isomer 163 as a sole product in excellent yield. At last, cleavage of methyl ether moiety in 165Z using BBr3 smoothly proceeded, resulting in the formation of the desired alkaloid denigrin B (166) in satisfactory yield (Scheme 4.21). All spectral data

SCHEME 4.21 Total synthesis of denigrin B (166).

136 Applications of Name Reactions in Total Synthesis of Alkaloids

of this species were in excellent accord with those of the sample previously reported in the chemical literature [210]. The Amaryllidaceae [221] alkaloids are a family of herbaceous, chiefly perennial and bulbous (rarely rhizomatous) flowering plants in the monocot order Asparagales. Among this family, lycoricidine and narciclasine have received much attention due to their biological activities such as antitumor, antiviral, antibacterial, antifungal, and antimalarial properties as well as showing analgesic potency [222]. (þ)-Lycoricidine was initially isolated from the bulbs of Lycoris radiata [223]. Its structural elucidation revealed several chiral centers, thus inspiring curiosity about the synthesis of this alkaloid, which was difficult to attain on a multigram scale from nature. The first total synthesis of lycoricidine was published by Ohta in 1976 [224], and since then, approximately 20 articles have been published and have revealed different synthetic strategies [225]. Yan and co-workers achieved concise total synthesis of (þ)-lycoricidine (176) and disclosed their outcomes in 2019 [226]. Their brief, facile, and diversity-oriented synthetic approach started from inexpensive C2-symmetric L-tartaric acid. In this synthetic strategy, the crucial epoxide was generated as a communal intermediate to achieve eight diverse target molecules in 6 to 11 steps. Accordingly, different allyl-amine-type conduramines were prepared in a diastereoselective fashion, Heck arylation was employed for construction of a phenanthridone ring, and the desired alkaloid (þ)-lycoricidine (176) was obtained in 11 steps and in 10% overall yield. The synthesis of 1,2-antitype azido alcohol 168 was achieved in four steps from inexpensive commercially accessible L-tartaric acid 167 [227,228]. L-tartaric acid 167 was converted to 1,2-type azido alcohol 168 in four steps in 39% overall yield. The latter was then protected with TBS, and subsequently, the azido group was reduced using LiAlH4 to afford allyl amine 170 in excellent yield. Amidation of 170 with 6-iodo piperonylic acid 171 [229] in the presence of N,N’-dicyclohexylcarbodiimide and 4-dimethylaminopyridine gave rise to the desired amide 172 as an appropriate precursor for Heck arylation in excellent yield. The latter was then subjected to intramolecular Heck arylation [in the presence of Pd(OAc)2, as catalyst, PPh3, Tl(OAc) as base, in CH3CN] to afford the required tetracyclic phenanthridone ring (174) in good yield. Upon treatment of 174 with a catalytic amount of Mg(ClO4)2 in acetonitrile, compound 175 was obtained. Upon removal of the TBS group using TBAF in tetrahydrofuran at ambient temperature, the desired alkaloid, (þ)-lycoricidine (176), was obtained in satisfactory yield (Scheme 4.22). Physical and spectral data of (þ)-lycoricidine (176) were found to be in full agreement with those of the authentic sample isolated from nature [226]. Daphniphyllum, the sole genus in the flowering plant family Daphniphyllaceae, was described as a genus in 1826 [230]. The genus Daphniphyllum

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137

SCHEME 4.22 Total synthesis of (þ)-lycoricidine (176).

has long been used as folk Chinese medication [231] and shows diverse biological activities [231,232]. Daphniphyllum alkaloids isolated from shrubs and trees are mainly from native Daphniphyllum collected from east and southeast Asia but can also found on the Indian subcontinent and in New Guinea [231]. To date, hundreds of Daphniphyllum alkaloids have been isolated and categorized into over 10 subfamilies based on their discrete structural scaffolds [231]. Yue and co-workers in 2016 isolated ()-himalensine A, as an exceptional member of the calyciphylline A-type subfamily from Nepalese Daphniphyllum himalense [234]. The structural elucidation of himalensine A revealed that it has a highly congested pentacyclic ring system that involves an exceptional 2-azabicyclo[3.3.1]nonane moiety, six chiral centers, and a quaternary center. When these structural features of the aforementioned alkaloids are combined with their gifted biological activities, it makes them highly challenging but desirable synthetic targets [233a,233c,233d,236].The total syntheses of several Daphniphyllum alkaloids have been achieved and reported [235e243]. Dixon and co-workers developed a stylish protocol for the total synthesis of himalensine A and revealed their results in 2017. They employed a new catalytic asymmetric sequential prototropic shift/furan DielseAlder cascade reaction [242]. In 2019, Xu and co-workers selected the total synthesis of himalensine A to establish a general approach for the synthesis of

138 Applications of Name Reactions in Total Synthesis of Alkaloids

Daphniphyllum alkaloids. Thus, they designed a brief protocol to accomplish the general and diversifiable entree to various Daphniphyllum alkaloids by attempting the asymmetric synthesis of ()-himalensine A, which was achieved in 14 steps in 1.8% overall yield [244]. They started from already known ketone 178 with a well-determined absolute configuration. Its enone motif was chemoselectively transformed into methyl enol ether 179 as a precursor for subsequent homologation and oxidation. Compound 179 was converted after several steps to compound 180 as an appropriate Heck reaction precursor on a multigram scale. Having compound 180 in multigram scale in hand, it was subjected to intramolecular Heck cyclization conditions [(Pd(OAc)2, Ph3P, Et3N in dioxane under MWI] to afford the required tetracyclic compound 181, containing the critical 2-azabicyclo[3.3.1]nonane moiety, in good yield. The latter was then transformed in several steps to the required ketone 182 as the final intermediate in the Dixon synthesis [242]. Stimulated by this effort, ketone 182 was subjected to Ir-catalyzed hydrosilylation (Vaska’s complex ¼ [IrCl(CO) (PPh3)2]) with subsequent reduction using TFA and Et3SiH at room temperature [240d,244,247], which furnished the desired alkaloid ()-himalensine A (183) in respectable yield (Scheme 4.23). The synthesized 183 was found to be identical in all respects to the alkaloid isolated from the natural source [233] as well as to a sample of ()-himalensine A already synthesized by Dixon et al. [242]. Worthy of mention is that the optical rotations of all three samples were in acceptable agreement.

SCHEME 4.23 Total synthesis of ()-himalensine A (183).

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139

The guaipyridine alkaloids are a small family of sesquiterpenoid natural products. The rupestines, a family of guaipyridine alkaloids, are isolated from the plant Artemisia rupestris. This plant was used as folk Chinese medication for quite a long time. Owing to their antitumor, antibacterial, and antiviral activities as well as activity against two liver cancer cell lines [246,247], and because rupestines can only be isolated from their parent plants in small quantities, the total synthesis of these guaipyridine alkaloids has received much attention from synthetic organic chemists. Recently, rupestine G was synthesized by Huang et al. in 10 steps starting from 5-bromo-2methylpyridine through construction of a seven-membered carbocycle via RCM. The target compound and its stereoisomers were obtained as a mixture that was separated by chiral HPLC [248,249]. Very recently, in 2020, the total synthesis of rupestines B (192) and C (193), two guaipyridine sesquiterpene alkaloids, was reported by Vyvyan and co-workers [250]. Accordingly, the total synthesis of rupestines B (192) and C (193) was accomplished via an intramolecular Heck reaction as the key step to construct the seven-membered carbocycles. This strategy was achieved in six steps to provide racemic rupestines B (192) and C (193) in six steps starting from allyl 3-oxopentanoate (184) in overall yields of 9% and 18%, respectively. The total synthesis commenced by alkylation of allyl 3-oxopentanoate (184) [251] with bromide 185 to generate intermediate 186 in excellent yield. The latter then underwent alkylation using 4-iodo-1-butene (187) to give ketone ester 188 in acceptable yield. Next, 188 treated with Pd(0) in basic methanol resulted in the removal of both allyl groups and in situ decarboxylation of the intermediate keto acid to afford the corresponding 3-hydroxy pyridine derivative 189. The hydroxyl group in 189 was triflated to provide an appropriate Heck reaction precursor without incident. In a key step, the latter was subjected to an intramolecular Heck reaction in the presence of tetrakis Pd(PPh3)4 in hot, basic dioxane to afford the seven-membered carbocycle of 191 in respectable yield. At the last stage, the latter was hydrogenated in the presence of Pd/C, resulting in the hydrogenation of exocyclic alkene present in 191 to afford the desired target, racemic rupestines B (192) and C (193), in virtually quantitative combined yield as a 1:2 mixture of stereoisomers. These diastereomers were not separable using normal phase flash column or radial chromatography, so they were separated by employing reverse phase MPLC. The spectroscopic data of these synthetic compounds [rupestines B (192) and C (193)] were in full accord with those already reported for samples isolated from natural sources (Scheme 4.24) [252].

140 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 4.24

Synthesis of rupestines B (192) and C (193).

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(l) J.B. Cox, J.L. Wood, Tetrahedron 74 (2018) 4539; (m) L. Gao, B. Cheng, H. Yue, S. Cao, J.-L. Wang, L. Xu, Org. Chem. Front. 6 (2019) 813. (a) C.H. Heathcock, S.,K. Davidsen, S. Mills, M.A. Sanner, J. Am. Chem. Soc. 108 (1986) 5650; (b) R.B. Ruggeri, M.M. Hansen, C.H. Heathcock, J. Am. Chem. Soc. 110 (1988) 8734; (c) R.B. Ruggeri, K.F. McClure, C.H. Heathcock, J. Am. Chem. Soc. 111 (1989) 1530; (d) R.B. Ruggeri, C.H. Heathcock, J. Org. Chem. 55 (1990) 3714; (e) J.A. Stafford, C.H. Heathcock, J. Org. Chem. 55 (1990) 5433; (f) S. Piettre, C.H. Heathcock, Science 248 (1990) 1532; (g) C.H. Heathcock, J.A. Stafford, D.L. Clark, J. Org. Chem. 57 (1992) 2575; (h) C.H. Heathcock, Angew. Chem. Int. Ed. 31 (1992) 665; (i) C.H. Heathcock, D. Joe, J. Org. Chem. 60 (1995) 1131; (j) C.H. Heathcock, J.C. Kath, R.B. Ruggeri, J. Org. Chem. 60 (1995) 1120; (k) C.H. Heathcock, Proc. Natl. Acad. Sci. U.S.A. 93 (1996) 14323; (l) G. Wallace, C.H. Heathcock, J. Org. Chem. 66 (2001) 450. M.E. Weiss, E.M. Carreira, Angew. Chem. Int. Ed. 50 (2011) 11501. (a) A. Shvartsbart, A.B. Smith III, J. Am. Chem. Soc. 136 (2014) 870; (b) A. Shvartsbart, A.B. Smith III, J. Am. Chem. Soc. 137 (2015) 3510. (a) Z.Y. Lu, Y. Li, J. Deng, A. Li, Nat. Chem. 5 (2013) 679; (b) X. Xiong, Y. Li, Z. Lu, M. Wan, J. Deng, S. Wu, H. Shao, A. Li, Chem. Commun. 50 (2014) 5294; (c) J. Li, W.H. Zhang, F. Zhang, Y. Chen, A. Li, J. Am. Chem. Soc. 139 (2017) 14893; (d) Y. Chen, W.H. Zhang, L. Ren, J. Li, A. Li, Angew. Chem. Int. Ed. 57 (2018) 952; (e) W.H. Zhang, M. Ding, J. Li, Z.C. Guo, M. Lu, Y. Chen, L.C. Liu, Y.H. Shen, A. Li, J. Am. Chem. Soc. 140 (2018) 4227. A.K. Chattopadhyay, V.L. Ly, S. Jakkepally, G. Berger, S. Hanessian, Angew. Chem. Int. Ed. 55 (2016) 2577. R. Yamada, Y. Adachi, S. Yokoshima, T. Fukuyama, Angew. Chem. Int. Ed. 55 (2016) 6067. X. Chen, H.-J. Zhang, X. Yang, H. Lv, X. Shao, C. Tao, H. Wang, B. Cheng, Y. Li, J. Guo, J. Zhang, H. Zhai, Angew. Chem. Int. Ed. 57 (2018) 947. H. Shi, I.N. Michaelides, B. Darses, P. Jakubec, Q.N.N. Nguyen, R.S. Paton, D.J. Dixon, J. Am. Chem. Soc. 139 (2017) 17755. B. Xu, B. Wang, W. Xun, F.G. Qiu, Angew. Chem. Int. Ed. 131 (2019) 5810. Y. Chen, J. Hu, L.D. Guo, W. Zhong, C. Ning, J. Xu, Angew. Chem. 131 (2019) 7468. (a) S. Park, M. Brookhart, J. Am. Chem. Soc. 134 (2012) 640; (b) C. Cheng, M. Brookhart, J. Am. Chem. Soc. 134 (2012) 11304; (c) A.D. Gammack Yamagata, D.J. Dixon, Org. Lett. 19 (2017) 1894; ´ .L. Fuentes de Arriba, E. Lenci, M. Sonawane, O. Formery, D.J. Dixon, Angew. (d) A Chem. Int. Ed. 56 (2017) 3655; (e) C. He, T.P. Stratton, P.S. Baran, J. Am. Chem. Soc. 141 (2019) 29. M.B. Thomas, A.X. Zhu, J. Clin. Oncol. 23 (2005) 2892. H.B. El-Serag, F. Kanwal, Hepatology 60 (2014) 1767. A. Yusuf, J. Zhao, B. Wang, P. Aibibula, H.A. Aisa, G. Huang, R. Soc. Open Sci. 5 (2018), 172037/1. A. Aisa, A. Yusupu, G. Huang, J. Zhao, Faming Zhuanli Shenquing, 2018. CN 108164461 A 20180615.

152 Applications of Name Reactions in Total Synthesis of Alkaloids [250] E.S. Starchman, M.S. Marshall, J.R. Vyvyan, Tetrahedron Lett. (2020) 151837. [251] R. Deziel, E. Masaki, US 4841043, June 20, 1989. [252] Z. Su, H.-K. Wu, H. He, U. Slukhan, H.A. Aisa, Helv. Chim. Acta 93 (2010) 33.

Chapter 5

Recent advances in applications of Mannich reaction in total synthesis of alkaloids Chapter outline 1. Introduction 1.1 Mechanism of the Mannich reaction 1.2 Asymmetric Mannich reactions

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1. Introduction The Mannich reaction [1] is one of the most important and significant carbonecarbon bondforming methodologies in organic synthesis. The Mannich reaction is generally an amino alkylation of an acidic proton placed next to a carbonyl functional group by formaldehyde, a primary or secondary amine, or ammonia in which its product is a b-amino-carbonyl compound. This reaction was named after German chemist Carl Mannich (March 8, 1877, in Breslau to March 5, 1947, in Karlsruhe), who discovered and disclosed the reaction in 1912 [1]. The discovery of such an important organic transformation attracted much attention from organic chemists worldwide and led to varied and extensive investigations. These investigations have resulted in continuous development in the organic chemistry arena. The Mannich reaction has been shown to tolerate a large assortment of functional groups and is thus considered a perceptive name reaction in organic transformations. A literature survey on the Mannich reaction discloses outstanding confirmation for the assortments and applications of this reaction [2]. Mannich reactions, and modified Mannich reactions in particular, offer a vigorous and powerful strategy for synthesizing aminocarbonyl compounds and many their other derivatives [3]. The importance of the Mannich reaction is partly due to its products, the aminocarbonyl Recent Applications of Selected Name Reactions in the Total Synthesis of Alkaloids https://doi.org/10.1016/B978-0-12-824021-2.00007-8 Copyright © 2021 Elsevier Inc. All rights reserved.

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154 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 5.1 Mannich reaction.

compounds. These compounds are useful precursors for the synthesis of a wide variety of beneficial compounds such as b-lactams [4e9], g-amino alcohols [10], a and b-amino acid derivatives [10], peroxy acetylenic alcohols [11] and ethers [11], and a wide range of medicinally important compounds [12]. The Mannich reaction can be employed to convert a primary or secondary amine and two carbonyl compounds (one nonenolizable and the other enolizable) to a b-aminocarbonyl compound, also known as the Mannich base, using an acid or base catalyst [1]. As an example, the synthesis of b-aminocarbonyl compound 4 via the Mannich reaction is illustrated in Scheme 5.1. Despite showing high diversity, usefulness, and synthetic value, the Mannich reaction, like other name reactions, has a number of serious drawbacks such as competitive aldol reactions leading to undesired side products and the inability to control regio- and stereoselectivity in satisfactory ratios [13]. To overcome these limitations, several successful modifications have resulted in Mannich reaction variants in which enolates, imines, and iminium salts [14] in the presence of appropriate catalysts, optimal reaction conditions, and other elements can be conducted effectively [2,12,15]. In addition, basic nanocrystalline magnesium oxide [16a], recyclable Cu nanoparticles [16b], and poly(amidoamine)-catalyzed Mannich reactions have been accomplished to lessen its limitations [16c]. Apart from these, several Mannich reactions have been conducted under MWI to obtain the expected products within shorter reaction times and with higher yields [16d]. Mannich products are nitrogen-containing compounds and these compounds, especially alkaloids that contain nitrogen heterocycles as their cores, are extensively distributed in nature and well recognized as biologically important molecules [12]; thus, the Mannich reaction has attracted much attention from synthetic organic chemists, especially those engaged in the total synthesis of natural products [17,18].

1.1 Mechanism of the Mannich reaction A plausible mechanism has been suggested for the Mannich reaction as depicted in Scheme 5.2. In the acid-catalyzed mechanism of this reaction, the enolizable carbonyl compound initially deprotonates to generate an enol intermediate. The nonenolizable carbonyl compound reacts with amine to create an iminium ion. The enol intermediate then attacks the iminium ion, which after deprotonation affords the final Mannich base as product.

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SCHEME 5.2 Mechanism of the Mannich reaction.

SCHEME 5.3 Essentials of the Mannich reaction.

A key element in all Mannich reactions is an iminium intermediate, 5, liable to nucleophilic attack by a wide variety of nucleophiles such as enolized ketones (4) or equivalents that lead to CeC bond formation adjacent to the nitrogen atom. The products, the so-called Mannich bases (6), are 1,3-amino ketones, which are versatile intermediates in organic synthesis. Their value has been confirmed in the total synthesis of alkaloids in particular. This type of conversion has now become firmly established as a viable approach to prepare the same products in enantio- and diastereomerically pure form via the asymmetric Mannich reaction (Scheme 5.3).

1.2 Asymmetric Mannich reactions Asymmetric Mannich reactions provide useful routes for the synthesis of chiral b-amino ketones or b-amino aldehydes in optically active form, which are prevalent as the backbone in natural products and frequently used in the total synthesis of nitrogen-containing compounds and show diverse biological activities. Due to the importance of the Mannich reaction in the total synthesis of natural products, the development of its asymmetric variant was in great demand and thus received enormous attention from the synthetic community.

156 Applications of Name Reactions in Total Synthesis of Alkaloids

Therefore, extensive progress has been made toward asymmetric Mannich reactions with continued strong growth. The importance of the asymmetric Mannich reaction can be better realized when used in the total synthesis of several naturally occurring compounds [19], in particular those of the famous Taxol side chain [20] as well as aboricine [21]. Nowadays, the asymmetric Mannich reaction is considered an important method for asymmetric CeC bond formation. In its classical form, it provides the optically pure b-amino ketones and aldehydes found widely in natural products [1], and the progress and success of drug discoveries and medicinal chemistry were based mainly on their effective and stereoselective synthesis. Obviously, during the total synthesis of nitrogen-containing natural products, the construction of the CeN bond is still a key challenge, as is the CeC bond formation. Asymmetric Mannich reactions are frequently catalyzed by chiral transition-metal complexes [48e50] as well as metal-free organic (organocatalyst) catalysts (Scheme 5.4) [43,44]. Over the last 3 decades, various catalytic systems have been developed for asymmetric Mannich reactions. For simplicity, these developments can be classified as follows (1) bifunctional thiourea catalysts, (2) sulfonamide catalysts, (3) Metal-catalysts, especially transition-metal catalysts, (4) amino acid catalysts, (5) alkaloid derived catalysts, (6) enzyme catalysts, (7) cyclopropenimine catalysts and (8) miscellaneous catalysts [22e39]. The first asymmetric Mannich reactions were diastereoselective and involved the use of modified enolates and enamines or imines, using stoichiometric amounts of chiral auxiliaries [40]. Several chiral auxiliaries have been used in asymmetric Mannich reactions [2b,41]. The products of asymmetric Mannich reactions, so-called Mannich bases, are 1,3-amino ketones that in enantiopure form are worthy and versatile intermediates in organic synthesis, particularly in the total synthesis of alkaloids. This type of conversion by now has also been firmly established as a viable approach to prepare the same products in enantio- and diastereomerically pure form via organocatalysis. Organocatalysts have been emerged as new types of efficient catalysts, effectively and extensively being used in asymmetric synthesis. In this regard, the effects of various chiral organocatalysts were extensively examined in several synthetically important organic transformations, including Mannich and related reactions [42]. Asymmetric organocatalysis is a branch of catalysis that uses chiral small organic molecules in substoichiometric quantities to promote organic

SCHEME 5.4 The first proline-catalyzed asymmetric Mannich reaction.

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reactions [43,44]. Furthermore, it is possible to obtain chiral organic products in enantioenriched form. Obviously, the value of the reaction is determined by the optical purity of the product itself. Asymmetric organocatalysis started to boom in 2000 [22] and grew rapidly to become the third and logical area for catalyzed-asymmetric synthesis. For example, the first important asymmetric Mannich reaction with an unmodified aldehyde used (S)-proline as a naturally occurring chiral organocatalyst [45]. Proline enters a catalytic cycle by reacting with aldehyde to form an enamine [45]. Other organocatalysts, such as chiral amines [10] and chiral derivatives of thiourea, have also been used effectively as catalysts in asymmetric Mannich reactions [46]. In 2000, proline was used as an effective organocatalyst in asymmetric Mannich reactions [47]. A one-pot three-component reaction comprising a ketone, an aldehyde, and a primary amine in the presence of L-proline provided the desired Mannich product in enantiopure form. Reaction of p-nitrobenzaldehyde (7), acetone (8), and p-anisidine (9) in the presence of L-proline in DMF gave the desired Mannich adduct 13 in 50% chemical yield with 94% ee (Scheme 5.5). It was proposed that the reaction proceeds via the chiral proline-derived enamine 11, which reacts with in situ generated iminium intermediate 10 in an enantioselective fashion. Initially generated iminium adduct 12 is hydrolyzed in the process, and the released proline enters the next catalytic cycle. Since the influential report by List, which resulted in the successful prolinecatalyzed three-component Mannich reaction, the asymmetric version of the Mannich reaction has become one of the most reliable processes to produce optically active amines in high yields and with excellent enantioselectivities [47]. Since then, organocatalysts have emerged as new types of effective catalysts and been successfully and widely used in asymmetric synthesis.

SCHEME 5.5 Asymmetric Mannich reaction.

158 Applications of Name Reactions in Total Synthesis of Alkaloids

In this regard, the effects of various chiral organocatalysts were extensively examined in several synthetically important organic transformations including Mannich and related reactions [17,18,22]. When properly functionalized, the newly formed ethylene bridge in the Mannich adduct has two prochiral centers giving rise to two diastereomeric pairs of enantiomers. As indicated earlier, symmetric Mannich reactions can be catalyzed by chiral transition-metal complexes [48e50] as well as metal-free organic catalysts (Scheme 5.4) [43,44].

2. Applications of the Mannich reaction in total synthesis of alkaloids Aspidosperma is a genus of flowering plant in the family Apocynaceae and was first designated as a genus in 1824. It is native to South America, Central America, southern Mexico, and the West Indies. This family of alkaloid is one of the major families of indole alkaloids identified, and over 250 inimitable alkaloids have been isolated from plentiful plant sources [51]. Alkaloids belonging to this family have long received attention from synthetic organic chemists due to the interesting and diverse biological potencies found in several of their members. Several Aspidosperma alkaloids contain a pentacyclic backbone with an ethyl group or a functionalized ethyl group at C20, as can be seen in the structure of aspidospermidine. Nevertheless, a small group of Aspidosperma alkaloids is associated with pandoline, which contains a proton at the C14 bridgehead position. Pseudotabersonine (37), initially isolated from Pandaca caducifolia in 1975 [52], is a good example member of this family of alkaloids. The first total synthesis of (
)-pseudotabersonine (37) was achieved by Martin and co-workers and reported in 2010 [53]. Then, a new strategy for the Aspidosperma group of alkaloids was developed and applied to a brief total synthesis of (
)-pseudotabersonine, which was achieved in 11 steps by the same research group in 2015 [54]. It featured a stepwise variant of a Mannich-like multicomponent installation process, a sequential double ring-closing metathesis (RCM), and a deprotection/cyclization sequence in one-pot fashion. Consequently, market purchasable aldehyde 16 was initially condensed with allylamines 17 and 18 to give corresponding intermediate imines 19 and 20, respectively, with nearly quantitative yields. Upon treatment of imines 19 and 20 in crude form with 21 under already secured optimal reaction conditions, branched adducts 22 and 23 were obtained with high (>10:1) regioselectivity. These adducts without purification were directly reacted with ethylene oxide in MeOH in a sealed tube to give the respective alcohols 24 and 25 in satisfactory overall yields. Protection of the hydroxyl group of these primary alcohols 24 and 25 as their TBS ethers then delivered 26 and 27. Next, introducing a vinyl group at the C2 position of 27 was planned. This was readily accomplished by treating 27 with LDA followed by addition of

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acetaldehyde to afford the alcohol 28, which was efficiently converted to tetraene 29 upon treatment with Tf2O and Hu¨nig’s base with respectable overall yield. Then, the opportunity for a double RCM sequence was contemplated. For this purpose, an initial solution of 29 containing 5% Hoveyda-Grubbs catalyst was heated at 100  C. The progress of the double RCM was monitored by TLC, showing that the RCM proceeded smoothly and gently gave a mixture (7:10) of D/E cis-fused and D/E transfused tetracycles 31 and 32, respectively, with excellent combined overall crude yield. Worthy of note is that pseudotabersonine (37) has a cis-fused D/E ring junction, but the desired 31 was inappropriate, as the minor diastereoisomer was produced by the RCM. Captivatingly, when this RCM process was conducted at lower temperatures, the ratio of 31 to 32 improved to approximately 1:1, but overall conversion was still low. Communally, these findings proposed that the desired D/E cis-fused product 31 was unstable at high temperatures, as it suffered sequential 1,4-elimination and aromatization reactions that resulted in the construction of undesired 33 [55]. Due to the ostensible thermal instability of 31, the temperature and time for the double RCM of 29 was cautiously monitored to obtain optimal quantities of 31. Because tetracycles 31 and 32 were not easily separable by column chromatography, the crude mixture was subjected to regioselective catalytic hydrogenation of the less substituted carbonecarbon double bond, with subsequent acid-promoted deprotection of the TBS ether to give an easily separable mixture (3:5) of 34 and 35 in respectable overall yield from 29. Transformation of 34 to pentacycle 36 was accomplished via a sequential N-deprotection/O-sulfonylation sequence followed by cyclization in a one-pot fashion [56]. For this purpose, a solution of 34 in DME was added to a solution of KOt-Bu in THF to give 36 in satisfactory yield. Finally, in accord with a procedure developed by Rawal [57], pentacycle 36 was deprotonated upon treatment with LDA, and the intermediate imine anion was allowed to react with Mander’s reagent to produce the desired alkaloid, (
)-pseudotabersonine (37), in good yield (Scheme 5.6). The spectral data of this synthetic sample were found to be in excellent agreement with those of 37 reported by Kuehne et al. [58]. This sequential reaction was then used for the total synthesis of (
)-14-epipseudotabersonine (39). Notably, the conversion of 35 into 38 proceeded smoothly, resulting in the C-carbomethoxylation of 38 to give 39 in accord with the Rawal strategy by extensive N-acylation. In this way, the carbamate analog of 39 was obtained in modest yield (Scheme 5.7). The significant difference in regioselectivity in the acylation of the anions provided from 35 and 38 by means of Mander’s reagent is remarkable and unanticipated, but it was conjectured that differences in ring strain in the two systems may play a role [54]. The inversion of two stereocenters at C3 and C7 of 38 via a reversible retro-Mannich/sequence including the intermediacy of 41 to give pentacycle 42 was observed when the cis D/E fusion was attempted. This process has

160 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 5.6 Total synthesis of (
)-pseudotabersonine (37).

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SCHEME 5.7 Synthesis of (
)-14-epi-pseudotabersonine (39) and attempt to prepare 42.

precedence for related compounds bearing a cis-fused D/E ring system [59]. Disappointingly, all attempts to epimerize 38 under different acidic conditions (TsOH, TFA, AcOH, BF.3Et2O, Cu(OTf)2 and HCl) were unsuccessful. Thus, imine 38 was subjected to an acid-assisted cyanide addition to give 40 in good yield. Treatment of 40 with AgOTf resulted in a Grob-like fragmentation to create the tetracyclic iminium ion intermediate 41, which was cyclized via a Mannich-like reaction to afford 42. Nevertheless, treatment of 40 with AgOTf in CH3CN at 120  C under pressure resulted in the regeneration of 38. Seemingly, loss of the cyanide ion from 40 took place without cleavage of the C3 and C7 carbonecarbon bond, and thus none of the isomerized product 42 was generated (Scheme 5.8) [54]. Concise enantioselective total synthesis of naturally occurring ()-isonitramine (52), an alkaloid-containing spirocyclic amine framework, and the first total synthesis of (þ)-sibirinine (53) were achieved in 11 steps and 36% overall yield from commercially accessible diallyl pimelate. The first total synthesis was made of (þ)-sibirinine (53), a tricyclic alkaloid featuring an N,O-acetal, a tertiary amine N-oxide, and two pairs of vicinal stereocenters, including an all-carbon quaternary center. In 2015, Stoltz and co-workers successfully achieved a reverse strategy for generation of a-quaternary and tetrasubstituted tertiary Mannich-type products via strategic enolate generation to obtain the required products in mild to excellent yields and with good to excellent ee [60]. This strategy tolerates a wide range of ketones, amides, and vinylogous esters even in the presence of basic tertiary amines and

SCHEME 5.8 Other attempts to isomerize 38 to give 42.

162 Applications of Name Reactions in Total Synthesis of Alkaloids

relatively acidic NeH groups. Successful development of this inverted approach permitted fast and stereoselective total synthesis of ()-isonitramine (52) and (þ)-sibirinine (53) [61e63]. In addition, this strategy allowed the effective assemblage of the spirocyclic amine-containing framework. The total synthesis started with the reaction of sulfonylmethyl carbamates 44 as versatile and easily accessible imine precursors [64] generated in the presence of Cs2CO3 that reacted after Boc-protection with b-keto ester 43 [65] via a Mannich-type reaction. This reaction proceeded smoothly at room temperature to deliver a Mannich-type product, b-aminoketone 46, with excellent yield and ee. Asymmetric allylic alkylation using 46 proceeded in the presence of Pd(dba)3 in toluene at 23  C to deliver 48 in gram scale without any loss of enantioselectivity. Next, reduction of b-amino ketone 48 using diisobutylaluminum hydride (DIBAL-H) as reductive agent followed by acetylation of the expected corresponding alcohol afforded carbamate 49 as a single diastereomer. Carbamate 49 was subjected to hydroboration of the terminal alkene to give primary alcohol 50 in satisfactory yield in three steps. The mesylate derived from primary alcohol 50 was submitted to cyclization, which cleanly delivered spirocycle 51. Cleavage of the acetyl and Cbz moiety using KOH provided the desired alkaloid, ()-isonitramine (52), in respectable yield. Next, ()-isonitramine (52) was reacted with excess acetaldehyde to furnish the desired hemiaminal, which upon exposure to a mild oxidative reagent such as m-CPBA furnished the desired target, (þ)-sibirinine (53), with excellent yield in two steps. Outstandingly, transformation of ()-isonitramine to (þ)-sibirinine (53) can be achieved in one-pot fashion by generation of the hemiaminal intermediate under an oxygen atmosphere, albeit with lower yield (Scheme 5.9). The spectroscopic data analyses of 52 and 53 was found to be in full agreement with those already published in the literature [62,63]. Notably, the total synthesis of ()-isonitramine (52) and its structural characterization endorsed the absolute configuration of 48 [62]. Alkaloids containing a piperidine framework are extensive and often further subdivided in accord with their incidence and biogenetic origin. Piperidine alkaloids make up one of the major classes of alkaloids and have been the subject of several investigations and many reviews [66]. Functionalized piperidine rings are very communal groups incorporated in a wide range of naturally occurring alkaloids and complex synthetic compounds used as pharmaceuticals [66]. Indeed, piperidine is probably the most commonly employed nonaromatic ring in prescribed drugs approved and listed by the US Food and Drug Administration book [67]. Among these series of compounds, 2 and/or 6 substituted piperidines are predominantly communal and stimulating [68] because such substitution patterns block the metabolism of the piperidine ring and hypothetically partake in an important impact on the ring’s 3D conformation. Thus, the assemblage of a substitution next to the piperidine nitrogen is typically used as a protocol in medicinal chemistry research to tune either biological potencies or pharmacological activities. Practically, the

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SCHEME 5.9 Total synthesis of ()-isonitramine (52) and (þ)-sibirinine (53).

methyl group is one of the most communal and modest substituents helping this resolution. Captivatingly, a-methyl multisubstituted piperidines are also found in natural piperidine alkaloids such as ()-pinidinol, (þ)-241D (59a), and isosolenopsin A (62) [69]. The biosynthetic pathway of several piperidinebased natural alkaloids has been extensively investigated. Encouraged by the understanding of biosynthesis of piperidine natural products, Yang and coworkers in 2015 [70] established a common strategy to install multisubstituted chiral piperidines. The structure of (þ)-241D (59a) comprises an all-cis 2,4,6trisubstituted piperidine scaffold containing three stereogenic centers. The asymmetric synthesis of (þ)-241D (59a) has been accomplished previously by several research groups through different approaches using between 8 and 18 steps [71]. The vinylogous Mannich-type reaction (VMR) approach was applied for the generation of useful optically active dihydropyridone intermediates, followed by their conversions to a wide range of stimulating piperidine comprising natural alkaloids and complex compounds of biological interest. Applications of these chiral piperidine intermediates by the VMR strategy to the asymmetric synthesis of piperidine-containing natural alkaloids were contemplated and implemented. Dendrobate alkaloid (þ)-241D (59a) and its enantiomer ()-241D (59b) were chosen as the first targets.

164 Applications of Name Reactions in Total Synthesis of Alkaloids

Dendrobate alkaloid (þ)-241D (59a) was initially isolated from the methanolic skin extracts of the Panamanian poison frog Dendrobates speciosus [72]. Yang and co-workers in 2015 used the newly developed VMR strategy, and the resulting asymmetric synthesis of (þ)-241D (59a) and its enantiomer were accomplished simply in two steps beginning from inexpensive commercially available starting materials. Accordingly, the total synthesis of (þ)-241D (59a) started from optically active a-methyl benzylamines 55a or 55b to control stereochemistry. The reaction of decanal 54 with bistrimethylsilyl enol ether 56 with either of optically active a-methyl benzylamines 55a or 55b gave optically active adducts 57 and 58, respectively. Subsequent reduction of 2,3-dihydro-4-pyridones 57 or 58 by Pd-catalyzed hydrogenation in MeOH afforded (þ)-241D (59a) or its enantiomer ()-241D (59b) as the desired target in satisfactory yield (Scheme 5.10). Solenopsin is an alkaloid found in the venom of fire ants (Solenopsis). It is considered the primary toxin in the venom and may be the component responsible for cardiorespiratory failure in people who experience excessive fire ant stings. It has shown other interesting bioactivities including antibiotic, antifungal, anti-HIV, blockade of neuromuscular transmission, and selective inhibitory activity toward the neuronal nitric oxide synthase [73]. Structurally, solenopsins make up a piperidine ring bearing an Me group at position 2 and a long hydrophobic chain at the 6 position [74]. The versatile efficacy of such a VMR strategy in installation of the piperidine ring was further redeemed in total synthesis of naturally occurring alkaloid isosolenopsin A, which includes cis-2,6-dialkylpiperidine as a backbone. Similarly, the corresponding VMR adduct, 2,3-dihydro-4-pyridone 61, was provided from the reaction of dodecanal 60, chiral amine 55b, and bis-trimethylsilyl enol ether 56. The Pdcatalyzed reduction on 61 was performed in MeOH in AcOH (50%) under 40 psi hydrogen pressure in a Parr hydrogenator. Corresponding deoxygenated product isosolenopsin A was furnished as the major product in modest yield (45%) (Scheme 5.11). This approach is indeed the shortest pathway for asymmetric synthesis of isosolenopsin A (62)dshorter than any other previously reported strategies [75].

SCHEME 5.10 Total synthesis of (þ)-241D (59a) and ()-241D (59b).

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SCHEME 5.11

165

Asymmetric total synthesis of natural alkaloid isosolenopsin A (62).

The VMR strategy was also utilized in the synthesis of optically active quinolizidine derivatives. Quinolizidine derivatives structurally connect two fused piperidine rings sharing mutual nitrogen. Similar to piperidine, quinolizidine derivatives are interesting from both chemical and biological points of view. In the plant kingdom, several hundred quinolizidine compound derivatives have been recognized from plants and amphibian skin [76]. Several natural quinolizidine alkaloids show interesting biological properties [76] and serve as significant starting points for drug discovery [77]. Cyclic enaminone 68 was thought to be a valued polyfunctional quinolizidine intermediate for the total synthesis of natural alkaloid ()-epimyrtine (70). 5-Chloropentanal (65) was provided from the oxidation of 5-chloropentan-1-ol (64), and the corresponding three-component VMR reaction was performed to afford adduct 66 in anticipated excellent diastereoselectivity as a single stereoisomer. Having dihydropyridinone 66 available in hand, the second ring for a quinolizidine core was constructed. The a-methyl benzyl group was cleaved smoothly via the treatment of 66 with TFA at ambient temperature to deliver compound 67 in nearly quantitative yield. The latter in the presence of NaH in DMF resulted in the formation of the desired quinolizidine intermediate 68. ()-Epimyrtine (70), isolated from Vaccinium myrtillus (Ericaceae) [78,79], is a quinolizidine alkaloid. This alkaloid family exhibits potential pharmacological properties such as anticancer, antibacterial, antiviral, and antiinflammation activities (Scheme 5.12) [80e82]. Upon the reduction of cyclic enaminone 68 using “super hydride” (LiEt3BH) in the presence of BF3.Et2O in THF, the alkene functionality was selectively reduced, giving ()-epimyrtine (70) as natural quinolizidine alkaloid in satisfactory yield. The Myrioneuron alkaloids are a small yet increasing family of structurally diverse polycyclic (tri-, tetra-, penta-, hexa-, and decacyclic) alkaloids believed to share a common biosynthetic origin from lysine [83,87]. The first Myrioneuron alkaloids, from Myrioneuron nutans, were reported in 2002, with 10 structures reported altogether to date [83]. Since 2013, many new alkaloids have been isolated from Myrioneuron faberi [84], Myrioneuron tonkinensis, and Myrioneuron effusum [85,86]. From the structural point of view, these alkaloids have a cis-decahydroquinoline system that frequently include 1,3oxazine and/or 1,3-diazine rings. In 2014, two clusters including four new Myrioneuron alkaloids (
)-a,b-myrifabral A (78 and 79) and B (81 and 82)

166 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 5.12 Total synthesis of natural quinolizidine alkaloid ()-epimyrtine (70).

were isolated by Hao et al. from M. faberi, an exceptional plant largely dispersed in China [88]. Dissimilar to all other formerly identified Myrioneuron alkaloids, the four new members have a cyclohexane-fused octahydroquinolizine scaffold together with a six-membered cyclic hemiacetal. In addition, these alkaloids comprise four continual stereogenic centers involving a quaternary chiral center surrounded in the bridgehead. In addition to their stimulating structural features, a number of these alkaloids possess a range of biological activities such as antimalarial properties, KB cell cytotoxicity, antimicrobial, and hepatitis C virus replication inhibition even as racemic mixtures. Despite showing promising biological potencies and being a synthetically attractive and appealing architectural target for the discovery of new drugs, relatively few of these alkaloids have been prepared by total synthesis attempts [84]. Thus, for a further and detailed structureeactivity relationship study, a convenient, concise, and scalable synthetic pathway to (
)-a,b-myrifabral A and B was realized to be essential. She and co-workers accomplished the first total synthesis of Myrioneuron alkaloids (
)-a,b-myrifabral A (78 and 79) and myrifabral B (81 and 82) and reported their results in 2016 [89]. Their strategy involved just four steps from commercially available or readily accessible starting materials. This brief total synthesis was designed based on a key sequential Mannich/amidation cascade reaction to construct the core backbone and two carbon stereogenic centers to conveniently and rapidly provide the desired alkaloids in significant quantities for biological screening. As illustrated in Scheme 5.13, this synthetic route started with the easily accessible iodide 72 that was provided in one-step fashion from commercially available acrolein using Gil’s conditions [90].

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SCHEME 5.13 Synthesis of (
)-a,b-myrifabral A and B.

Then, the iodide 72 was coupled with commercially available methyl 2-oxocyclohexanecarboxylate 73 to give the needed alkylative product 74 [91]. On the other hand, supplementary prerequisite unit, imine 75 was easily prepared from inexpensive commercially available piperidine [92]. With segments 75 and 74 available in hand, the key tandem Mannich/amidation reaction was attempted. Delightfully, the required tricyclic 76 was obtained from the tandem Mannich/amidation reaction of compound 74 in the presence of MeONa in MeOH under reflux in acceptable yield. Worthy of mention is that the procedure was performed on a gram scale with slightly decreased yield from inexpensive market-purchasable staring materials together with effective generation of two new stereogenic centers in one-step, one-pot fashion. After construction of the core backbone, the two carbonyl groups at C12 of 76 were concurrently reduced. As expected, the reduction of 76 with LiAlH4 furnished a 6.75:1 mixture of two diastereomers, and the major product 77 was easily isolated via column chromatography in high yield. Upon deprotection of 77 using 2 N HCl with subsequent impulsive hemiacetalization, the desired alkaloid (
)-a,b-myrifabral A was smoothly furnished as a cluster in excellent overall yield. Delightfully, (
)-a-myrifabral A (78) could be recrystallized from the EtOAc solution of cluster A, and its structure was confirmed unambiguously by X-ray diffraction analysis surprisingly against the

168 Applications of Name Reactions in Total Synthesis of Alkaloids

information reported by Hao and co-workers [88]. Upon treatment of (
)-a,b-myrifabral A with a labile aza-acetal 80 [93] generated in situ, the desired alkaloid (
)-a,b-myrifabral B was obtained in moderate yield, while some unchanged (
)-a,b-myrifabral A was also detected and easily separated. The spectral data (1H and 13C NMR spectra and HRMS) of pure (
)-a,b-myrifabral B were in full accord with those of the sample isolated from nature [88]. Lobeline is a pyridine alkaloid found in a variety of plants, particularly those of the genus Lobelia, including Indian tobacco (Lobelia inflata), devil’s tobacco (Lobelia tupa), cardinal flower (Lobelia cardinalis), great lobelia (Lobelia siphilitica), Lobelia chinensis, and Hippobroma longiflora. In its pure form, it is a white amorphous powder that is freely soluble in water. It was initially isolated from the leaf of Lobelia nicotianaefolia along with many other alkaloids such as lobeline, which was apparently observed at higher concentrations [94,95]. In fact, piperidine rings are abundant structural moieties in alkaloids and medications and correspondingly communal in their possession of 2- or 2,6-substitution patterning that involves a b-carbonyl and/ or alcohol functionality [96]. Such molecules as these natural products are illustrative samples isolated from various plants and many insects [97]. It was suggested that these side chains were generated via Mannich-type additions of carbonyl-derived nucleophiles onto piperidine-derived iminium intermediates biosynthetically [97f,98]. Relying on previous reports, two strategies can be used practically for the total synthesis of these alkaloids with high enantioselectivity. The first strategy involves the use of L-proline to influence direct Mannich-type reactions between imines and the corresponding ketones to deliver aminoketones [99]. The second approach involves utilization of an optically active Cu(I)-conjugated BrØnsted base pair to promote a sequential stepwise ring-opening/aldol addition/dehydration tandem reaction with subsequent stereoselective aza-Michael reaction [100] commencing from cyclic hemiaminal and methyl ketones [101]. Nitrones, both cyclic and acyclic, have been found to be suitable active substrates to react with b-ketoacids as well as any appropriate methyl ketones via Mannich-type additions merely upon dissolution. When chiral thioureas were used as suitable organometallic catalysts in the aforementioned process, the reaction made progress with good to excellent enantioselectivity and can function as a foundational method to produce the key stereogenic centers, resulting in the fast and stereoselective total synthesis of 2,6-disubstituted alkaloids such as ()-lobeline (92) and ()-sedinone (93). Snyder et al. accomplished the total synthesis of ()-lobeline (92) and ()-sedinone (93), publishing their results in 2018 [102]. Their strategy involved two Mannichtype additions to nitrones, one employing b-ketoacids in the absence of any catalyst and another employing methyl ketones in the presence of chiral organocatalysts such as thioureas, producing a wide range of 2-substituted materials as well as other ring systems in the form of b-N-hydroxy-aminoketones.

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The combination of these two strategies, along with other important steps, has permitted eight-step total synthesis of the 2,6-disubstituted the piperidine alkaloids ()-lobeline (92) and ()-sedinone (93) as the desired targets. Although dozens of biologically active 2-substituted and 2,6-disubstituted piperidines have been recognized, only a limited number of approaches exist for their synthesis, and only two have been described: (1) Mannich-type additions to nitrones, using b-ketoacids under catalyst-free conditions and (2) methyl ketones used in the presence of chiral thioureas to generate a broad array of such 2-substituted materials as well as other ring variants in the form of b-N-hydroxy-aminoketones. Both processes have shown broad scope, with the latter providing products with high enantioselectivity (up to 98%). The combination of these methods, along with other critical steps, has enabled eight-step total synthesis of the 2,6-disubstituted piperidine alkaloids ()-lobeline (92) and ()-sedinone (93). These approaches encompass a diverse substrate scope and potential for late-stage functionalizations, with one also affording opportunities for enantioselective synthesis with cyclic six-membered nitrones to generate the corresponding b-N-hydroxy-aminoketones in up to 98% ee. As a result of the oxidation state of the products, purification is facile, and racemization is slow. Finally, the serial execution of both methods, along with other unique operations, has enabled eight-step total synthesis of ()-lobeline (92) and ()-sedinone (93) via formation of a common intermediate. As illustrated in Scheme 5.14, the total synthesis started with the application of the developed catalytic approach for the synthesis of 86, from the reaction of nitrone 83 and methyl ketone 84 in the presence of Jacobsen catalyst 85 performed on mmol scale to produce gram quantities of the product in a one-pot fashion. Then, upon selective syn-reduction of 86 utilizing

SCHEME 5.14

Total synthesis of ()-lobeline (92) and ()-sedinone (93).

170 Applications of Name Reactions in Total Synthesis of Alkaloids

Zn(BH4)2 [103], the desired alcohol was produced as a 9:1 mixture of diastereomers, which was subsequently silylated by BSOTf in the presence of i-Pr2NEt to give the required hydroxyamine 87 with respectable yield in two steps without a noteworthy drop in enantiomeric excess (89% ee). The absolute (S,S)-configuration of 87 was established by single crystal X-ray diffraction. By employing the b-ketoacid variation of the nitrone addition, hydroxyamine 87 was next oxidized using IBX [104] in high regioselectivity to deliver a 4:1 ratio of aldonitrone 88 and its respective ketonitrone form. Then, the two requisite b-ketoacids (89, R ¼ Ph or Me) were added to crude nitrone 88 separately to provide the corresponding disubstituted hydroxylamines smoothly, but mainly the compound with a trans-2,6-arrangement on the piperidine ring (w4:1 dr for both) was formed. Next, reductive cleavage of their NeO bonds indeed gave the desired secondary amines; however, these products were liable to equilibration, probably through the sequential retroaza-Michael/aza-Michael route [105,106], to eventually favor the formation of 2,6-cis-isomers [107]. All efforts for the N-alkylation of the cis-isomers failed, but the trans-isomers underwent reductive amination smoothly. Fortunately, the trans-isomers can be transformed into cis-isomers at a later stage (vide infra) [108]. Therefore, the two operations were combined to minimize isomerization by utilization of Zn/AcOH in the presence of aqueous formaldehyde [109]. This process produced N-methylamines 90 and 91 with 75% and 76% yield, respectively, via communal intermediate 88. For these products, equilibration was still witnessed, with the dr of 90 being batch dependent (w1:1), while 91 was less liable to epimerization (dr ¼ 1:5.4 preferring the trans-isomer). Lastly, upon acidic TBS cleavage [106] followed by the basic work-up procedure, desired targets aminoalcohol 92 and 93 were obtained in respectable yields and with the same dr. A new class of bisindole pigment, iheyamine A (101), has been isolated from a colonial ascidian, Polycitorella sp. collected from the island of Iheya by Higa and co-workers in 1999 [110]. The aromatic nature of iheyamine A (101) was apparent from the high unsaturation requirement (16 sites) and characteristic aromatic signals in its 1H-NMR spectrum. In addition, careful interpretation of the XH and X3C NMR, COSY, and HOHAHA spectra resulted in the partial structural elucidation of 1A [110], consisting a central azepane ring between two indole rings. This alkaloid has received much attention from synthetic organic chemists due to its fascinating structural features and cytotoxicity against tumor cells [111]. The first stylish total synthesis of iheyamine A (101) was achieved by Sperry et al. in 2016 and involved an intermolecular cross-coupling reaction between 5-methoxy-3acetoxyindole and tryptamine to afford 2,20 -bisindole as a key step [112]. The Sperry research group also accomplished the associated synthetic investigation of iheyamine A (101) via intramolecular cyclization at the C4 position of 5-methoxyindole instead of the C2 position [113].

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Abe and co-workers achieved an elegant approach toward the total synthesis of iheyamine A (101) and revealed their results in 2018 [114]. In their brief total synthesis, they made use of an indole-2,3-epoxide equivalent. It involved the formal C3 electrophilic reaction of an indole-2,3-epoxide equivalent with tryptamine to construct a 3-aminoindoline and an innovative in-catalyzed dehydrative Mannich-type reaction of the hemiaminal to obtain the azepinobisindole scaffold. Consequently, the total synthesis started with the construction of 3-amino-2-hydroxyindoline (95), HITAB (94a) [115], which was provided in pure form from commercially accessible indoles in one-pot fashion and gram scale. A C3 electrophilic reaction of 94a with tryptamines 95a gave 97a via indole-2,3-epoxide 96a-c in respectable yields with trans selectivity. Having compound 97 in hand, the feasibility of the key dehydrative Mannich-type reaction for the construction of the azepinobisindole scaffold was examined. Under secured optimal reaction conditions, compound 97 was refluxed in MeCN in the presence of InCl3$4H2O to deliver required azepinoindoles 98a in respectable yield. Then, upon hydrogenation of 98a in the presence of PdeC in AcOH/AcOEt, deprotection of the benzyl group occurred and delivered 99 in excellent yield. Upon treatment of the latter with sodium amalgam, the detosylated compound 100 was achieved in satisfactory yield. At last, DDQ oxidation of 100 gave the desired target, iheyamine A (101) in high yield (Scheme 5.15). The spectroscopic data of this synthetic sample were compared with those of authentic samples isolated from natural sources and found to be in excellent agreement [110,112]. Actinophyllic acid (117) is a biologically potent indole alkaloid with an exceptional structural backbone that includes five adjoining chiral centers. In 2005, Carroll et al. isolated this monoterpene indole alkaloid from the leaves of the Australian tree Alstonia actinophylla [116]. The same authors characterized acid 117, named it as (
)-actinophyllic acid (117), and reported their studies in the same paper [116]. (
)-Actinophyllic acid (117) was also reported to inhibit carboxypeptidase U during a coupled enzyme assay, showing potentially promising anticancer activity, one of which induces cell death in a wide range of cancer cell lines [117]. Structurally, (
)-actinophyllic acid (117) consists of a bridged core that is unique among known natural products. Especially, the pyrrolidine ring, the cyclic hemiketal, the carboxylic acid attached to a quaternary carbon atom, the indol-3-ylmethanamine group, and the five adjoining stereogenic centers are all inspiring features in the synthesis of this interesting molecule. This combination of attractive structural complexity and powerful biological activities has made (
) actinophyllic acid (117) a striking target for total synthesis. In 2008, the first total synthesis of (117) was achieved and reported by Overman and co-workers via sequential aza-Cope/cascade protocol [118a]. The same research group later reported the asymmetric total synthesis of ()-actinophyllic acid [118b]. In 2013, Martin and co-workers reported a short total synthesis of (
)-actinophyllic acid (117) through a protocol involving a cascade reactions of N-stabilized carbocations

172 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 5.15 Total synthesis of iheyamine A (101).

with p-nucleophiles [119]. Kwon et al. in 2016 revealed a catalytic asymmetric total synthesis of ()-actinophyllic acid relied on a chiral phosphinecatalyzed [3 þ 2] annulation [120]. Chen et al. in 2017 revealed a desymmetrization-based total synthesis of (
)-actinophyllic acid [121]. Qin et al. in 2018 disclosed a formal synthesis of both ()- and (þ)-actinophyllic acid [122]. Furthermore, total synthesis of (
)-actinophyllic acid (117) has been achieved recently [123]. Although all inventive strategies for the abovementioned synthesis of 117 are noteworthy, the catalytic asymmetric routes are confusing and sporadic. Particularly, a new resolution relying on fast construction of the stereochemistry for the adjoining stereogenic centers C(16), C(15), C(20), and C(19) (the actinophyllic acid numbering is used for the intermediates) has not yet been disclosed. Yang and co-workers in 2018 reported a synthetic protocol for the catalytic asymmetric total synthesis of ()-actinophyllic acid (117). It involved highly effectual and enantioselective steps allowing the rapid introduction of the four

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adjoining stereogenic centers (C16, C15, C20, and C19) via an unprecedented dual Ir/amine catalytic allylation of 2-indolyl vinyl carbinol 102 and an aldol reaction of resulted optically active aldehyde 106 with 2-pyrrolidinone 107. The vital indol-3-ylmethanamine group and 1-azabicyclo[4.2.1]nonane ring system were easily created via a selective Mannich-like cyclization and an intramolecular N-alkylation to produce tetracycle 113, respectively [124]. Total synthesis of ()-actinophyllic acid started with the reaction of 2-indolyl vinyl carbinol derivative 102 with 4-pentenal (103) in the presence of benzoic acid along with (S)-105 and [Ir/(S)-104] as catalysts to afford the required product 106 in good chemical, excellent ee, and 20:1 dr. The latter was reacted with N-Boc-protected 2-pyrrolidinone 107 to afford the required tricycle 108 in good yield and a high diastereoselectivity (dr > 10:1). The stereochemistry of the resulting new chiral centers at C(20) and C(19) could have been anticipated considering the Anh model [125]. The obtained tricyclic alcohol 108 was protected as a TBS silyl ether (110) using TBSOTf and 2,6lutidine. The configuration of C(19) was inverted by the enolization of 110 with subsequent addition of AcOH, and as expected, gave completely inverted tricycle 111. Oxidative cleavage of 111 via a LemieuxJohnson oxidation produced the prerequisite aldehyde, which was then submitted to Pinnick oxidation followed by methylation of the resulting carboxylic acid to give the corresponding methyl ester 112. To forge the C(7)eC(21) bond, the lactam group of tricycle 112 was selectively reduced using lithium triethylborohydride to produce a hemiaminal intermediate. This hemiaminal intermediate was utilized without purification, being treated with Tf2O in which the sevenmembered ring rapidly opened, apparently via an N-acyliminium ion, affording 113 as a 6.5:1 mixture of diastereomers at C(21) in an overall respectable chemical yield. Pleasantly, the required 113, exhibiting cis stereochemistry between the C(21) and C(19), was favorably generated over the trans-isomer. This tetracycle key intermediate 113 was characterized by 2D NMR analysis. Then, the latter was submitted to hydrogenolysis in the presence of Pearlman’s catalyst to produce alcohol 114 in a respectable isolated chemical yield. For ring closure, alcohol 114 was initially transformed to its mesylate as a better leaving group, and in the meantime, deprotection of the N-Boc was achieved by employing trimethylsilyl triflate and Et3N to produce the amine intermediate, which then was treated with K2CO3 in CH3CN at 60  C to deliver a precarious pentacycle 115, an azabicyclo[4.2.1]nonane ring system, in satisfactory overall yield. At this stage, the latter was TBS deprotected upon treatment with 5 N HCl followed by oxidation of the resulting secondary alcohol using DessMartin periodinane to afford ketone 116 in good yield. Upon cleavage of the Boc group on N(1) of 116 using TFA, the amino ester trifluoroacetate salt intermediate was obtained. Deprotonation of this intermediate using LDA at 78  C with subsequent addition of freshly provided monomeric formaldehyde delivered an aldol adduct, [118], which upon hydrolysis using 5 N HCl at 70  C furnished the desired alkaloid

174 Applications of Name Reactions in Total Synthesis of Alkaloids

()-actinophyllic acid hydrochloride 117 in good overall yield from ketone 116 (Scheme 5.16). All spectroscopic data of this synthetic sample were in full accord with those obtained for the sample isolated from nature [116]. In addition, the synthetic ()-117$HCl showed an optical rotation of 178.6 (c 0.22, MeOH), which was essentially identical to that recorded for the natural product and reported in the literature [116]. Aspidosperma is a genus of flowering plant in the family Apocynaceae, first described as a genus in 1824. It is native to South America, Central America, southern Mexico, and the West Indies. The genus Aspidosperma has

SCHEME 5.16 Total synthesis of ()-actinophyllic acid (117).

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over 250 exceptional members and shows substantial structural diversity [126]. The structures of these members are outstanding, as they comprise a cagelike [6.5.6.6.6] fused pentacyclic backbone with three adjoining cis-stereogenic centers, two of which are all-carbon quaternary centers. Vincadifformine, with the chemical name of methyl (1S,12R,19R)-12-ethyl-8,16-diazapentacyclo [10.6.1.01,9.02,7.016,19]nonadeca-2,4,6,9-tetraene-10-carboxylate (132), is one of the most important representative members among this family. It was isolated from Vinca difformis in 1962 by Djerassi and co-workers [127]. Both vincadifformine and its congeners showed outstanding cytotoxicity in vitro toward a total of 60 human tumor cell lines derived from nine cancer types [128]. Considering its captivating structure and well-known biological activities, it has attracted much interest from synthetic chemists, who have dedicated much effort toward its total synthesis [129]. In 2011, Pandey and coworkers developed a tandem approach to construct C/E rings as well as the C12/C19 stereogenic centers concurrently and in one-pot fashion [130]. In 2012, Andrew and co-workers achieved a sophisticated strategy to introduce the enantioenriched E ring and C19/C5 stereogenic centers via the domino Michael/Mannich/N-alkylation sequential reactions [131]. In 2017, Jiang et al. accomplished a divergent and applicable synthesis toward vincadifformine (132) and its congeners via Fischer indolization reaction and reported their results in 2017 [132]. In addition, MacMillan and co-workers successfully completed a series of monoterpene indole alkaloids synthesis based on an impressive organocatalytic cascade method [133]. Despite several positive strategies toward synthesis of vincadifformine (132), the asymmetric synthesis of vincadifformine employing chiral cation-directed catalysis as a required vestige is a rare example of this catalytic protocol applied to total synthesis. The most important and common features in the members of this family are a tertiary carbon stereogenic center next to indoline and a tertiary amine that are frequently shared by these alkaloids [134]. Thus, Zhao and co-workers in 2019 hypothesized anew that this communal core could be introduced by the reaction between N-Boc indole aldimine 118 and a nucleophile reagent [135]. Encouraged by their previous work that successfully used amino acid derivatives as chiral organocatalysts, they obtained the related products in excellent yield and enantiopurity [136] and developed a new strategy to build up the vital required intermediate 121. Their strategy for reaching into vincadifformine (132) in enantioenriched form involved a chiral cation-directed catalysis. The pathway comprised thiourea phosphonium salts catalyzed by a Mannich-type reaction, phosphine-assisted aza-Morita-Barrie-Hillman reaction, and TFA-promoted deprotection/amidation tandem sequence. In their strategy, an addition to aromatic electron-rich N-Boc indole aldimine 118 with relatively low electrophilicity was contemplated. Although this reaction seemed to be a challenging task, it has been used by the Johnson group to

176 Applications of Name Reactions in Total Synthesis of Alkaloids

synthesize enantioenriched b-amino-keto esters via dynamic kinetic resolution [137]. Encouraged by the Johnson group’s result, initially N-Boc indole aldimine 118 was reacted with dimethyl ethylmalonate in the presence of a suitable thiourea phosphonium salt 120 as a catalyst via asymmetric Mannich˚ molecular sieves as additive to obtain 121 in type reaction in toluene using 4A high yield and satisfactory enantiopurity. Notably, the yield of this reaction was easily improved to the gram scale (increased to 97%) simply by recrystallization without impacting its efficacy as well as the enantiopurity of the major diasomer downstream at the tert-butyldimethylsilylation stage. The prepared 121 was then reduced intermediately using DIBAL-H to obtain diol 122 in high chemical yield and ee. Selective protection of one of the hydroxyl group in 122 using TBSCl in the presence of NaH in THF at room temperature gave a mixture of 123 and 1230 in good combined yield. Both intermediates 123 and 1230 were then used for installation of vincadifformine (132). As depicted in Scheme 5.17, acetylation of the remaining hydroxyl group in 123 using (AcO)2O with subsequent desilylation delivered the intermediate 124 in high yield. The latter was then subjected to Dess-Martin periodinane oxidation to afford the corresponding aldehyde, which in turn was submitted to HornereWadswortheEmmons olefination using trimethyl phosphonoacetate to deliver 125, which upon deprotection of the acetyl group under basic conditions afforded a, b-unsaturated ester 126 in excellent yield. Having optically pure intermediate 126 as the key intermediate with a C19 stereogenic center (90% ee) in hand, several attempts for functional group transformations were made to provide, finally, the desired cyclization precursor 129. Lastly, compound 126 was submitted to Pd/C-catalyzed hydrogenation of the a, b-unsaturated double bond followed by oxidation and HornereWadsworthe Emmons olefination to furnish 127 with respectable yield in three steps. The construction of the D ring was resourcefully accomplished through a TFAassisted deprotection/amidation tandem reaction in high yields. To ease selective reduction in further steps, the respective amide was transformed to thioamide in the presence of Lawesson’s reagent to give 128 in excellent yield. The latter, upon treatment with Raney-Ni, delivered the cyclic amine. The crude product without any purification was reacted with bromoacetyl chloride to afford 129 in excellent yield. The absolute configuration of 129 was determined by X-ray analysis. Upon treatment of 129 with silver trifluoromethanesulfonate in a mixture of Et3N and DCM followed by the procedure used by Heathcock and Toczko in the total synthesis of aspidospermidine [138] efficiently delivered spirocyclic indolenine 130 in excellent yield [138]. Having spirocyclic indolenine 130 available in hand, construction of the E ring was planned. Thus, the latter was initially subjected to a stylish procedure similar to that used by Kwon and co-workers for the synthesis of ibophyllidine and spirocyclic indolenine (PMe3, toluene/MeOH

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SCHEME 5.17

177

Total synthesis of vincadifformine (132).

14:1) [131], but disappointingly, the reaction was found to be rather slow, and only a trace amount of the desired product was detected by LC-MS. After exhaustive attempts, it was determined that the reaction was best conducted using trimethylphosphine PMe3 as the nucleophile in MeOH, which afforded

178 Applications of Name Reactions in Total Synthesis of Alkaloids

131 in excellent yield. The structure and absolute configuration of the resulting pentacyclic framework was characterized and established unambiguously using X-ray crystallography data analysis. Amide 131 was then transformed to thioamide in the presence of Lawesson’s reagent with subsequent reductive desulfurization with Raney-Ni and oxidation of the indoline segment with DDQ to furnish the desired alkaloid vincadifformine (132) with satisfactory yield in three steps (Scheme 5.17). It should be noted that the 1H and 13C NMR spectra of the synthetic sample of vincadifformine (132) was found to be in full accord with those of the sample isolated from nature [139]. Daphniphyllum macropodum is a shrub or small tree found in China, Japan, and Korea. Like all species in the genus Daphniphyllum, D. macropodum is dioeciousdthat is, male and female flowers are borne by different plants. The timber is used in China in construction and furniture manufacturing. It is grown as an ornamental plant, chiefly for its flora [140]. Daphniphyllum alkaloids are structurally discrete alkaloids with a wide variety of biological potencies [141]. The first total synthesis of the complex hexacyclic Daphniphyllum alkaloid ()-daphlongamine H (152) was accomplished by Hugelshofer and co-workers in 2019. Key to the success of this strategy were the Mannich reaction, efficient cyclization, and a highly diastereoselective hydrogenation to assemble multigram quantities of the tricyclic core bearing four contiguous stereocenters. The calyciphylline B-type alkaloids are a structurally discrete subfamily among Daphniphyllum alkaloids that involve a distinctive hexacyclic scaffold (rings AF) with a central piperidine group decorated with seven adjoining stereogenic centers. Following the isolation of calyciphylline B (152) from Daphniphyllum calycinum [142], its related congeners deoxycalyciphylline B, deoxyisocalyciphylline B [143], and daphlongamine H [144] were also isolated [145]. After the revolutionary synthetic investigation by Heathcock et al. [146] on a subset of these alkaloids, and finding their complete complexity and diverse biological potencies, the targets received the attention of the synthetic community, and several research groups have been tempted to develop or complete their total synthesis of the desired targets and other congeners [141]. Particularly, calyciphylline A-type and daphmanidin A-type alkaloids have attracted much interest from synthetic organic chemists in worldwide in the past decade. For instance, several research groups of Carreira [147], Li [148], Smith [149], Fukuyama [150], Zhai [151], and Dixon [152] have smartly circumvented several difficult synthetic problems related to the total synthesis of these formidable complex molecules. In addition, the basic tertiary amine occupant in all calyciphylline B-type compounds augments the problem of their handling and purification [153]. Conspicuously, among all calyciphylline B-type alkaloids isolated from natural sources to date, only the structure of deoxycalyciphylline B has been unambiguously confirmed by X-ray crystallographic analysis [143].

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The total synthesis of the hexacyclic Daphniphyllum alkaloid ()-daphlongamine H (152) was achieved by Hugelshofer et al., who reported their results in 2019 [154]. Furthermore, the same authors reported the synthesis of ()-isodaphlongamine H (148) which resulted in alteration of the reported structure of deoxyisocalyciphylline B (153). Their strategy, which led to successful total synthesis of ()-daphlongamine H (152), featured efficient cyclizations and a highly diastereoselective hydrogenation to install the tricyclic core bearing four adjoining stereogenic centers in multigram scale. In addition, construction of the hydro-indene substructure via a PausonKhand reaction and endgame redox manipulations played an important role, resulting in construction of the desired natural product. Outstandingly, their synthetic investigation also revealed the structure of ()-isodaphlongamine H (148), unambiguously resulting in a revision of the uncertain reported structure of deoxyisocalyciphylline B [154]. Accordingly, the total synthesis started with the reaction of easily accessible allylated valerolactone 133 [155] and sulfinyl imine 134 [156] in the presence of LDA in THF at 78  C to afford the b-amino lactones (SS-135 and SR-135), which under already secured optimal reaction conditions ultimately delivered an w1:1 mixture of C8 epimers in high combined yield on a multigram scale. The abovementioned reaction is believed to proceed via the reaction of 134 with the lithium enolate derived from 133, resulting in an interesting Mannich-retro-equilibration. It should be noted that chromatographic separation of this mixture in addition to the separation of undesired b-amino lactone SS-135 was recycled into the unreacted precursors 133 and 134. The cleavage of SR-135 with HCl in MeOH resulted in the cleavage of the sulfinyl moiety with simultaneous methanolysis of lactone, and reaction of the resultant with 2,3-dibromopropene in the presence of iPr2NEt in CH3CN at 80  C delivered N-alkylated vinyl bromide 137, which upon silylation of its hydroxy group and acetylation of its secondary amine furnished amide 138. The latter was next submitted to a stepwise sequential tricyclization starting with an RCM in which the resulting intermediate in the presence of LiHMDS smoothly underwent a Dieckmann condensation to deliver bromo bicycle 139. To provide the tricyclic substructure 141, compound 139 was initially subjected to organoborane-initiated (Bu3SnH, Et3B, O2) [157] reductive radical ring closure (H2, Ph(OH)2) to generate a tricyclic core (in excellent yield) bearing an exocyclic olefin that was reduced with excellent diastereoselectivity (20:1 dr). Markedly, under the already secured optimal hydrogenation conditions, fast initial isomerization of the exo-olefin to enamide 140 occurred. This improved process furnished the required tricycle 141 in multigram quantities. Notably, the structure of tricycle 141 was confirmed by single crystal X-ray diffraction. For the construction of the E and F rings, tricycle 141 was alkylated to give alkene 143, and upon reduction of its d-lactam carbonyl

180 Applications of Name Reactions in Total Synthesis of Alkaloids

group, enaminone 144 was produced. Enaminone 144 was first activated with TMSOTf followed by the addition of ethynylmagnesium bromide to deliver the respective silyl enol ether (20:1 dr), which upon hydrolysis gave C6epimeric enynes 145 and 146 (3.6:1 ratio) in high combined yield. At this stage, by careful examination of the structures of the desired targets, daphlongamines 152 and 148, enyne 145 was considered a suitable precursor. The latter was reacted with excess methyllithium to give the corresponding tertiary alcohol bearing enyne moiety in excellent yield (20:1 dr) [158]. Delightfully, treatment of 147 with excess NaCNBH3 in the presence of a Lewis acid [160] led to effective one-step deoxygenation of the enone moiety to deliver the respective cyclopentene. Followed by Jones oxidation, the cislactone was forged, and thus the total synthesis of isodaphlongamine H (148) was completed. The spectral data for synthetic sample 148 were found to be in complete accord with those of the authentic sample reported by Hanessian et al. [161]. Finally, considering the biosynthetic pathway suggested for the calyciphylline B-type alkaloids [143,161] for completing the total synthesis of daphlongamine H (152), formal stereochemical inversion of the tertiary alcohol in pentacyclic enone 147 was contemplated. Compound 147 was initially treated with TFAA and then SOCl2, and by protection of the primary and elimination of the tertiary hydroxy groups, the corresponding exocyclic alkene was generated, which upon treatment with trifluoroperacetic acid [162] delivered epoxide 149. The latter was then subjected to ring-opening of epoxide at the terminal position using LiAlH4-generating triol that in turn was submitted to formal deoxygenation conditions with subsequent Jones oxidation to afford trans-seco acid 150. The latter, after four steps involving treatment with cyanuric chloride as a viable reagent [163] for the final bond formation, was converted to the desired natural product daphlongamine H (152) possessing the highly strained and sensitive trans-lactone. Surprisingly, initial comparison of NMR spectral data for this synthetic sample of daphlongamine H (152) did not match the reported spectroscopic data of 152 [144] but interestingly were in good accord with the reported NMR spectral data for deoxyisocalyciphylline B (153) [143]. In addition, comparison and interpretation of 2D NMR data of both the synthetic sample 152 and deoxyisocalyciphylline B (153) disclosed that the SeC6 configuration in 153 had been misassigned. In summary, the authors who synthesized daphlongamine H (152) concluded that the isolated deoxyisocalyciphylline B (revised structure) and their synthetic daphlongamine H (152) are the same natural product and claimed that the structure for deoxyisocalyciphylline B (153) had been misassigned and thus must be revised. Therefore, the total synthesis of all members of the calyciphylline B-type alkaloids and their full structural characterization are in much demand, because they may result in the revision of their structural assignments and the proposed biosynthetic pathways previously reported (Scheme 5.18) [143,160,161].

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SCHEME 5.18 Total synthesis of isodaphlongamine H (148) and daphlongamine H (152).

182 Applications of Name Reactions in Total Synthesis of Alkaloids

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Chapter 6

Applications of PausoneKhand reaction in the total synthesis of alkaloids Chapter outline 1. Introduction 191 2. Mechanism of the PausoneKhand reaction 192

3. Applications of the PausoneKhand reaction in the total synthesis of alkaloids 194 References 220

1. Introduction The PausoneKhand reaction (PKR) is formally a chemical reaction in which a triple bond, a double bond, and carbon monoxide are subjected to a [2 þ 2 þ 1] cycloaddition to form a a,b-cyclopentenone [1]. This entails the formation of three new bonds and one or two rings in an intermolecular or intramolecular fashion, respectively (Scheme 6.1) [1]. The first example of this reaction was achieved and reported in 1973 [2] using a stoichiometric amount of dicobalt octacarbonyl [Co2(CO)8)] for the transformation of norbornene by reaction with the phenylacetylenehexacarbonyldicobalt complex to afford the respective cyclopentenone in a 45% yield (Scheme 6.2) [3]. The reaction was discovered by Ihsan Ullah Khand (1935e80), who was working as a postdoctoral fellow with Peter Ludwig Pauson (1925e2013) [4] at the University of Strathclyde in Glasgow. The main drawback of the original PKR was its generally low efficacy. It was examined only in an intermolecular manner, mediated by stoichiometric amounts of dicobalt octacarbonyl (Co2(CO)8)) as the only cluster, and carried out thermally under relatively harsh reaction conditions to achieve the desired

SCHEME 6.1 Formation of three new bonds in PausoneKhand reaction resulting in synthesis of cyclopentanones. Recent Applications of Selected Name Reactions in the Total Synthesis of Alkaloids https://doi.org/10.1016/B978-0-12-824021-2.00001-7 Copyright © 2021 Elsevier Inc. All rights reserved.

191

192 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 6.2 First example of PausoneKhand reaction with no regioselectivity.

transformation results. The original PKR also showed a relatively low substrate scope covering a narrow range of substrates. The use of strained olefins was necessary to obtain acceptable yields. In addition, if unsymmetrical alkynes and alkenes were employed, the reactions stereotypically afforded a mixture of regioisomers. In several cases, the PKR showed poor conversion, and most important, its selectivity from different points of view (chemo-, regio- and stereoselectivities) was poor. An important breakthrough was therefore needed and was obtained through a paper published by Schore and co-workers [5,6], who reported that carbon-tethered enyne precursors can be subjected to an intramolecular PausoneKhand reaction (IPKR) with good yield and complete control of regioselectivity. In 1983, Schore et al. achieved and demonstrated the IPKR [6]. A series of 5,5-gem-disubstituted enynes 9 were subjected to PKR conditions to obtain 5,6-used bicycles 8 or 10 under PKR (and thus IPKR) conditions with good efficacy and conversion [7] (Scheme 6.3) [5].

2. Mechanism of the PausoneKhand reaction Although the PKR was discovered in 1973, its plausible mechanism was proposed by Magnus et al. in 1985, as illustrated in Scheme 6.4 [8]. Nowadays, this mechanism is believed to be undisputable, as it has recently been confirmed by detailed negative electrospray collision testing [9]. Accordingly, the PKR is believed to commence with the generation of the alkyneeCo2(CO)6 complex 11, olefin 12 coordination, followed by insertion occurring at the end of the alkyne, which is less hindered to furnish the in situegenerated metallacycle 13. The latter reacts promptly under insertion of CO ligand 14, and followed by reductive elimination of 15, proceeds to furnish the desired target,

SCHEME 6.3 Regioselective intramolecular PausoneKhand reaction.

Applications of PausoneKhand reaction Chapter | 6

193

SCHEME 6.4 Suggested mechanism for PausoneKhand reaction.

cyclopentenone 16. It should be noted that all bond-forming steps take place on a single cobalt atom. The other cobalt atom present in the complex is supposed to function as an anchor having extraelectronic effects on the bondforming metal atom via the present metalemetal bond [10]. Although the prominence and importance of all kinds of PKRs have been extensively covered by previously published reviews [10e18], applications of the PKR in the total synthesis of natural products has largely been overlooked and are limited to a subsection mentioning some amount of total synthesis using PKR. They are vincristine (Oncovin), Navelbine (vinorelbine), etoposide (VP-16), teniposide (VM-26), Taxol (paclitaxel), and most recently, in 1996, Taxotere (docetaxel), topotecan (Hycamtin), xestobergsterol, spatane, daphane, iridomyrmecin, dendrobin, kalmanol, and bcuparenone [19]. Today, this strategy remains an essential route to new pharmaceuticals enabled by the vast array of bioactive secondary metabolites from terrestrial and marine sources to be discovered. PKR has gained a central role in recent years due to its broad applicability and excellent overall performance in intermolecular [20], intramolecular [21], and asymmetric variants [22,23]. In continuation of our interest in the total synthesis of natural products, especially those using name reactions in their crucial steps [24e36], in this chapter we attempt to review and describe the total synthesis of alkaloids using PKRs. Notably, the total synthesis of five alkaloidsdLycoposerramine-C, Phlegmariurine, Huperzine, Fawcettimine, and Fawcettidinedusing PKR has already been described [37].

194 Applications of Name Reactions in Total Synthesis of Alkaloids

3. Applications of the PausoneKhand reaction in the total synthesis of alkaloids ()-Dendrobine (26) is the chief alkaloid component initially isolated from the extract of Chinese ornamental orchid [38] in 1932 by Suzuki and co-workers. It showed remarkable antipyretic and hypotensive potencies that were disclosed in 1967 by Porter [39]. Its structure was fully characterized in 1964 by Inubushi et al. [40]. Since then, it has shown biological properties similar to those of picrotoxinin [41e43]. More important, dendrobine (26) has attracted much attention from synthetic organic chemists due to its exceptional and perplexing molecular structure, which involves a compressed tetracyclic backbone containing seven stereogenic centers and a quaternary center at C(11). The total synthesis of ()-dendrobine (26) was first reported in the 1970s [41], but effective and stereoselective pathways to this molecule, resulting in two formal [44,45] and one total enantioselective syntheses, were accomplished over just the last decade [46]. Cassayre and co-workers in 2001 achieved and reported the total synthesis of ()-dendrobine (26) in 13 steps via radical processes with PKR as a key step [47]. Accordingly, the total synthesis of 26 began from ()-trans-verbenol 18 provided by allylic oxidation of ()-aepinene (17) following the procedure reported previously [48]. Compound 18 was successively treated with 1,10 -carbonyldiimidazole, N-methylhydroxylamine, and then benzoyl chloride to afford 19 in a 49% overall yield. Pleasantly, treatment of the latter with tributyltin hydride and 1,10 -azobis(cyclohexanecarbonitrile) in refluxing toluene gave the important and desired oxazolidinone 20 in a 71% yield. Upon hydrolysis of the latter with aqueous ethanolic potassium hydroxide, aminoalcohol 21 was obtained. Next, the N-propargylated derivative 22 was obtained from 21 in several steps including the reaction of the latter with propargyl bromide followed by acetylation of the hydroxy group [49]. Then, alkyne 22 underwent the PKR and cyclization in CH3CN, providing the desired cyclopentenone 23 in a 72% yield as a pure single diastereoisomer. The latter was converted into a 1:1 mixture of epimers 24a and 24b after eight steps. Then, mixtures 24a and 24b underwent acid-catalyzed hydrolysis to afford ()-dendrobine (26) in a 44% yield with unreacted 24b, which unpredictably was not hydrolyzed selectively under the aforementioned conditions. This surprising chemoselectivity may be due to the initial acid-catalyzed cyclization of 24a to the iminolactone 25, which is more rapidly hydrolyzed than the tougher nitrile 24b. This assumption was confirmed by treating 24a,b to anhydrous acid (PTSA, toluene, 110  C), giving the iminolactone 25 in good yield mixed with unreacted nitrile 24b. Consequently, 18 was transformed into 26 in a 49% overall yield without isolation of the intermediates (Scheme 6.5) [47]. The Higa research group in 1985 [50], for the first time, isolated manzamine A (38) from marine sponge Haliclona sp. It exhibited an inhibitory

Applications of PausoneKhand reaction Chapter | 6

Me

1. Im2CO, THF, 20 °C 2. MeNHOH.HCl, Et3N, THF, 20 °C

Me

1. Pb(OAc)4, toluene, 70 °C

OH

2. AcOH, 20 °C 3. KOH,MeOH, 49% 17

18 Me

Me N

Bu3SnH, ACCN, toluene

O O

110 °C, 71% Me

Me Me O

3. BzCl,Et3N, THF, 0 °C 49% Me

KOH/H2O/EtOH,

Me NH

Me

20

Ph

N O

O

19 1. Propargyl bromide, K2CO3, CH3CN

OH

20 °C, 68%

Me

195

2. Ac2O, pyridine, CH2Cl2,

Me

88%

21 H

Me N

Me

OAc Me

1. Co2(CO)8, CH2Cl2

N Me

O

2. NMO.H2O, CH3CN, 25 ºC

Me

H

H OAc

Me

22

23

PTSA, dioxane, water,

H O Me

HN Me 25

H OH

H N Me

N Me H

N Me H R1

R2 Me Me 24a: R1 = H, R2 = CN 24b:R1 = H, R2 = CN

Me

H

100 °C, 44%, 2 steps, 75%

8 steps

H O

Me

H O Me

26:(-)-Dendrotine

SCHEME 6.5 Total synthesis of ()-dendrobine (26).

effect toward the growth of P388 mouse leukemia cells [50]. From a structural point of view, manzamine A (38) was found to have a complex structure of disguised manzamines and simple biogenetic linking to the 3-alkylpiperidine alkaloids [51,52]. Several different and complex structures derived from 3-alkylpiperidines have been isolated and fully characterized; among them, the structural connection to manzamine A (38) with ircinal (37) is well known and has motivated the interest of organic synthetic chemists. A literature survey has revealed several approaches to the synthesis of manzamine A (38) with ircinal (37) [53e58]. The Winkler [59] and Martin [60] research groups have achieved and reported the total synthesis of 38 and 37. In addition, the structure of nakadomarin A (36) has recently been elucidated [61]. It was isolated from an Amphimedon sponge sp. and showed cytotoxicity against murine lymphoma L1210 cells, inhibition of cyclin-dependent kinase, and antimicrobial activity against a fungus and a gram-positive bacterium. Nakadomarin A (36) contains a tricyclic core structure involving AeBeC rings 35.

196 Applications of Name Reactions in Total Synthesis of Alkaloids

The tricyclic core structure of nakadomarin, comprising AeBeC rings 35 (manzamine lettering), can in principle be synthesized via a key intramolecular PKR reported by Magnus and co-workers in 2001 [62]. The total synthesis of the core AeBeC rings of nakadomarin (35) has been achieved via an intramolecular PKR as a key step reported by Clark and co-workers in 2016 [63]. This approach was started with compound 27, and upon treatment with LiN(SiMe3)2/THF and subsequent reaction with methyl chloroformate, it afforded 28 [64]. The latter was reduced using diisobutylaluminum hydride in THF with subsequent dehydration using quinolinium camphor sulfonic acid as a chiral catalyst to afford 29 [65]. The latter then was subjected to reductive amination with 1-amino-3-butyne hydrochloride 30 [66] (Et3N/MeOH/ NaBH4) to furnish the corresponding sec-amino 31 as a respective PKR precursor. The latter was treated with Co2(CO)8 to achieve PKR, but a mixture was obtained. To circumvent this problem, the sec-amino group in 31 was protected as its p-toluenesulfonamide derivative 32. Now, the latter was subjected to PKR under various conditions to obtain 33, which afforded either no reaction or led to decomposition into a complex of mixtures in just-detectable amounts, which was not anticipated. After this failure, 33 was obtained via LivinghouseePagenkopf reaction conditions [67]. The yield of 33 was further improved using Sugihara’s procedure [68]. Treatment of 32 under PKR reaction conditions (Co2(CO)8/n-BuSMe in CH2Cl2 under reflux) provided 33 in a 63%e69% yield. Upon hydrogenation of the latter, it was converted to 34 (65%). After several steps, 34 was transformed into the core AeBeC rings of nakadomarin (35). Investigations are under way to improve the stereoselectivity of the reduction of 34 to 35, in which, if achieved the total synthesis of nakadomarin A (36) can be contemplated and executed (Scheme 6.6) [62]. Initially, in 1959, tecomine (53) was isolated from the extract of Tecoma stans and by Hammuda et al. [69], and then by Jones research group [70,71], from leaves of Tecoma stans and also the bark of Tecoma arequipensis eaves of Tecoma stans and similarly from the bark of Tecoma arequipensis. Tecomanine is one of a unique number of alkaloids found in nature, bearing cyclopentanopyridine- or cyclopentanopiperidine-based structures [72]. It was screened which showed antidiabetic properties [73e75]. Tecomanine (53) also exhibited a powerful hypoglycemic potency. A second new alkaloid isolated from the fruits of Tecoma stans was identified to be 4-hydroxy-tecomanine [72]. In 2003 Schore and co-workers [76] achieved and reported the total synthesis of the N-carboethoxy precursor to ()-tecomanine (53) in 11 steps starting from 2-methyl-1-buten-3-yne 39 via PausoneKhand cyclization of a methylated 5-aza-6-nonen-1-yne 49. First the terminal carbon of 2-methylbutenyne 39 upon sequential epoxidation/ring opening and displacement afforded the protected 2-methyl-3-butyn-1-amine 44 in a 35% overall yield. The latter was subjected to desilylation immediately after N-trifluoroacetylation without complication, followed by alkylation at

Applications of PausoneKhand reaction Chapter | 6

197

SCHEME 6.6 Total synthesis of manzamine A (38), nakadomarin A (36), and ircinal A (37).

nitrogen with crotyl chloride, which upon hydrolysis was converted to the corresponding carbamate, which cyclized to give precursor 49 in a 36% overall yield. Compound 49 was then subjected to PKR upon treatment with Co2(CO)8 and NMO in CH2Cl2 to give the desired natural product 53 disappointingly in a low 16% yield (Scheme 6.7) [76]. ()-Physostigmine (62), an indole alkaloid, was initially extracted from the seeds of Physostigma venenosum as “ordeal beans.” These seeds have been employed in trials for witchcraft [77] as well as therapeutically in ophthalmology [78]. Its structure was determined in 1925 by Stedman and Barger [79]. The chemical structure was found to be (1,2,3,3a,8,8a-hexahydro-1,3a,8trimethyl-pyrrolo[2,3-b]indo-5-ol-methylcarbamate) [79]. From a biological point of view, it has shown prolonging effects on acetylcholine action. Loewi and Navratil discovered its involvement in the inhibition of AChE [80,81]. As a salicylate salt, physostigmine has been found to be active in the treatment of

198 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 6.7 Total synthesis of ()-tecomanine (53).

Alzheimer’s disease. Total synthesis of ()-physostigmine (62) was successfully achieved and reported by Mukai et al. in 2006 [82] based on hetero-PKR as a key step. The total synthesis was started from already known alkyne 54, which upon treatment with triphosgene and Et3N was converted to the corresponding N-methyl urea 55 in high yield. The latter was transformed into the corresponding carbodiimide (56) by reaction with triphenyl phosphine, CBr4, and Et3N. The latter was converted to pyrrolo[2,3-b]-indol-2-one 57 as the key intermediate with a 55% yield via PKR (Co2(CO)8, TMTU, benzene, CO, 70  C). Reductive methylation of 57 with NaCNBH3 in the presence of aq. HCHO/AcOH prompted sequential reduction/hydroxymethylation and Nmethylation to afford 58 in satisfactory chemical yield and as a sole optically active stereoisomer. Cleavage of the TMS group from 58 using TBAF afforded 59 in nearly quantitative yield. The latter was converted to the iodo derivative 60 in satisfactory yields. The iodo compound 60 was transformed to ()-esermethole (61) following the already reported standard procedure [83,84]. Then, compound 61, upon treatment with CBr3 at 0  C in dichloromethane followed by reaction with methyl isocyanide in the presence of NaH at room temperature, gave the desired natural product ()-physostigmine (62), albeit as racemic mixture (Scheme 6.8) [83,84]. In 2012, the Zhao research group initially isolated [85] lycopalhine A (81) from the extract of Palhinhaea cernua. By comparing the structure of lycopalhine A (81) with that of the fawcettimine-type lycopodium alkaloid, it was

Applications of PausoneKhand reaction Chapter | 6

199

SCHEME 6.8 Total synthesis of ()-physostigmine (62).

revealed that it has an additional nitrogen atom participating in the formation of a pyrrolidine ring and an aminal motif [86e88]. The crystal structure of this alkaloid reveals a complex hexacyclic ring system composed of one sixmembered and two five-membered carbocycles, a piperidine and a hexahydropyrimidine heterocycle, and a compactly substituted pyrrolidine backbone. The complicated backbone comprises nine chiral centers, eight of them adjoining. Trauner and co-workers in 2016 [89] achieved and reported the first total synthesis of lycopalhine A (81). In their strategy, a compactly functionalized hexacyclic scaffold was stylishly constructed via a PKR. This strategy also involves another key reaction, which is an L-proline-mediated 5-endo-trig intramolecular Mannich reaction [89]. This research group accomplished and reported the total synthesis of lycopalhine A (81) [89], starting from dimethyl ester 64, which in turn was provided from l-glutamic acid 63 on a decagram scale in a one-pot procedure [90]. The crystal structure of this alkaloid revealed a complex hexacyclic ring system composed of one six-membered and two five-membered carbocycles, a piperidine and a hexahydropyrimidine heterocycle, as well as a compactly substituted pyrrolidine backbone. The complicated backbone comprises nine chiral centers, eight of them are adjoining. Trauner and co-workers in 2016 [89], achieved and reported the first total synthesis of lycopalhine A (81). In their strategy, compactly functionalized hexacyclic scaffold was stylishly constructed via a PKR. This strategy also involves another key reaction, which is an l-proline-mediated 5-endo-trig intramolecular Mannich reaction [89].

200 Applications of Name Reactions in Total Synthesis of Alkaloids

This research group accomplished and reported the total synthesis of lycopalhine A (81) [89], starting from dimethyl ester 64, which in turn was provided from l-glutamic acid 63 on a decagram scale in a one-pot procedure [90]. Next dimethyl ester 64 was allylated in accordance with the previously reported procedure [91] with high anti-diastereoselectivity. The latter was transformed into alkyne 69 [92] after several steps involving different functional group transformations as well as protectionedeprotection procedures. The enone 69 was then subjected to PKR, which proceeded under thermal conditions and gave 70 diastereoselectively, which has already been proven by Zard [93], Takayama [94], and Mukai [95]. Trauner et al. suggested chair-like conformations of intermediate 70, which was reacted with butenylmagnesium bromide 71 to translate to the desired configuration of the bicyclo-[4.3.0] nonane 72 [96,97]. After several steps, compound 72 was transformed to 79 [98]. The diastereoselectivity of the reaction likely reflects the thermodynamic preference of 79 for a b-hydroxyl group positioned on the concave face of the molecule away from the congested inner ring system, which upon LemieuxeJohnson oxidative cleavage of the olefin [99] with subsequent dual deprotection and acid-catalyzed aminal formation afforded the desired natural product lycopalhine A (81) along with an inseparable side product, epi-80 (Scheme 6.9). In 1976, Castillo and co-workers initially isolated three alkaloids, magellanine (101) [100], magellaninone (102) [101], and paniculatine (99) [102,103] from the extract of Lycopodium paniculatum and Lycopodium magellanicum [103]. From a structural point of view, they bear a 6-5-5-6 tetracyclic scaffold having five to seven chiral centers. ()-Magellanine (101) and (þ)-magellaninone (102) have six and five adjoining stereogenic centers, respectively. Due to their exceptional and interesting structures, several attempts [104,105] have been made to assemble the core tetracyclic framework of the aforementioned alkaloids. Overman and co-workers in 1994 [106] achieved and reported the first total synthesis of ()-magellanine (101) and (þ)-magellaninone (102) through a Prins-pinacol rearrangement, while Paquette et al. [107,108] accomplished and reported the total synthesis of both of the aforementioned alkaloids in a racemic form via a tandem Michaele Michael addition in the same year [107]. In 2007, Mukai et al. achieved and reported the total syntheses of ()-magellanine (101), (þ)-magellaninone (102), and (þ)-paniculatine (99) in highly stereoselective fashion. This work was started from diethyl L-tartrate (82), which after six steps was converted to 83 [96]. Then, with improvement in the stereoselectivity of the PKR of 83 under Sugiharaʼs procedure [(Me2S, (CH2Cl)2, 45  C], isomer 84 (89%), highly favored over its isomer (3%), was provided. After several steps involving protectionedeprotection and functional group transformations, compound 84 was converted into the desired enyne 91 in high overall yield. The latter was protected to give the corresponding TMS derivative 92 as a desired precursor for the second PKR. Then, the latter was

Applications of PausoneKhand reaction Chapter | 6

NHBoc

NH

201

65

MeO C

CO Me

63

64 O (MeO) P

BocHN

66

67

69

71

70

72

74

76

73

75 Boc

Boc

Boc

H

N

N

1. IBX

78

N

H

H

N

OsO , NaIO , TFA dr: epi-80:81(1:5.5), 56%, O

epi-80

OH +

OH O 79

N

H H

H H

2. K CO , MeOH 98% 77

Boc H N

H

N

H

H H OH

O 81: Lycopalhine A

SCHEME 6.9 Total synthesis of lycopalhine A (81).

subjected to PKR under Sugihara’s conditions [68] to give the tetracyclic compound 93 stereoselectively in good overall yield from 91 along with its epimer (16%). After several steps, compound 93 was transformed into the desired intermediate, the a,b-unsaturated compound 97. The latter was then subjected to the highly stereoselective 1,4-conjugate addition with Me2Cu(CN)Li2 to give 98, which was next oxidized with N-tertbutylbenzenesulfinimidoyl chloride 99 to furnish 5-epimagellanine 100 after removal of the methoxymethyl (MOM) group [107] in a 44% overall yield from 97. Compound 100 was then subjected to conventional Mitsunobu reaction with subsequent basic hydrolysis [109], furnishing ()-magellanine (101) in satisfactory yield, while 100, upon oxidation using DMP, gave (þ)-magellaninone (102) in high yield. On the other hand, compound 98 was converted into (þ)-paniculatine (99) as follows. Initially, compound 98 was

202 Applications of Name Reactions in Total Synthesis of Alkaloids

reduced stereoselectively using L-selectride to give the respective alcohol with the proper stereochemistry followed by protection with a benzoyl group [110]. Then, the MOM group on the secondary hydroxyl group of the B ring was cleaved under acidic condition, and the consequential hydroxyl derivative was sequentially oxidized using DMP to afford (þ)-99 in a 55% overall yield upon removal of the benzoyl group. As a result, the total synthesis of three Lycopodium alkaloids, ()-magellanine (101) (43 steps, 1.7%), (þ)-magellaninone (102) (43 steps, 1.9% overall yield), and (þ)-paniculatine (99) (45 steps, 2.8% overall yield), was accomplished starting from diethyl L-tartrate (82) in a stereoselective fashion. The remarkable strategic feature of this approach comprises two PKRs of enynes 83 and 93 (Scheme 6.10). The macroline/sarpagine alkaloids involve an assorted class of biologically potent natural products such as an aza-bicyclo[3.3.1]nonane annulated to an indole ring [111]. A typical member of the macroline family of alkaloids is alstonerine (115), and its total synthesis has already been reported [112e114]. Macroline indole alkaloids isolated from various species of Alstonia represent multiple biological activities, including hypotensive, antiamoebic, and antimalarial properties [115,116]. Alstonerine, along with 12 other alkaloids isolated from the root bark of Alstonia macrophylla, was recently reported to exhibit cytotoxic activity against two human lung cancer cell lines [117]. In addition to its challenging structural features, compound 115 showed cytotoxic potency toward two lung cancer cell lines [117]. Several approaches have successfully been achieved with this structural scaffold, comprising a PicteteSpengler reaction/Dieckmann condensation [118]/ring-closing metathesis [119]/phosphine-catalyzed [4 þ 2] annulation/FriedeleCrafts cyclization [112]/aza DielseAlder/intramolecular Heck reaction sequence [120]. A new approach for a brief enantioselective total synthesis of aza bridged in the macroline alkaloid ()-alstonerine (115) was discovered and reported by Martin et al. in 2008 using PKR. They started from enyne 104 that had already been prepared from L-tryptophan 103 in four steps [119]. Enyne 104 was subjected to the PKR, which proceeded smoothly to afford the cyclopentenone 105 in excellent yield as a single diastereomer to give azabridged bicyclic cyclopentenone [119]. At this point, launch of the relative stereochemistry of the newly generated chiral stereocenter on the cyclopentenone ring was required; however, 105 did not obtain as crystal. Nonetheless, when the indole nitrogen atom was protected with a Boc group, compound 106 was obtained, which, upon hydrosilylation using Pt divinyltetramethyldisiloxane complex (Karstedt’s catalyst) 107 in the presence of iPr3SiH at high temperature, afforded 108 in excellent yield [121]. After several steps involving various functional group transformations and protectionedeprotection processes N, N0 -dimethylated 114 was obtained. The latter was then converted into the desired natural product, ()-alstonerine (115), via reaction with MeI to methylate the bridging secondary amine with subsequent treatment by NaH and MeI to alkylate the indole nitrogen atom.

Applications of PausoneKhand reaction Chapter | 6

203

SCHEME 6.10 Total synthesis of magellanine (101), magellaninone (102), and paniculatine (99).

204 Applications of Name Reactions in Total Synthesis of Alkaloids

The total synthesis of 115 required only 15 steps from L-tryptophan 103 and proceeded to a 4.4% overall yield (Scheme 6.11) [122]. (þ)-a-Skytanthine (127) was initially isolated from Skytanthus acutus (Apocynaceae) as a minor monoterpene piperidine alkaloid along with its diastereoisomers, b-g- and d-skytanthines, by Djerassi and co-workers in 1962. Its structure was elucidated, and its absolute stereochemistry was determined based on its partial total syntheses [123,124]. Due to its interesting structure and the lack of enough natural sources in quantity of (þ)-a-skytanthine (127) for biological assay, its total synthesis has attracted enormous attention from organic synthetic chemists. A literature survey revealed four different asymmetric protocols for the total synthesis of (þ)-a-skytanthine (127), including a magnesium-ene reaction reported by the Oppolzer research group [125], an aza-Claisen rearrangement accomplished by Pombo-Villar

SCHEME 6.11 Total synthesis of alstonerine (115).

Applications of PausoneKhand reaction Chapter | 6

205

et al. [126], a cyclization under Mitsunobu reaction conditions achieved by Tsunoda and co-workers, and a successful SN20 antireaction reported by Helmchen [127] as crucial reactions. In 2007, Honda et al. accomplished and reported the asymmetric total synthesis of incarvilline, which was found to be an effective analgesic monoterpene piperidine alkaloid, using an intramolecular PKR as a vital step [128]. In addition, this group investigated the total synthesis of a similar monoterpene alkaloid, so-called tecomanine, reported by Schore and coworkers [76], noticing the poor stereoselectivity obtained during their key reaction. Armed with these valuable experiences, and noticing the structural resemblance between the already reported incarvilline [76] and that of isolated (þ)-a-skytanthine (128), the same research group contemplated designing a pathway for the total synthesis of 128. Due to successful use of PKR [128], they thought it worthwhile to involve PKR in their design for the total synthesis of (þ)-a-skytanthine. Accordingly, the total synthesis started with 2butyn-1-ol (116) with N-Boc derivative, which was reacted with 117 in the presence of diethyl azodicarboxylate and PPh3 in tetrahydrofuran at ambient temperature [109] to give alkynylamide 118 in excellent yield. Then, the Boc group of 118 was cleaved thermally in DMF at 120  C to afford secondary amide 119, which upon further reaction with (R)-2-methylbut-3-en-1-ol (120) [129] under Mitsunobu reaction conditions furnished enyne 121 as an appropriate PKR precursor in excellent yield. In the key step, the enyne 121 was subjected to PKR conditions in the presence of dicobalt octacarbonyl [Co2(CO8)] along with trimethylamine N-oxide [130] as the additive in aqueous THF at ambient temperature to afford the desired product 122 in good yield. Upon platinum oxide-catalyzed hydrogenation of the obtained enone 122 in MeOH, ketone 123 was provided as an inseparable mixture of diastereoisomers (in a ratio of ca. 1:1) in satisfactory chemical yield, which was further treated NaOMe/MeOH under reflux to furnish ketone 124 as a single isomer. After several steps, the latter was converted into amine 127. As the final step, the latter was N-methylated using formaldehyde and formic acid to give the desired natural product (þ)-a-skytanthine (128). It should be mentioned that the spectral data obtained for the synthesized product (þ)-a-skytanthine (128) were found to be in agreement with those previously reported for the isolated compound from natural sources [126,131]. In conclusion, an alternative asymmetric total synthesis of (þ)-a-skytanthine (128) was achieved using an intramolecular PKR of an appropriate enyne as a crucial reaction (Scheme 6.12). The axinellamines (150 and 151), the massadines (152 and 153), and palau’amine (154) are placed among the pyrrole-imidazole marine alkaloid family [132e134]. The axinellamines (150 and 151) were initially isolated by Quinn and co-workers in 1999 from the Australian marine sponge Axinella sp [132]. The axinellamines (150 and 151) contain an exceptional perhydrocyclopenta-imidazo-azolo-imidazole carbon framework. They have

206 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 6.12

Total synthesis of (þ)-a-skytanthine (128).

shown high bactericidal potency toward Helicobacter pylori at 1000 mM [132]. Due to their interesting chemical structure and biological activities, their total synthesis has attracted interest from the chemical community [135,136]. Despite the synthesis of 150e154 being prepared only at the milligram scale in laboratory, it looked quite feasible to develop their total synthesis because the decisive challenge of obtaining them in large quantities required for any simple biological screening follow-up had yet been largely overlooked. In this regard, several attempts have also been made in recent years. In fact, one of the serious problems in the total synthesis of these alkaloids via the Scripps route [135,137,138] was the synthesis of an important intermediate, spirocycle 143, which was synthesized through a lengthy 20-step strategy but obtained only a 1% overall yield. Furthermore, in that strategy, the formation of spirocycle 143 proceeded with no stereocontrol at C-7, which is absolutely essential. To circumvent this problem, 4-6 additional steps were mandatory to transform 143 with stereocontrol into 150e154 that were identical to the desired natural products. Thus, development of a facile, effective, scalable, and stereocontrolled synthesis of the key intermediate en route to 150e154 was in much demand. In this regard, Baran and co-workers in 2011 [139] accomplished and reported a strategy that overcome the aforementioned problem, giving the axinellamines on a gram scale by employing a catalyzed PKR, a Zn/Incatalyzed Barbier-type reaction, and a TfNH2-promoted chlorinationspirocyclization. The total synthesis starting with the reaction of bis-allylic trimethyl silyl ether 129 and propargyl amine 130 proceeded via PKR

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207

conditions. After wide-ranging trial and error [140,141]), the combination of ethylene glycol and NMO was selected as the catalytic system for PKR, improving the yield of the desired cyclopentenone 132 (to gram scale) to afford the desired cyclopentenone 132. It is worth mentioning that intermolecular PKR reactions of unactivated alkenes have rarely been reported [140,142,143], and thus, the use of ethylene glycol-catalyzed in this pathway is in fact is a remarkable novel methodology. Cyclopentenone 132 was converted into spiroaminoketone 143 in several steps with full control of stereochemistry. Then, spiroaminoketone 143, after several steps, was transformed into a mixture of diazido compounds 147-a and 147-b in gram scale (2.7:1 b:a). In the final sequential step, the azido groups on the acylpyrrole side chains were catalytically reduced, prompted by the presence of PtO2 and followed by acylation with 2,3-dibromo-5-trichloroacetylpyrrole in one-pot fashion to give the desired natural products (150 and 151). In the total synthesis of 150 and 151, it should be noted that the features of the stereocontrolled synthesis of 143 involved the strength, ease, and expediency of the pathway regardless of the absolute complexity of 150 and 151. Considering that all steps were performed on a gram scale, none needed high temperatures and most proceed smoothly in inert atmosphere to give the corresponding intermediate without a requirement for purification. The key steps in this total synthesis were an ethylene glycol-catalyzed PKR, chemoselective Zn-assisted Barbier-type reaction; and a TfNH2-catalyzed chlorination-spirocyclization (Scheme 6.13). Meloscine (167) is classified as a Melodinus alkaloid. In 1970, the Bernauer research group isolated it from extract of Apocynaceae species such as Melodinus scandens Forst [144]. From a structural point of view, it has the unique pentacyclic carbon scaffold typical of a group of monoterpenoid indole alkaloids. It is supposed that meloscine 167 is biosynthetically generated from the Aspidosperma alkaloid [145,146]. Overman et al. in 1989 achieved and reported the first total synthesis of meloscine [147,148], which involved a sequential aza-Cope rearrangement/Mannich cyclization reaction. In addition, Bach and co-workers [149] reported the first enantioselective total synthesis of ()-meloscine, which relied on a template-controlled [2 þ 2] photocycloaddition reaction [149,150]. In 2011, Mukai and co-workers [151] accomplished and reported a brief and highly stereoselective total synthesis of ()-meloscine through intramolecular PKR for the construction of the tetracyclic scaffold within the target natural product 167. It was started from 4-(2-aminophenyl)-2,3-dihydro-Nmethoxycarbonylpyrrole, which was easily prepared from (2-nitrophenyl) acetonitrile [152]. Compound 155 was then condensed with propiolic acid to give the propiolamide 156 in high yield. After examination of several PausoneKhand conditions [142,153,154], treatment of the latter with dicobalt octacarbonyl in MeCN at ambient temperature gave the corresponding dicobalt hexacarbonyl complex of 156, which was successively treated with trimethylamine N-oxide [130,154e156] at ambient temperature to result in the

208 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 6.13 Total synthesis of the axinellamines (150, 151), the massadines (152, 153), and palau’amine (154).

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209

SCHEME 6.13 cont’d

construction of the desired intermediate, tetracyclic derivative 157, in satisfactory yield. After several steps including different functional group transformations, compound 157 was converted into bis(vinyl) derivative 166. The latter was then subjected to the HoveydaeGrubbs-II ring-closing metathesis catalyst [157] in toluene at 60  C to afford the desired natural product, ()-meloscine (167), in a 99% yield (Scheme 6.14). Cephalotaxine (176) actually has the paternal structure of a complex of naturally occurring compounds, the Cephalotaxus alkaloids. It was initially isolated by Paudler and co-workers in 1963 from the Asian plant Cephalotaxus drupacea or Cephalotaxus fortune [158e160]. A plethora of its natural ester derivatives have shown strong anti-leukemic activity, demonstrating severe toxicity toward P388 and L1210 leukemia cells with IC50 values in the mg/mL range [161]. The exceptional biological activity of these natural ester derivatives has attracted the attention of synthetic organic chemists to attempt their total synthesis, leading to several efforts worldwide. The first successful attempt for the total synthesis of ()-cephalotaxine (176) was achieved and reported by Weinreb and co-workers in 1972 [162] and followed by several other innovative and successful attempts [163e166]. The structural elucidation of cephalotaxine (176) revealed the presence of a unique spirocyclic amine moiety whose construction was found to be the most challenging step in its total synthesis [166e170]. In 2012, a brief and highly regioselective total synthesis of ()-cephalotaxine (176) was accomplished and reported by Jiang and co-workers based on an intermolecular PKR as a vital step [171]. This protocol started with easily accessible alcohol 168 with its hydroxyl group protected upon treatment with mesyl chloride in the presence of Et3N at ambient temperature to give 169. The latter was reacted with pent-4-yne-1-ol under standard Sonogashira cross-coupling reaction conditions [172] to

210 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 6.14 Total synthesis of meloscine (167).

provide the important intermediate 170 in high yield. Subsequently, the latter was subjected to the intermolecular PKR to afford the expected cyclized product 171. Although the construction of two region isomers is theoretically possible from the above reaction, due to the direction of the carbonyl group [173], only the desired isomer 171 was obtained in satisfactory yield under optimized PKR conditions (in the presence of n-butyl methyl sulfide as promoter and DMSO as oxidant at 100  C). Afterward, the hydroxyl group in the latter was transformed into the benzylamino moiety in 173 in two steps including pyridinium chlorochromate oxidation in the first step and reductive amination in the second step. Next, the latter was cyclized, resulting in the construction of the 10-membered ring compound 174, which was further transformed into the important intermediate 175. After five steps, the latter was transformed into the desired natural product cephalotaxine (176)

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211

following the procedures already reported, with an overall yield of 20% over eight steps (Scheme 6.15) [167,170]. Ileabethoxazole (188) is a novel perhydroacenaphthene-type diterpene alkaloid involving the unusual benzoxazole moiety. It was initially isolated from the Caribbean Sea whip, Pseudopterogorgia elisabethae [174]. Its structure was fully characterized in 2006 by the Rodrı´guez research group by broad spectroscopic data analysis. Rodrı´guez et al. [175] described the isolation of ileabethoxazole from specimens taken near the Island of Providencia, Columbia. It exhibited excellent inhibition of Mycobacterium tuberculosis (H37Rv) (ATCC27294) at the concentration variety of 128e64 mg/mL. In 2003, Davidson et al. accomplished and reported a total synthesis route resulting in pseudopteroxazole [176] starting from (S)-limonene. Worthy of mention is that these attempts have also resulted in a revision of the consigned stereochemistry already mentioned [176,177]. Williams and co-workers in 2014 focused on the anti-tubercular activity of a drug that was found useful in the treatment of disease-related deaths worldwide [178]. Tuberculosis continues to be a major cause of mortality and disease statistics reported by the World Health Organization. Williams et al. in 2014 [178] explored an enantiocontrolled total synthesis of ileabethoxazole (188) starting from commercially available ethyl-1,3oxazole-4-carboxylate 177, which was converted into the Weinreb amide 178 and provided 179, the corresponding MOM ether, by addition of methylmagnesium bromide. The latter was then transformed into the desired iodide 180 by sequential ring metalations. The latter was then cross-coupled by Stille cross-coupling reaction with the propargylic stannane 181 to give the allene 182 in good yield. Elimination of silyl-protecting moieties of the 182, upon

SCHEME 6.15 Total synthesis of cephalotaxine (176).

212 Applications of Name Reactions in Total Synthesis of Alkaloids

treatment of methanol with pyridinium tosylate, gave 184. Then, the ironcatalyzed [2 þ 2þ 1] carbocyclization of the latter proceeded smoothly in THF from 50  C to 5  C, giving the expected dienone 185 (61% yield) via PKR. Cleavage of the MOM acetal of the latter along with cyclization and aromatization provided 187. Finally, the latter was transformed into the desired natural product (þ)-ileabethoxazole (188) after six steps with an 87% overall yield (Scheme 6.16). In 1997, Kobayashi et al. initially isolated the marine alkaloid ()-nakadomarin A (36) from extract of a sponge of Amphimedon sp. They also showed that ()-nakadomarin A (36) has an exceptional hexacyclic structure featuring fused 5-, 6-, 8-, and 15-membered rings [61]. The latter showed cytotoxicity toward murine lymphoma L1210 cells as well as exhibiting antimicrobial and inhibitory activity toward cyclin-dependent kinase [179]. The fascinating biological activities and unique structure of nakadomarin A (36) have attracted much attention from synthetic organic chemists for its total synthesis. In fact, earlier study has been replicated by several subsequent examinations that have been dedicated to its synthesis [180]. Nishida [181,182] Kerr [183], Dixon

SCHEME 6.16 Total synthesis of ileabethoxazole (188).

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213

[184e187], and Evans et al. [188] completed the striking and advanced total synthesis of nakadomarin A (36). In all previous synthetic approaches for nakadomarin A (36), a furan-containing starting material had been used [181]. In 2016, Clark et al. [63] achieved and reported an approach to the total synthesis of ()-nakadomarin A (36) via PKR as a key step [189] as well as an Overman rearrangement reaction [190e192], a ring-closing metathesis reaction, and an amination reaction. Their strategy started from the already known enyne 189 [193], which was provided by alkylation of market purchasable N-tosyl propargylamine with 4-bromobut-1-ene [194]. The enyne 189 initially was transformed into the fused bicyclic enone 190 in satisfactory yield and with an excellent ee value using the asymmetric cobalt-catalyzed PKR developed by Hiroi and co-workers in 2000 [195]. Enone 190, after several steps involving various functional group transformations, was converted into lactam (Z)-203. The tetracyclic intermediate 198 was synthesized enantioselectively in just seven steps with high efficiency and overall yield. The total synthesis of ()-nakadomarin A (36) was completed via the reduction of the latter using Red-Al under refluxing toluene. A brief and asymmetric total synthesis of ()-nakadomarin A (36) from the simple acyclic enyne 189 was achieved in a linear sequence of 12 steps (Scheme 6.17). Daphniphyllum is an alkaloid family having more than 320 members with captivating molecular structures that mostly show diverse and important pharmacological potencies [196]. Hybridaphniphylline B (234) is classified within this alkaloid family. It was initially isolated by the Liu research group in 2018 from the extract of Daphniphyllum longeracemosum [197,198]. Structurally, it has 11 rings and 19 chiral centers. In 2018, Li and co-workers [199] achieved and reported the total synthesis of hybridaphniphylline B (234) based on PKR as a key step. This strategy started from compound 206 [200], which underwent the Krapcho demethoxycarbonylation [201e204] to give the corresponding ester compound 207 in the presence of LiCl in water. The latter, in several steps including a-selenation followed by oxidative elimination, the Claisen rearrangement, selective hydroboration of the terminal C]C bond followed by Swern oxidation and SeyferthGilbert homologation, and using Lawesson reagent, provided alkyne 212 as an appropriate PausoneKhand substrate. The latter was subjected to PKR conditions in the presence of MeCN, as an efficient promoter to give the alkyne dicobalt complex, which furnished the anticipated products 214 and 215 in good yield (2.4:1 ratio). This mixture, in several steps including different functional transformations, was transformed into a mixture of cycloadducts 230e233. Ultimately, compound 230 was reduced in the presence of Raney Ni followed by inclusive deacetylation using Et3N in EtOH to give the desired natural product, hybridaphniphylline B (234) (Scheme 6.18). Securinega alkaloids are an exceptional class of alkaloids isolated from Securinega (Flueggea) [205]. Securinine (247) [206] was first isolated in 1956 by Murav’eva from the leaves of the Securinega suffruticosa plant. It was the

214 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 6.17 Total synthesis of ()-nakadomarin A (36).

first member of the so-called Securinega alkaloids, and several interesting biological activities have been reported for the neosecurinane group [207e209]. Thus, these groups of alkaloids have become attractive targets for

Applications of PausoneKhand reaction Chapter | 6

SCHEME 6.18 Total synthesis of hybridaphniphylline B (234).

215

216 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 6.18 cont’d

total synthesis, and many synthetic approaches have been developed [207]. Securinine (247), the most plentiful and important derivative, was first reported as a g-aminobutyric acid GABAA antagonist and employed as a CNS agent [210]. Norsecurinine (248) and its analogues showed inhibition of myeloperoxidase, an enzyme responsible in immune inflammatory disorder [211]. Norsecurinine (248) also exhibited anti-HIV potency [212,213]. It features an a,b-unsaturated g-lactone moiety. It also contains a compact tetracyclic scaffold allocated into four subgroups. The total synthesis of securinine (247), which is the C2-epimer of securinine (247), was achieved using [2 þ 2þ1]-hetero-PausoneKhand cycloaddition as a key step. The total synthesis of the securinine core started with inexpensive market-purchasable L-OH proline 235, which was converted to 236 in four steps. The latter was transformed to alkyne 245 as the appropriate precursor of the PKR after several steps involving different functional form transformations as well as the protectionedeprotection of different functional groups. The substrate appropriate precursor of PKR, 245 was then treated with the W(CO)6 complex, which pleasantly gave the desired natural product allosecurinine 246 as the C2-epimer of securinine (247) in pure form after column chromatography,

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albeit in a 12% yield [214], as well as norsecurinine (248) and securinine (247) (Scheme 6.19) [211]. Daphniphyllum alkaloids are known as a group of structurally discrete natural products showing diverse pharmacological activities [196,215,216]. A plethora of Daphniphyllum alkaloids have been isolated from 13 species of the genus Daphniphyllum, and several of them characterized, so far [196]. Daphniphyllum alkaloids are a structurally diverse group of naturally occurring compounds found in the genus Daphniphyllum (Daphniphyllaceae), a genus of dioecious well-known evergreen trees and bushes native to Japan. Yagi and co-workers in 1909 isolated daphnimacrine, which is a member of the C30-type Daphniphyllum alkaloids [217]. The successful total synthesis of a subset of these alkaloids [218,219] was achieved and reported by Heathcock et al. in 1986 [218] opened a new gateway, tempting synthetic organic chemists worldwide to attempt the total synthesis of other congeners. Among them, calyciphylline A-type and daphmanidin A-type alkaloids have attracted much attention from the research groups of Dixon [220], Fukuyama [221], Zhai [222], Carreira [223], Li [224], and Smith [225], who have circumvented the difficult problems allied with the total synthesis, sophisticatedly achieving and reporting the preparation of these formidably complex structures. Along these lines, the first total synthesis of hexacyclic Daphniphyllum alkaloid ()-daphlongamine H (267) using a PKR as a key step was achieved by

SCHEME 6.19 Total synthesis of allosecurinine (246), securinine (247), and norsecurinine (248).

218 Applications of Name Reactions in Total Synthesis of Alkaloids

Hugelshofer and co-workers in 2019 [226]. The calyciphylline B-type alkaloids with divergent structures are classified among the Daphniphyllum alkaloids. They contain an exceptional hexacyclic skeleton (rings AeF) along with a central piperidine motif bearing seven adjoining chiral centers. This type apparently bears a labile d-lactone moiety that may have been opened during isolation or characterization. In addition, the presence of the basic tertiary amine in the calyciphylline B-type causes other problems such as their handling and purification [227]. Conspicuously among all natural calyciphylline B-type alkaloids, the structure of deoxycalyciphylline B has been analyzed by X-ray crystallography and been confirmed [228] unambiguously. In addition to calyciphylline B [229], in recent years, other interrelated members such as deoxycalyciphylline B, deoxyisocalyciphylline B (268) [228], and daphlongamine H (267) [230], have been isolated and fully characterized [231]. The total synthesis of isodaphlongamine H (264) [232] was accomplished and reported by Hanessian and co-workers in 2016 [233,234]. The pathway designed for this total synthesis mainly [229] relied on the computational investigations of Hanessian et al., which provided invaluable insight [233,234]. In fact, Hanessian’s investigations presented isodaphlongamine H (264) as perhaps the “missing” diastereomeric member of the calyciphylline B-type alkaloid in a group of four that has not yet been isolated from natural sources. The total synthesis started with the reaction of allylated valerolactone 249 [235] and sulfinyl imine 250 [236] in the presence of LDA to give a mixture of interesting Mannich-retro-Mannich equilibration of the mixture of b-amino lactones SS-251 and SR-251, which upon optimization studies finally gave a w1:1 mixture of C8 epimers in high combined yield on a multigram scale. Treatment of SR-251 with HCl/MeOH resulted in the cleavage of the sulfinyl group with simultaneous methanolysis of the lactone, which was then N-alkylated to furnish vinyl bromide 253. The latter, after several steps, was converted to enyne 261 as an appropriate precursor of PKR. Reaction of 261 with methyllithium gave the corresponding tertiary alcohol in excellent yield (20:1 d.r.) [237], which was then subjected to PKR in the presence of CO2(CO8) to afford pentacyclic enone 263. Reaction of the latter with excess NaCNBH3 in the presence of a suitable Lewis acid [238] resulted in one-step deoxygenation of the enone moiety effectively to provide the anticipated cyclopentene, which ultimately was submitted to Jones oxidation and copied the cis-lactone to thus complete the total synthesis of the desired target, isodaphlongamine H (264). The spectral data obtained from different spectroscopic techniques for 264 were found in full agreement with those already reported by Hanessian et al. (Scheme 6.20) [232]. On the other hand, upon initial treatment of 263 with TFAA and then SOCl2, which protected the primary and removed the tertiary hydroxy groups, furnished epoxide 265. Upon opening of the epoxide at the terminal position and treatment of the resultant with LiAlH4, the anticipated triol was obtained,

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219

OH

SCHEME 6.20 Total Synthesis of isodaphlongamine (264), ()-daphlongamine H (267), and deoxyisocalyciphylline B (268).

220 Applications of Name Reactions in Total Synthesis of Alkaloids

which upon submission to oxidation using Jones reagent gave the corresponding amino diol. Noticeably, the resulting, highly polar trans-seco acid in this case was not subjected to facile lactonization, which is dissimilar to the case of isodaphlongamine (264), but possesses the cis-lactone in the desired target, ()-daphlongamine H (267) (Scheme 6.20).

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Chapter 7

Applications of PicteteSpengler reaction in the total synthesis of alkaloids Chapter outline 1. Introduction 2. Application of PicteteSpengler reaction in the total synthesis of alkaloids

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1. Introduction Indole and isoquinoline derivatives have traditionally been synthesized via an old but important reaction, the PicteteSpengler reaction (PSR). Although old, PSR continues to be the long-standing choice for application in several new methods and significant approaches in the art of organic synthesis, and gratifyingly, in the total synthesis of natural products. Frequently nowadays, PSR is used as a key step in the total synthesis of naturally occurring compounds, particularly those containing indole and isoquinoline alkaloids as backbones in their complex structures [1e3]. Tetrahydroisoquinolines are normally constructed via PSR. In this reaction, an a-aryl ethylamine is subjected to acidpromoted condensation with a suitable aldehyde or ketone followed by simultaneous ring closure. The driving force for this reaction is the electrophilicity of the iminium ion generated from condensation of the aldehyde and amine under acid conditions. PSR was discovered by Ame` Pictet and Theodor Spengler in 1911. In the original reaction, Pictet and Spengler heated b-phenylethylamine and formaldehyde dimethylacetal in the presence of HCl to obtain 1,2,3,4-tetrahydroisoquinoline as the final product (Scheme 7.1) [4].

SCHEME 7.1 PicteteSpengler reaction. Recent Applications of Selected Name Reactions in the Total Synthesis of Alkaloids https://doi.org/10.1016/B978-0-12-824021-2.00003-0 Copyright © 2021 Elsevier Inc. All rights reserved.

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Remarkably, PSR has been utilized for synthesis of a great variety of azaheterocyclic compounds for more than a century. Interestingly, an influential asymmetric variant of PSR was already accessible from Pictet and Spengler’s work examining phenylalanine and tyrosine in the aforementioned reaction. Noticeably, tryptamine as the amine component was presented 20 years later [5], permitting the construction of the 1,2,3,4-tetrahydro-b-carboline scaffold. Accordingly, asymmetric synthesis of several indole alkaloids of extraordinary physiological and therapeutic significance was accomplished, and the strategy is still frequently used as a key step in the total synthesis of alkaloids as one of the most important classes of natural products [6]. Mechanistically, PSR is believed to commence from the generation of an imine that is converted under acidic reaction conditions into an iminium ion, followed by nucleophilic attack by the aryl group to result in concurrent cyclization. Notably, when tryptamine is used, the attack on the iminium ion can take place either directly at position 2 (Scheme 7.2, the red route, which excludes step 6, following the top and bottom arrows in step 5 and then proceeding from 5 to 7 to 8) or at position 3 of the indole to construct a spiroindolenine (Scheme 7.2, the blue route, which includes step 6, following the middle arrow of step 5 and then proceeding from 5 to 6 to 7 to 8) [7,8]. Nevertheless, spiroindolenine is subjected to rapid rearrangement; indeed, the carbonium ion is generated [9,10]. After the innovation of PSR, its first asymmetric variant was accomplished and formally disclosed in 1977 when an enzyme of the PS class was discovered [11]. Enzyme-catalyzed PSR has been extensively investigated from various points of view, and the results have been described in a comprehensive review. This review will deliver an overview of asymmetric PSR, in which the chirality arises from optically pure amines or carbonyl compounds that are both obtained from natural sources or could be provided via asymmetric synthesis in which the reaction partners are combined [12]. In addition to asymmetric introduction by chiral catalysts, the appropriate optically active derivatives can also be utilized in asymmetric PSR [13e17].

SCHEME 7.2 Plausible mechanistic route of the PicteteSpengler reaction.

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During the last 3 decades, rapid growth in the development of asymmetric PSR in the presence of chiral catalysts or chiral pools has shaped outstanding progress in emerging novel and highly enantioselective variants of this reaction. The asymmetric variant of PSR has been applied in several different instances, especially in the total synthesis of a wide variety of indole-, oxindole-, and bisindole-based alkaloids, where its stereospecific receptivity plays a vital role [18e25]. In 2016, Dalpozzo et al. published a comprehensive review on asymmetric PSR in which chirality was induced using optically pure amines or carbonyl compounds that could be provided from natural sources or asymmetric synthesis using appropriate reaction partners [26]. Among the amassed natural products, tetrahydroisoquinolines are scaffolds for several important alkaloids. Tetrahydroisoquinolines, isoquinoline, and b-carboline alkaloids have attracted much attention because of their extensive existence in plants and even in the animal protectorate. They are one of the most significant and widespread scaffolds among the various alkaloid natural product families in the plant kingdom [27]. Furthermore, the aforementioned frameworks, particularly those including the isoquinoline backbone, usually show a relative supremacy of physiological properties [28]. Their wide biological activities, which range from exceedingly toxicdfor example, strychnine [29]dto the antihypertensive agents ajmalicine [30] and reserpine [31]. Alkaloids making up the indole moiety are a significant class of naturally occurring compounds. Predominantly, the indolo[2,3-a]quinolizidine framework is a communal scaffold present in several biologically active important compounds [32,33]. Captivatingly, all of these biologically active alkaloids principally contain indoles from tryptamine attained from tryptophan and a terpenoid part that in turn is biosynthesized via the iridoid glucoside secologanin. Tryptamine and secologanin are condensed stereoselectively to generate strictosidine, which is employed as precursor for the total synthesis of virtually all alkaloids bearing the indole moiety in their structures [34]. Due to our interest in nitrogen heterocycles [35e37], we review application of asymmetric PSR in the total synthesis of natural products and relevant biologically active compounds [38]. Armed with that experience, in this chapter, we will attempt to underscore the applications of PSR as a relatively old but imperative name reaction in the total synthesis of alkaloids, particularly those showing important biological activities.

2. Application of PicteteSpengler reaction in the total synthesis of alkaloids Ageladine A is an imidazopyridined1H-imidazo[4,5-c]pyridin-2-amine substituted by a 4,5-dibromo-1H-pyrrol-2-yl group at position 4. Ageladine A ([4-(4,5-dibromo1H-pyrrol-2-yl)]-1H-imidazo[4,5-c]pyridin-2-amine trifluoroacetate) (19) was initially extracted from the sponge Agelas wiedenmayeri [39]. Later, in 2003, it was

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isolated from the marine sponge Agelas nakamurai [40]. It functions as an inhibitor of matrix metalloproteinases, the key enzymes involved in tumor growth, migration, angiogenesis, invasion, and metastasis. Several scientific publications have provided a clearer picture of its properties. It also shows antiangionetic effects [41]. Since the initial extraction of ageladine A ([4-(4,5-dibromo-1H-pyrrol-2-yl)]-1H-imidazo [4,5-c]pyridin-2-amine trifluoroacetate) (19) in 2003 [40], several scientific publications have provided a clearer picture of its properties. As a brominated molecule of small molecular mass, it is characterized by its capability to pervade membranes as well as its low toxicity, and it presents a challenging and interesting core structure for related structures with similar properties [42]. A literature survey shows several approaches to synthesizing ageladine A [43,44]. In addition, Mineno et al. reported a construction of ageladine A commencing from commercially available pyridine derivatives [45]. Alternatively, ageladine A can be readily synthesized via an appropriate PSR product [46e49]. In 2015, Mordhorst and co-workers in 2015 developed a method for the total synthesis of ageladine A (19) via PSR in easily managed reaction steps that offered gram-scale batch synthesis [50]. Their synthetic approach begins with two options: (1) commencing bromination of 4-hydroxy-2-butanon 11 using PBr3, pyridine in CHCl3, to afford 12 and the combined reaction of the generated bromide 12 with phthalimide potassium salt [51] to give 10; or (2) the preferred one-step synthesis using the highly toxic methyl vinyl ketone and phthalimide [52], both of which result in 2-(3-oxobutyl)isoindoline-1,3-dione 10. Upon bromination of the terminal methyl group [52e54], the phthalimide-protected bromomethyl-ketone obtained 13, which was then coupled with acetylguanidine for construction of imidazole ring 14 [55]. Upon deprotection of the terminal amino-group following the previously procedure reported by Osby et al., 2-acetylamino-histamine (15) was obtained in pure form and high yield. In a key step, PSR of the latter with 4,5-dibromo-1-SEM-pyrrol-2-carbaldehyde (16) in a sequential two-step synthesis, commencing with the bromination of pyrrol-2-carbaldehyde [56,57] by 4,5-dibromo-1-SEM-pyrrol-2-carb-aldehyde followed by its protection using trimethyl-silylethoxymethyl chloride [48], furnished N0 -SEM-50 -(2-acetylamino-4,5,6,7-tetrahydroimidazo[4,5-c]pyridin4-yl)-20 ,30 -dibromo-pyrrole 17 in respectable yield. Later dehydrogenation using activated manganese(IV) oxide resulted in doubly protected ageladine A 11 [58]. Finally, upon cleavage of both protecting groups conducted in a boiling ethanolic hydrochloric acid base, ageladine A (19) was obtained as a free base that precipitated as trifluoroacetate salt (Scheme 7.3). Canthines are an important group of b-carboline alkaloids, and nearly 200 canthinone alkaloids possessing a wide range of potential bioactivities have been introduced in the chemical literature [59]. Cordatanine (4-methoxycanthin-6-one) (24) was isolated from Drymaria cordata in 1986 and then from Drymaria diandra in 2004 by Hsieh and co-workers [59]. Several sophisticated synthetic pathways for this class of compounds have appeared in the contemporary chemical literature [60,61].

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SCHEME 7.3 Total synthesis of ageladine A (19).

In 2009, Wetzel and co-workers contemplated the total synthesis of 5methoxycanthin-4-one (drymaritin). The obtained synthetic sample showed spectral data provocatively different from those of the presumed-to-be cordatanine (4-methyoxycanthin-6-one) (24) [60]. Total synthesis of cordatanine (24) was a challenging task and is still of current interest due to its structural features, potential bioactivities, and periodic changes that affect its concentration in natural sources. Based on long-term interest in canthin-6-one, Hung and co-workers in 2015 reported the total synthesis of cordatanine (24) bearing a canthin-6-one skeleton via a four-step procedure with an overall yield of 8% to confirm the exact structure [61]. Their strategy involved PSR using tryptamine and methyl glyoxylate as a key step. The spectral data of synthesized cordatanine was in full agreement with those of drymaritin isolated by Hsieh et al. [59], confirming the need to revise the creative structural consignment. In addition, kumujian A, a synthetic intermediate, showed significant antiinflammatory effects, inhibiting both superoxide anion generation (IC50 4.87 mg/mL) and elastase release (IC50 6.29 mg/mL).

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The initially reported total synthesis of cordatanine (24) suffered from low yields in the aldol condensation step employed for the ring closure of its D ring. This problem was circumvented by Soriano-Agato´n and co-workers in 2005 by means of beginning from tryptamine as starting material [62]. Following the previously procedure reported by Takasu et al. [63] through PSR, ethyl glyoxylate (20) was reacted with tryptamine 3 in the presence of HCl in EtOH followed by direct oxidative aromatization catalyzed by Pd/C to give kumujian A (21) in modest yield. Aldol condensation of kumujian A (21) and ethyl acetate using sodium bis(trimethylsilyl) amide generated an acetate carbanion, which was converted to 22 in good yield. Under basic conditions in the presence of Cs2CO3 using MeOMs, an a-proton from the b-keto ester 22 was removed, generating a tautomeric enolate anion. This enolate anion, upon O-methylation under different reaction conditions including in the presence of Cs2CO3 or K2CO3 as base as well as in various polar solvents and methylating agents, such as methyl methanesulfonate in the presence of cesium carbonate, gave the best yield (51%) of 23aþ23b. Finally, 23a/23b in a 3:1 ratio was subjected to ring closure via intramolecular nucleophilic substitution using sodium hydride in dilute THF to furnish the desired alkaloid cordatanine (24) in respectable yield (Scheme 7.4). Spectral data of this cordatanine (24) synthetic sample were in excellent agreement with those of the sample isolated by Hsieh et al. [59]. Don is one of the most imperative medicinal plants and produces a plethora of structurally diverse secondary metabolites in a group known as the monoterpenoid indole alkaloids (MIAs). More than 130 types of MIAs have been derived from the whole plant and have significant biological potencies. Alstonia MIAs include approximately 400 compounds that are very striking

SCHEME 7.4 Total synthesis of cordatanine (24).

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due to their complex structures and diverse biological activities [64]. Alstoscholarisines HJ, as novel MIAs, possess an unprecedented backbone generated through the formation of a C-3/N-1 bond that has been isolated from Alstonia scholaris [65]. Its structure was elucidated by wide spectral data analysis and then well established by single-crystal X-ray diffraction data analysis. In 2016, Luo and co-workers reported the successful total synthesis of alstoscholarisine H (32) through regioselective nucleophilic addition of pyridinium via a bioinspired iminium ion intermediate with subsequent PictetSpengler-type cyclization. The total synthesis of alstoscholarisine H (32) and ()-16-epi-alstoscholarisine H (29) were achieved in seven steps and five steps, respectively, beginning from market-purchasable or easily accessible starting materials. Interestingly, in this strategy no protectionedeprotection was used. It involved a formal [3 þ 3] annulation to build up the tetracyclic core backbone of the alstoscholarisines in a single step and an epimerization for the installation of the sterically hindered hydroxymethylene moiety in exact configuration [66]. The regioselectivity and yield of the addition of enolates to N-alkylpyridinium depended on the presence and type(s) of C-3 electron-withdrawing groups on the pyridinium [67]. To facilitate the regioselective addition at C-4 of the pyridinium, three different C-3 substitution groups were examined: ester (26a), a,b-unsaturated ester (26b) [68], and ketone (26c). This strategy started with reaction of nucleophiles 25 with 26a using LDA as a base followed by treatment with TfOH to give a mixture of three tetracyclic compounds (27a, 27a0 , and 27a00 ) in a ratio of 1/1/2 and with acceptable yields that were separated and then structurally fully characterized. In this reaction, it is believed that exo product 27a and endo product 27a0 were created via C-4 nucleophilic addition and possessed the desired backbone of alstoscholarisine H (32), while compound 27a00 was constructed via C-6 addition. This reaction is believed to proceed via regioselective nucleophilic addition of pyridinium through a bioinspired iminium ion intermediate with subsequent PictetSpengler-type cyclization [66]. Both 27b and 27b0 , upon refluxing in HCl, gave the same exo product 28, and with subsequent reduction using NaBH4, gave compound 29, an epimer of alstoscholarisine H (32), in excellent yield. On the other hand, ester 28 was treated with KHMDS under air conditions to induce the hydroxyl group to give the anticipated compound 30 for which the hydroxyl group was located in the exo position. The latter, upon reduction using LiAlH4, gave diol 31. Finally, treatment of diol 31 with Et3SiH under acidic conditions furnished the desired alkaloid alstoscholarisine H (32) in high yield (Scheme 7.5) [66]. Many natural products, especially alkaloids, contain the imidazole ring. When fused to a pyrimidine ring, it forms a purine, which is the most widely occurring nitrogen-containing heterocycle in nature. Imidazole alkaloids are a subclass of nitrogen-containing aromatic polycycles [69]. Typically, the heterocyclic aromatic ring of such compounds is biogenetically derived from

234 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 7.5 Total synthesis of ()-16-epi-alstoscholarisine H (29) and alstoscholarisine H (32).

the amino acid histidine or its decarboxylated counterpart histamine [70]. Imidazole alkaloids have also been isolated from several distinct plants [70] and marine organisms [71]. Two lactam isomers, glochidine (36) and glochidicine (38), are the histamine derivative of N-(4-oxodecanoyl)-histamine [72] isolated from the leaves of the New Guinea tree. In fact, N-(4-oxodecanoyl)-histamine can be thought of as the biogenetic precursor to both related alkaloids glochidine (36) and glochidicine (38). This postulation has been confirmed practically because compounds glochidine (36) and N-(4-oxodecanoyl)-histamine have been converted into glochidicine (38) upon refluxing in acetic acid [72]. It has also been disclosed that both glochidine (36) and glochidicine (38) can be obtained from the histamine amide by a site-selective N-acyliminium cyclization [73]. In 2016, Vassilikogiannakis and co-workers reported total synthesis of the alkaloids glochidine (36) and glochidicine (38), which had already been isolated and characterized [74]. This strategy involved intramolecular PSR as a key step. The total synthesis started with 2-hexylfuran 33, which was photooxygentated (in a 40 mM methanolic solution) in the presence of rose bengal (RB, 10e4 M) as a photosensitizer followed by reduction of the generated hydroperoxide group using Me2S with subsequent addition of commercially accessible histamine resulted in sole formation of 2-pyrrolidinone 35

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SCHEME 7.6 Synthesis of glochidine (36) from 2-hexylfuran.

(elucidated by spectroscopic data analysis). This reaction presumably takes place by generation of singlet oxygen as oxidant and histamine as a nitrogen source. The result of the cascade sequential reaction was successfully controlled by the cautious choice of both the photosensitizer and the solvent. The latter, without purification, was stirred in formic acid at ambient temperature to afford the desired natural product glochidine (36) in satisfactory isolated yield. This reaction proceeded to completion via the attack of nitrogen to afford kinetic product glochidine (36) via PicteteSpengler-type cyclization (Scheme 7.6) [74]. For total synthesis of glochidicine (38), the solution of 35 was initially refluxed in formic acid to give desired product 38 but also oxidized analogue 37 in a 2:3 ratio (Scheme 7.7) [75].

SCHEME 7.7 Transformation of intermediate pyrrolidinone 35i into unsaturated lactam 37 or 39.

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SCHEME 7.8 Synthesis of glochidicine (38) from 2-hexylfuran (33).

To circumvent this unsuccessful attempt and for exclusive synthesis of glochidicine (38) in the photooxidation of 33, RB was replaced by methylene blue (MB), which resulted in the formation of oxidized product 39 seemingly via the formation of 35i, presumably via a proton-coupled electron-transfer reaction [76]. Applying this reasoning, the histamine in CH2Cl2 instead of MeOH, and MB instead of RB, were used to generate 35i, which was refluxed in formic acid and resulted in the construction of the favored thermodynamic compound, the desired alkaloid glochidicine (38), in 58% isolated yield via Spengler-type cyclization (Scheme 7.8). Tetrahydro-b-carbolines alkaloids are putative and attractive ring systems for synthetic target selection. Tetrahydro-b-carboline alkaloids are structural cores of many indole alkaloids and medicines, such as deplancheine (43), tangutorine, geissoschizine, and vallesiachotamine [77]. The structure of deplancheine, an indoloquinolizidine alkaloid of a novel type, has been established from its spectral properties and total original synthesis. The interesting architecture and important biological activities of these tetrahydrob-carboline alkaloids have garnered much interest in the synthetic and medicinal communities [78]. Deplancheine (43), an alkaloid isolated from the New Caledonian plant Alstonia deplanchei [79], has been synthesized as racemic mixture, signifying the assembly of the indolo[2,3-a]quinolizine ring system [77bed]. As a consequence of the work of Meyers and co-workers in 1986, an asymmetric strategy to deplancheine was accomplished. Notably, the absolute configuration of this alkaloid was also established to be R [79a]. You and co-workers achieved the total synthesis of (þ)-deplancheine (43) and disclosed their outcomes in 2017. Their approach for formal synthesis of tangutorine and total synthesis of deplancheine (43) involved an effective preparation of the enantioenriched tetrahydro-b-carbolines utilizing a chiral phosphoric acid-catalyzed PSR of indolyl dihydropyridines [80]. Accordingly, an appropriate 1,4-dihydropyridine 40 was easily provided from the reaction of 3-(2-bromoethyl)-1H-indole and 3-acetylpyridine [81]. 1,4-Dihydropyridine 40 in the presence of a range of chiral phosphoric acids bearing different substituents and frameworks was converted to the desired tetrahydro-b-carboline 42a in capricious yields and modest enantioselectivity (90% yield and 91% ee). Several attempts indicated that the (R)-SPINOL derived was the catalyst of choice [82], and the reaction proceeded smoothly in the presence of 3Amolecular sieves as an additive, toluene as solvent, and at

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SCHEME 7.9 Total synthesis of tangutorine (45).

room temperature, which provided the best reaction conditions to obtain the required 42a. The absolute configuration of 42a was determined by comparison of its specific rotation with the value given in the chemical literature [83]. With 42a in hand, it was subjected to PSR via treatment with Boc2O in the presence of DMAP to afford the Boc-protected indole 44 in 95% yield and 91% ee. Interestingly, the Boc-protected indole 44 is known as the key intermediate for the total synthesis of tangutorine (45) [84]. Finally, the reduction of 42a was successfully performed using NaBH4 as the reducing reagent [83], thus furnishing (þ)-deplancheine (43) with high E/Z selectivity and excellent enantioselectivity (Scheme 7.9). Monoterpene indole alkaloids (MITAs) constitute a wide range class of nitrogen-containing plant-derived natural products comprising more than 3000 members. This natural product class is found in hundreds of plant species from the Apocynaceae, Loganiaceae, Rubiaceae, Icacinaceae, Nyssaceae, and Gelsemiaceae families. MITAs are the structurally related Aspidosperma and Kopsia genera [85,86]. One important structural variance between these families is the ring-fusion geometry of the octa- or decahydroquinoline motif restricted within the polycyclic core. Aspidosperma alkaloids characteristically

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bear a cis-fused azadecalin moeity [87]. In contrast, members of the Kopsia genus frequently bear a trans-fused azadecalin substructure [88]. In 1979 Di Genova and co-workers reported the isolation of (þ)-limaspermidine (56) from the trunk bark of the small tree Aspidosperma rhombeosignatum Markgraf [87b]. Its structure was fully characterized, disclosing that it contains the complex and characteristic [6.5.6.6.5]-pentacyclic ABCDE scaffold of the Aspidosperma alkaloids bearing four adjoining stereogenic centers involving two all-carbon quaternary stereogenic centers [89]. On the other hand, Gao et al. in 2011 isolated (þ)-kopsihainanine A with an unprecedented skeleton with a 6/5/6/6/6 pentacyclic rearranged ring system from the leaves and stems of the Chinese plant Kopsia hainanensis [88a]. The structure of (þ)-kopsihainanine A was elucidated by means of spectral data analysis. In addition, the absolute configuration of (56) was determined by ECD calculation. Due to its complicated polycyclic structures and broad and diverse range of biological potencies, this alkaloid (56) has received much attention from the synthetic community for more than half a century, and to date, several total syntheses and one formal synthesis have been reported [90]. Stoltz and co-workers accomplished the total synthesis of (þ)-limaspermidine and (þ)-kopsihainanine A and reported their results in 2017 [91]. Their strategy involved asymmetric palladuim-catalyzed allylic alkylations of dihydropyrido[1,2-a]indolone (DHPI) substrates for generation of the C20quaternary stereogenic centers of multiple monoterpene indole alkaloids as well as sequential stereodivergent PicteteSpengler and BischlereNapieralski cyclization/reduction cascades to construct the cis- and trans-fused azadecalin subunits present in Aspidosperma and Kopsia alkaloids, respectively. The total synthesis of (þ)-limaspermidine (56) was achieved in eight linear steps and in 25% overall yield commencing with unsubstituted tricyclic DHPI 46. The latter is easily accessible in multigram scale via a four-step reaction starting from indole. A highly productive one-pot hydroamination/reduction/ PSR sequence enabled the synthesis of the cis-fused decahydroquinoline moiety present in (þ)-56. Direct C-acylation by allyl cyanoformate followed by C-alkylation by (2-benzyloxy)ethyl iodide 47 afforded bamidoester 48 in high overall yield over two steps. The latter was treated in solution of Pd2(pmdba)3 with (S)e(CF3)3et-BuPHOX in TBME to generate a quaternary DHPI 50 in high yield and excellent 94% ee. The latter was then subjected to a formal anti-Markovnikov hydroamination successfully using a hydrozirconation/amination methodology, as reported previously by Hartwig et al. [92]. Upon treatment of the generated intermediate primary amine (51) (without being isolated) with LiAlH4 followed by vigilant quenching with AcOH/H2O, indoleeiminium cyclization occurred, leading to the construction of cis-fused tetracycle 52 in good yield. Tetracycle 52 without purification upon chemoselective piperidine alkylation afforded the corresponding ethanolamine 53 in high yield (50% over two steps) to afford ethanolamine 53 in an improved 62% overall yield over two steps. Pyrrolidine cyclization of the

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SCHEME 7.10 Asymmetric total synthesis of (þ)-limaspermidine (56).

latter followed by successive hydride reduction delivered O-benzyl limaspermidine 55, which was subjected to debenzylation in the presence of BF3$Et2O in ethanethiol to furnish the desired alkaloid (þ)-limaspermidine (56) in satisfactory yield over the final three steps (Scheme 7.10). Encouraged by the successful total synthesis of (þ)-limaspermidine (65) containing cis-fused azadecalin, this research group [91] endeavored the total synthesis of trans-fused (þ)-kopsihainanine A (65). They started from the same tricyclic DHPI core 46, which upon C-acylation followed by Michael addition with methyl acrylate gave b-amidoester 57 in high yield over two steps. Pleasingly, compound 57 underwent enantioselective palladuimcatalyzed decarboxylative allylic alkylation to give a-quaternary DHPI 58 in high chemical yield and 92% ee. The latter, upon Rh-catalyzed hydroboration,

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SCHEME 7.11 Asymmetric formal synthesis of (þ)-kopsihainanine A (65).

delivered the corresponding primary alcohol 59 in high yield [93]. Facile transformation of the latter into azide 60 took place fruitfully. The latter was subjected to Staudinger reduction using polymer-bound triphenylphosphine with simultaneous translactamization to give d-lactam 61 in respectable yield. The latter was subjected to BischlereNapieralski cyclization in which 61 with a combination of triflic anhydride and 2-chloropyridine were utilized. This reaction proceeded smoothly to afford trans-fused tetracycle 62 in high yield [94]. The latter, in the presence of guanidine base 1,5,7-triazabicyclo[4.4.0] dec-5-ene 63, efficiently promoted the desired cyclization to afford strained pentacycle 64 in respectable yield. The latter was then converted to the desired alkaloid, (þ)-kopsihainanine A (56), in 91% yield using LDMA, HMPA (TMSO)2 in THF (Scheme 7.11). The tetracyclic indole alkaloids constitute an important class of alkaloids. A new tetracyclic indole alkaloid, (þ)-arborescidine C (77), was isolated from marine tunicate Pseudodistoma arborescenswas collected from the northeast New Caledonian barrier reef and from the sponge Verongula rigida collected from Key Largo, Florida [95]. Its structure was unambiguously elucidated by

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spectroscopic methods. Particularly, these families of alkaloids showed a broad spectrum of biological potencies such as antiviral, antibacterial, antinematode, and antidepressant potencies, and several of them have been approved by the FDA as prescribed drugs [96]. Therefore, the tetracyclic indole alkaloids have attracted much attention from the synthetic community, resulting in several sophisticated total syntheses [97]. Koomen and co-workers accomplished and reported the first total synthesis of ()-arborescidine C (77) [98]. Later, Rawal et al. achieved and reported the first asymmetric synthesis of ()-arborescidine C (77) in eight steps [99]. Then, Santos et al. reported the improved synthesis and investigated the antiproliferative potencies of the products [100]. Due to the aforementioned biological activities, potencies, and synthetic accomplishments, a brief and effective asymmetric synthesis of these tetracyclic indole alkaloids seemed a persuasive subject as envisioned by Hong et al., who took advantage of PSR using a chiral organocatalyst [101] such as Jacobsen-type thiourea as well as utilizing a pot-economy approach to report an efficient and asymmetric total synthesis of ()-arborescidine C (77). The synthetic approach was demonstrated to be the most straightforward and concise approach to this tetracyclic indole alkaloid with high overall yield (35%) and high ee (up to 97% ee). This approach started with tryptamine carbamate 66a, which in the presence of DPP (diphenylphosphate) and MgSO4 reacted with a protected aldehyde 67a under PSR conditions to afford tryptoline 68 in high yield (Scheme 7.12). Reduction of the latter using LiAlH4 in THF at ambient temperature gave amine 69 in high yield. The latter was deprotected in the presence of 2 N HCl in THF at ambient temperature to deliver cyclization product ()-70 in respectable yield [102]. Encouraged by this result, the authors attempted asymmetric catalytic acylPSRs [103] through investigation of catalytic acyl-PSRs of tryptamine 66b and aldehyde 67a using different organocatalysts. Acyl-PSR of tryptamine 3 with aldehyde 67a was conducted in the presence of Jacobsen-type thiourea organocatalyst (71, R1 ¼ R2 ¼ allyl) to provide amide 72 in respectable chemical yield and excellent 93% ee. Reduction was performed in a one-pot operation to give 63% yield of 72 with excellent ee (93%). The latter, upon reduction using

SCHEME 7.12 Synthesis of ()-desbromoarborescidine C (70).

242 Applications of Name Reactions in Total Synthesis of Alkaloids

LiH2BH3, gave the corresponding amine 73 in satisfactory yield. The latter, upon reductive amination using formaldehyde and NaBH3CN, followed by hydrolysis of the resulting acetal and the cyclization reaction, furnished desbromoarborescidine C (70) in high chemical yield but excellent ee (97% ee). The structure, comprising absolute configuration of synthetic intermediate (þ)-70, was unambiguously established by single-crystal X-ray analyses. Dehydration of the alcohol 70 via its treatment with MsCl in the presence of Et3N in CH2Cl2 delivered the desbromoarborescidine B (74) in high yield (Scheme 7.13) [102].

SCHEME 7.13 Synthesis of desbromoarborescidine C (70) and desbromoarborescidine B (74).

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SCHEME 7.14 Synthesis of arborescidine C (77) and arborescidine B (78).

With the suitable synthetic route recognized, the same reaction sequence of acyl-PSR was applied in the synthesis of arborescidine C (77) and arborescidine B (78), beginning from bromotryptamine 66b instead of 3 and aldehyde 67a. This reaction gave the respective amide 75 which was productively converted to the desired natural product arborescidine C (77) with the aforementioned sequential reduction/reductive formylation. Arborescidine C (77), upon hydrolysis using MsCl in the presence of Et3N, furnished the other desired alkaloid, arborescidine B (78), in nearly quantitative yield (Scheme 7.14) [102]. A concise account of isolation, characterization, bioactivity, reasonable biogenetic routes, and most important, total synthesis of structurally fascinating and biologically imperious indole-based subincanadine alkaloids and their biogenetic congeners have been described. In 2002, Ohsaki et al. isolated quantities of about 10 mg of the structurally stimulating and biologically important cytotoxic alkaloids subincanadines AG from 100 g bark of the Brazilian medicinal plant Aspidosperma subincanum [104,105]. On the other hand, in 1982, Sto¨ckigt et al. isolated (þ)-subincanadine E, which was also named pericine Picralima nitida [106,107]. Kam et al. recently suggested that the (S)-pericine is a communal biogenetic precursor for the two structurally unprecedented MIAs (þ)-arborisidine and ()-arbornamine [108]. (þ)-Subincanadine E has been fully characterized, and it sustained an exceptional structural architecture. They also in vitro showed potent cytotoxicity against murine lymphoma and human epidermoid carcinoma KB cells [104]. Among other research groups [109e116], in 2014, Zhai et al. reported an effective total synthesis of ()-subincanadine E [116]. Due to unique structural architecture and gifted and diverse biological activity as well as establishing stereochemistry, the development of a novel synthetic pathway for the total synthesis of (þ)/()-subincanadine E is still vital and in much demand.

244 Applications of Name Reactions in Total Synthesis of Alkaloids

Retrosynthetically, an appropriate tryptamine-derived maleimide was selected as a potential precursor for total synthesis of ()-subincanadine E (90). Abstractly, the starting maleimide contained appropriate functional groups for 1,2-and 1,4-addition of the Grignard reagent sequence followed by intramolecular PSR to provide the desired tetracyclic hexahydroindolizinoindolone contemplated for this total synthesis. Reaction of the suitably protected lactam with acetaldehyde to form the exocyclic CeC double bond and essential functional group interconversions to afford the known diol intermediate, resulting in the required target compound. Moreover, (R)- and (S)-acetoxysuccinimides may also serve as suitable starting materials for asymmetric total synthesis of (þ)- and ()-subincanadines E (90). An effective and direct total synthesis of ()-subincanadine E (90) and its natural isomer (þ)-subincanadine E, were achieved by Argade et al., who disclosed their results in 2017 [117]. Total synthesis of ()-subincanadine E (90) commenced with maleimide 79 which reacted with 4 equivalents of allylmagnesium chloride at 78  C followed by acidification with HCl in onepot fashion straightforwardly caused the two allyl groups introduced and one of the double bond rearranged to afford the cyclized product ()-81 in moderate yield. The aforementioned Grignard reaction was then quenched using saturated aqueous ammonium chloride to obtain intermediate product ()-80, which was immediately treated with 2 N HCl to provide required product ()-81 in moderate yield. In the construction of required product ()-81, the allylic rearrangement was eventually found to be useful to suitably alter the carbon chain at an angular position. From a mechanistical point of view, the aforementioned intramolecular PSR most probably occurred via a flat iminium ion intermediate and arriving nucleophile approaches from the less hindered side of the favored intermediate, giving rise to syn-product ()-81 [110,118]. For the stepwise conversions of terminal and internal olefins in compound ()-81, primary alcohol ()-83 initially was provided in excellent yield, and then the required ()-diol 84 in high yield was obtained. The structure of key intermediate ()-diol 84 was determined unambiguously by X-ray crystallography. The latter was converted into essential ()-85 virtually in quantitative yield by Boc-protection of the indole nitrogen atom, and two primary alcohol units in compound ()-84 were also protected to give 85. Condensation of ()-lactam 85 with acetaldehyde followed by mesylation of the resultant alcohol along with stereoselective removal of mesylate gave a mixture of a,b-unsaturated lactam ()-87a as a major and ()-87b as a minor product. This mixture was directly subjected to alane reduction to give ()-amine 88 in excellent yield, which upon treatment with trifluoroacetic acid resulted in deprotection of three Boc groups to give ()-diol 89 in nearly quantitative yield. ()-Diol 89 under the Zhai et al. protocol [116] furnished desired alkaloid ()-subincanadine E (90) in good yield (Scheme 7.15). The physical and spectroscopic data of this synthetic sample were in excellent accord with those of sample, as reported previously [104,116].

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SCHEME 7.15 Total synthesis of ()-subincanadine E (90).

Next, asymmetric synthesis of (þ)/()-subincanadine E (90) from (S)-acetoxysuccinimide 91 [119] was planned. As anticipated, Grignard reagent attacked the more reactive imide carbonyl of (S)-acetoxysuccinimide 91 regioselectively and furnished respective deacylated single diastereomer ()-92 directly in high yield. The latter was subjected to acid-catalyzed PSR

246 Applications of Name Reactions in Total Synthesis of Alkaloids

but not diastereoselectively, giving a nearly 1:1 mixture of the respective diastereomers in satisfactory yield. However, ()-hydroxy-lactamol 92, upon treatment with pivaloyl chloride in the presence of Et3N, delivered the respective sterically hindered lactamol intermediate 93 selectively in nearly quantitative yield. The latter, without purification and structural elucidation, was submitted to acid-catalyzed PSR to give the anticipated double bond rearranged cyclized syn-product ()-94 in good yield. The structure of ()-94 was characterized by X-ray crystallographic data unambiguously, and the synrelationship between the angular alkenyl chain and O-pivaloyl group was well established. Base-assisted removal of the pivaloyl moiety in ()-94 led to the formation of a,b-unsaturated lactam 95 in excellent yield. Then, allylcuprate was added to the latter ()-lactam 95 in a highly diastereoselective manner but unpredictably resulted in syn-product ()-81 in high yield and in excellent de/ ee (>99%). The spectroscopic data obtained for this sample were in excellent accord with those of syn-product ()-81 reported previously [120,121].This kind of syn-addition preference is known, but the origin of stereoselection still presents an unanswered question [120,121]. Then, syn-product ()-81 was converted to (þ)-diol 89 in high overall yield by repeating the same eight steps. Again, three-step conversion of (þ)-diol 89 following the Zhai et al. protocol [116] in one-pot fashion furnished another desired target, (þ)-subincanadine E (90), in satisfactory yield. The spectroscopic data obtained for (þ)-subincanadine E (90) were found to be in complete accord with those of already published [104,116]. Thus, the first asymmetric total synthesis of (þ)-subincanadine E (90) was achieved from (S)-acetoxysuccinimide 91 with 18% overall yield (Scheme 7.16), and S configuration was established for this synthetic sample based on the obtained results for the sample isolated from natural source [120,121]. The pyrrole-imidazole alkaloid (PIA) family comprises hundreds of secondary metabolites originating from marine sponges. PIAs are a structurally diverse family of oroidin-derived marine natural products that can be categorized mostly as monomeric, dimeric, and tetrameric derivatives of oroidin. There are numerous speculations, some uncommon in the literature, on the biogenesis of PIAs [122]. While the biosynthesis and role in the sponge economy of most of these alkaloids still lies in the realm of speculation, significant biological activities for some of them have clearly emerged [122]. An exceptional biosynthetic route for cylindradines was suggested including an “ipso” rearrangement process [123]. Several PIA analogues show stimulating biological activities comprising antitumor, a2B adrenoceptor agonist, and immunosuppressive activities [124].

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SCHEME 7.16 Enantioselective synthesis (þ)-subincanadine E (90) from (S)-acetoxysuccinimide.

Cylindradines A and B are monomeric-type PIAs isolated from the marine sponge Axinella cylindratus by Kuramoto and co-workers. They represent an important family of marine alkaloids for their extraordinary biological potency and intriguing chemical structure. Owing to these biological properties and their characteristic common tetracyclic structure, they garnered much attention from synthetic organic chemists [125]. Cylindradines A and B, as members of the oroidin-derived PIA family, have a characteristic pyrrole-3-carbamoyl moiety that is unusual among PIAs. In 2017, Nagasawa and co-workers reported the total synthesis of (þ)-cylindradine B (109), which possesses a trans-diol on the D ring, based on a modified improved version of the previously reported total synthesis of cylindradine A [126] involving a PictetSpengler-type reaction followed by oxidative cyclization in the presence of hypervalent iodine to construct the pyrrole-3-carbamoyl and cyclic guanidine with N,N0 -aminal moieties at C6 and C10 of its structure. Accordingly, the condensation reaction of prolinol 96 [127a] with NTs-protected pyrrole-3-carboxylic acid 97 [127b] employing 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide in the presence of DMAP provided amide 98 in high yield. The p-toluenesulfonyl moiety on the pyrrole was converted to a Boc group by hydrolysis with KOH followed by a reaction with (Boc)2O in the presence of Et3N to provide the Boc-protected pyrrole in good yield over two steps. Upon oxidation of the resulted alcohol using IBX, the required aldehyde 98 was obtained in high yield. The latter was then

248 Applications of Name Reactions in Total Synthesis of Alkaloids

reacted with benzyl carbamate in the presence of trifluoroacetic acid (TFA) as catalyst in (AcO)2O to furnish aminal 99 in a respectable yield. Having aminal 99 in hand, PSR was scrutinized under acid-catalyzed reaction conditions to stimulate in situ formation of imine 100 followed by intermolecular cyclization to construct a-101 as the major product in a ratio of 8:1e10:1 in THF or CH2Cl2 or toluene as a solvent, but the yield was extremely low (5%e8%) at room temperature. Yield and selectivity were improved by conducting the reaction at 100  C in toluene, from which a-101 was obtained with 70% stereoselectivity. Interestingly, the best results in terms of chemical yield and diastereoselectivity for construction of the required a-101 was attained when aldehyde 98 was reacted with benzyl carbamate in the presence of ()-1,10 binaphthyl-2,20 -diyl hydrogen phosphate ()-102 with the mixture heated at 100  C in toluene under PictetSpengler-type reaction conditions to afford a-101 selectively and in high yield. Then, the Cbz group from the latter was cleaved in the presence of 10% Pd/C, and the resultant was reacted with S-methyl N-(2,2,2-trichloroethoxysulfonyl)-carbon-chloroimidothioate (103) [128] in the presence of Et3N to give 104 in high yield over two steps. The latter was then converted to a mixture of tris- and tetra-Boc-protected 107, as proven by MS analysis. Next, bromination of the pyrrole motif in the latter using bromine in the presence of sodium bicarbonate provided Boc-protected cylindradine B (108). Finally, the Boc groups in the latter were cleaved using TFA to furnish the desired alkaloid (þ)-cylindradine B (109) in an acceptable overall yield (Scheme 7.17). Pavines and isopavines are two relatively small subgroups of the isoquinoline alkaloids represented by 22 and 11 compounds, respectively, of isopavine alkaloids (117) and were originally isolated from plants of the Papaveraceae family. They have a typical tetracyclic tetrahydroisoquinoline core structure bearing a doubly benzannulated azabicyclo[3.2.2]nonane [129,130]. Isopavines have been found to show stimulating biological potencies such as anti-Alzheimer and anti-Parkinson’s disease [131aec] characteristics and opioid receptor-binding potency [131d]. Due to fascinating structural features as well as interesting biological activities, the total synthesis of isopavine alkaloids has garnered much attention from the synthetic community. Thus, many sophisticated strategies for total synthesis of isopavine have been successfully achieved and reported over the years [131a,132e141]. Jiang and co-workers accomplished a brief, versatile, and asymmetric protocol to natural and nonnatural isopavine alkaloids (117) and reported their results in 2017 [142]. Their protocol consisted of a catalytic asymmetric reaction to generate the essential chiral center in highly enantioselective fashion (95% e98% ee) and intramolecular PSR to construct the core tetracyclic scaffold also in a facile and stereoselective manner. This protocol started with easily

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SCHEME 7.17 Total synthesis of (þ)-cylindradine B (109).

accessible 2-(2,2-dimethoxyethyl) benzaldehydes (110aLc) [143], which reacted with nitromethane and proceeded in the presence of KOH to initially afford the nitroaldol products, and upon dehydration using methanesulfonyl chloride and an excess of triethylamine, b-nitrostyrenes (111a-c) were provided in satisfactory yield. Having compound 111 in gram scale in hand as one of vital key intermediates of the total synthesis, it was reacted with arylboronic acids (112) in an asymmetric fashion. To achieve this enantioselective reaction successfully, two catalytic systems could be used, the tertbutanesulfinylphosphine-Rh catalyst developed by Liao and Zhang’s and the

250 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 7.17 cont’d

iPr-IsoQuinox-Pd catalyst [144,145]. In this case, Zhang’s catalyst provided better results than Liao’s. Under Zhang’s reaction conditions, b-nitrostyrenes (111) reacted with arylboronic acids 112 [146] in the presence of Pd(Tf)2ligand to give required compounds 113aae113ac in respectable yields and excellent ee (95%e98% ee). For this total synthesis intramolecular PSR was planned as another crucial step. Accordingly, nitroacetal 113 was reduced chemoselectively using NaBH4, in the presence of NiCl2.6H2O [147] to give the required aminoacetal 114 in a respectable yield. However, acid-catalyzed cyclization of aminoacetal 114 via sequential hydrolysis/intramolecular PictetSpengler cascade reaction in the presence of various Lewis acids failed. It is well understood that carbamates are more reactive than the corresponding free amines in PSR [148]. Therefore, aminoacetal 114 was first acylated with alkylchloroformate in the presence of Et3N to give the respective carbamate 115 in nearly quantitative yield. Upon treatment of the latter with p-TsOH in CH2Cl2 under reflux, carbamoyl isopavine 116 was successfully provided in a satisfactory yield. Finally, carbamoyl isopavine (116) was reduced using LiAlH4 to furnish corresponding ()-amurensinine (117b), ()-reframidine (117c), ()-Omethylthal-isopavine (117e), ()-reframine (117f), benzylated ()-thalidicine (1170 d), and nonnatural isopavine (1170 a) in respectable yields. The 1170 d, 1170 a, and 1170 g were subjected to debenzylation/hydrogenolysis in the presence of a catalytic amount of Pd/C to furnish the desired natural alkaloid, ()-thalidicine (117d), and nonnatural isopavines ()-117a and ()-117g in excellent yields, respectively. Spectral data of the aforementioned synthetic samples were in full agreement with those of authentic samples isolated from nature for [129b,136a,140] 117c, [132a,134b] ()-117d [149], 117e [132a,139,140,150], and 117f [132a,135,151] as reported in the chemical literature (Scheme 7.18).

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SCHEME 7.18 Total synthesis of isopavine alkaloids (117).

251

252 Applications of Name Reactions in Total Synthesis of Alkaloids

C-19 methyl-substituted macroline/sarpagine and ajmaline alkaloids are indole alkaloids with a remarkable history [152]. These alkaloids were initially isolated from various medicinal plants of the Apocynaceae family. These alkaloids have not been biologically tested extensively due to their scarcity from natural sources. However, some of these alkaloids have exhibited significant biological potencies ranging from antihypertensive to anticancer activities. Macrocarpines AeC were initially isolated by Kam and co-workers in 2004 from the stem bark of Alstonia macrophylla [153]. On the other hand, talcarpine was isolated from A. macrophylla and Pleiocarpa talbotii and showed potent antimalarial properties [154]. In addition, N(4)-methyl-N(4),21secotalpinine 128 was first isolated from P. talbotii and Alstonia angustifolia and showed hopeful antileishmanial potency [153,154b,155]. While the aforementioned alkaloids (128e132) have the b methyl configuration at C-19, a couple, such as dihydroperaksine 135, are also known as dihydrovomifoline and deoxyperaksine 137 and encompass the a C-19 methyl function [156]. Noticeably, all of the aforementioned alkaloids contain either an Na-methyl or Na-hydrogen substituted indole nitrogen atom. These alkaloids also bear six or seven stereogenic centers that give them a structurally more complex architecture, and thus their total synthesis is interesting and challenging for organic synthetic chemists. Cook and co-workers in 2017 accomplished the total synthesis of ()-macrocarpines A (132), B (129), and C (130), ()-talcarpine (131), (þ)-N(4)-methyl-N(4),21-secotalpinine (128), (þ)-dihydroperaksine (135), and ()-deoxyperaksine (137) with complete stereocontrol of the methyl function at C-19 [157]. Their strategy included asymmetric PSR as key step. The design started with reaction of tosylate units 119b with amine 118 in the presence of K2CO3 in CH3CN to give 120b in high yield via the SN2 reaction. Nb-alkylated intermediate 120a, upon reaction with the actetal 121 under asymmetric PSR, gave the required trans-diester 122a with satisfactory yield and >95:5 de. Notably, this reaction is controlled under thermodynamical conditions [158]. This trans-transfer 122a of chirality set the required (S) stereochemistry at C-3 of the macroline-sarpagine related alkaloids, and thus upon methylation of its indole nitrogen using MeI in the presence of NaH in DMF at 0  C, the NaeCH3 intermediate 123 was obtained in virtually quantitative yield. Treatment of the latter with 3 equivalents of NaOMe (generated in situ) in predried toluene under reflux in accordance with the Dieckmann cyclization protocol proceeded smoothly to afford the desired b-keto ester (124a) in a respectable yield. Decarboxylation of b-keto ester 124a under acidic conditions afforded Nb-ethinyl tethered tetracyclic ketone 125a without deprotection of the TIPS group. The latter, after three steps, was converted to another key intermediate, quaternary ammonium salt 126, needed to enter the macroline system [159]. Following, the work of Le Quesne and co-workers [160], quaternary salt 126 was subjected into a retro-Michael ring opening via treatment with sodium hexamethyldisilazane in THF occurring

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stereospecifically and thus furnishing the required a, b-unsaturated aldehyde 127a The geometry of olefin 127a was determined to be (Z) by NOE observed upon irradiation of the aldehyde hydrogen atom with the b-methyl group and vice versa. Upon cleavage of the TIPS group under slightly acidic conditions followed by Michael reaction of the deprotected alcohol, the desired a, b-unsaturated aldehyde generated the E-ring of the macroline type alkaloids in a respectable yield. The stereochemistry of the C-19 methyl group was determined to be entirely the b-stereochemistry confirmed by NMR experiments, which showed the formation of (þ)-N(4)-methyl-N(4),21-secotalpinine (128) (major) and the desired natural product, ()-talcarpine (131) (minor). This result showed that the aldehyde at C-20 was in the thermodynamically more stable position in the a-configuration. Both ()-131 and (þ)-128 could easily be separated by silica gel chromatography. Noticeably, ()-talcarpine (131) could also be transformed entirely into (þ)-128 under mild basic conditions (Et3N in MeOH). The spectral properties of ()-talcarpine (131) and (þ)-N(4)-methyl-N(4),21-secotalpinine (128) were in excellent accord with those of the corresponding products isolated from nature [153]. Upon an aqueous workup procedure leading to the cleavage of the TIPS function under somewhat acidic conditions (0.1 N aq. HCl), followed by treatment with t-BuOK in THF, (þ)-N(4)-methyl-N(4),21-secotalpinine (128) was isolated as the sole product. Reduction of (þ)-128 using NaBH4 in EtOH gave the desired alkaloide, ()-macrocarpine B (129), in satisfactory yield, and its spectral data and optical rotation were in full agreement with those of the authentic sample isolated from natural source [153]. Acetylation of alcohol ()-129 using (AcO)2O and pyridine in DCM furnished another desired alkaloid, ()-macrocarpine C (130), in a respectable yield, whose physical and spectral data were in excellent accord with those of authentic sample isolated from nature [153]. Finally, upon reduction of aldehyde ()-131 using NaBH4 in EtOH, the desired natural product, ()-macrocarpine A (132), was obtained in virtually quantitative isolated yield (Scheme 7.19). All spectral data of this synthetic sample were in full accord with those of authentic samples isolated from nature except for the optical rotation [153]. After successful completion of total synthesis of the C-19 b-methylsubstituted macroline-related alkaloids, the same research group endeavored the synthesis of C-19 a-methyl-substituted sarpagine alkaloids (þ)-dihydroperaksine (135) and ()-deoxyperaksine (137) [157]. This time, instead of 122a, they used the trans-diester 122b containing the a-methyl [(R)] group, which was provided from 120b through the process described previously (Scheme 7.20). The latter was subjected to Dieckmann cyclization in the presence of 9 equivalents of NaH and excess MeOH in refluxing toluene to provide the desired cyclized product, b-keto ester 124b, which upon subsequent acid-promoted decarboxylation furnished the ketone intermediate 125b in nearly quantitive yield. The latter, after six steps, was converted to the corresponding primary alcohol 134 in high yield as the sole product.

254 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 7.19 Total synthesis of ()-macrocarpines A (132), B (129), and C (130), ()-talcarpine (131), (þ)-N(4)-methyl-N(4),21-secotalpinine (128), (þ)-dihydroperaksine (135), and ()-deoxyperaksine (137).

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SCHEME 7.20 Total synthesis of (þ)-dihydroperaksine (135) and ()-deoxyperaksine (137).

Deprotection of the TIPS moiety of the latter using aqueous HF in CH3CN furnished the desired alkaloid, (þ)-135, which could be isolated in pure form after chromatography in high yield. The spectral data and optical rotation of synthetic (þ)-135 were in excellent accord with those of the authentic sample isolated from natural source [156c]. Next, the already prepared primary alcohol 134 was activated by tosylation using tosyl chloride and 4-(N,Ndimethylamino)pyridine (DMAP) in DCM to afford 136. Deprotection along with formation of the ether ring furnished the desired alkaloid ()-deoxyperaksine (137) in excellent yield. Synthetic ()-137 was characterized by 1H, 13 C, 2D NMRs, IR, and MS because by comparison, they were not found in the literature [161]. Several specific plant families are rich in various alkaloids. A good example is the Apocynaceae family, which comprises at least 150 different types and 1700 different species of alkaloids. The Apocynaceae family is spread over a tropical region of Africa, Asia, and Central America [162]. A. macrophylla from the Apocynaceae family has been used as folk medicine in Thailand for various purposes [163]. Recently, it was found that

256 Applications of Name Reactions in Total Synthesis of Alkaloids

macrophylla has shown diverse antimalarial, antioxidant, antidiarrheal, antidiabetic, and antimicrobial antiinflammatory biological activities. Plants of Alstonia have been recognized as an affluent source of new alkaloids containing an azabicyclo[3.3.1] motif annulated to an indole ring such as macroline, sarpagine, and ajmaline [164]. Over the years, several pentacyclic macroline indole alkaloids such as N1-demethylalstophyllal, alstohentine, macrocarpines AC, talcarpine, N4-methyl-N4,21-seco-talpinine have been isolated mainly from this genus [165]. A tetracyclic indole base, macroline (148), structurally similar to 149 but with an exomethylene moiety, has still not been isolated from nature [165e]. However, it is assumed that 148 is a possible biosynthetic precursor of various monomeric indole alkaloids such as alstonisine [166e168] and bisindole alkaloids such as villalstonine [169e171] and is a degradation product of villastonine [172]. This has structural features similar to the ring opened secomacroline oxindole and alstonoxine A [173] Additionally, it is a degradation product [173], monomeric unit [174], and proposed biosynthetic precursor of several novel and bioactive alkaloids [175]. The challenging structure of indole alkaloids macroline (148) and alstomicine (149) fascinated Sudhakar and co-workers, who attempted and achieved total synthesis and reported their results in 2018 [176]. Interestingly, the latter could be appropriate precursors for a wide range of indole alkaloids that rely on suggested biosynthetic approaches. Their strategy involved two key steps of the IrelandeClaisen rearrangement (ICR) and PSR taking place in a highly stereocontrolled fashion. Accordingly, all chiral centers present in the target molecules were induced by the commercially accessible starting material L-tryptophan, which in two steps was transformed to known acid 138 [177]. The latter in turn was converted to 139 in two steps involving the treatment of 138 with Et3N, isobutyl chloroformate followed by addition of diazomethane generating the diazoketone intermediate with subsequent onecarbon homologation in the presence of a catalytic amount of silver acetate to afford homologated acid 139 in high yield. Then, the coupling of 139 with allylic alcohol segment 140A/140B [178] afforded essential allylic esters 141A/141B in good yield, setting the stage for vital ICR. Then, allylic ester 141A, upon treatment with LDA and TMSCl, gave the (E)-trimethylsilyl ketene acetal [179], which upon reaction with excess diazomethane gave separable esters 142A and 142A0 with high combined yield. Likewise, 141B was subjected to ICR conditions to afford an inseparable mixture of acids with improved diastereoselectivity (dr 9:1), which upon reaction with diazomethane gave separable 142B and 142B0 with a high combined yield. The exact stereochemistry of chief products 142A and 142B was established. The facile selectivity and minimization of steric parameter in a chairlike transition state was assumed to be responsible for the formation of chief diastereomers 142A and 142B in the ICR [180].

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To achieve the goal, already prepared ester 142B was subjected to DIBAL-H reduction to yield the primary hydroxyl group protected as tertbutyldimethylsilyl (TBS) ether to afford 143 in high yield over two steps. Next, the latter was subjected to a sequential two-step reaction involving hydroboration/DesseMartin periodinane oxidation to give the expected aldehyde 144 in a good yield. Subsequently, the latter underwent silyl ether deprotection using tetra-n-butylammonium fluoride (TBAF) followed by oxidation of the resultant hemiacetal with TPAP to afford the six-membered lactone 145 in high yield over two steps. Then, the latter was subjected to captivating PSR in the presence of TFA in dicholoromethane to construct pentacyclic core 147 in high yield as solely one isomer, probably via transition state III. The structure and relative stereochemistry of 147 were unambiguously established using 1D and 2D NMR data analysis. It was disclosed that core 147 possesses the same stereoconfiguration at C(3), C(5), C(15), and C(16) as those in the macroline class, signifying the common feature of the isolated indole alkaloids [181]. Having core structure 147 in hand in gram scale, the total synthesis of 148 and 149 was completed in an effective fashion. First, macroline (148) in moderate yield was accomplished in a sequential two-step reaction involving the introduction of exomethylene with subsequent addition of methyllithium [182]. Then, highly anticipated first total synthesis of alstomicine (149) was achieved in satisfactory yield upon treatment of pentacyclic core 147 with methyllithium [182b]. The spectroscopic data of synthesized 148 and 149 were in excellent agreement with those of authentic sample, already reported in the chemical literature (Scheme 7.21). Notably, the specific rotation of macroline (148) was found to be similar to the one reported in the chemical literature [183], but the specific rotation of alstomicine (149) varied against the value previously reported in the literature [165e]. b-Carboline (9H-pyrido[3,4-b]indole), also known as norharmane, is a nitrogen-containing heterocycle. It is also the prototype of a class of indole alkaloid compounds known as b-carbolines [184]. b-Carboline alkaloids show a broad spectrum of biological potencies such as antitumor, antimalarial, antimicrobial and antiinflammatory activities [185]. Peharmaline A (161) is a rare b-carboline-vasicinone hybrid alkaloid ()-peharmaline A enantiomer with a hitherto unknown hybrid dimeric system. In 2017, it was isolated by Wang and co-workers from the seeds of Peganum harmala L [186]. Newly discovered ()-peharmaline A (161) contains an unprecedented linkage of vasicinone and b-carboline units. Due to its motivating structure, important bioactivity activity, and material shortage in nature, its total synthesis has attracted much attention from organic synthetic chemists, leading to the initiation of several projects. The first total synthesis of the rare b-carbolinevasicinone hybrid alkaloid ()-peharmaline A was achieved by Reddy and co-workers, who disclosed their results in 2018 [187]. Interestingly, it was completed in just three steps, commencing with easily accessible compounds

258 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 7.21 Total synthesis of macroline (148) and alstomicine (149).

via asymmetric PSR to a nitrogenated tertiary carbon center in a one-pot manner. Accordingly, commercially accessible tryptamine was chosen for scaffold A. For the second segment (B), already known Boc-protected pyrrolidinone compound 152 in gram scale was provided from the reaction of 150 with methyl chlorooxoacetate (151) as a suitable acylating agent in the presence of LHMDS. The nitrogenated tertiary carbon center present in the tetrahydrob-carboline segment of the alkaloid was constructed by employing PSR [188]. Having both units in hand, the reaction between compound 152 and hydrochloride salt of tryptamine (3) under mild reaction conditions in the presence

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of Na2SO4 in refluxing MeOH, followed by a simple aqueous workup produced required intermediate 153 in high yield. Excellent distereoseletivity in this formation of 153 was observed at a good level that equated to a w9:1 mixture (based on crude NMR). Then, activated ester 153 in the presence of K2CO3 as a base was reacted with compound 154 in DMF as solvent, which resulted in chemoselective Nacylation at the pyrrolidinone nitrogen to give 155 in a respectable yield. Upon reduction of the nitro group of N-acylated compound 155 utilizing 10% Pd/C, an intermediate was generated and spontaneously subjected to intramolecular condensation with the amide carbonyl to provide the required demethoxypeharmaline 156 in good yield. The structure of the latter was elucidated by comparison of its spectral data with those of an authentic sample isolated from nature for ()-peharmaline. Because the present compound, 156, lacks an OMe group, it is called demethoxypeharmaline. For supplementary validation, compound 156 was recrystallized from MeOH/CH2Cl2 and hexane as a solvent system, and its structure was thus established unambiguously by single-crystal X-ray diffraction (Scheme 7.22). With an optimal pathway secured and in hand, the synthesis of the desired alkaloid ()-peharmaline A was endeavored. In this regard, PSR of already prepared 6-methoxytryptamine hydrochloride salts 157 and 152 under optimal reaction conditions furnished a mixture of diastereomers 158 and 1580 in satisfactory yield. Although the observed diastereoselectivity was not inspiring (w3:1) in this case, both diastereomers 158 and 1580 were easily and cleanly separated by silica gel column chromatography. Next, the chief diastereomer, 158, was easily N-acylated in the presence of K2CO3 in DMF at room temperature to afford 160 in good yield, which upon reductive condensation furnished natural alkaloid ()-peharmaline A (161) in modest yield. All the physical and spectroscopic data of the synthetic sample were compared with those of the authentic sample isolated from nature

SCHEME 7.22

Synthesis of demethoxypeharmaline A (156).

260 Applications of Name Reactions in Total Synthesis of Alkaloids

and found to be in good accord with the literature [186]. Next, minor diastereomer 1580 provided from PSR was subjected to the same procedure involving an N-acylation/reductive condensation sequence to obtain product 1600 . Surprisingly, the spectral data of this obtained compound were in agreement with those obtained for 160, signifying conceivable epimerization at the center next to the pyrrolidinone carbonyl group. For final confirmation, N-acylated compound 1600 was synthesized from minor diastereomer and then submitted to reductive cyclization, and its spectral data were analyzed and found to be identical to those of the naturally occurring compound ()-peharmaline A (161). Having access to the route for the synthesis ()-peharmaline, the same authors tried to adopt different conformation to the molecule by keeping the unique dimeric skeleton intact by changing the five-membered pyrrolidine ring size. Accordingly, keto ester derivative of piperidin-2-one 163 and azepan-2one 164 were synthesized for use in PSR. These compounds were treated with tryptamine/L-tryptophan methylester under identical reaction conditions to those used previously to obtain desired b-carboline derivatives 165e167 in excellent yield with varying diastereomeric ratios. Then, all three compounds 165, 166, and 167 were submitted to N-acylation with subsequent reductive cyclization to fabricate the final dimerism products 171, 172, and 173, respectively. The structures of all the compounds were well elucidated when employing their various spectral data analysis, while the structure of intermediate 165 was characterized unambiguously by X-ray crystallographic analysis (Scheme 7.23). Tylophorine (184) (C24H27NO4) is a bioactive secondary metabolite present in Tylophora indica. It contains organonitrogen heterocyclic and organic heteropentacyclic compounds. Its IUPAC name is (13as)-2,3,6,7tetramethoxy-9,11,12,13,13a,14-hexahydrophenanthro[9,10-f]indolizine. Tylophorine (184) was first isolated from the T. indica plant family. ()-(R)-Tylophorine is a chief alkaloid of T. indica. It is a phenanthroindolizidine alkaloid featuring a pentacyclic motif. It was initially isolated from the T. indica plant family [189]. It is an immunosuppressant that inhibits inflammation. In tumor cells, (þ)-(S)-tylophorine exhibited antiproliferative potency and induction of apoptosis, showing extraordinary antitumor [190], antiinflammatory [191], and antifungal potencies [192], and thus it has grabbed a great deal of global attention from many research groups. In this regard, the total synthesis of racemate tylophorine [193], (R)-tylophorine [194,195], and its antipode, (S)-tylophorine [196,197], have been successfully accomplished and reported. Li et al. achieved an effective and concise total synthesis of (R)-tylophorine (118) and proposed, implemented, and disclosed their pathway in 2018. It involved seven steps starting from a known phenanthryl aldehyde and completed in 14.2% overall yield [198]. It consisted of asymmetric hydrogenation of an allyl alcohol for generation of a stereogenic center with good ee, azidation, oxidation, Schmidt reaction, stereospecific

Applications of PicteteSpengler reaction Chapter | 7

SCHEME 7.23

Total synthesis of ()-peharmaline A (161) and analogues 171e173.

261

262 Applications of Name Reactions in Total Synthesis of Alkaloids

1,2-migration, and finally, sequential deformylation/PSR. Accordingly, it commenced with reaction of phenanthryl aldehyde 174 [199] and substituted phosphonate 175 following the procedures reported previously in the chemical literature [199a,200]. Consequently, phenanthryl aldehyde 174 was reacted with phosphonate 175 in the presence of 2.0 equivalents of NaH under HornereWadswortheEmmons condensation conditions, affording a,b-unsaturated ester 176 as the E isomer in high yield with absolute control of the stereochemistry of the double bond. The latter was reduced using KBH4 in the presence of LiCl to give allyl alcohol 177 in a satisfactory yield. Ir-oxazoline complex was used as catalyst for efficient hydrogenation of allyl alcohol 177 to afford u-chloro alcohol 179 with high conversion, enantioselectivity, and nearly quantitative chemical yield. Next, azidation of u-chloro alcohol 179 using sodium azide in DMF gave the respective u-azido alcohol 180 in virtually quantitative yield. Oxidation of the latter using DesseMartin reagent cleanly afforded azido aldehyde 181 in nearly quantitative yield. The latter was subjected to intramolecular Schmidt reaction using TFA to deliver the required formamide 182 (alkyl migration) and a small amount of lactam 183 (hydride migration) in a respectable yield. Formamide 182, upon formylation followed by sequential PSR of the resultant amine with the phenanthryl ring in one-pot fashion, furnished the desired alkaloid (R)-tylophorine (184) in a respectable yield. The ee value of the synthetic sample of 184 was defined to be 96% using chiral high-performance liquid chromatography analysis, which also proved that the Schmidt reaction of u-azido aldehyde 181 was a stereospecific process (Scheme 7.24). The spectroscopic data and optical rotation of the synthetic sample fully matched those of the authentic sample reported previously in the chemical literature [194e]. ()-Lundurine A (196) is [201] an indole alkaloid that shows moderate cytotoxicity in drug-resistant human oral epidermoid carcinoma cells [202] and has therefore attracted much interest from the synthetic community. It was successfully synthesized in 2018 by the Tambar research group. Their protocol involved a new vinylogous PSR for the construction of indole-annulated medium-sized rings. This strategy allowed the construction of tetrahydroazocinoindoles along with generation of a fully substituted carbon center, which is a predominant structural moiety in several biologically potent alkaloids [203]. This total synthesis started with tryptamine derivative 185, which was easily accessible from 5-methoxytryptophol. Coupling of the corresponding tryptamine derivative 185 with Grignard reagent 186 resulted in the formation of 187. The latter was then subjected to vinylogous PSR in the presence of Me3SiCl to deliver tetrahydroazocinoindole 188 in high yield. Tetracycle 188 via a two-step reaction including hydrogenation followed by TBS protection of the resulted primary alcohol was converted into corresponding silyl ether 189. Carboxymethylation of the indole nitrogen atom of the latter with imidazole carbamate 190 [204] followed by TBAF-assisted removal of the TBS group gave corresponding alcohol 191. The latter was

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SCHEME 7.24 Total synthesis of (R)-tylophorine (184).

subjected to Swern oxidation followed by treatment with Et3SiCl under soft enolization conditions to give the corresponding silyl enol ether 192 as an insignificant mixture of double-bond isomers. Then, the latter underwent a tungsten-catalyzed dehomologation reaction that resulted in proper removal of a methylene group in the side chain that gave rise to the corresponding aldehyde 194 [205]. This conversion apparently makes progress via formation of silyloxy epoxide 193, with subsequent oxidative cleavage. Transformation of aldehyde 194 to its hydrazone and BF3$Et2O-promoted cyclopropanation installed the strained polycycle 195. In conclusion, amide 195 was converted into an a-phenylsulfinyl lactam with subsequent syn elimination to assemble the vital a,b-unsaturation in the alkaloid. The spectral data obtained for this synthetic sample of ()-lundurine A (196) were compared with those data reported previously by Kam et al. for the authentic sample and found to be identical (Scheme 7.25) [201].

264 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 7.25

Total synthesis of ()-lundurine A (196).

Over the years, many attempts to accomplish the total synthesis of several caged indolenine alkaloids isolated from an array of plant species have served as an engine to drive novelty with targets such as 10-methoxyperakine vincawajine10-methoxyvinorine [206]. Vincadifformine, j- and 20-epi-j-vincadifformines, tabersonine, ibophyllidine, and mossambine [207], among others [208e211], have been strongly established in trials as available chemical tools. Due to their constrained backbones, the development of new effective synthetic approaches for their total synthesis have classically been in much demand. Arborisidine (206) [108] is a new and prized addition to this pool, It was initially isolated in relatively minute scale from Malayan Kopsia arborea trees by Kam and coworkers and fully characterized by the same research group [108]. It exhibited gastric cancer inhibitory in vivo when employed in combination with pimelautide [212]. Arborisidine (206) have some general structural features in common with other caged alkaloids. Its most conspicuous element contains a fully substituted cyclohexanone core involving two quaternary centers, one of

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which is an azaquaternary carbon not detected in associated molecules. Due to their interesting structures and because a literature survey disclosed just one published paper involving the total synthesis of arborisidine (206) [213], it is considered a noteworthy and challenging target for initial scrutiny for total synthesis. Snyder and co-workers in 2019 reported the first total synthesis of arborisidine (206) as an exceptional Kopsia indole alkaloid with a racemic mixture. The target compound (206) contains a fully substituted cyclohexanone and two quaternary carbons. Its total synthesis was accomplished in seven steps commencing from tryptamine and in nine steps in optically pure form starting from D-tryptophan methyl ester. For this total synthesis, in addition to an intelligently well-orchestrated decyanation approach to finalize asymmetric generation of an azaquaternary center that was perplexing to achieve in optically active form through direct PSRs with tryptamine, the metal-promoted 6-endo-dig cyclization of an enone was also required to generate the second core quaternary center for regiospecific functionalizations of the required diene to finalize the total synthesis. The discrete and effective nature of this advanced solution was observed by several ineffective tactics and unanticipated rearrangements [214]. Accordingly, total synthesis of arborisidine (206) commenced with commercially available tryptamine (3) that was reacted with 2,3-butadione in acidic MeOH at 60  C via PSR to provide 197 in modest yield. However, it was provided in the gram-scale quantities required to probe the leftover elements of the sequence. In contrast, merging to accomplish asymmetric synthesis of the same compound based on the existing PictetSpengler precedent was nonobvious and thus could not be reasonably contemplated. Thus, the preparation of tryptophan methyl ester (198) was planned as an effective diastereoselective alternative. A robust example of that general consequence of PSRs between the two D-/L-tryptophan methyl esters with aldehydes has already been recognized [215], but not with diketones [216]. Satisfyingly, moderate diastereoselectivity was indeed obtained, favoring the formation of 199 versus its separable diastereomer in a 1.9:1 ratio when L-/L-tryptophan methyl ester as salt 198 was used instead of reacting 3 with 2,3-butadione under PSR conditions. In this key reaction, compound ent-199 was obtained in good yield, and its structure and absolute configuration were established by X-ray analysis. Then, the conversion of ester 199 into the corresponding nitrile 201 through a sequential aminolysis/dehydration cascade reaction in one-pot fashion was contemplated [215b] (Scheme 7.26). Armed with both racemic and asymmetric pathways to 197, the preparation of cyclic dienes was envisioned and accomplished in three steps via propyne addition; dehydration of the resulting alcohol catalyzed by trifluoroacetic anhydride and a 6-endo-dig cyclization [209c,e] was assisted by a mixture of catalytic amounts of both Au(I) and Ag(I) salts in methanol as solvent. Auspiciously, a regiospecific bromination of the diene motif at its exocyclic terminus in 202 was easily accomplished using bis(2,4,6-trimethylpyridine)

266 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 7.26 Total synthesis of arborisidine (206).

bromine(I)hexafluorophosphate [217] under mild reaction conditions followed by solvent removal and redissolution in 1,4-dioxane and direct conversion of the intermediate into methyl ester 204 via a Pd-promoted carbonylation using xantphos in a respectable yield [218]. The latter was then transformed into alcohol 205 in four steps involving different functional conversions in acceptable yield. Upon oxidation of the latter using DesseMartin periodinane [219], the secondary alcohol was oxidized to furnish the desired alkaloid, arborisidine (206), in 34% yield along with partially oxidized 205 in 40% yield in a single operation. The desired natural product could be easily separated by column chromatography. All physical and spectroscopic data of this synthetic sample were found to be in full accord with the spectral and optical rotation data of the 206 natural sample, as reported by Kam et al. [108]. In addition, the structure of synthetic 206 was further confirmed by X-ray diffraction analysis. b-Carboline (9H-pyrido[3,4-b]indole), also known as norharmane, is a nitrogen-containing heterocycle. It is also the prototype of a class of indole alkaloid known as the b-carbolines. The b-carboline backbone is present in many natural products and synthetic complex compounds. Moreover, some

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b-carboline derivatives, both natural and synthetic, have reportedly displayed antitumor activities [220e221]. Kumujian C (1-formyl-9H-b-carboline, 211a), as a natural member of this alkaloid family, was employed for the synthesis of more complex compounds. A literature survey revealed several reports of the synthesis of b-carboline beginning from commercially available tryptamine or its derivatives, which included construction of the b-carboline backbone through PSR with subsequent aromatization of the C-ring using a dehydrogenation catalyst or with an oxidizing agent, and resulted in construction of the aldehyde functional group at the C1 position with generally good overall yield [222e231]. Pityriacitrin (214), trigonostemine A (215), trigonostemine B (216), and hyrtiosulawesine (218) alkaloids, all contain b-carboline scaffold in their structures, having also an indol-3-carbonyl moiety at position 1. They were isolated from various natural sources. Pityriacitrin (214) was initially extracted from a marine bacterium of the genus Paracoccus in 1999 by Nagao and co-workers [232]. Later, it was also was isolated from the human pathogenic yeast Malassezia furfur [233] and recognized as a secondary metabolite from the marine fungus Dichotomomyces cejpii F31-1 [234]. Several total syntheses of pityriacitrin (214) were achieved and reported previously [235,236], and the synthetic sample was screened for various biological potencies [237,238]. On the other hand, hyrtiosulawesine (218) was initially isolated from an Indonesian specimen of the marine sponge Hyrtios erectus [239]. A couple years later, alkaloid 218 was extracted from the Asian medicinal plant Alocasia macrorrhiza. It was biologically evaluated, exhibiting antiproliferative potencies toward human nasopharyngeal carcinoma epithelial [240]. Later, hyrtiosulawesine (218) was isolated from two other natural sources such a marine sponge Ircinia sp [241]. and from the roots of Aristolochia cordigera [242]. It showed antimalarial activity toward chloroquine resistant [238] and 3D7 [242] strains of the protozoan parasite Plasmodium falciparum showed antiphospholipase A2 [243] as well as antioxidant activities [238]. The total synthesis of hyrtiosulawesine (218) was achieved by Zhang et al. in eight steps and disclosed in 2010 [244]. Later, Liew et al. accomplished a new nine-step synthetic pathway for the total synthesis of compound 218 [238]. On the other hand, both trigonostemine A (215) and trigonostemine B (216) alkaloids were isolated from plants that are members of the spurge family, the leaves of Trigonostemon lii along with other b-carboline alkaloids [245]. Later, Wang et al. isolated alkaloids 215 and 216 from ethanolic extract of the brushwood of Trigonostemon filipes [246]. Comparatively, compounds 215 and 216 showed higher cytotoxic activity toward different human cancer cell lines than that of cisplatin, a medication used in chemotherapy [244,245]. A literature survey showed no records of the total synthesis of these biologically gifted alkaloids, trigonostemine A (215) and trigonostemine B (216). Milen and co-workers accomplished total synthesis of the aforementioned alkaloids, pityriacitrin (214) and hyrtiosulawesine (218), as well as the first

268 Applications of Name Reactions in Total Synthesis of Alkaloids

total synthesis of trigonostemines A (215) and B (216), and revealed their results in 2019 [247]. These alkaloids containing b-carboline have exhibited significant biological potencies. The key intermediates, differently substituted 1-formyl-b-carbolines, were provided in five steps including PSR. The method reported herein represents the first total synthesis of the two trigonostemines and a new pathway to pityriacitrin and hyrtiosulawesine. 1-Formyl-9Hb-carboline intermediates 211 were obtained in five steps commencing from tryptamine 3 using commercially available or easily accessible and easy-tohandle starting materials. These intermediates were then converted to four b-carboline alkaloids in two or three steps, whereas for trigonostemines 215 and 216, this was denoted as the first published total synthesis. Notably, the strategy under discussion was also successfully applied to the total synthesis of pytiriacitrin (214) and hyrtiosulawesine (218), demonstrating a basic novel synthetic strategy in addition to those already reported for the two aforementioned alkaloids. The total synthesis of all four aforementioned alkaloids started from the various tryptamine derivatives 3a, c, and d, which were reacted with glyoxylic acid monohydrate in an ethyl acetate-water biphasic system under PSR conditions to give [248] tetrahydro-b-carboline-carboxylic acids (207aec) in nearly quantitative yields under mild reaction conditions. Compounds (207aec) were converted to their respective methyl esters, 208aec, following a previously reported procedure (thionyl chloride, methanol) [249]. Compounds 208aec were submitted to aromatization of the C-ring when they were treated with elemental sulfur in mixtures of xylene isomers [250] under reflux conditions to provide dehydrogenated products 209aec with good to excellent yields (71%e100%). Then, esters 209aec were reduced by employing lithium chlorideactivated sodium borohydride [251] in EtOH/THF as a solvent system at ambient temperature to afford alcohols 210aec. Next, alcohols 210aec were selectively oxidized utilizing MnO2 on Celite provided by Attenburrow’s procedure [252,253] in refluxing 1,4-dioxane, to give the required target, aldehydes 211aec, in excellent isolated yields. For the synthesis of alkaloids 3e6, the provided 1-formyl-9H-b-carbolines (211aec) above were initially coupled with indole (212a) or substituted indole derivatives 212bec under basic conditions to furnish secondary alcohols (213aed) in modest yields. Next, the isolated secondary alcohols (213aed) were oxidized to the corresponding ketones by means of activated MnO2 under the same secured optimal reaction conditions for the preparation of 1-formyl9H-b-carbolines (211aec).The oxidation of hydroxyl groups to carbonyl moiety furnished the desired alkaloids pityriacitrin (214) and trigonostemines 215 and 216 in excellent to high yields (92%e97%). For completion of the total synthesis of another desired target, hyrtiosulawesine (218), an additional double O-demethylation step was a prerequisite; thus, O-demethylation of 217

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via treatment with pyridine hydrochloride [254] at 145  C resulted in preparation of hyrtiosulawesine (218) selectively in good yield (71%) after 36 h to complete the total synthesis of all four desired targets. Finally, the O-demethylation of 217 with pyridine hydrochloride [254] at 145  C led to hyrtiosulawesine (218) selectively in good yield (71%) after 36 h. Worthy of mention is that the overall yields of the synthesized alkaloids calculated from tryptamines 3a, c, d for pityriacitrin (214), trigonostemine A (215), and trigonostemine B (216) were 31%, 33%, and 48% over seven steps, respectively, and for trigonostemine B (216) was 19% over eight steps. The spectral data of all synthetic samples were in full agreement with those isolated from nature (Scheme 7.27) [245,246]. Fontanesines A, B, and C are pyrano[3,2-e]indole alkaloids that were initially isolated by Queiroz and co-workers in 2016 from the stem bark and leaf fractions of Conchocarpus fontanesianus [255]. These compounds feature pyrano[3,2-e]indole motif fused to quinazolinone. A critical task in the total synthesis of the aforementioned fontanesines is the regioselective construction of the pyrano[3,2-e]indole moiety. Despite their intriguing and unprecedented structures, their total syntheses have been largely disregarded. The significance of the regioselective construction of pyrano[3,2-e]indole scaffold in the total synthesis of natural products has stimulated research by several groups

SCHEME 7.27 Synthesis of b-carboline alkaloids 214e216 and 218.

270 Applications of Name Reactions in Total Synthesis of Alkaloids

worldwide [256e259]. Most of these strategies have been based on the Claisen rearrangement [256e258] and Pt-catalyzed cyclization [259]. Recently, Abe et al. developed a method for the synthesis of the pyrano[3,2-e]indole framework leading to the total synthesis of alkaloid fontanesine B (227). In this regard, in 2019, Abe and co-workers revealed their results, which involved complete regioselectivity controlled by C4 PSR in which an iminium ion functioned as a transient-directing group [260]. Additionally, the carbolines were formed by a novel BischlereNapieralski-type cyclization in which an unprecedented trichloromethyl carbamate functioned as a reactive group. This protocol commenced with benzyl protected 5-hydroxytryptamine (219), which reacted with 3-methyl-2-butenal (220) in the presence of Et3N in refluxing 2-propanol to deliver the required pyrano[3,2-e]indole 221 in a one-pot manner. Interestingly, under these reaction conditions, conventional PSR took place at the C2 position of the indole ring under basic conditions, which was a key to its attainment. When 221c was reacted with triphosgene in the presence of Et3N followed by the addition of HBr [261], the required 223c was provided along with unstable brominated product 224. Upon deprotection of lactam 223c in the presence of p-TsOH, compound 225 was obtained in a respectable yield [262]. Ultimately, the condensation of 225 and anthranilic acid (226) in the presence of POCl3 in toluene furnished the desired alkaloid, 227. The physical and spectral properties of this synthetic sample were in excellent agreement with those of the authentic sample isolated from natural source (Scheme 7.28) [255]. Conolidine a 5-nor-stemmadenine type, is an indole alkaloid [263e265]. Preliminary reports proposed that it could provide analgesic effects with few

SCHEME 7.28 Total synthesis of fontanesine B (227).

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of the detrimental side-effects associated with opioids such as morphine, although at present it has been evaluated only in mouse models. Conolidine was initially isolated by Kam and co-workers in 2004 from the bark of the Tabernaemontana divaricata (crepe jasmine) shrub, which has been used for some time as a folk Chinese medicine [266]. This alkaloid has a strained 1-azabicyclo[4.2.2]decane scaffold with an E-exocyclic trisubstituted double bond. In contrast to other congeners associated as opioid analgesics [267], ()-conolidine (239) and both enantiomers were found to exhibit significant nonopioid analgesic potency as reported by Bohn and co-workers in 2011 [268]. The first total synthesis of ()-conolidine (239) was achieved by Micalizio and co-workers in nine steps and in 18% overall yield. It featured a [2,3]-Wittig rearrangement and PSR and a developed asymmetric strategy toward both enantiomers [268]. Several other efforts have been made toward the total synthesis of conolidine (239) [269e277]. Li and co-workers achieved a brief (6 steps from N-tosylindole 228) total synthesis of ()-conolidine, a potent nonopioid analgesic, in 19% overall yield and reported their results in 2019. It involved an Au(I)-catalyzed Conia-ene reaction (Toste cyclization) and an important PSR assisting as vital conversions for installation of the 1-azabicyclo[4.2.2]decane core. The same authors also determined the geometry of the exocyclic double bond [278]. Accordingly, this total synthesis began from the coupling of N-tosylindole (228) and N-tosylpyrrolidone (229) as commercially available or easily accessible starting materials. Upon treatment of N-tosylindole (228) with n-butyllithium, the corresponding organolithium reagent was added into the N-tosylpyrrolidone (229) at low temperature to provide sulfonamide 230 in a reasonable yield. The latter was then subjected to a nucleophilic reaction with 1-bromo-2-butyne in the presence of K2CO3 in CH3CN to afford alkynyl ketone 232 in satisfactory yield. Upon treatment of alkynyl ketone 232 with TBAF, it was selectively deprotected from the N-1-tosyl group. Practically, after sulfonamide 230 reacted with 1-bromo-2-butyne, TBAF was added to the reaction mixture dropwise to deliver compound 233 in one-pot fashion. Ketone 233 was then exposed to triisopropylsilyl trifluoromethanesulfonate in the presence of 2,6-lutidine (3.0 equiv.) at 35  C, exclusively afforded 234 as a pair of stereoisomers (E/Z ¼ 8:92), the prevailing form of which was a byproduct in the Fujii et al. synthesis [270]. Gratifyingly, when compound 234 was treated with iPrAuCl/AgSbF6 as the catalyst, mixtures of 6-exo-dig 236 and 7-endo-dig 237 products were obtained in 29% and 49% yields, respectively. According to the calculation predictions, utilization of Au(I) with the JohnPhos ligand improved the yield of 236. Having 236 in multigram scale available in hand, the desired alkaloid conolidine (239) was obtained in two steps in good yields. Treatment of 236 with sodium naphthalenide [270,279] deprotected the tosyl group to afford compound 238. Then, PSR of amine 238 under the Micalizio et al. reaction conditions [268] gave conolidine (239), and its spectral data were in full agreement with conolidine isolated from natural source (Scheme 7.29) [266].

272 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 7.29

Total synthesis of conolidine (239).

MITAs are derived from a unit of tryptamine and a C9/C10 unit of terpenoid origin [280]. Biosynthetically, it is generally believed that tryptamine and secologanin are the elementary components [77c]. Historically, they have assisted as treasured lead compounds in drug discovery [280]. Several MITAs such as vinblastine, reserpine, and strychnine have fascinated the synthetic and medicinal communities as high-profile targets for total syntheses and biological evaluations. In 2007, Luo et al. isolated two geometrically isomeric MITAs called (E)-alstoscholarine (252a) and (Z)-alstoscholarine (252b) from the leaves of A. scholaris. They have been distributed in South Asia and have been used as folk medication for a long time [65a]. Alstoscholarine alkaloids have an uncommon pentacycle including a [3.1.3] bicyclic bridge where an indole and a pyrrole ring seldom coexist. This typical structure and indeed the highly structural rearrangement of 252a and 252b renders a tryptamine subunit as an idyllic objective to rectify the synthetic approaches and methods. Along this line, in 2011, Zhu et al. reported

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a well-designed total synthesis of alstoscholarine alkaloids 252a and 252b [281,282] via adoption of a desymmetrization of meso-anhydride to generate the suitable chiral centers in the first step, and Pd-catalyzed synthesis of the indole ring at the late stage. Yang et al. achieved a catalytic asymmetric total synthesis of MITA () alstoscholarine alkaloid 252a and described their results in 2019 [283]. Their strategy involved an Ir-amine dual-catalyzed asymmetric allylation of aldehyde 241 with 3-indolyl vinyl carbinol derivative 240 to generate chiral aldehyde 244 as an important asymmetric step. Other significant reactions involved the construction of the 2-ketopyrrole moiety through Nicolaou’s protocol and Tf2O assisted PSR to provide intermediate 251. The total synthesis of ()-alstoscholarine started with providing of the strategic chiral aldehyde 244. Under optimal conditions, we were pleased to find that by using reaction of 3-indolyl vinyl carbinol 240 [284] with aldehyde 241 [285] in the presence of (S)-242 and [Ir/(S)-243] as catalysts delivered the chiral aldehyde 244 in respectable yield and in >99% ee and 9:1 dr. Subsequently the latter was subjected to Pinnick oxidation conditions to furnish carboxylic acid 245 in high yield. The latter was transformed to the corresponding carboxylic acid in the presence of 2-pyridylthioester, and PPh3 in toluene followed by addition of pyrrylmagnesium bromide using Nicolaou’s procedure afforded the indole pyrrole derivative 246 in high yield [286]. A sequential three-step oxidative cleavage of the alkene moiety of 246 afforded methyl ester 247 in satisfactory overall yield. Hydrogenolysis of the p-methoxybenzyl ether of the latter in the presence of Pearlman’s catalyst proceeded smoothly, resulting in the formation of the corresponding alcohol 248. Upon selective oxidation of the latter using DesseMartin periodinane, the corresponding aldehyde 249 was obtained. Pleasantly, in a key step, aldehyde 249 in the presence of a catalytic amount of DBU in CH3CN was effectively and neatly transformed to the required hemiaminal (250) in virtually quantitative yield but as a mixture of two diastereoisomers. The stereochemistry of the resulting hemiaminal was unimportant because this chiral center was wrecked in the subsequent PSR. Upon treatment of the hemiaminal (250) with Tf2O the pentacyclic core of alstoscholarine was obtained from which the Boc group was removed with TFA to deliver the Zhu’s intermediate 251 in respectable overall yield. Worthy of mention is that obtained synthetic 251 is a crystalline compound in which the structure was established unambiguously by single-crystal X-ray analysis. The two left over steps of this total synthesis could then be performed in accordance with Zhu’s previously reported strategy [281]. Upon treatment of 251 with Takeda’s reagent (using divalent titanocene reagents) followed by Vilsmeier Haack formylation using (phosphorus oxychloride in o-dichlorobenzene), the desired target ()-alstoscholarine (252) was obtained in satisfactory yield (Scheme 7.30). Indole alkaloids are known for both their dominance in nature and diverse bioactivities, and they have been extensively used in drug discovery [287]. PSR constructs plant alkaloids such as morphine and camptothecin, but it has

274 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 7.30

Total synthesis of ()-alstoscholarine (252).

not yet been perceived in the fungal kingdom. Indole alkaloid chaetoglines C (260), D (261), E (263), and F (266) are natural products with unprecedented skeletons, of which chaetoglines B and F are potently antibacterial, with the latter inhibiting acetylcholinesterase. Chaetoglines C (260), D (261), E (263), and F (266) were isolated from supplemented fungal culture. Interestingly, the first fungal metabolites derived from this PS reaction are the indole alkaloids chaetoglines A-H produced by C. globosum [288], followed by polyketides azacoccones AE found in A. flavipes [289]. One of the main frameworks for the biosynthesis of most indole alkaloids is b-tryptamine, which is indeed the decarboxylation product of tryptophan. The biosynthetic machinery of indole alkaloids comprising the b-carboline building block included the initial formation of a Schiff base from the condensation between b-tryptamine and aldehyde or ketone with subsequent ring closure to

Applications of PicteteSpengler reaction Chapter | 7

275

form tetrahydro-carboline [290]. In the total synthesis, PSR played a key role [12]. Relying on the already disclosed metabolism experiment, the authors suggested that chaetoglines may be biosynthetically formed, and PSR should be the key step to constructing the basic skeletons of chaetoglines A, B, E, and F. The initial biological screening, chaetoglines B and F exhibited better antibacterial activity than the frequently employed antibiotic, tinidazole. Lei et al. reported the first total synthesis of chaetoglines CeF in 2019 via a bioinspired pathway that had been a popular notion of research for some time, but achieving such complexity through synthetic techniques offers considerable challenges [291]. Their divergent synthetic pathways to chaetolines C (260) and D (261) involved the condensation of hemiacetal and tryptophan methyl ester frameworks, including transformations of several functional group transformations. For the total synthesis of chaetogline E, the diastereoselective PSR and construction of the tetrahydrcarboline skeleton was further utilized as a precursor for an oxidative aromatization reaction to install the b-carboline moiety of chaetogline F(266). The total synthesis began with the known lactone 254a, which was provided in accord with the reported procedure from 253 after two steps [292]. Upon protection group maneuvers of 254a, compound 254b was obtained and subjected to aminolysis by treatment with trimethyl aluminum and diethyl amine the corresponding benzyl alcohol released, which was subsequently oxidized to the corresponding benzyl aldehyde by pyridinium dichromate followed by hydrolysis and spontaneous cyclization delivered the racemic hemiacetal 255 in a combined 75% yield [293]. Next the latter was condensed with N-methyl tryptophan methyl ester 255 [294] which in the presence of excess Et3N proceeded cleanly delivered the hemiaminal 257. The latter, without further purification [295], was reduced to compound 258 in high yield. The latter was then treated with boron tribromide [296], furnished the chaetoglines C (260) and D (261) in 23% and 42% isolated yield, respectively. Notably, hemiacetal 258 also served as a precursor of 259 for PSR. Having chaetoglines C and D secured in hand, the synthesis of chaetoglines E and F was contemplated. Intermediate 257 submitted to asymmetric PSR for the construction of the b-carboline structure of the target molecules [103,297]. Initially, compound 257 was treated with of TFA led to the formation of a single diastereomer, even though in low yield. The yield was improved using a number of acids, of which trimethylsilyl trifluoromethanesulfonate was eventually selected as the optimal catalyst to effectively catalyze asymmetric PSR with high and excellent stereoselectivity (Scheme 7.31). Next, the complete total synthesis of chaetoglines E and F was envisioned. In this regard, methyl ester 259 was initially transformed to the acid 262 under mild reaction conditions. Transformation of 262 into the desired alkaloid 263 prerequisite the removal of three protecting groups various orthodox protecting moieties for the phenol groups, such as the methyl, methoxymethyl, isopropyl, or benzyl group, were practically examined. In conclusion, the isopropyl group was confirmed to be apathetic in most conditions except the

SCHEME 7.31 Synthesis of chaetoglines C (260) and D (261).

276 Applications of Name Reactions in Total Synthesis of Alkaloids

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277

presence of BBr3 or AlCl3 [298]. As a result, inclusive deprotection of 262 completed the synthesis of chaetogline E (263) in nine steps in 21% yield over nine steps. To achieve the total synthesis of chaetogline F (266), the extra carboxyl group of 262 was initially cleaved by the Barton decarboxylation protocol [299]. Next, the provided compound 264 was oxidized using selenium dioxide in refluxing AcOH [295], with subsequent methylation using trimethylsilyl diazomethane to deliver compound 265. In conclusion, the synthesis of chaetogline F was achieved by global deprotection in good yield. With sufficient quantities of synthetic chaetoglines C to F (266) accessible and in hand, their biological potencies were evaluated. The outcome disclosed that chaetogline F (266) has high activity inhibition toward acetylcholinesterase, a potential molecule for the treatment of Alzheimer’s disease (Scheme 7.32) [300]. ()-Quinocarcin (286) belongs to a significant subclass of the large family of tetrahydroisoquinoline (THIQ) alkaloids [301]. It was found to be a highly active antitumor antibiotic. ()-Quinocarcin (286) was initially isolated from Streptomyces melanovinaceus by Takahashi et al. in 1983 [302]. The foremost agents of this subclass are ()-quinocarcin, DX-52-1, quinocarcinol, tetrazomine, and lemonomycin, which contain the tetracyclic THIQ-pyrrolidine framework. They also bear a THIQ as the AB ring and a chiral 3,8diazabicyclo[3.2.1]octane framework as the CD ring [301]. Compound 286 showed outstanding antiproliferative potency toward lymphocytic leukemia [303]. Its complicated polycyclic structure and gifted biological potencies have attracted much attention of synthetic organic chemists toward its total synthesis [304,305]. In 1988, Fukuyama and co-workers reported the first racemic total synthesis of ()-quinocarcin [304]. Total synthesis of the racemic form of the more stable quinocarcinol methyl ester and quinocarcinamide has also been achieved [306].

SCHEME 7.32 Synthesis of chaetoglines E (263) and F (266).

278 Applications of Name Reactions in Total Synthesis of Alkaloids

Shi and co-workers developed the total synthesis of ()-quinocarcin and revealed their results in 2019 [307]. This scalable strategy was based on the Pd(II)-catalyzed C(sp3)H arylation PSR for stereoselective synthesis of the tetrahydroisoquinoline moiety (AB ring) and involved Cu(I)-catalyzed exoselective asymmetric multicomponent [C þ NC þ CC] coupling reaction developed by Garner [308,309] to generate the chiral pyrrolidine motif (D ring). This protocol allowing the construction of ()-quinocarcin (286) was completed in 13 steps and in 4.8% overall yield using N-phthaloyl-L-alanine as a chiral pool. As a matter of fact, the crucial point of this protocol was based on the utilization of suitably substituted chiral b-aryl-a-amino acids as general precursors (273 þ 274 / 279). After broad studies, 3-iodophenyl benzoate 267e was selected as the arylation reagent because it afforded the best results for both yield and scalability. The latter was reacted with alanine derivative 268 in the presence of Pd(OAc)2, AgBF4 in t-BuOH/DCE at 78  C under N2 atmosphere to obtain 269e in high yield. Upon cleavage of the 8-aminoquinoline moiety and esterification of 269e in the presence of TsOH in MeOH with concurrent removal of the benzoyl group, the respective methyl ester 270 was obtained in good yield. The latter was brominated using HBr in DMSO via a stylish method developed by Jiao et al. [310] to give the required brominated product 272 in excellent yield. The phthalimide moiety in 272 was cleaved in the presence of ethylenediamine to provide the free amine 273 in respectable yield with complete retention of the configuration from alanine derivative 268 (268%, 96% ee; 273%, 97% ee). Next, in the crucial step, amido phenol 273 and acetaldehyde derivative 274 were reacted under acidic PSR conditions to afford tetrahydroisoquinoline 275 in multigram scale (dr 7:1) [305f,311]. Protecting of the secondary amine of 275 as N-tert-butoxycarbamate afforded 276 in high yield. Subsequently, the latter was methylated with TMSCHN2 to give 277 in nearly quantitative yield. The latter was then treated with LiBH4, resulting in the reduction of ester to primary alcohol to provide the required 278 also in virtually quantitative yield. Alcohol 278 was selectively oxidized to THIQaldehyde 279 via DesseMartin oxidation in excellent yield. With the vital scaffold THIQaldehyde 279 available in hand, it was subjected to direct asymmetric construction of functionalized pyrrolidine. In this way, [C þ NC þ CC] coupling reaction of THIQaldehyde 279, with Oppolzer’s L-glycylsultam 280 and methyl acrylate 281 with Cu(CH3CN)4PF6/dppb, proceeded smoothly at ambient temperature, furnishing the desired 4,5-transpyrrolidine 282 in high yield on gram scale. Although the structure of this novel constructed pyrrolidine 282 was elucidated by its spectral data, its stereochemistry could not be determined unequically using essentially standard spectroscopic techniques. However, the expected configurations were hesitantly determined on the basis of Garner’s model [308] and later established by correlation with well-known intermediate 285. Transesterification of the chiral sultam moiety to methyl ester 283 with simultaneous cleavage of the N-Boc function from 282 was recognized in a one-pot manner to give the required 283 in good yield. Upon heating in toluene, the newly formed secondary amine

was selectively converted to lactams 284 in virtually quantitative yield. It was expected that the aryl bromide and the OBn protecting group could potentially be removed under the same conditions as those for the N-reductive methylation by a judicious choice of reaction conditions. Finally, upon concurrent deprotection and N-methylation of the unprotected amine over Pd/C in the presence of aqueous solution of formaldehyde, quinocarcinol methyl ester 285 was obtained in high yield on a milligram scale. Compound 285 was used as a well-known precursor in Stoltz’s total synthesis of ()-quinocarcin (286) in a two-step process, and its spectroscopic data were found to be in full agreement with those of authentic samples reported previously (Scheme 7.33) [305g].

SCHEME 7.33 Formal synthesis of quinocarcin (286).

280 Applications of Name Reactions in Total Synthesis of Alkaloids

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Chapter 8

Applications of the Sonogashira reaction in the total synthesis of alkaloids Chapter outline 1. Introduction 2. Mechanism

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3. Applications of the Sonogashira reaction in the total synthesis of alkaloids References

297 316

1. Introduction The Sonogashira cross-coupling reaction is an important and useful name reaction in organic synthesis in which carbonecarbon bonds are generated. It uses a Pd species as a catalyst and copper as a cocatalyst to form a carbonecarbon bond between a terminal alkyne and an aryl or vinyl halide [1] The Pd-catalyzed CeC bond formation process, which can couple a terminal sp hybridized carbon from an alkyne with an sp2 carbon of an aryl or sp2 vinyl halide (or triflate), is generally known as a Sonogashira cross-coupling reaction. The reaction arose in 1975 from the development of a CeC bond formation by a Pd species such as PdCl2(PPh3)2 as catalyst combined with a cocatalytic amount of CuI and an amine at ambient temperature by a research group led by Kenkichi Sonogashira [2]. Notably, this discovery was introduced several months after Cassar [3] and Dieck and Heck [4] discovered that it was possible to perform this coupling not only under Pd catalysis but also by proceeding at high temperature. Sonogashira’s conception was to combine Cumediated transmetalation of alkynes, which was known, with a more adaptable, influential, and prevailing metal in catalytic terms, such as palladium, thus providing an extension of Cassar and Heck’s results that yielded a strong CeC bond-formation procedure. What he understood was that the addition of copper was advantageous in terms of increasing the catalytic activity of the system under ambient conditions in aqueous media and with a mild base. The addition of Cu compensated some inadequacies, the principle being the Recent Applications of Selected Name Reactions in the Total Synthesis of Alkaloids https://doi.org/10.1016/B978-0-12-824021-2.00002-9 Copyright © 2021 Elsevier Inc. All rights reserved.

295

296 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 8.1 The Sonogashira coupling reaction.

necessity of avoiding the presence of oxygen in order to block the undesirable generation of alkyne homocoupling through a copper-mediated Hay/Glaser reaction [5]. The “Sonogashira coupling reaction” is currently a comprehensive depiction applied to the Pd(0)-catalyzed coupling of a sp2 (or even sp3) halide or triflate with a terminal alkyne (sp) irrespective of whether copper(I) salts are used (Scheme 8.1). The obtained products from the Sonogashira coupling reaction have found extensive use in many areas of organic synthesis, such as the total synthesis of natural products. Several metabolites found in nature involve alkyne or enyne groups; thus, the Sonogashira reaction has found much applicability in the total syntheses of such metabolites [6]. For example, in the total synthesis of the alkaloid bulgaramine, the key intermediate is an alkyne obtained from the reaction of an iodinated alcohol and tris(isopropyl)silylacetylene [7]. The Sonogashira reaction, including differently employed catalysts, reaction conditions, and applications in dye fabrication, medicine, and agrochemistry, have been widely reviewed [8e13]. As a result, intermolecular, intramolecular, and cyclization Sonogashira reactions to construct the spesp2 bond are used extensively in the total synthesis of natural products, therapeutic agents, and several other organic materials [14].

2. Mechanism Despite its widespread application, the mechanism of Pd/Cu-cocatalyzed cross-coupling has remained uncertain or difficult to understand. Presumably, it proceeds via the combination of Pd-catalyzed and Cu-catalyzed cycles. In the Pd-catalyzed cycle, in situ reduction of Pd(II) complexes may generate a catalytically active species, Pd(0)L2, that simplifies the rapid oxidative addition of R-X. The rate of oxidative addition of R-X depends on the electronic properties of the R-X bond and the reactivity of X (I
OTf
Br > Cl). Typically, electron-withdrawing groups activate the R-X bond by reducing its electron density. Then, in the Cu-catalyzed cycle, Cu-acetylide is subjected to transmetalation. This stage, which is also the rate-determining reaction step, creates a RPd(-ChCR0 )L2 species that is then submitted to reductive elimination to give the desired coupled alkyne and recreate the Pd(0)L2 catalyst. A drawback of the Pd/Cu-cocatalyzed reaction is that the alkyne may undergo

Applications of the Sonogashira reaction Chapter | 8

297

SCHEME 8.2 The proposed mechanism of the Sonogashira coupling reaction.

homocoupling in the presence of oxygen via the already known Hay/Glaser reaction [15]. To circumvent this side reaction, researchers have explored the Cu-free Sonogashira coupling reaction [14]. While the mechanism of this reaction is not implicit, it is believed that reversible p-coordination and deprotonation, analogous to those in the Cu-catalyzed cycle of Pd/Cucocatalyzed coupling, creates an alkyneePd (II) complex [RPd(-ChCR0 )L2] (Scheme 8.2). Due to the importance and usefulness of the Sonogashira reaction, we have recently published about its applications [16e27]. Owing to the significance of Sonogashira reactions in the art of organic synthesis, in this chapter we focus on underscoring applications of Sonogashira reactions in the total synthesis of one the most important, widespread, and prevalent families of natural products showing diverse biological properties, the so-called “alkaloids.”

3. Applications of the Sonogashira reaction in the total synthesis of alkaloids Calothrixins A and B are cyanobacterial metabolites with a structural assembly of quinoline, quinone, and indole pharmacophores. Calothrixin B (14) is a pentacyclic quinone with an indolo[3,2-j]phenanthridine or quinolino[4,3b]carbazole framework and is exceptional among natural alkaloids. The marine environment is host to unparalleled biological and chemical diversity, making it an attractive resource for the discovery of new therapeutics for a

298 Applications of Name Reactions in Total Synthesis of Alkaloids

plethora of diseases. Compounds extracted from cyanobacteria are of special interest due to their unique structural scaffolds and capacity to produce potent pharmaceutical and biotechnological traits. Calothrixin B (14) was initially isolated in 1999 from Calothrix cyanobacteria [28]. Biological investigations of calothrixin B have shown several biological potencies, such as antimalarial and anticancer activities [29,30]. Due to interesting structural features and many biological potencies, it has received much attention from the synthetic community, thus several pathways toward its total synthesis have been achieved and reported via various synthetic methodologies comprising a metallation protocol [31], palladium-catalyzed coupling [32], the HeteroeDielseAlder reaction [33], FriedeleCrafts acylation/alkylation [34], and a radical reaction [35]. Furthermore, two biomimetic strategies for the total synthesis of calothrixin B have been accomplished and disclosed [36]. The Sonogashira cross-coupling reaction is used extensively in the synthesis of the 1,n-enyne system, which is a significant segment in biologically potent natural products [37]. Cu-catalyzed oxidative cyclization of 1,n-enynes is a powerful tool for construction of the 4-carbonyl quinoline system prevalent in several natural products [38]. In 2015, Nagarajan and co-workers developed a novel total synthetic strategy for calothrixin B involving sequential Sonogashira cross-coupling and Cu-catalyzed oxidative cyclization reactions [39]. This synthetic protocol offers a facile and promising podium to synthesize novel indolonaphthyridine ring systems. A concise total synthesis of the antimalarial indolo[3,2-j]phenanthridine alkaloid calothrixin B began with the preparation of a crucial intermediate, ketoester 10. It was installed via sequential intermolecular Sonogashira coupling intermolecular/intramolecular Cu-catalyzed oxidative cyclization reactions in five steps. Initially, the free NH in 2-ethynyl-1H-indole (4) was protected with a benzyl group to afford 1-benzyl-2-ethynyl-1H-indole (5). In the key reaction, the latter was subjected to the Sonogashira coupling reaction with (E)-ethyl 3-((2-iodophenyl)-amino)acrylate (6) in the presence of catalytic amounts of Pd(PPh3)2Cl2, CuI and diisopropylamine in tetrahydrofuran (THF) at ambient temperature. These reactions afforded compound 8 in excellent yield. With the coupled product 8 in hand, the key intermediate 10 was obtained by intramolecular Cu-catalyzed oxidative cyclization reactions. After several examinations, it was found that high conversion of 8 to 10 proceeded cleanly in the presence of a catalytic amount of CuCl2$2H2O (phen and 1,4-diazabicyclo[2.2.2]octane in DMF at 100  C under an oxygen atmosphere. This transformation was assumed to proceed smoothly via cascade intramolecular carbocupration of alkyne 8 followed by isomerization/elimination and oxidation sequential reactions to afford desired product 10 [40]. At this stage, having the key intermediate 10, further functional group manipulations were conducted involving ester hydrolysis, cyclodehydration, and debenzylation. In fact, the ketoester 10 was hydrolyzed using NaOH/EtOH to create ketoacid 11, which was in turn transformed into known N-benzyl

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299

SCHEME 8.3 Total synthesis of calothrixin B (14).

calothrixin 13 via stirring in conc. H2SO4 at 140  C. Next, compound 13 was readily deprotected upon treatment with 10% Pd/C and HCOONH4 in refluxing MeOH to furnish desired alkaloid 14 in respectable yield. The spectral data of this synthetic sample 14 were compared with those of natural sample 13 and found to be in full agreement with those reported previously in the literature (Scheme 8.3) [28,33]. Canthin-4-one alkaloids exemplify a very small chemotype of natural products [41]. Based on the chemotype with moderate antimicrobial activity, to date, just three representatives, tuboflavine (5-ethylcanthin-4-one), norisotuboflavine (19a, R ¼ methyl), and isotuboflavine (19b, R ¼ ethyl), have been found and isolated from plants [42,43]. In vitro evaluations for antimicrobial activity disclosed that two 5-substituted canthin-4-ones (3-pyridyl, 2bromophenyl) show remarkable potency against Streptococcus entericus by

300 Applications of Name Reactions in Total Synthesis of Alkaloids

coupling with high selectivity and a lack of cytotoxicity against mammalian cells. More importantly, the complete and intact canthin-4-one ring system was shown to be vital for antibacterial activity. The substituted canthin-4-ones showed phosphodiesterase-inhibitory activity [44]. In addition, canthin-4-ones were found to be useful intermediates for the synthesis of antimicrobial polycyclic compounds [45,46]. Decades ago, total synthesis of canthin-4-one was achieved, albeit with very poor overall yieldsdjust enough for the synthesis and structural elucidation of the three alkaloids [47e49]. Another strategy for multistep synthesis of the canthin-4-one framework has been patented [44]. Bracher and co-workers in 2015 accomplished multistep synthesis of the canthin-4-one ring system (19) via a condensation of 1-acylb-carbolines with amide acetals or Bredereck’s reagent (tert-butoxybis(dimethylamino)methane) to obtain enaminoketones that were subjected to cyclization under the reaction conditions [50,51]. In continuation of their study, the same research group explored an alternative strategy to this tetracyclic ring system with the vision of being capable to conduct diverse functionalizations as well as polyfunctionalizations on the ring system. In this regard, they modified their previously reported strategy by substitution of the orthocarboxylic acid derivatives such as amides and acetals. With these frameworks, they synthesized 1,3-diketones from 1-acyl-b-carbolines via a Claisen-type condensation. Cyclization of the diketones was likely to afford the canthin-4-one framework (19). In their second attempt, they developed alternatives to the 1-acyl-b-carboline intermediates, because these are available only by means of lengthy methods (radical reactions [51e53] or organometallic chemistry [54]) or commercially available but expensive organostannane building blocks [55]. Bracher and co-workers in 2015 developed two successful new protocols to the canthin-4-one ring system: (1) Claisen-type condensation of 1-acetylb-carboline with N-acyl benzotriazoles to afford the canthin-4-one ring through intermediate 1,3-diketones, 6-alkylcanthin-4-ones in one-pot operation; and (2) reaction of 1-ethynyl-b-carboline and 1-isoxazolyl-b-carbolines with subsequent reductive isoxazole cleavage and cyclization. This route was found more versatile because 5,6-disubstituted canthin-4-ones were provided via iodination at C-5 followed by a Pd-catalyzed Sonogashira cross-coupling reaction [56]. Initially, some derivatives of isoxazol-5-yl-b-carbolines were obtained by Pd-catalyzed coupling of 1-bromo-b-carboline (15) [54] and 3-substituted isoxazoles under CH-activation at C-5 of the isoxazole ring. The essential 1-ethynyl-b-carboline (16) was provided in nearly quantitative yield by reaction of 1-bromo-b-carboline (15) with (trimethylsilyl)acetylene under Sonogashira cross-coupling [57] followed by desilylation using K2CO3 as a mediator [58]. Then, alkyne 16 was transformed to the isoxazoles 17aec via cycloaddition with nitrile oxides, which in turn were provided in situ by treatment of the oximes of acetaldehyde, propionaldehyde, and benzaldehyde

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301

with N-chlorosuccinimide [59]. Isoxazoles 17, upon reductive cleavage by Pdcatalyzed hydrogenation, afforded the primary enaminoketones 18aec in excellent yield by Pd-catalyzed hydrogenation in ethanolic KOH solution [60]. After extensive investigation, the authors found that for final cyclization leading to the desired target, an E-configured tertiary enaminoketone must be used. Thus, Z-configured primary enaminoketone 18a was converted to an Econfigured tertiary enaminoketone related to the reactive intermediate of the previous canthin-4-one synthesis. To this end, enaminoketone 18a was heated in piperidine at 125  C for a couple days, leading to formation of a nearly quantitative cyclization to norisotuboflavine (19a) as the desired target. Apparently, in this isomer conversion and cyclization, piperidine did not act just as simple solvent but indeed functioned in the sense of organocatalysis [61]. When enaminoketone 18a was refluxed under anhydrous DMF or DMSO at 170  C, norisotuboflavine (19a) was also obtained, indicating that the reaction is also possible by heating at significantly higher temperatures, but catalyzed cyclization was the preferred method. This novel strategy afforded 6-substituted canthin-4-ones 19aec in high yields starting from easily accessible 1-ethynyl-b-carboline (16). In contrast to the 1,3-diketone pathway, this protocol is appropriate for introduction of the bulky phenyl residue at C-6. In addition, this strategy permitted the first high-yield total synthesis of the alkaloid isotuboflavine (19b) (Scheme 8.4). An extract of the marine bryozoan Caulibugula inermis was collected in the Indo-Pacific off Palau and isolated by Milanowski and co-workers in 2004 [62]. Bioactivity-directed fractionation of the extract along with isolation showed that the extract involved caulibugulones AeF, which are actually isoquinoline quinone alkaloids [63]. They produced a distinct pattern of differential cytotoxicity in the National Cancer Institute’s 60 cell line antitumor screen [62]. The structures of these novel metabolites were elucidated by spectrochemical analyses involving LC-MS, HRFABMS, and 1-D and 2-D NMR experiments as well as by comparison with related

SCHEME 8.4 Synthesis of canthin-4-ones 19aec via isoxazoles.

302 Applications of Name Reactions in Total Synthesis of Alkaloids

compounds. The structures of compounds 27 and 28 were confirmed by chemical interconversion. Caulibugulones AeF were found to have interesting cytotoxic activity against murine tumor cells [62]. For the first time, in 2012, Valderrama and co-workers achieved and disclosed the synthesis of 4-methoxycarbonyl-3-methylisoquino -line-5,8-quinone containing the caulibugulone core and their analogues, which exhibited valuable in vitro cytotoxic activity against MRC-5 [64]. Then, Brission et al. revealed that caulibugulones are selective in vitro inhibitors of the Cdc25 family of cell cycle-controlling protein phosphatases [65]. Despite these interesting and important biological activities, a literature survey revealed just three reports on the synthesis of caulibugulones [66e68]. Tamagnan and co-workers in 2004 achieved and disclosed the first total synthesis of caulibugulones from 5,8-isoquinolinedione [66]. Wipf et al., in the same year, independently reported the total synthesis of caulibugulones AeF [62e67] from oxidation of 5-hydroxyisoquinoline by iodobenzene bis(trifluoroacetate) (PIFA) in H2O/EtOH followed by the in situ addition of methylamine [67]. Most recently, the concise total synthesis of caulibugulones AeD was accomplished in six steps commencing from 2,5dimethoxybenzaldehyde [68]. Nagarajan et al. in 2015 contemplated a facile pathway for the preparation of the key intermediate 5,8-dihydroxyisoquinoline, resulting in total synthesis of the marine cytotoxic alkaloids caulibugulones A (26) and D (29). The synthesis was achieved in just three steps with overall yields of 60% and 62%, respectively, from commercially available or readily attainable starting materials [69]. In their protocol, the vital features involved the Sonogashira cross-coupling reaction, the construction of the isoquinoline-5,8-diol core by ammonia-promoted iminoannulation of 2-ethynyl-3,6-dihydroxybenzaldehyde, and finally, in situ oxidative amination. The same authors also showed that caulibugulones B, C, and E (27, 28, and 30) can be readily prepared from caulibugulone A (26) by the previously reported procedure [67]. Accordingly, 2-bromo-3,6-bis(methoxymethoxy)benzaldehyde (20) was easily provided in high yield by bromination and followed by MOM protection of 2,5-dihydroxybenzaldehyde [70]. Next, in a key step, compound 20 was reacted with trimethylsilylacetylene under Sonogashira cross-coupling reaction conditions in the presence of PdCl2(PPh3)2,CuI to give the expected coupled product 22 as yellow oil in excellent yield. The latter was then reacted with the trimethylsilyl (TMS) group, and the resultant was subjected to cyclization in the presence of an excess of aqueous ammonia K2CO3, in ethanol under reflux conditions to deliver the anticipated product, 5,8bis(methoxymethoxy)isoquinoline (23), in high yield. The hydroxyl groups in compound 23 were deprotected upon its treatment with THF/H2O/conc. HCl (6:2:1 ratio) with heating at 50  C to give isoquinoline-5,8-diol, which upon in situ oxidation delivered the important intermediate isoquinoline-5,8-dione (25). Awkwardly, the dione 25 was not

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303

SCHEME 8.5 Total synthesis of caulibugulones A (26) and D (29).

stable enough to be isolated. Thus, crude compound 25 without isolation was directly submitted to aminolysis [71] using 3 equivalents of methylamine (33 wt% in ethanol). The crude product was purified by column chromatography on silica gel to furnish the desired alkaloid caulibugulone A (26) in decent yield over the two steps. When dione 25 was subjected to aminolysis with ethanolamine (2 equivalents) in DME, the other desired target, caulibugulone D (29), was also obtained in respectable yield. The regioselective oxidative amination of 25 and generation of the chief isomer can be justified by the resonance stabilization of compound 25 [66]. This means that the C-7 position of isoquinoline-5,8-dione is more preferred for oxidative amination than C-6 is, and thus the required regioisomer was generated as a single product. The structure of caulibugulone D (29) was unambiguously established by single-crystal X-ray diffraction analysis (Scheme 8.5). Having caulibugulone A synthesized, it was transformed into caulibugulones B (27), C (28), and E (30) by following the formally reported investigations of Wipf et al. [67] (Scheme 8.6). Acridone alkaloids are a large family of biologically potent naturally occurring compounds found in the bark, wood, leaves, and roots of rue plants, especially in the roots and suspension cultures of rue [72]. Several of them have exhibited noteworthy anticancer activity [73]. Among acridone alkaloids, chlorospermines A (39) and B (40) are two polycyclic members that were isolated by Litaudon et al. in 2014 from the stem bark of Glycosmis chlorosperma [74]. The total syntheses of several members of the acridone alkaloids have been achieved and reported in the chemical literature [75e82]. The aforementioned syntheses of acridone alkaloids are often designed based on FriedeleCrafts reactions, which need strongly acidic media as well as electron-rich arene substrates. Due to the sporadic availability of natural sources of these alkaloids for obtaining sufficient amounts for full screening to

304 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 8.6 Formal synthesis of caulibugulones B (27), C (28), and E (30).

evaluate their biological activities, novel effective and brief total syntheses are in much demand; this is especially true of a modular strategy for attaining the tetracyclic core of chlorospermines that has attracted much attention from the synthetic community. These strategies require to be pertinent to a wide variety of substrates and in addition constructing the acridone core under optimized neutral conditions. Despite several attempts, the synthesis of multisubstituted arenes leftovers poses a serious challenge for contemporary organic chemistry [83e90]. Nicolaou and co-workers opened a gateway for the stylish synthesis of endiandric acids via electrocyclization proven to be a powerful tool for installation of functionalized ring systems [91e101]. Remarkably, multisubstituted arenes can be constructed in a highly effective and convergent manner only when 6pelectrocyclization is strategically combined with oxidative aromatization [102e107]. Li et al. effectively employed such protocols for the total syntheses of several naturally occurring products made up of aromatic moieties, such as daphenylline [108], tubingensin A [109], xiamycin A, oridamycins A and B [110], rubriflordilactone A [111], and clostrubin [112]. Armed with these valuable experiences, the Li research group in 2015 achieved and revealed their results leading to a brief pathway toward the tetracyclic core of chlorospermines A and B as biologically important acridone alkaloids, employing 6p-electrocyclization/aromatization as a vital step [113]. In their strategy, the two segments were installed via Sonogashira crosscoupling reaction, and a cis-triene intermediate was provided by applying hydrosilylation/desilylation. Notably, sequential 6p-electrocyclization/ aromatization played a vital role in their approach, in which the tetrasubstituted arene motif was constructed in one-pot fashion. Accordingly, the total synthesis started with the provision of two units, a-iodoquinolone (32) and alkynylpyran 35. Compound 32 was provided from known compound 31 [114]. The latter, upon iodination using N-iodosuccinimide,

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305

gave the respective 2-iodoenone, which was further subjected to N-protection (TsCl, Et3N, 4-DAMP) to obtain the required 32 in excellent overall yield. The synthesis of the pyran segment was achieved via a BaeyereVilliger oxidation. Silylation of b-hydroxy ketone 33 with subsequent treatment with m-CPBA under buffered conditions delivered lactone 34 in respectable yield over two steps. The latter was treated with lithiated TMS-acetylene in the presence of BF3.OEt2 to form an unstable lactol intermediate, which upon dehydration using trifluoroacetic acid (TFA) created the conjugate enyne [115], which followed by desilylation in K2CO3/MeOH gave 35 in good yield over three steps. Having the two essential units 32 and 35 in hand, the tetrasubstituted arene was constructed via Sonogashira cross-coupling reaction (Pd(PPh3)2Cl2, CuI, Et3N) to deliver dieneyne 36 in decent yield. The triene product 37 was found to be unstable and thus had to be provided under mild reaction conditions along with fast purification. Thus compound 36 was subjected to smooth Pt-catalyzed hydrosilylation [Pt(dvds), (Et2CHO)Me2SiH] to furnish a regioisomeric mixture of alkenylsilanes [116e118], which next underwent desilylation conditions [119e122] in the presence of AgF in water to deliver 37 in moderate overall yield. Lastly, 6p-electrocyclization/aromatization took place, proceeding smoothly under thermal conditions (125  C) in the presence of air to afford tetracyclic acridone 38 in good yield. The latter may be used as an important common intermediate for the total synthesis of several chlorospermine analogues including chlorospermines A (39) and B (40) (Scheme 8.7). Conolidine (55) is an indole alkaloid belonging to the C5-nor stemmadenine family of alkaloids. Primary reports showed that it possesses analgesic effects with few of the detrimental side-effects associated with opioids such as morphine, though at present it has been evaluated only in mouse models. Conolidine was first isolated by Kam and co-workers in 2004 from the bark of the Tabernaemontana divaricata (crepe jasmine) shrub, which is used in traditional Chinese medicine [123]. In 2011, Micalizio achieved the first asymmetric total synthesis of conolidine (55) [124]. Due to biological evaluations observing that the latter showed a unique analgesic activity that differed from that of many common opioids, including morphine [124], it has grabbed considerable attention from synthetic community. Although many effective strategies have been accomplished for the synthesis of C5-nor stemmadeninetype indoles [124e126], the development of a diversity-oriented pathway appropriate for assessing the structureeactivity relationships of these compounds was still in much demand. Fujii and co-workers successfully attempted the total synthesis of (þ)-conolidine and disclosed their protocol in 2016 [127]. Their strategy involved a Pd-free Sonogashira cascade cyclization of a conjugated enyne because the Pd-catalyzed classic Sonogashira reaction had failed. Instead of Pd, they used Au(I) catalyzed for the cyclization of a conjugated enyne. Homogeneous gold catalysis has stirred up interest in the organic synthetic community due to the strong p-acidity of gold as well as its ability to stabilize cationic reaction intermediates [128]. The multipurpose

306 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 8.7 Total synthesis of the tetracyclic core of chlorospermines A (39) and B (40).

reactivity of Au(I) catalysts for the design of several powerful cascade reactions for the direct step and atom-economical synthesis of complex molecules [129]. Nowadays, homogeneous gold catalysis is a standard as one of the most efficient strategies for the electrophilic activation of alkynes for the synthesis of naturally occurring products [129f]. Curiously, this protocol permitted for the concurrent of the indole ring and the ethylidene-substituted piperidine moiety of (þ)-conolidine under homogeneous Au(I) catalysis in an enantioselective manner (88%e91% ee). This investigation exhibited that the feasibility and effectiveness of catalytic asymmetric reactions involving chiral gold(I) complexes for the construction of stemmadenine-type framework. Consequently, conjugated enynes 50a and 50b bearing different silyl enol ether groups were initially provided according to the pathway depicted in Scheme 8.8. Thus, the total synthesis started with tosylamide 41 [130], which was initially alkylated using ethyl 4-bromobutanoate (42) to afford ester 43, which upon reduction with DIBAL delivered the corresponding aldehyde followed by 1,2-addition of lithium (trimethylsilyl)acetylide (44), which resulted in

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307

the aldehyde, followed removal of the TMS group with tetra-n-butylammonium fluoride delivered terminal alkyne 46 in nearly quantitative yield. The latter alkyne was reacted with o-iodoaniline (47) under Sonogashira coupling reaction conditions to give alkynylaniline 48 in excellent yield. The latter was oxidized with MnO2 to afford the corresponding ketone 49 in good yield, which was upon treatment with TIPSOTf or TBSOTf in the presence of Et3N delivered conjugated enyne-type silyl enol ethers 50a and 50b in 75% and 81% yields, respectively. It is worth noting that the E and Z isomers [131] of 50 could be separated, as required, by column chromatography over silica gel followed by PTLC. Next, the application of the Au(I)-catalyzed cascade reaction of enol ethertype conjugated enynes 50a and 50b was studied (Table 8.1). The treatment of enyne 50a with L1Au(MeCN)SbF6 (Fig. 8.1) in toluene-d8 at room temperature gave the desired product 51 (16%) as well as the two monocyclization products, 52 (34%) and 53 (14%). To direct the reaction to completion, the use of an additive as a proton source as well as a silyl scavenger were studied. Auspiciously, the addition of H2O4 improved the yields of 51% to 38%, while the use of MeOH was less effective. Then, the enantioselective gold(I)catalyzed cascade reaction of the conjugated enyne 50a was studied. Relying on the findings revealed by Toste and co-workers including the asymmetric carbocyclization of a silyl enol ether [132], biarylphosphine-type dinuclear chiral gold complexes were used, which affected the desired reaction, drastically (Fig. 8.1). The treatment of conjugated enyne 50a with (R)-DTBM-SEGPHOS(AuCl)2 (5 mol %)/AgSbF6 (10 mol %) in the presence of H2O (1.5 equivalents) led to generation of the nonrequired ketone 53 as the major product (Table 8.1, entry 1). However, when (R)-MeO-DTBM-BIPHEP was used, the desired product (S)-51 was obtained, albeit in poor (13%) yield, but with high 89% ee (entry 2). Supposing that the sterically less hindered Z isomer has better reactivity, the reactions of both isomers (Z)- and (E)-50a were tested. Remarkably, the use of (Z)-50a resulted in an improvement in the yield of (S)-51% to 32% (entry 5), whereas the reaction of (E)-50a to give the desired product was unsuccessful (entry 4). In conclusion, these results proved that generation of required product 51 is possible from the Z isomer of 50a only when its E/Z mixture was used as the substrate (entries 2 and 3). Interestingly, the use of 50a in conjunction with a decreased loading of H2O (1.0 equiv) resulted in an improvement in the ee to 91%, although the yield dropped to 18% (entry 6). Lastly, the conversion of bis-cyclization product (S)51 (91% ee) to (þ)-conolidine (55) was examined. The treatment of (S)-51 with Na/naphthalene led to the cleavage of the Ts protecting group to afford known conolidine precursor 54 in respectable yield. In comparison with Micalizio et al. [124], (þ)-conolidine (55) was furnished in 34% yield and 84% ee. The spectral dada analysis as well as specific optical rotation data for the synthetic sample were compared with those of conolidine isolated from nature and found to be identical [123,124], thus confirming the work of Fujii et al. [127] (Table 8.2).

308 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 8.8 Total synthesis of (þ)-conolidine (55).

In 2014, Hu and co-workers isolated aspergilline A (73) and its four other congeners (BE) from the fungus Aspergillus versicolor [133]. Aspergilline A (73) showed potency toward tobacco mosaic virus and many human cancer cell lines as well as many synthetically inspiring structural complexities. Aspergilline A (73) comprises a caged hexacyclic (6/5/6/5/5/5) heterocyclic ring system as well as six adjoining stereogenic centers and a polysubstituted tetramic acid. A literature survey did not disclose any reports or attempts to date regarding its total synthesis. Nevertheless, the total syntheses of some related but far less functionalized natural products, such as cyclopiazonic acid, have been accomplished and reported [134]. In 2017, Mina and co-workers reported their efforts leading to the total synthesis of most biologically potent congener ()-aspergilline A (73) in 16 steps from commercially available bromoisatin 56 [135]. Their strategy involved Sonogashira cross-coupling reactions, pyrrolinone formation via reaction of an intermediate propargyl amine with a methyl malonyl chloridederived ammonium enolate, and a formal [3 þ 2] cycloaddition between an imidate and cyclopropenon as vital steps. The total synthesis of

TABLE 8.1 Optimization of reaction conditions.a Yield (%)b Ligand

Additive

R

Time (h)

9

28

29

1

L1

e

TIPS (50a)

24

16

34

14

2

L1

H2O

TIPS (50a)

24

38

e

2

3

L1

MeOH

TIPS (50a)

19

29

e

2

4

IPr

H2O

TIPS (50a)

24

3

45

10

H2O

TIPS (50a)

24

14

5

45

L1

H2O

TIPS (50a)

24

16

e

43

L1

H2O

TBS (50b)

24

33

e

e

5 6 7 a

L1 d

c

Unless otherwise noted, all of these reactions were conducted using 50a (79:21 Z:E) or 50b (71:29 Z:E) with L1Au(MeCN)SbF6 (5 mol %) or IPrAuCl (5 mol %)/AgSbF6 (5 mol %) in toluene-d8 (0.2 M) at r.t. in the presence of an additive (1.5 equiv). b NMR yields were evaluated using mesitylene as an internal standard. c Using L1AuCl/NaBARF. d Using CD2Cl2 as a solvent instead of toluene-d8.

Applications of the Sonogashira reaction Chapter | 8

Entry

309

310 Applications of Name Reactions in Total Synthesis of Alkaloids

FIGURE 8.1 Ligands and cocatalysts screened in this study.

TABLE 8.2 Enantioselective gold(I)-catalyzed cyclization.a Time (h)

Yield of 51 (%)b

% ee [(S)-51]c

(R)-DTBMSEGPHOS(AuCl)2/AgSbF6

24

NDd,e

e

53:47

(R)-MeO-DTBMBIPHEP(AuCl)2/AgSbF6

19

13

89

3f

53:47

(R)-MeO-DTBMBIPHEP(AuCl)2/AgSbF6

19

w10

76

4

E only

(R)-MeO-DTBMBIPHEP(AuCl)2/AgSbF6

20

NDe

e

5

Z only

(R)-MeO-DTBMBIPHEP(AuCl)2/AgSbF6

17

3

88

6g

83:17

(R)-MeO-DTBMBIPHEP(AuCl)2/AgSbF6

14

18

91

Entry

Z:E (50a)

1

53:47

2

a

Catalyst

Unless otherwise noted, these reactions were conducted using 50a in toluene (0.2 M) at r.t. in the presence of H2O (1.5 equiv) with a catalyst loading of 5 mol % (for the bimetallic gold complex) or 10 mol % (for AgSbF6). b Isolated yields. c Determined by chiral HPLC. d Ketone 53 was obtained as the major product. e Not detected. f The catalyst loading was increased to 10 and 20 mol %. g Using H2O (1.0 equiv).

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()-aspergilline A (73) commenced from commercially available bromoisatin (56), which upon N-methylation delivered 57 [136]. Next, compound 57 and propargyl amine 58 were subjected to Sonogashira coupling conditions using Pd(PPh3)4 and CuI to give the corresponding isatin 59 [137] as an important intermediate composed for transformation to pyrrolinone 62 via a two-step strategy developed by Marinelli [138]. Then, compound 62 was reduced using Raney Nickel under 420 PSI H2, which gave the desired pyrrolinone but was mixed by undesired product resulted from reduction of the isatin. Thus, the derived product was oxidized by Dess-Martin Periodinane to have access the essential aldol substrate (64). Delightfully, conversion of 64 to the corresponding silyl ketene acetal followed by treatment with TiCl4 proceeded smoothly to deliver compound 65 as a single diastereomer in decent yield [139]. The 2,4-dimethoxybenzyl protecting group in 65 was cleaved using DDQ afforded amide 66 and set the stage for introduction of the tetramic acid [140]. Of many cyclization options for introduction of the tetramic acid, the authors were fascinated by the work of Hemming, who has shown that cyclopropenones easily react with various imidates to undergo formal [3 þ 2] cycloaddition products [141]. To examine this transformation, 66 reacted with a large excess of methyl triflate to give an O-methyl imidate (67), which upon mild warming in CH3CN with cyclopropenone [142] gave pentacyclic vinylogous amide 69 as a minor mixture of diastereomers (2:3, a:b) in excellent yield. The structure of major diastereomer (69b) verified the regiochemical course of this captivating conversation as well as the relative stereochemical result of the previous aldol reaction. To convert 69a:b to the requisite a-hydroxy tetramic acid, 70 was exposed to several oxidation conditions, which ultimately revealed that PIFA reacts readily with 70 to afford a highly unstable product, thus providing spectral data in agreement with those expected to the desired oxidation change [143]. Immediate subjection of the resultant to a degassed solution of TFA:H2O (3:1) at 55  C smoothly cleaved the TMS group and resulted in the formation of a stable hemiacetal (71). Auspiciously, 71 was produced as a single diastereomer and unambiguously proved agreeable characterization by single-crystal X-ray analysis. To complete the preparation and isolation of 71, it was treated to sodium phenyl selenide in THF to give an intermediate carboxylic acid, which upon peracetylation and Hunsdiecker iodinative decarboxylation gave an intermediate iodide (72), which was subjected to reductive deiodination and acetate methanolysis to furnish the desired target ()-aspergilline A (73) as the sole isolable product in 7% yield over the five steps (Scheme 8.9) [144,145]. Anatoxin-a, also known as very fast death factor, is a secondary bicyclic amine alkaloid and cyanotoxin with acute neurotoxicity [146]. It is structurally related to (þ)-homoanatoxin-a [(þ)-90], which are both cyanobacterial neurotoxins generally originated by several species of both benthic and planktonic cyanobacteria [147,148]. (þ)-Anatoxin-a is about 50 times more potent than ()-nicotine and

312 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 8.9 Total synthesis of ()-aspergilline A (73).

20 times more potent than acetylcholine [149,150]. These properties make (þ)-anatoxin-a one of the most active agonists of nicotinic acetylcholine receptors and the slightest toxic alkaloid so far identified. (þ)-Homoanatoxin has also similar toxicological properties [151]. Anatoxin-a was initially discovered in the early 1960s in Canada and was isolated in 1972 [152].

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Due to its high toxicity and potential presence in drinking water, anatoxin-a poses a threat to animals, including humans [153,154]. Due to its powerful biological potencies and exclusive structural features including the 9azabicyclo[4.2.1]nonane ring system, several research groups have attempted various approaches toward the total synthesis of anatoxin-a [155e160]. Most of these efforts ended to racemic, but some of them were stereoselective resulting in (þ)-anatoxin-a [161], or in some cases to the unnatural enantiomeric form, ()-anatoxin-a with high to excellent ee [161b,e,f,i,162]. However, the total syntheses of anatoxin-a and homoanatoxin-a are still attractive as the bench target of several research groups worldwide and scientists have called for more research to improve the reliability and efficacy of their total syntheses. However, only two total syntheses have been achieved and reported so far for providing homoanatoxin-a as a racemat [163,164]. Abad-Somovilla and co-workers in 2018 accomplished the total synthesis of both the natural and unnatural enantiomers of the cyanotoxins [(þ)-87 and (þ)-90] and [()-87 and ()-90], respectively [165]. Their simple and effective approach, involving construction of the azabicyclic homotropane scaffold in both enantiomeric forms from cis-5,6-epoxycyclooctene, relied on a microwave-irradiation-assisted epoxide ring-opening reaction by a chiral benzyl amine followed by a transannular amineealkene cyclization, then expansion of the distinctive methyl or ethyl enone via the Sonogashira crosscoupling reaction of an enol triflate with a C2 or C3 terminal alkyne. The total synthesis began with the prochiral epoxide 9-oxabicyclo[6.1.0] non-4-ene (74), whose desymmetrization was conducted to afford an approximately easily separable 1:1 mixture of diastereoisomeric aminoalcohols 76 and 77. The separation was achieved effectively in a high level of diastereomeric purity and high chemical yield through an elegant combination of crystallization and column chromatography. Then, secondary hydroxyl group of amino alcohols 78 and 79 were oxidized under Swern conditions to deliver the corresponding ketones 81. The amine protecting-group exchange through hydrogenolysis of the benzylamino moiety of the latter in the presence of di-tert-butyl dicarbonate provided NBoc ketones ()-82 as (1R,6R) and (þ)-82 as (1S,6S). All spectroscopic data of both enantiomeric N-Boc ketones were in full agreement with those previously reported for the racemic compound [166]. Having the homotropane frameworks in hand, initially the carbonyl group of N-Boc ketones ()-82 and (þ)-82 was converted into enoltriflate (þ)-83 and ()-83 using potassium bis(trimethylsilyl)amide (KHDMS) in THF followed by treatment with Comins’ reagent. The enyne moiety was introduced to triflates (þ)-83 and ()-83 in the form of their corresponding enol triflate via the Pd(0)-catalyzed Sonogashira cross-coupling reaction of the corresponding enol triflate, which was easily provided by trapping of the kinetic potassium enolate with Comins’ reagent under standard conditions with trimethylsilylacetylene as protected liquid acetylene replacement [8] to give

314 Applications of Name Reactions in Total Synthesis of Alkaloids

the terminal alkyne moiety; thus, trimethylsilyl enynes ()-84 and (þ)-84 were provided unprotected upon treatment with base in MeOH at room temperature to afford enynes ()-85 and (þ)-85, respectively, in respectable overall yield over three sequential steps. After achieving the enyne moiety, the triple bond was hydrated using a solution of mercury(II) oxide in MeOH and boron trifluoride etherate in the presence of catalytic amounts of trichloroacetic acid and HgO to create the corresponding ketone carbonyl group providing the corresponding methyl enones ()-86 or (þ)-86, after aqueous workup and purification by column chromatography, with an excellent yield. It was believed that chemo- and regioselectively arose from the treatment of the enyne compound with a methanolic solution of mercury(II) oxide and boron trifluoride etherate in the presence of catalytic amounts of trichloroacetic acid. Under these conditions, the triple-bond hydration reaction proceeds very effectively, providing, the corresponding methyl enones ()-86 or (þ)-86, with an excellent yield after aqueous workup and purification by column chromatography [167,168]. Noticeably, sometimes small amounts of dimethyl ketal and/or enol ether intermediates were identified by the 1H NMR spectra of the hydration crude product. The physical and spectral data of enantiomeric enones ()-86 and (þ)-86 were compared with those of N-Boc derivatives of natural and unnatural anatoxin-a, respectively, and were found to be in full agreement [161b]. The ees of both N-Boc derivatives of anatoxin-a were set to be >99% based on chiral HPLC analysis. Finally, the synthesis of both enantiomers of anatoxin-a was accomplished by cleavage of the N-Boc protecting group in acidic conditions. Consequently, treatment of ()-86 and (þ)-86 with a 1:1 mixture of TFA and CH2Cl2 at ambient temperature directly delivered the respective trifluoroacetate salts (þ)-87$TFA and ()-87$TFA. On the other hand, treatment of ()-86 and (þ)-86 with 4 M HCl in dioxane at ambient temperature delivered the equivalent hydrochlorides (þ)-87$HCl and ()-87$HCl (Scheme 8.10), whose physical properties and spectral data were in accord with those already reported in the literature [161b,i,m]. Accordingly, the synthesis of homoanatoxin-a in each enantiomeric form was performed following the procedure similar to that employed for the synthesis of anatoxin-a, which relied on the Sonogashira reaction of the same intermediate enoltriflates (þ)-83 and ()-83, in this case using propyne with subsequent hydration reaction of the triple bond. Seemingly, as exhibited after aqueous workup and purification by column chromatography of the reaction mixture, the reaction between enoltriflate (þ)-83 and propyne was completely effective employing both propyne gas or a commercially available 4% solution of propyne in DMF under rather similar conditions to those mentioned for the after aqueous workup and purification by column chromatography synthesis of anatoxin-a. With modification in the cross-coupling reaction of enoltriflates (þ)-83 or ()-83 with propyne [169], the respective enynes ()-88 or (þ)-88 were respectively prepared in decent yield. Having enantiomeric enynes

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SCHEME 8.10 Synthesis of (þ)- and ()-anatoxin-a trifluoroacetate and hydrochloride salts.

()-88 and (þ)-88 accessible in hand, the synthesis of both enantiomers of homoanatoxin-a was easily achieved following the same procedure utilized for the aforementioned synthesis of structurally related anatoxin-a enantiomers. Therefore, chemo- and regioselective hydration of the triple bond of enynes ()-88 and (þ)-88 using the HennioneNieuwl and catalytic system delivered N-Boc ethyl enones ()-89 and (þ)-89, respectively, which upon treatment with a 1:1 mixture of TFA and CH2Cl2 at ambient temperature afforded the respective trifluoroacetate salts of natural and unnatural homoanatoxin-a, (þ)-90$TFA and ()-90$TFA, in decent overall yield from the starting enol triflates (Scheme 8.11). The spectroscopic NMR data of both homoanatoxin-a

316 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 8.11 Synthesis of (þ)- and ()-homoanatoxin-a trifluoroacetate salts.

enantiomers were compared with those of the authentic samples isolated from natural sources [170] and the synthetic racemic form and were found to be identical [163,164].

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Chapter 9

Recent advances in applications of Suzuki reaction in the total synthesis of alkaloids Chapter outline 1. Introduction 2. Reaction mechanism

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3. Applications of Suzuki reaction in total synthesis of alkaloids 329 References 369

1. Introduction Undoubtedly, coupling reactions, and especially cross-coupling reactions, are the most imperative and vital class of reactions in the art of organic synthesis. In general terms, a coupling reaction (homocoupling) in organic chemistry is referred to as the reaction when two similar fragments are joined together with the aid of a catalyst to form a new bond. A cross-coupling reaction is a subset of the coupling reaction in which two different components interact in the presence, usually, of a metal catalyst to form a new bond. Cross-coupling reactions are employed as useful and powerful tools for the synthesis of complex molecules from simple commercially available or easily accessible compounds. As a well-established and powerful tool in the art of organic synthesis, coupling reactions enable complex molecules to be synthesized from simple molecules. Therefore, cross-coupling reactions are extensively used in both academia and industry, especially in the production of fine chemicals and pharmaceuticals [1,2]. In general, coupling reactions can be categorized into two main types, homocoupling and cross-coupling, which refer to the interaction of two similar and two different molecules, respectively. In general, cross-coupling reactions comprise the reaction of organometallic reagents with organic electrophiles in the presence of an appropriate metal catalyst in which Pd-based catalysts have extensive, and literally the Recent Applications of Selected Name Reactions in the Total Synthesis of Alkaloids https://doi.org/10.1016/B978-0-12-824021-2.00008-X Copyright © 2021 Elsevier Inc. All rights reserved.

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most, applicability. Cross-coupling reactions are frequently employed for the formation of a wide range of CeC, Ce H, CeN, CeO, CeS, CeP, or CeM bonds in the synthesis of a wide variety of organic compounds [3]. The “name reaction” in organic chemistry is a type of shorthand that avoids the need to give a lengthier explanation of the features of a particular transformation of interest but to knowledgeable readers or listeners induces much expectation, trust, reliance, and dependability. Several “name reactions” in organic chemistry exist to describe the significance of crosscoupling reactions. They are known as the CadioteChodkiewicz [4], Heck [5], Stille [6], SuzukieMiyaura [7], Kumada [8], Sonogashira [9], Negishi [10], Hiyama [11], and Fukuyama [12] coupling reactions. Undoubtedly, among the foregoing name reactions, The Suzuki crosscoupling reaction (SCCR) (in many publications, this reaction also goes by the name SuzukieMiyaura reaction) is one of the most useful and important and is rendered attractive as the method of choice in terms of effectiveness, versatility, higher activity, and the relatively low toxicity of organometallic (organoborons) or boronic acid derivatives and their ease of synthesis, utilization, and handling. The SCCR is an important type of coupling reaction, a designation that encompasses a variety of processes that combine (or “couple”) two hydrocarbon fragments with the aid of a catalyst (in the SCCR, palladium, Pd, is in a basic environment). The reaction is able to conjoin a variety of aryl halides and alkenyl halides to alkenylboranes and arylboronic acids [7,13]. It was first accomplished and reported in 1979 by Akira Suzuki, who shared the 2010 “Nobel Prize in Chemistry” with Richard F. Heck and Ei-ichi Negishi for their efforts in the discovery and development of Pd-catalyzed cross-coupling in organic synthesis. A classic and widely used SCCR is represented in Scheme 9.1. SCCR is extensively used for the synthesis of polyolefins, styrenes, and substituted biphenyls. Several useful reviews have been published describing advancements and developments of the SCCR [14e26]. Since its introduction in 1979 by Akira Suzuki et al. [7a], the SCCR of halobenzenes and organoborons (which was fruitfully conducted with several homogeneous and heterogeneous Pd-based catalysts with the addition of a base as cocatalyst) has been extensively used for CeC bond formation in the synthesis of complex organic molecules from simple starting materials [27e32]. Although the Pd species is the predominant main metal used in most research in academia and R&D centers, other transition metals, such as Ni

SCHEME 9.1 Suzuki cross-coupling reaction of halobenzene and phenylboronic acid derivatives.

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[33e35], Fe [36,37], Rh [38e40], and Cu [41] have also been found to be active in SCCR, and despite being rarely employed, their applications in that context have been extensively studied [33e41]. Over the past 2 decades, many homogeneous complexes and heterogeneous catalysts have been designed, prepared, and tested for their activity and suitability in the SCCR. A wide range of aryl halides and organoborons, especially phenylboronic acid derivatives have been widely examined, affording a wide variety of desired coupled products [27e41]. The SCCR shows a wide substrate scope range achieved successfully using different halobenzenes and phenylboronic acid derivatives bearing electron-releasing and electron-withdrawing groups. Furthermore, the addition of electron-withdrawing groups to halogen in the ortho or para positions increases its reactivity in oxidative addition compared with halogens that have electron-donating groups. Frequently, iodobenzenes are more active than or have the same activity as bromobenzenes, whereas chlorobenzenes are often found to be much less active. The other version of SCCR is acyl SCCR. This reaction involves the coupling of an organoboron with an acyl electrophile, which replaces the halobenzenes, i.e., aryl halides, in the orthodox SCCR [23,42e44].

2. Reaction mechanism The mechanism of the SCCR is best observed from the viewpoint of the palladium species as catalyst. Initially, the oxidative addition of Pd species to the halide 1 generates organopalladium species 4. Reaction (metathesis) of the latter with base creates intermediate 5 followed by transmetalation [45] with boronate complex 7 (generated by the reaction of boronic acid 6 with base) gives the organopalladium species 8. Upon reductive elimination of the latter, the desired product 4 is obtained, and concurrently, the original palladium catalyst is regenerated, completing the catalytic cycle. Although the SCCR takes place in the presence of a base, the role of the base was not fully understood for quite a long time. At first, the base was suggested to form a trialkyl borate (R3B-OR) in a reaction of a trialkylborane (BR3) and alkoxide (
OR); this species could be assumed to be more nucleophilic, and thus more reactive, toward the Pd complex existing in the transmetalation step [45e47]. In 2011, Duc et al. studied the role of the base in the reaction mechanism for the SCCR and concluded that the base presumably plays three roles: (1) assisting in the formation of the palladium complex [ArPd(OR)L2], (2) promoting generation of the trialkyl borate, and (3) assisting in the acceleration of the reductive elimination step via interaction of the alkoxide with the Pd complex (Scheme 9.2) [46]. Originally, and more often, simple soluble Pd salts, such as PdCl2 or Pd(OAC) [48], are used as the catalyst in SCCR. However, these Pd salts are commonly reduced under reaction conditions and converted to palladium black, which is less active than the originally used Pd species. This problem has been

328 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 9.2 Suggested probable mechanism for Suzuki cross-coupling reaction.

circumvented by the addition of a ligand, usually a phosphine-based ligand [49,50] or an N-heterocyclic carbene ligand [51,52] that not only stabilizes the Pd species but also often makes it more active. The widespread use of Pd species, despite being the most efficient catalyst in SCCRs, is somewhat undesirable because of their tedious and difficult separation from the reaction mixture and lack of recovery and thus reusability. To circumvent these drawbacks, several heterogeneous Pd-based catalysts [17,53,54] including Pd nanoparticles [55,56] have been designed, prepared, and used that can be readily recovered and reused several times without any loss of appreciable activity. Over the most recent 2 decades, the development of green protocols in all organic transformations has received much attention from the chemical community worldwide. In this regard, the SCCR has also been under continuous development, and as a result, several environmentally benign and clean synthetic strategies have been successfully developed and operationally tested. A great number of SCCRs have been conducted in green solvents, such as water and ionic liquids, and under solvent-free conditions [57], in the presence of easily recovered heterogeneous Pd species as catalyst and under microwave irradiation (MWI) as the green source of energy [57] instead of conventional heating. Nowadays, attempts are made to design SCCRs that will comply with the defined and well-established “Principles of Green Chemistry.” In 2012, our group published a report covering applications of SCCR in the total synthesis of natural products in tetrahedron [25], which seems to have attracted much attention from synthetic organic chemists based on the numerous citations it has gained and is still gaining. Due to the ever-growing number of articles published from 2012 to 2018 on applications of SCCR, we were encouraged to update our previous review, which we did, and we reported it in 2018 [26]. In this chapter, we try to underline the recent applications of SCCR in the total synthesis of alkaloids as one of the most prevalent, widespread, and important natural products found and isolated from the plant kingdom.

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3. Applications of Suzuki reaction in total synthesis of alkaloids Proaporphine [58], stepharine (19) [60], and homoproaporphine-type alkaloids [60] have been isolated from plants of the genus Stephania [59]. Such plants have been employed as folk medications for the treatment of medical ailments in Asia and Africa [59]. The proaporphine alkaloids were initially pronounced by Barton and co-workers in 1957 long before any members of the family had been isolated and characterized [61]. The first total synthesis of stepharine (19) was accomplished by Bernauer and co-workers and reported in 1968 [62]. In 2010, Honda et al. reported the total synthesis of stepharine (19) in nine steps with an overall yield of 29% [63]. In 2015, Magnus et al. accomplished and reported the total synthesis of stepharine (19) in eight steps with an overall yield of 29%. Accordingly, this approach used standard SCCR, a traditional nitroaldol reaction, and conjugatively reduced with DIBAL-H. The total synthesis started from easily accessible aryl boronate anhydride 11 reacted with 10 under standard aryl SCCR to afford 12 in excellent yield. The latter was transformed to primary amine 14 in excellent yield and was then converted to 18 after four steps. Upon exposure of the latter to KOH/ethylene glycol at 100  C, the desired natural product, ()-stepharine (19), was obtained in high yield and 29% overall yield though eight steps (Scheme 9.3) [64].

SCHEME 9.3 Total synthesis of ()-stepharine (19).

330 Applications of Name Reactions in Total Synthesis of Alkaloids

Calothrixins A and B are pentacyclic quinones categorized within the family of quinolino[4,3-b]carbazole alkaloids [65]. In 1999, they were isolated by Rickards et al. from the strain of Calothrix cyanobacteria [66]. Calothrixins A and B exhibited biological potency toward malaria parasites and human cancer cells [66,67]. Owing to their invaluable potent activities as well as their exceptional structural framework, which is new among natural products, calothrixins A and B have attracted enormous attention from synthetic organic chemists and the medicinal chemistry community [68]. Hibino et al. in 2009 performed a comprehensive review of the chemistry and synthesis of calothrixins in which six different total syntheses and two biomimetic pathways were defined [69]. They involved a Pd-mediated domino cyclization/cross-coupling reaction followed by Cu-catalyzed electrocyclization [70], Pd-catalyzed intramolecular arylation [71], FeCl3-assisted tandem reaction [72], thermal electrocyclization [73], oxidative radical reaction [74], Pb(OAc)4-catalyzed rearrangement [75], palladium-catalyzed multiple crosscoupling reaction [76], Pd-catalyzed cross-coupling/CeH activation [77], and FriedeleCrafts hydroxyalkylation with subsequent ketone directed ortholithiation protocols [78]. Nagarajan and co-workers in 2015 reported a total synthesis of calothrixin B and its N-benzyl analogues. This strategy comprised SCCR and Cu-catalyzed tandem reactions to afford N-benzylcalothrixins in good to moderate yields. This strategy is in fact the first example of preparing a series of N-benzylcalothrixins via an SCCR and Cu-mediated cascade reaction commencing from market purchasable benzylamines, (2-chlorophenyl)boronic acid, and 8-bromophenanthridine-7,10-dione in satisfactory yields [79]. Accordingly, the formal total synthesis commenced from 8bromophenanthridine-7,10-dione (22) that was provided from 8-bromo-7,10dimethoxy-5-(methoxymethyl)phenanthridin-6(5H)-one (20) in two steps using typical conversions [80]. Having compound 22 available in hand, in a key step, it was reacted with market purchasable or easily accessible (2chlorophenyl)boronic acid 23 as a coupling partner via SCCR [employing Pd(PPh3)4, (10 mol%) K2CO3 (2 equiv.) in DMF at 140  C] to obtain the corresponding coupled product 24 in satisfactory yield. The compound 26 as the key intermediate was provided from the reaction of benzylamines 25 with 24 in high yield. In conclusion, calothrixin B (27) was obtained by the N-deprotection of derivative 26 in the presence of 5 equiv. of AlCl3 in anisole at 100  C with an overall yield of 36.1% over five steps from compound 20 (Scheme 9.4). The largest family of monoterpenoid indole alkaloids is indeed Aspidosperma, comprising more than 250 members [81]. Their exceptional structural features and biological potencies have received much attention recently from the synthetic and medicinal communities [82]. In fact, the Aspidosperma family of alkaloids has provided a fruitful filed for improvement and to date has remained as an active and stimulating ground in the art of synthetic organic chemistry [83].

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SCHEME 9.4 Synthesis of calothrixin B (27).

In 1979, Di Genova et al. initially isolated (þ)-limaspermidine from the trunk bark of the small tree Aspidosperma rhombeosignatum [84]. Its structural elucidation revealed that it has the complex and characteristic [6.5.6.6.5]pentacyclic ABCDE scaffold of the Aspidosperma alkaloids bearing four adjoining chiral centers, involving two all-carbon quaternary chiral centers [85]. On the other hand, in 2011 Gao et al. achieved and reported the isolation of (þ)-kopsihainanine A from the leaves and stems of Kopsia hainanensis, the plant which has been used as Chinese traditional medicine [86]. Kopsihainanine A has an extraordinary strained [6.5.6.6.6]-pentacyclic scaffold. Owing to its chemical structure and biological potency, this naturally occurring compound rapidly received much attention from the synthetic community, thus so far, several pathways for its total synthesis have been accomplished and reported [87]. From a structural point of view, (þ)-limaspermidine and (þ)-kopsihainanine A bear a communal ABCD tetracyclic scaffold with the identical configuration of quaternary carbon center, while the trans-fused C/D ring is found in kopsihainanine A and the cis fused C/D ring is found in limaspermidine. Jia and co-workers in 2015 achieved and reported the proper total synthesis of (þ)-kopsihainanine A (41) via asymmetric reduction of tetracyclic iminium ion intermediates (33), an SCCR, a cyclization reaction mediated by trifluoromethanesulfonic anhydride, as key steps [88]. This strategy began with the SCCR of easily accessible N-Boc indole 2-boronic acid (28) as a partner [89]. The SCCR of 28 with 29 gave 30 in excellent yield. The latter was transformed to single trans-fused C/D ring 34 after several steps. With compound 34 available in hand, it was converted to 40 [87d] after seven steps. The

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SCHEME 9.5 Total synthesis of (þ)-kopsihainanine A (41).

formal total synthesis of (þ)-kopsihainanine A (41) was completed by a onestep oxidation of 40 [87d] (Scheme 9.5). In 2003 Fusetani and co-workers [90] isolated dictyodendrins AeE from rom the Japanese marine sponge Dictyodendrilla verongiformis as telomerase inhibitors. In addition, dictyodendrins F
J were isolated, showing a potent inhibitory against b-site amyloid-cleaving enzyme 1 [91], as well as showing potent inhibition for cancer chemotherapy by telomerase [92]. Structurally, dictyodendrins AeE and dictyodendrins FeJ contain a common structural feature, containing a polysubstituted pyrrolo[2,3-c]carbazole core [93], owing to the interesting chemical structures as well as diverse biological potencies,

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dictyodendrins AeE and dictyodendrins FeJ have received much interest in the synthetic organic chemistry community. Fu¨rstner and co-workers in 2005, next, in 2009 et al. and then in 2010 by Tokuyama [94] achieved and reported the total synthesis of dictyodendrins B, C, and E [95]. In 2013, the total synthesis of dictyodendrins B, C, and E were achieved in 21 linear steps by Jia et al. [96]. The formal total synthesis of dictyodendrins A and F were accomplished and reported by in 2015 by Yamaguchi et al. employing a sequential CeH functionalization approach by means of a Rh(I)-catalyzed CeH arylation at the C3-position, Rh(II)-mediated double CeH insertion at the C2- and C5-positions, and an SCCR at the C4-position, while the total synthesis of dictyodendrins A and F were finalized via formal 6p-electrocyclization to create the pyrrolo[2,3-c]carbazole core of the desired natural products [97]. The total synthesis of dictyodendrin F (54) as the representative member was started from N-alkylpyrrole 42, which was easily provided from reaction of dimethoxytetrahydrofuran and the N-alkyl amine via a Paal
Knorr synthesis [98]. The latter was converted into the corresponding coupling product 43 in gram scale upon C3-selective arylation using 4-iodoanisole in the presence of RhCl(CO){P[OCH(CF3)2]3} followed by hydrolysis and deprotection using Ag2CO3 and DME in m-xylene, under reflux condition. Compound 43 via double CeH insertion approach followed by bromination of the remaining CeH bond of the pyrrole in one-pot manner gave compound 45. Then in a key step the latter was reacted with indole-3-boronic acid pinacol ester 46 via SCCR in the presence of Pd[P(t-Bu)3]2 as catalyst and K3PO4 as base in 1,4-dioxane as solvent to give the required pentasubstituted pyrrole 47 in modest yield. The latter was converted to the pyrrolo[2,3-c]carbazole 48, probably via a common 6p-electrocyclization of dianion intermediate with subsequent methylation of the resulting phenol to afford 49 in excellent yield. Upon elimination of the Boc moiety of 49 with subsequent debenzylation in one-pot manner, compound 50 was obtained. It had been used as an intermediate in a previously synthetic route to dictyodendrin A (51) [94]. Thus, compound 50 can be transformed to the desired natural product 51 via Tokuyama’s strategy over three steps (Scheme 9.6) [94]. On the other hand, treatment of 48, with CF3CO2H initially led to removal of Boc group and then upon treatment of the resultant with PhI(OAc)2 gave 52. The latter was readily converted to dictyodendrin F (54) upon sequential hydrolysis and deprotection. In conclusion, an effective total synthesis of dictyodendrin A through 12 longest linear steps and 15 steps in total involving the synthesis of 44 and 46 as well as the synthesis of dictyodendrin F in a longest linear sequence of 10 steps were successfully accomplished and disclosed (Scheme 9.7) [97]. Amaryllidaceae family, are the plants involving about 1100 species and more than 85 genera, which are distributed far and wide on the hot and humid regions worldwide. Many of Amaryllidaceae plants have been cultivated and utilized for the pharmaceutical purpose. For example, lycorine [99], a well-

334 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 9.6 Formal synthesis of dictyodendrin A (51).

recognized amaryllidaceae alkaloid, which was found in Lycoris’ bulb and different Amaryllidaceae species, enjoys multi-medicinal purposes. Structurally, Amaryllidaceae alkaloids are a nitrogen polycyclic compounds, frequently show expressively pharmacological deeds involving antiviral, antifungal antitumor, and antimalarial properties [100e104]. The total synthesis of alkaloids, crinasiadine (60) [105], trisphaeridine (64) [106], bicolorine (65) [107], N-galanthindole (76), lycosinine A (79), and lycosinine B (80) were accomplished by Jen-Chieh Hsieh and co-workers and disclosed, in 2016 [108]. Their strategy involved [109] copper catalysis and Pd-catalyzed SCCR as the vital steps. This strategy commenced from the synthesis of substrate 59 in accordance with a procedure, previously achieved and reported [109]. Accordingly, upon cyanation of the market purchasable or easily accessible aldehyde 55, followed by borylation of the resulting bromide 56 using diboron boronic ester was obtained 57. In a key step, the latter was reacted with 1-bromo-2-iodobenzene via SCCR to give compound 59 in good

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SCHEME 9.7 Synthesis of dictyodendrin F (54).

yield. Next, the latter was converted to the required crinasiadine (60) via already reported copper-mediated coupling reaction in satisfactory yield (36% overall yield, over four steps) [109a]. Notably, crinasiadine (60) was used for the semisynthesis of the other four desired alkaloids. Upon treatment of crinasiadine (60) with Tf2O in pyridine, compound 61 was obtained rapidly and in satisfactory yield. The latter was hydrogenated in the presence of Pd to give trisphaeridine (62) in high yield (25% overall yield over six steps). Methylation of trisphaeridine (62) accompanied with exchange of the counteranion afforded bicolorine (63) (here, chloride as the counteranion) in good yield (21% overall yield, over eight steps). Furthermore, methylation of intermediate crinasiadine (60) using MeI as methylating agent, CS2CO3 as base in THF gave the target alkaloid N-methylcrinasiadine (64) [110]. Upon reduction of 64 using LiAlH4 the desired alkaloid 5,6-dihydrobicolorine (65) [107] was provided in satisfactory yield (Scheme 9.8). Moreover, the bicolorine was also obtained by a brief synthetic pathway from the market purchasable 6-bromo-1,3-benzodioxole-5-carboxaldehyde (55) with shorter steps and higher overall yield [111]. This protocol began from borylation of compound 55 followed by the reaction of the resultant 67 with 1-bromo-2-iodobenzene under SCCR conditions (PdCl2(PPh3)/ K3PO4.nH2O in toluene at 100  C) to afford compound 68. The latter then underwent copper-assisted annulation to give bicolorine with bromide as the counteranion (69) in 58% overall yield over three steps, starting from commercially available 55 (Scheme 9.9). In fact, this approach is the shortest way reported so far to synthesize bicolorine and its analogs [108].

SCHEME 9.8 Total synthesis of amaryllidaceae alkaloids.

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SCHEME 9.9 Total synthesis of bicolorine with bromide as the counteranion (69).

SCHEME 9.10 Total synthesis of 5,6-dihydrobicolorine (65).

Furthermore, compound 67 was employed and converted to 5,6dihydrobicolorine (65) via a pathway involving a sequential cascade reaction with SCCR/reduction (64% overall yield over three steps) (Scheme 9.10) [108]. The SCCR was employed for the production of galanthindole-type [112] alkaloids by changing the structures of coupling partners. For synthesis of the other three members of Amaryllidaceae alkaloids, galanthindole (76), lycosinine B (79), and lycosinine A (80) [113], having similar structures. Initially, 2-bromonitrobenzene was reacted with vinyl magnesium bromide in dry THF at
45  C in one step in one-pot fashion via Bartoli reaction [114]. The latter then, upon methylation or reductive methylation, was converted to the corresponding bromide substrates 73 and 74, respectively [114]. Then, bromide 73 was reacted with the already prepared compound 67 via an SCCR in the presence of PdCl2 with additional bidentate ligand dppf in CH3CN at 100  C with a further reduction to give the desired alkaloid, galanthindole (76) (Scheme 9.11) [108]. Moreover, two other Amaryllidaceae alkaloids, lycosinines B (79) and A (80), each with a structure similar to that of galanthindole, were also prepared by similar reaction conditions by increasing the reaction temperature and modifying the bidentate ligand. Compound 78, a coupling partner for lycosinine B, was prepared through a Miyaura coupling reaction. Bis(pinacolato) diboron 66 was reacted with 2-bromo-4,5-dimethoxybenzaldehyde 77 in the presence of PdCl2(dppf) and KOAc as a base in dry 1,4-dioxane under N2 at 80  C

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SCHEME 9.11 Total synthesis of galanthindole (76).

SCHEME 9.12 Synthesis of lycosinines B (79) and A (80).

to afford the target alkaloid, lycosinine B (79), in satisfactory yield. Upon the reduction of the carbonyl group of the latter using LiAlH4, the desired alcohol lycosinine A (80) as the desired alkaloid was obtained in excellent yield (Scheme 9.12) [108]. The structural segment of phenanthridinone is prevalent in naturally occurring compounds and complex molecules with remarkable biological activities [115]. Phenanthridinones showed significant bioactivities such as antitumor, antiviral, and cytotoxicity [116]. Owing to these biological potencies and interesting structural features, the development of an operative and

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efficient method for the synthesis of phenanthridinones is in much demand and has thus attracted enormous attention from synthetic organic chemists [117]. In 2013, Tanimori and co-workers accomplished and reported the Pd-assisted synthesis of phenanthridinones starting from 2-aminophenylboronic acid and 2-halobenzoic acid esters via one-pot cascade CeC and CeN bond formations [118]. Armed with this experience, the same research group in 2016 reported the total synthesis of the natural product phenanthridinones and related alkaloids crinasiadine (83), dihydrobicolorine (91), trisphaeridine (88), and bicolorine (89) based on Pd-mediated cascade CeC and CeN bond formation and SCCR [119]. Accordingly, reaction of ester 82 [120] with 2aminophenylboronic acid 81 in the presence of Pd(OAc)2, SPhos, and K3PO4 in dioxin/water at 100  C under SCCR afforded [118] an Amaryllidaceae alkaloid, crinasiadine (83), in high yield. The latter was alkylated under standard alkylation reactions using various alkyl halides to give Nalkylcrinasiadines 84e87 and 90 [121] in modest yields. Compound 90, upon hydride reduction using LiAlH4, afforded the desired natural product, 5,6dihydrophenanthridine alkaloid, 5,6-dihydrobicolorine (91). On the other hand, reaction of easily accessible aldehyde 55 with boronic acid 81 under the SCCR conditions (in the presence of Pd(OAc)2, SPhos, and K3PO4 in dioxin/ water at 100  C) gave the desired natural product 88, so-called trisphaeridine. Notably, the latter exhibited topoisomerase I inhibition potency [122]. Noticeably, the alkaloid trisphaeridine (88) was easily converted to another desired natural product, bicolorine (89), upon treatment with excess methyl iodide (Scheme 9.13) [119].

SCHEME 9.13 Short-step synthesis of phenanthridinones and related alkaloids.

340 Applications of Name Reactions in Total Synthesis of Alkaloids

The isocarbostyril alkaloids, as a significant class of naturally occurring compounds showing striking biological potencies, are placed among the Amaryllidaceae family of plants. Among them, specially lycoricidine, narciclasine, 7-deoxypancratistatin, and pancratistatin are well-recognized anticancer agents [123], showing submicromolar inhibition toward multiple cancer cell lines [124]. From a structural point of view, these alkaloids contain a polyfunctionalized aminocyclitol core with four adjoining stereogenic centers in the case of lycoricidine (105) and narciclasine (108) and six in the case of 7-deoxypancratistatin and pancratistatin. Due to their low natural abundance and interesting biological activities, these metabolites have received much attention from synthetic organic chemists, leading to several synthetic investigations resulting in the publication of many papers on their total synthesis to date [125e127]. However, only a few general synthetic strategies have been developed for dearomatization processes [128] that can provide the highly functionalized cyclohexenyl or cyclohexyl moieties present in these natural products; these are limited to only the microbial arene oxidation employed effectively by the Hudlickly [126g,127c] and Banwell research groups [126n,127f]. Sarlah and co-workers accomplished and reported in 2017 the total synthesis of ()-lycoricidine (105) and ()-narciclasine (108) in 7 and 10 steps, respectively. This strategy involved an arenophile-catalyzed dearomatization and dihydroxylation of bromobenzene followed by transpositive SCCR and cycloreversion to furnish a vital biaryl dihydrodiol intermediate that was then transformed into lycoricidine via site-selective syn-1,4-hydroxyamination and deprotection and the late-stage amide-directed CeH hydroxylation of a lycoricidine intermediate. The total synthesis of ()-narciclasine (108) started with arenophile-mediated dihydroxylation of bromobenzene. Thus, visiblelight irradiation of bromobenzene (95) and arenophile MTAD (97) followed by oxidation of the resultant by osmium tetroxide (OsO4) and NMO followed by addition of boronic acid 96 gave bicycle 98 in good yield. With intermediate 98 available in hand, it was subjected to transpositive SCCR in the presence of Pd(dppf)Cl2 as an already secured optimal catalyst along with Et3N as a base in THF to afford the coupled product 99 in moderate yield. In this way, the benzodioxole ring generally assembled to the carbon scaffold of the alkaloids with similar structures to provide the key intermediate. The latter was transformed in three steps to lactam 103 as sole diastereo-constitutional isomer. Upon deprotection of 103 using tetra-n-butylammonium fluoride (TBAF) (103 to 104) followed by one-pot sequential oxidative cleavage and acetonide/deprotection, the desired natural product lycoricidine (105) was obtained in respectable overall yield over seven steps (Scheme 9.14) [129]. On the other hand, upon silylation of alcohol 103 and hydroxylation of 106 under Uchiyama’s conditions with in situ acetylation, the intermediate 107 was obtained. In this transformation, protection of the hydroxyl moiety after hydroxylation was ascertained to be vital for the subsequent oxidative

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SCHEME 9.14 Total synthesis of ()-lycoricidine (105) and ()-narciclasine (108).

342 Applications of Name Reactions in Total Synthesis of Alkaloids

deprotection of the tertiary amide. Then, inclusive deprotection of 107 using (1) TBAF, (2) (bis(trifluoroacetoxy)iodo)benzene, (3) trifluoroacetic acid (TFA), and (4) K2CO3) furnished the desired alkaloid ()-narciclasine (108) in satisfactory overall yield over 10 steps (Scheme 9.14) [129]. Benzylisoquinoline alkaloids signify a huge group of plant secondary metabolites that involves more than 2500 already recognized and wellcharacterized structures. In addition to simple benzylisoquinolines, more complex tetracyclic ring systems such as aporphines and morphinane-type alkaloids are categorized in this class. Biosynthetically, they result from 1-benzyltetrahydroisoquinoline (S)-norcoclaurine. An exceptional subclass of the aporphinoid alkaloids are the oxoisoaporphines (7H-dibenzo[de,h]quinolin-7-ones), e.g., menisporphine (116), which at first glance gives the impression of not being derived from 1-benzyltetrahydroisoquinoline intermediates, albeit a hypothesis by Kunitomo postulates biosynthesis from a benzylisoquinoline precursor consisting of a rearrangement [130]. Menisporphine (116) was initially isolated from Menispermum dauricum DC by Kunitomo and a co-worker in 1982 [130] and exhibited an antiangiogenic property. In addition to menisporphine (116), the related oxoisoaporphine alkaloid dauriporphine (117) was also isolated from Menispermum dauricum DC and a few other plants [131e133]. Very strong cytotoxicity was found for 6-O-demethylmenisporphine (113), with an IC50 value of 0.06 mM, and for dauriporphinoline (114) at 0.23 mm [134].The total syntheses of menisporphine (116) [132] and dauriporphine (117) have been achieved by Kunitomo and co-workers and reported in 1985 [135]. In this strategy, 1-(2-bromoaryl) isoquinolines were constructed via a Bischlere Napieralski reaction with subsequent tiresome replacement of the bromine by cyanide followed by transformation to a carboxylate and FriedeleCraftsetype cyclization in the presence of polyphosphoric acid. In 2017, Bracher and coworkers accomplished and reported a facile synthesis of oxoisoaporphine alkaloids via direct ring metalation of alkoxy-substituted isoquinolines at C-1 followed by treatment with iodine and consequent SCCR of the resulted 1iodoisoquinolines to methyl 2-(isoquinolin-1-yl)benzoates and intramolecular acylation of the respective carboxylic acids upon treatment with Eaton’s reagent [136]. For the introduction of ring D of the oxoisoaporphine alkaloids, (4-methoxy-2-(methoxycarbonyl)phenyl)boronic acid pinacol ester (110) [137] was reacted with the iodinated isoquinolines 108aec in the presence of Pd(PPh3)4 via SCCR to provide 1-arylisoquinolines 111aec in satisfactory isolated yields. The esters 111aec are actually valuable intermediates for further transformations to the desired target, oxoisoaporphines. Compound 111a, upon hydrolysis with concentrated hydrochloric acid, then gave carboxylic acid 112a, which was conveniently subjected to cyclization to 6-O-demethylmenisporphine (113) using Eaton’s reagent. Demethylation of the methoxy group at C-6 of methyl ester 111b using the same protocol once again, under hydrolysis of the 6-methoxy group, gave dauriporphinoline (114).

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SCHEME 9.15 Total synthesis of 6-O-demethylmenisporphine (113), dauriporphinoline (114), bianfugecine (115), menisporphine (116), and dauriporphine (117).

Syntheses of the desired alkaloids menisporphine (116) and dauriporphine (117) were achieved by O-methylation of the alkaloids 6-O-demethylmenisporphine (113) and dauriporphinoline (114), respectively, in accordance with Kunitomo’s observations [132,135] (Scheme 9.15). Daphniphyllum alkaloids are the biologically potent components of the genus Daphniphyllum, which has been employed in Chinese traditional medicine for a long time in the treatment of tonsillitis, fever, and bone fracture [138,139]. More than 320 alkaloid yuzurines have been isolated and their structures characterized to date. Yuzurine (132) was initially isolated in 1974 by Yamamura and co-workers from the bark and leaves of Daphniphyllum macropodum and Dacrydium gracile [140]. It consisted of a unique piperidine spiro tetrahydropyran (ring A spiro ring E) moiety as a scaffold. Owing to its unprecedented chemical structure and interesting biological activities, much effort has been paid to its total synthesis by the organic synthetic community.

344 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 9.16 Synthesis of the AE bicyclic system 131 of Daphniphyllum alkaloid yuzurine (132).

Yang and co-workers attempted the synthesis of the AE bicyclic system of Daphniphyllum alkaloid yuzurine (132) and reported their results in 2017. The synthetic sequence features a Dieckmann condensation to construct ring A, SCCR, reduction of the a, b-unsaturated double bond, and propargylation of a-position of the lactone to generate relative chiral centers C-3, C-4, and C-5 and an acid-catalyzed cyclization for the installation of ring E [141]. This pathway was started by the synthesis of g-butyrolactone 123. As illustrated in Scheme 9.16, the latter was provided from the reaction of market purchasable or easily accessible 4-(bromomethyl)furan-2(5H)-one (120) and sarcosine methyl ester hydrochloride [142] through N-allylation reaction with subsequent hydrogenation of ester 122 in the presence of Pd(OH)4. Having 123 provided, it was converted to compound 125 in two steps involving Dieckmann condensation. Consequently having 125 in hand, it was reacted with 4-methoxyphenyl boronic acid via SCCR to afford the key intermediate 126 in high yield, which upon hydrogenation of its double piperidine analog 127, was provided in satisfactory yield. The latter was transformed into dihydroxyl compound 130 in several steps involving different functional group transformations. Then, the latter, upon treatment with HCl/dioxane in THF at 0  C,

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was converted to the desired and vital intermediate 131 containing D and E rings. The latter is an important intermediate for the synthesis of yuzurine (132). As a result, this group reported a brief strategy for the synthesis of the AE bicyclic system of the Daphniphyllum alkaloid containing the D and E rings of yuzurine [141]. The quinolones, as naturally occurring alkaloids, are significant bioactive frameworks found in several natural products. They show a wide and versatile tangle of biological activities. Quinolones are categorized into two classes. One is 2(1H)-quinolone, and the other is 4(1H)-quinolone, which can be provided from 2-hydroxy and 4-hydroxy quinolones, respectively [143]. George Lesher and co-workers initially isolated a compound, namely nalidixic acid, as a slight impurity during the synthesis of the known antimalarial agent chloroquine. Nalidixic acid has a quite fascinating biological activity and has been employed for the treatment of urinary tract infections in humans from the last decade, proving the significance of the presence of quinolones in natural products [144]. Consequently, quinolone scaffolds have been found in many naturally occurring compounds [145] exhibiting antimicrobial, antimalarial, antiviral, antiurinary, antiinflammatory, and antibacterial activities [146]. Owing to their intriguing biological potencies quinolone scaffolds have received much attention from the organic synthetic community and stirred interest from synthetic organic chemists as well as biochemists and pharmacists. Moreover, penicinoline alkaloids have shown antimalarial activity. Malaria is one of the life-threatening complications that chiefly distresses developing and underdeveloped countries. Surprisingly, in 2015, approximately 214 million new cases of malaria were observed and reported, and 438,000 people were killed by this disease globally [147]. In 2006, Lin and co-workers isolated marinamide alkaloid (143) but suggested the improper structure of pyrrolylquinolinone [148]. Next, in 2010, Lin and co-workers isolated the marinamide alkaloid (143) from mangrove endophytic fungus [149]. Following that, Ko¨nig and co-workers in 2011 reorganized the structure of the marinamide alkaloid (143) by X-ray crystallographic data analysis of methyl marinamide (142) [150]. In 2012, Li et al. isolated penicinoline E (137) along with known compounds marinamide (143) and methyl marinamide (142) from marine-derived fungus and elucidated their structures [151]. Nagarajan and co-workers in 2017 accomplished and reported the total synthesis of unusual pyrrole alkaloids penicinoline E, marinamide, and methyl marinamide. This total synthesis involved the SCCR followed by dearomatization as the vital steps. Accordingly, the total synthesis of penicinoline E (137) was started from the SCCR of Boc-protected 2-pyrrole boronic acid 134 with 133 in the presence of 2.0 mol % of Pd(PPh3)4 as a catalyst and Na2CO3 as a base in a DME/H2O mixture at 70  C to afford compound 135. The latter was subjected to consecutive debenzylation reaction in the presence of the catalytic amount of 10 mol% Pd/C at ambient temperature under an H2

346 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 9.17 Synthesis of penicinoline E (137).

atmosphere to furnish the enol compound 136, which was sluggishly transformed to penicinoline E (137) in virtually quantitative yield. Noticeably, the overall yield of penicinoline E (137) was calculated to be 97% over two steps, which sparked interest from medicinal chemists and pharmacists (Scheme 9.17) [152]. With this well-recognized synthetic pathway to penicinoline E (137), the syntheses of marinamide (143) and methyl marinamide (142) were examined [153]. In this route, the SCCR of compound 134 with compound 140 in the presence of Pd(PPh3)4 and Na2CO3 at 70  C resulted in the formation of product 141 in virtually quantitative yield. The latter was subjected to further dearomatization that resulted in the formation of the desired natural product, methyl marinamide (142), in satisfactory yield (72%). This natural product 142, upon base hydrolysis using aq. KOH at 50  C, led to the formation of another desired natural product, marinamide (143), in good yield. Pleasantly, the two desired natural products, methyl marinamide (142) and marinamide (143), were obtained starting from the appropriate 2-chloroquinoline derivative 140 in satisfactory overall yields through two and three steps, respectively (Scheme 9.18) [152]. In addition, by introducing the methoxy group at the 4-position of the quinoline core, the desired alkaloid penicinoline E (137) was prepared in two steps with 77% overall yield (Scheme 9.19) [152]. Fusetani et al. in 2003 for the first time isolated dictyodendrins AeE, a family of marine indole alkaloids isolated from the Japanese marine sponge Dictyodendrilla verongiformis [90]. These marine indole alkaloids were found to inhibit the activity of telomerase and therefore can potentially be anticancer agents. On the other hand, dictyodendrins FeJ were initially isolated by Capon et al. in 2012 from the southern Australian marine sponge Ianthella sp. They were found to show inhibitory activity toward b-site amyloid cleaving enzyme 1 and thus are recognized as active agents for the treatment of Alzheimer disease [91]. From a structural point of view, dictyodendrins contain a highly substituted pyrrolo[2,3-c]carbazole core and thus have attracted much attention from the

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SCHEME 9.18 Synthesis of methyl marinamide (142) and marinamide (143).

SCHEME 9.19 Synthesis of penicinoline E (137) using compound 144.

synthetic organic chemistry community. Fgrstner and co-workers in 2005 achieved and published the first total synthesis of dictyodendrins B, C, E, and F via an elegantly planned strategy consisting of the stepwise construction of the ring systems present in these compounds [95]. Later, the Ishibashi [154], Tokuyama [94], Jia [96], Gaunt [155], Yamaguchi/Itami/Davies [97], and Ready [156] research groups accomplished and reported the total synthesis of these fascinating alkaloids. A common feature of these protocols was the introduction of appropriate substituents prior to construction of the pyrrolo [2,3-c]carbazole core. In 2017, Ohno et al. achieved and reported the formal total synthesis of dictyodendrins B, C, E, and F consisting of the direct construction of the pyrrolo[2,3-c]carbazole core via the Au-catalyzed cyclization of a conjugated diyne, SCCR, and Ullman coupling reaction as key steps [157]. This strategy started from 1-fluoro-2-nitrobenzene (146), which was converted to the protected 2-amino-3-iodophenol 147 in four steps involving tert-butoxylation, reduction, and N-protection. The latter was converted to compound 156 after several steps involving common functional group transformations and protectionedeprotection processes. Next, compound 156 was subjected to sequential C1-bromination/N-alkylation in a one-pot fashion followed by an SCCR in the presence of [Pd(tBu3P)2] as a Pd species and K3PO4 to give the required 1,3-disubstituted product 159 [97]. For the introduction of a methoxy group at the less reactive C5 position, compound 159 was subjected to a sequential dibrominationedebromination process, NBS, to

348 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 9.20 Total synthesis of dictyodendrins C (163) and F (164).

obtain dibrominated product 160 in good yield. Upon treatment of the latter with NaBH4 in the presence of a catalytic quantity of Pd(OAc)2, the required intermediate, monobromide (161), was obtained [158]. Ultimately, the latter underwent Ullmann coupling reaction in the presence of CuI to give the known precursor 162 [94], which was fruitfully converted into the desired alkaloid, dictyodendrin C via a sequential three-step process following the procedure previously developed by Tokuyama et al. [94]. The total synthesis of dictyodendrin F (164) was accomplished by deprotection of 162 (Scheme 9.20). The total synthesis of dictyodendrin E (171) was completed by introduction of a C2 acyl group as a vital step [157]. To that purpose, the already prepared compound 159 was subjected to a regioselective monobromination using NBS to provide compound 165. The latter was then submitted to bromineelithium exchange with subsequent addition to p-anisaldehyde to obtain the respective C2-substituted product 166 in satisfactory yield [95]. The latter was then subjected to selective monobromination of the C5 position,

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SCHEME 9.20 cont’d

which proceeded smoothly and led to the formation of 167 in good yield. Upon oxidation of the latter following the LeyeGriffith protocol using TPAP and NMO [159], followed by the introduction of a methoxy group at the C5 position under Ullmann coupling reaction conditions, the suitable precursor 169 was obtained. Finally, the latter was transformed into the desired alkaloid, dictyodendrin E, by deprotection and construction of the sulfate moiety [94]. The total synthesis of dictyodendrin B (170) was also completed by selective removal of the tert-butyl group from compound 169 using BCl3 at
78  C, formation of a sulfate, and deprotection using BCl3 at 0  C to room temperature and Zn dust following the procedure developed and reported by Tokuyama et al. [94] (Scheme 9.21). In 1964, Hauth and co-workers isolated the alkaloid macronine from the plant Crinum macrantherum Engl. (Amaryllidaceae). Shortly thereafter, it was fully characterized by Wildman et al. [160,161]. The same research group noticed that macronine was actually the first example of a lactonic Amaryllidaceae alkaloid containing the tazettine ring system. Shortly thereafter, the same authors disclosed that a strained lactam merged within the haemanthidine alkaloid scaffold underwent rearrangement to afford N-demethylmacronine in buffer solution at pH 6.80 [160]. In 1999, Hesse et al.

350 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 9.21 Total synthesis of dictyodendrins B (170) and E (171).

isolated 3-O-demethylmacronine (186) from a Galanthus species of Turkish origin. Its structure was elucidated chiefly by NMR spectral data [162]. No biological screening of compound 186 has yet been claimed. Tsuda and co-workers in 1976 accomplished and reported [163] a concise total synthesis of ()-macronine consisting of a rearrangement reaction of the type developed by Wildman in 1964 [161]. Banwell et al. in 2017 accomplished a brief (10-step) total synthesis of racemic modification of ()-3-Odemethylmacronine [-(186)] and also described the synthesis of its C6a-epimer via an analogous but more efficient rearrangement. This total synthesis comprises an SCCR, an intramolecular Alder-ene (IMAE) reaction, and a lactam-to-lactone rearrangement of tetracycle 182 [164]. The total synthesis of ()-3-O-demethylmacronine [-(186)] commenced with the SCCR of boronate ester 172 [165] with cycloalkenyl bromide 173 [166] to give the arylated cyclohexene 174, which then easily propargylated at nitrogen employing 1-bromo-2-butyne mediated by sodium NaH to afford derivative

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SCHEME 9.22 Total synthesis of ()-3-O-demethylmacronine [()-186].

175 in high yield. Compound 175 was transformed to the corresponding ketone 178 after several steps. The latter, in turn after several steps, was transformed to the chromatographically separable lactone and lactam, respectively. After several steps, compounds 181 and 182 were provided. Upon treatment of silyl ether 181 with HF.pyridine in THF at room temperature afforded the anticipated allylic alcohol 183 in virtually quantitative yield. Upon treatment of the latter with MeI and KH in THF, the desired amine 184 as the C6a-epimer of ()-3-O-demethylmacronine was provided in virtually quantitative yield as depicted Scheme 9.22. Then, the already prepared haemanthidine-based hydroxylactam 182 was converted into the lactone 185 in the presence of p-toluenesulfonic acid as catalyst. Finally, lactone 185, upon

352 Applications of Name Reactions in Total Synthesis of Alkaloids

reductive N-methylation by employing, sodium cyanoborohydride and HCOH in AcOH at room temperatures afforded the desired natural product ()-3-Odemethylmacronine [()-186] in high yield. Fascinatingly, attempts to influence the O-methylation of compound ()-186 under a range of conditions ((1) MeI, NaH, THF; (2) MeI, NaH, DMF; (3) MeI, Ag2O, THF; and (4) (MeO)2SO2, K2CO3) were unsuccessful at generating ()-macronine, probably because of the close spatial arrangement of the OH and NH2 groups within compound ()-186 [164]. Guaipyridine sesquiterpene alkaloids are a family of naturally occurring compounds partaking of an exceptional structure containing a fused pyridine ring and seven-membered carbocycle [167]. For instance, patchoulipyridine and epiguaipyridine were initially isolated by Bu¨chi and co-workers in 1966 from the essential oil of Pogostemon patchouli Pellet [168]. From 2008 to 2012, a series of guaipyridine sesquiterpene alkaloids, so-called rupestines AeM (rupestine A; rupestine G) were isolated by Huang and co-workers from Artemisia rupestris L., which has been used as a well-recognized folk Chinese medicinal plant for the treatment of detoxification as well as being employed for its antitumor, antibacterial, and antiviral properties [169e171]. Due to their structural resemblances to cananodine, it has been proposed that rupestines may also show gifted cytotoxic potency. Biological screening of these alkaloids is rendered inadequate because of their rare obtainability from natural sources. Their limited availability and exceptional structural features solidify them as well-intentioned targets among synthetic organic chemists for their total synthesis. The total syntheses of rupestine G and its epimers were accomplished and reported in 2018 by Huang and co-workers using SCCR as a key step to construct a terminal diene moiety [172]. The diene was further transformed into the desired guaipyridine structure by a ring closure metathesis reaction. Overall, rupestine G and its three epimers were provided as a mixture in a sequential nine linear steps in 18.9% overall yield. The optically pure rupestine G and its isomers were isolated by chiral preparative HPLC, and their structures were elucidated by 1H, 13C NMR, HRMS spectral analysis, optical rotation value, and experimental and calculated electronic circular dichroism spectroscopy. Consequently, the total synthesis started from the 2-cyanopyridine (189) that was conveniently provided by m-CPBA oxidation and modified ReisserteHenze reaction of 5-bromo-2-methylpyridine (187) in accordance with the method developed and presented by Fife and co-workers [173,174]. Upon decarboxylative Blaise reaction of 189 using potassium methyl malonate, the methyl nicotinoylacetate (190) was obtained in high yield [175e178]. The latter was treated with allyl bromide in the presence of sodium ethoxide to afford compound 191 in excellent yield. The latter via SCCR using isopropenylboronic acid pinacol ester afforded compound 192 in excellent yield [179e183]. The latter was transformed to diene 196 after several steps. Upon hydrogenation in the presence of Pd/C in MeOH, the latter was converted to

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SCHEME 9.23 Total synthesis of rupestine G (198) and its epimers.

the desired natural product rupestine G (198) and its epimers as a mixture in 18.9% overall yield. Therefore, the desired target was obtained in an overall 18.9% yield from 5-bromo-2-picoline (187) in nine linear steps. The synthetic pathway for the total synthesis of rupestine G (198) is displayed in Scheme 9.23 [172]. Over the past 4 decades [184e189], a plethora of carbazole alkaloids have frequently been isolated from terrestrial plants. In addition, several carbazole alkaloids have been discovered in various algae and streptomycin species [186]. Hyellazole and 6-chlorohyellazole as carbazole alkaloids were initially isolated in 1979 by Moore and co-workers from the blue-green alga Hyella caespitosa, a marine source [190]. Even though the two aforementioned alkaloids are different in origin, they show structural similarity, with both bearing a methoxy moiety at 3-position, similar to other carbazole alkaloids, as well as a phenyl group at 1-position. Interesting structural features of these

354 Applications of Name Reactions in Total Synthesis of Alkaloids

alkaloids have attracted attention from research groups worldwide to develop different pathways for their total synthesis. After isolation and structural elucidation of the two aforementioned alkaloids, a wave of research interest resulted in the publication of more than 15 papers concerning their total synthesis [191e201]. In 1981, Kano and coworkers accomplished and reported [191] the total syntheses of both hyellazole and 6-chlorohyellazole from the appropriate 2,3-divinylindoles via a thermal electrocyclic ring closure with subsequent dehydrogenation. Eight years later in 1989, Kawasaki and co-workers [193] obtained carbazole moiety via electrocyclic ring closure on properly substituted 3-butadienylindoles, which upon desilylation provided hyellazole (215). Later, Moddy and coworkers [194] reported a convergent strategy to highly substituted carbazoles that relied on the DielseAlder cycloaddition reaction of pyrano[3,4-b]indol-3ones with alkynes leading to the concise synthesis of hyellazole. In 1995, Knoelkar and co-workers developed a versatile synthesis of 3-oxygenated carbazole alkaloids via consecutive Fe-catalyzed CeC and CeN bond formation, ultimately resulting in the total syntheses of hyellazole [197] and 6-chlorohyellazole [201]. Hibino and co-workers in 1996 achieved the total synthesis [198] of hyellazole via a novel type of allene-mediated electrocyclic ring closure with the partaking of the indole 2,3-double bond. In 2018, Chakraborty et al. accomplished and reported the total synthesis of hyellazole as well as the synthesis of 4-deoxycarbazomycin B [202] via JappeKlingemann reaction [203], Fischer indole synthesis [204], Grignard reaction, and SCCR as key steps. The total synthesis started with commercially available or readily accessible 2-methyl-3-nitroaniline (199), which upon Sandmeyer reaction [205] converted into 2-methyl-3-nitrobromobenzene (200). The latter in turn was transformed into 1-bromo-3-methoxy-2-methyl-9Hcarbazole (214) after several steps including Claisen condensation [206], JappeKlingemann coupling reaction [203], Fischer indole synthesis [204], and WolffeKishner reduction [207]. In a key and final step, bromo-3-methoxy-2methyl-9H-carbazole (214) was reacted with phenylboronic acid and methylboronic acid, respectively, in the presence of Pd as catalyst under SCCR to furnish the desired natural products, hyellazole (215) and 4deoxycarbazomycin B (216). Alternatively, hyellazole (215) and 4-deoxycarbazomycin B (215) were synthesized starting from readily accessible 208, which initially converted into 2-formylcyclohexanone (210). In a final and vital step, the latter was reacted with phenylboronic acid and methylboronic acid, respectively, in the presence of a Pd species as catalyst under SCCR (in the presence of Pd(PPh3)4, K2CO3 in DMF at 90  C) (Scheme 9.24). Carbazole was initially isolated from coal tar in 1872 by Graebe and Glazer [208]. Carbazole and its derivatives are well-recognized alkaloids for their versatile biological and pharmacological properties. Carbazole alkaloids and their derivatives are also important in the field of medicinal chemistry because

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SCHEME 9.24 Synthesis of hyellazole (215) and 4-deoxycarbazomycin B (216).

they have exhibited antitumor [209,210], antiplatelet aggregative [211], antiplasmodial [212], anticonvulsant [213], antibiotic [209,214,215], and antiviral [216e218] activities. Owing to these significant and versatile properties, they have received much attention from the organic synthetic community. Thus, several methods have been developed to construct the framework of carbazole derivatives. They are FischereBorsche synthesis [204,219], GraebeeUllmann synthesis [220], and conversion of indole derivatives to carbazoles [221]. In addition, several bioactive carbazole alkaloids have been isolated from natural sources [222e226]. Mukoeic acid (226) was isolated in 1969 by Chakraborty and co-worker from the bark of the Murraya koenigii [227]. Notably, its methyl ester (221)

356 Applications of Name Reactions in Total Synthesis of Alkaloids

was isolated in 1978 by Chakraborty and co-workers from M. koenigii [228] and later also by Wu et al. from Clausena excavata [211,229]. Compound 221 is an alkaloid isolated from the Indian curry-leaf tree M. koenigii that has been used as folk Chinese medication for the treatment of snakebites [224]. In 1985, Fiebig et al. isolated koenoline (224) from the root bark of M. koenigii [230]. The structure of (224) was determined as 1-methoxy-3-hydroxymethyl carbazole by its spectral data analysis. Murrayafoline A (223), which initially showed strong fungicidal potency toward Cladosporium cucumerinum, was isolated from the root of several species of the Murraya [231,232]. The first known 5-oxygenated tricyclic natural carbazole was glycoborine (232) isolated and fully characterized by Chakravarty et al. in 2001 [233]. Clauszoline K (235) was originally isolated [234] from the stem bark of the Chinese medicinal plant C. excavata in 1997 by Ito and co-workers. Glycozolicine (240) was isolated from the roots of Glycosmis pentaphylla by Bhattacharyya et al. in 1992 [235]. Initially, the structure of 240 was determined as the isomeric 5-methoxy-3-methyl-9H-carbazole, but Chakravarty et al. in 2001 reassigned its structure as 8-methoxy-3-methylcarbazole (240) based on total syntheses of both isomeric compounds and comparisons of their spectral data with those of the authentic compounds isolated from natural sources [233]. In 1982, Chakraborty and co-workers isolated mukolidine (242) and mukoline (243) from the root, leaves and fruit of M. koenigii Spreng [236], whose extracts exhibit antibacterial activity [237]. In 1982, Chakraborty and co-workers confirmed the structures for 242 and 243 by comparing their physical and spectral data with those of authentic compounds obtained through their formal total synthesis [236]. Tamariz and co-workers also accomplished the total synthesis of 242 and 243 and disclosed their results in 2011 [238]. Glycozoline (241) was the first member of this class of alkaloids, isolated from the roots of Gmelina arborea by Chakravarty and co-workers in 1999 [239]. Its careful structural inspection and elucidation proved that glycozoline (241) is in fact 6-methoxy-3-methylcarbazole [239,240]. Chemical support for this structural assignment was provided through its transformation into known carbazole derivatives [240] as well as its unambiguous total synthesis [241]. In 2019, Bhatthula and co-workers accomplished and reported a facile protocol for the total synthesis of 11 natural carbazole alkaloids, namely mukonine (221), koenoline (224), murrayafoline A (223), murrayanine (225), mukoeic acid (226), glycoborine (232), clauszoline K (235), glycozolicine (240), glycozoline (241), mukolidine (242), mukoline (243), and antiinflammatory drug carprofen (260a) and its analogues [242], through SCCR and Cadogan reaction [243] as key steps. The total synthesis of mukonine (221) commenced from 3-bromo-5-hydroxybenzoic acid (217) that was initially transformed into 3-bromo-5-methoxybenzoic acid methyl ester (218) in virtually quantitative yield. Upon treatment of ester 218 with bis(pinacolato) diboron 66 in 1,4-dioxane under a nitrogen atmosphere, 3-methoxy-5-(4,4,5,5-

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tetramethyl-[1,3,2]dioxaborolane-2-yl)-benzoic acid methyl ester (219) was obtained in good yield. In a key step, the latter was reacted with marketpurchasable o-bromonitrobenzene (71) in the presence of PdCl2(PPh3)2 under SCCR to give intermediate 220, which was subsequently subjected to reductive annulation to give a mixture of 3-methoxy-9H-carbazole-1-carboxylic acid methyl ester (221) (the final target) and its regioisomer 221a (221/221a, 2.5:1) in satisfactory yield. Indeed, mukonine (221), the desired natural product, was isolated and purified as a white, crystalline solid. The spectral data of synthetic 221 were obtained and compared with those of the authentic sample isolated from the natural source and found to be identical [244]. The synthetic, mukonine (221) was employed as starting material for the synthesis of alkaloids 223e226. Reduction of 221 using diisobutylaluminum hydride (DIBAL-H) in diethylether [245,246] gave another desired alkaloid, koenoline (224), in high yield, whereas its reduction with lithium aluminum hydride (LiAlH4) in Et2O provided murrayafoline A (223) in good yield. Murrayanine (225) [247] was provided in respectable yield by oxidation of koenoline (224) with manganese dioxide. Saponification of mukonine (221) was achieved using potassium hydroxide in water and ethanol, resulting in the obtaining of another desired target, mukoeic acid (226) [227,248] (Scheme 9.25). Worthy of mention is that the structures of alkaloids 223e226 were confirmed by comparison of their physical and spectroscopic data with those obtained for the samples isolated from natural sources and found to be in good agreement [230,245,249,250]. Regioisomer 222 was converted to the alkaloids 224a, 225a, and 226a in a few steps. Upon reduction using a mild reducing agent such as DIBAL-H, regioisomer 222 was transformed to (3-methoxy-9H-carbazol-1-yl)-methanol (224a) in high yield. The latter was oxidized with manganese dioxide (MnO2) and furnished 3-methoxy-9H-carbazole-1-carbaldehyde (225a) in high yield. Saponification of 222 using KOH in water/EtOH afforded the regioisomer 226a. The structures of 224a, 225a, and 226a were elucidated by mass, 1H, and 13C NMR spectral data analysis (Scheme 9.26) [242]. Glycoborine (232) was synthesized by treating of 2-bromoanisole (227) with bis(pinacolato)diboron (66) and bis(triphenylphosphine) PdCl2, KOAc in 1,4-dioxane to give 2-(2-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (229) in high yield. The latter was reacted with 2-chloro-4-methyl-1nitrobenzene (231) under SCCR conditions in the presence of catalytic amounts of tetrakis (triphenylphosphine)palladium, K2CO3, in toluene to give 20 -methoxy-5-methyl-2-nitrobiphenyl (233) in good yield. The latter, upon reductive cyclization, furnished the desired alkaloid glycoborine (232) in excellent yield. The spectral data of 232 were found to be in complete agreement with those obtained for the sample isolated from nature [233,251] as well as synthetic products [235,252]. Clauszoline K (235) was synthesized via a borylation reaction of p-bromoanisole (228) with bis(pinacolato)diboron (66), providing 2-(4-methoxy-

358 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 9.25 Total synthesis of mukonine (221), koenoline (224), murrayafoline A (223), murrayanine (225), and mukoeic acid (226).

SCHEME 9.26 Synthesis of (3-methoxy-9H-carbazol-1-yl)-methanol (224a), 3-methoxy-9Hcarbazole-1-carbaldehyde (225a), and 3-methoxy-9H-carbazole-1-carboxylic acid (226a).

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SCHEME 9.27

359

Synthesis of glycoborine (232) and clauszoline K (235).

phenyl)-4,4,5,5-tetra methyl-[1,3,2]dioxaborolane (230) in high yield. The latter was subsequently reacted with 2-chloro-4-methyl-1-nitrobenzene under SCCR conditions (Pd(Ph3)4 as catalyst, K2CO3 as base, in refluxing toluene), providing 40 -methoxy-5-methyl-2-nitrobiphenyl (232) in good yield. Upon reductive cyclization, the latter was converted to 2-methoxy-6-methyl-9Hcarbazole (234) with its methyl group at C-6 oxidized by treatment with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in a mixture of methanol/ water to furnish the desirable alkaloid, clauszoline K (235), in respectable yield (Scheme 9.27) [242]. The spectral data of synthetic 235 were compared with those of a sample isolated from nature and found to be in full accord [234,252]. The total synthesis of other carbazole alkaloids, namely, glycozolicine (240), glycozoline (241), mukolidine (242), and mukoline (243), commenced with methylation of 3-bromophenol (236) followed by boronic acid pinacol ester synthesis to provide 238 in high yield [242]. In a vital step, the latter was reacted with 2-chloro-4-methyl-1-nitrobenzene in the presence of a catalytic amount of tetrakis (triphenylphosphine)palladium along with K2CO3 in toluene under SCCR to afford 30 -methoxy-5-methyl-2-nitrobiphenyl (239) in acceptable yield. The latter, upon reductive cyclization, produced two desired natural products, glycozolicine (240) and glycozoline (241), in a combined yield of 76%, 9/10, 1:1 ratio. Having glycozolicine (240) available in hand, it was converted to the other desired targets, the alkaloids mukolidine (242) and mukoline (243) [236,238]. Oxidation of the methyl group at C-3 of

360 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 9.28 Total synthesis of glycozolicine (240), glycozoline (241), mukolidine (242), and mukoline (243).

glycozolicine (240) using DDQ gave mukolidine (242) in high yield. The latter was reduced using NaBH4 and provided the desired target, mukoline (243), in high yield (Scheme 9.28). The spectral data of the synthetic carbazoles 240, 241, 242, and 243 were in full agreement with those of authentic samples isolated from the corresponding natural sources [233,236]. Following that, the same research group [242] accomplished and reported the synthesis of alkaloid 2-methyl-9H-carbazole (248) commencing with borylation of 4-bromotoluene (244) using bis(-pinacolato)diboron (66) to obtain 4,4,5,5-tetramethyl-2-p-tolyl- [1e3]dioxa borolane (245) in high yield. The latter was reacted with 1-bromo-2-nitrobenzene (246) in the presence of Pd(PPh3)4, K2CO3 as base in toluene under reflux under SCCR to give 40 methyl-2-nitrobiphenyl (247). Upon reductive cyclization of the latter, the desired alkaloid 2-methyl-9H-carbazole (248) was obtained in excellent yield (Scheme 9.29).

SCHEME 9.29

Synthesis of 2-methyl-9H-carbazole (248).

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Carprofen (260) was also synthesized, beginning with commercially available or easily accessible 4-bromophenyl acetic acid (249) that initially was transformed into its methyl ester 250 upon treatment with methanol and in the presence of a catalytic amount of thionyl chloride. Treatment of the latter with LDA and MeI afforded the corresponding methyl derivative 251 [253]. Methyl derivative 251 was also provided by an alternative pathway starting from market-purchasable 40 -bromoacetophenone (252). Reduction of the acetophenone derivative afforded 1-(4-bromophenyl)ethanol (253) that was transformed into 1-bromo-4-(1-bromoethyl)benzene (254) utilizing PBr3 [254]. The latter was transformed to phenyl dioxaborolane ester 257 after several steps. Next, the latter in a vital step was reacted with an appropriate halonitrobenzene in the presence of PdCl2(PPh3)2 and K2CO3 in toluene via SCCR to afford the respective 2-nitro biphenyls 258 [255]. Reductive cyclization of the respective 2-nitro biphenyls 258 using triphenylphosphine in o-dichlorobenzene afforded the desired alkaloid carbazole esters 259, which were hydrolyzed to carbazole acids 260aed upon treatment in aqueous NaOH in excellent yields and in pure form (Scheme 9.30) [242]. Over the last 2 decades, a small family of biologically active compounds, the so-called 3-methoxy-4-quinolones, has attracted much attention. Noticeably dissimilar to the structurally related rutaceous alkaloids, 3-methoxy-4quinolones show a pendant C-5 (ar)alkyl moiety or a seven-membered ring fused to C-5 and C-6 to construct a cyclohepta[f]quinolinone core decorated with unsaturation or oxygen functionalities. Two members of this family are melochinone [256] and its possible biogenetic precursor melovinone (270). They were initially isolated by Kapadia and co-workers in 1978 from the Colombian shrub Melochia tomentosa L. (Sterculiaceae) [257]. In other work, melovinone, a nonrutaceous 3-methoxy-4-quinolone, was isolated from M. tomentosa L. The first total synthesis of melovinone was achieved and reported by Kaufman and co-workers in 2019 [258]. This strategy involved the SCCR between an orthonitrobenzoic acid acetonyl ester derivative followed by a chemoselective reduction of the nitro group and an MWI-and-AcOH-assisted cyclization along with rearrangement of the resulting acetonyl anthranilate as key steps. Accordingly, the total synthesis of the desired target 270 started from the acetylation of vanillin under orthodox conditions (Ac2O, DMAP) to afford 262 in excellent yield. The latter, after several steps, was transformed to 264, involving Williamson O-methylation and Jones oxidation as key steps. The aromatic substitution pattern of 264 was established by NMR spectroscopy, and the molecular structure was also approved by single-crystal X-ray diffraction. Without additional purification, the acid 264, upon treatment with chloroacetone and K2CO3 as base in DMF, gave the corresponding acetonyl ester 265, thus setting the stage for assemblage of the C-5 side chain. In another study, trifluoroborate salt 272 as the boron component was prepared from b-phenethyl bromide (271) in three steps [259]. The SCCR of

362 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 9.30 (A) Synthesis of methyl 2-(4-bromophenyl) propionate 251, (B) Synthesis of methyl 2-(4-bromo phenyl) propionate 251 by an alternative route, (C) Synthesis of carprofen 260a and its analogues.

bromoarene 265 with 272 in the presence of the hindered phosphine ligand ditert-butyl phosphinoferrocene (dtbpf) gave the coupled product 266 in high yield along with debrominated compound 267 (5%). Construction of the heterocyclic B-ring was then envisioned. Reduction of the nitro group of 266 using freshly prepared nickel boride in MeOH proceeded smoothly, providing the acetonyl anthranilate 268 in a respectable isolated yield [260]. Next, the latter was subjected to an intramolecular Niementowski cyclization/rearrangement sequence [261] of a dilute solution of the ester in glacial AcOH under MWI (150  C, 60 W) to afford the key intermediate 269. The latter was reacted with MeI in the presence of K2CO3 in anhydrous i-PrOH under reflux

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363

SCHEME 9.31 Total synthesis of melovinone (270).

condition to furnish the desired alkaloid melovinone (270) in satisfactory yield. In conclusion, this approach enabled attainment of the objective in 11 steps and with 18% overall yield (Scheme 9.31). The structure of 270 was established by comparing its 1H NMR spectrum with that of a sample isolated from natural source [257]. In 2010, Arnold and co-workers studied the culture extract of Sepedonium ampullosporum. This investigation led to isolation of exceptional ampullosine (287) [262] from S. ampullosporum. In fact, it was found that ampullosine (287) is in charge of the deep yellow color of its culture fluid. A literature survey revealed that this alkaloid is the first and only isoquinoline isolated from the genus Sepedonium. The unique structure of ampullosine (287) was characterized by various spectral data analyses. The total synthesis of ampullosine (287) was accomplished and reported by Larghi and co-workers in 2019 [263]. This strategy involved a Kolbe-type carboxylation and

364 Applications of Name Reactions in Total Synthesis of Alkaloids

assemblage of the three-carbon atom needed for the 3-methylpyridine ring and was performed by triflation of the remaining free phenol and Pd-catalyzed SCCR as key steps. This protocol began with commercially available or easily accessible 3,5dihydroxy-benzoic acid 273 that was first subjected to a KolbeeSchmitt-type carboxylation in the presence of KHCO3 under a CO2 atmosphere at 180  C [264] to provide 274 as a readily recoverable pale yellow solid in satisfactory yield. The latter was transformed to 277 after several steps. Next, the latter was reacted with potassium propenyl trifluoroborate (278) [265] under a modified SCCR pioneered by Molander in the presence of Cs2CO3 as base to provide compound 279. The latter was then converted to 286 in moderate yield. Treatment of 286 with aluminum and iodine (generating, in situ AlI3 as the powerful Lewis acid) [266] resulted in the concurrent elimination of both methyl groups, thus furnishing the desired alkaloid ampullosine (287) in moderate yield (Scheme 9.32).

SCHEME 9.32 Total synthesis of ampullosine (287).

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365

1-Oxoisoquinoline alkaloids are a trivial class of naturally occurring compounds extractable from different plants families such as Papaveraceae, Berberidaceae, and Ranunculaceae. These natural sources contain large and complex molecules such as benzylisoquinolines, bisbenzylisoquinolines, and protoberberines. [267]. The most frequently recognized compounds present in subclasses of this chemotype are 1-oxoisoquinolines 291bef, their naturally occurring 3,4-dihydro analogues (e.g., 292aef), and 1,3,4-trioxoisoquinoline (293) and have been found in Menispermum dauricum [268]. Moreover, two “dimeric” 1-oxoisoquinoline alkaloids, berbidine (298) [269] and berbanine (297) [270], have been isolated from Berberis species. It is worth mentioning that berbidine (298) contains a 1-oxo-3,4-dihydroisoquinoline moiety with a 1,2,3,4-tetrahydroisoquinoline segment, whereas berbanine (297) [270] involves one fully aromatic isoquinoline segment. Recently, Ramona and co-workers achieved a concise pathway to the total synthesis of 1-oxoisoquinoline alkaloids and reported their results in 2020. This brief total synthesis included construction of a C2 building block for assemblage of the C-3, C-4 segment of the isoquinoline scaffold and SCCR as a key step [271]. The same authors also improved the total synthesis of the monomeric oxoisoquinolines [271] as well as achieving the first total synthesis of the dimeric alkaloids berbanine (298) and berbidine (297). Accordingly, the first total syntheses of the “dimeric” 1-oxoisoquinoline alkaloids berbidine (298) and berbanine (297) were achieved in 18% and 16% overall yield, respectively, using another alkaloid thalifoline (292d) as a required framework. Based on o-brominated primary N-methylbenzamid 288, the overall yield along the longest sequences were 18% for berbanine (297) and 16% for berbidine (298), respectively. The total synthesis of berbanine (298) and berbidine (297) started from 288 reacted with 2-ethoxyvinylboronate 289 under Pd-catalyzed SCCR to provide [272] the expected ethoxyvinyl derivatives 290aef, which were not purified. Upon treatment of the crude 290a with excess TFA, intramolecular cyclization took place to provide 1-oxoisoquinoline 291a, which was most likely not a natural product. Compound 291a was hydrogenated in the presence of Pd/H to provide the required diydroxyquinoline 292a. In another case, protected compound 288b was reacted with 289 under SCCR in the presence of Pd(Ph3P)4 followed by treatment with TFA in CH2Cl2 with subsequent pyridinium chlorochromate oxidation to furnish the respective desired natural product, 1,3,4-trioxoisoquinolines 293 (Scheme 9.33B). Then, having the 1oxo-3,4-dihydroisoquinoline alkaloid thalifoline (292d) available in hand, the authors attempted to synthesize the “dimeric” alkaloids berbanine (297) and berbidine (298). Initially, the diaryl ether bridge 295 was constructed in modest yield via an Ullmann-type CeO coupling of 292d with an appropriately substituted benzaldehyde. Then, intermediate 295 was reacted with aminoacetaldehyde dimethyl acetal via a PomeranzeFritsch reaction [273] with subsequent treatment of the resultant with TFA and BF3/AcOH complex as Lewis acid via a procedure reported previously by Patel et al. [274] to

366 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 9.33

Total syntheses of alkaloids berbanine (297) and berbidine (298).

furnish alkaloid berbanine (297) in moderate yield. Finally, transformation of berbanine (297) into its N-methylated form berbidine (298) was accomplished in two steps following the strategy developed and reported by Chan et al. [275]. Accordingly, the aromatic isoquinoline moiety in 297 was fully methylated using methyl iodide to initially afford an isoquinolinium salt, which upon reduction using NaBH4, led to the formation of the desired natural product, alkaloid berbidine (298), in high yield over two steps (Scheme 9.33). Worthy of mention is that berbidine (298) has been previously synthesized by photooxidative degradation of the bisbenzylisoquinoline alkaloids isotetrandrine [276] and phlebicine [277]. In conclusion, in this extensive research, total syntheses of the monomeric oxoisoquinolines and the first total synthesis of the dimeric alkaloids berbanine (297) and berbidine (298) were successfully accomplished [271].

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Alkaloids containing tetrahydroquinoline motifs are widespread in the plant kingdom, and several of them have shown fascinating and diverse biological potencies [277,279]. Some members of the family of Hancock alkaloids, such as (
)-angustureine, (
)-cuspareine, (
)-galipeine, and (
)-galipinine, are good examples. All of the abovementioned alkaloids have been isolated by JacquemondeCollet research group from the bark of Galipea officinalis, found and collected from northern South America [278b]. Due to their biological potency profiles, the extracts of the abovementioned alkaloids have been used as traditional medicine for a long time for the treatment of dysentery and fever [280]. Very recently, in 2020, Breit et al. achieved and reported an approach to the brief total synthesis of the Hancock alkaloids (
)-angustureine (309) and (
)-cuspareine (311) involving Rh-catalyzed hydroamination leading to the asymmetric formation of the chiral secondary amine. Furthermore, the synthesis includes an allene synthesis via boronemagnesium exchange and the construction of the tetrahydroquinoline motif via sequential hydroboration/ SCCR [281]. In accord with the strategy, allenes 301 and 304 can be provided via two brief and effective pathways. The total synthesis of Hancock alkaloids (
)-angustureine (309) and (
)-cuspareine (311) started from n-hexyl allene (301), which can be easily provided via propargylic substitution using propargyl bromide 300 and the Grignard reagent, which in turn can be obtained from n-hexyl bromide (302) in the presence of a Cu species as catalyst [281]. On the other hand, the aryl functionalized allene 304 can be provided via a two-step sequential tandem reaction commencing from 2,3-dimethoxystyrene (302) using Ir-catalyzed linear selective hydroboration/boronemagnesium exchange [282]. The prepared Grignard reagent was then trapped in similar fashion with propargyl bromide (300) under Cu catalysis to afford allene 304 in good yield over two steps. Reaction of 2-iodo aniline (305) and n-hexyl allene (301) in the presence of Rh/Josiphos J003-2 as catalyst and DCE as an additive in EtOH as solvent at 80  C afforded the desired product 306. Reaction of aniline and an appropriate allene 304 in the presence of [{Rh(cod)Cl}2] as catalyst and J003-2 as ligand gave the allylic amine 307 in satisfactory yield. Having compound 306 available in hand, it was treated with 40 wt% solution of formalin in the presence of NaCNBH3 in a mixture of AcOH and MeCN at room temperature gave the corresponding N-methylated compound 308 via reductive amination in good yields. In the final step for the hydroboration of the allylic double bond, the latter was subjected to hydroboration via intramolecular SCCR under mild reaction using just 1 equiv. of 9-BBN at room temperature and furnished the desired hydroboration product, which upon consequent treatment with [Pd(dppf)Cl2] and an aqueous NaOH solution at 80  C, furnished the desired alkaloid (
)-angustureine in 94% and 83% yields over three steps commencing from allene. Next, the allylic amine 307

368 Applications of Name Reactions in Total Synthesis of Alkaloids

SCHEME 9.34 Total synthesis of (
)-angustureine (309) and (
)-cuspareine (311).

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369

was treated with formalin (CH2O) and NaCNBH3 in a mixture of AcOH/ MeCN as solvent at room temperature to give the corresponding N-methylated compound 310 in high yield, and upon treatment of 9-BBN in the presence of [Pd(dppf)Cl2], a palladium species, as catalyst and Cs2CO3 as base in a mixture of DMF/H2O as solvent under the SCCR, furnished the desired alkaloid (
)-cuspareine (311) in 25% overall yield over four steps beginning from market-purchasable or easily accessible 4-vinyl veratrole (302) (Scheme 9.34) [281].

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Index ‘Note: Page numbers followed by “t” indicate tables.’

A (S)-Acetoxysuccinimide, 245e247 Acid-catalyzed hydrolysis, 194 Acridone alkaloids, 303e304 Actinophyllic acid, 171e172 Acyl halides, 61 Ageladine A, 229e231 Agelas nakamurai, 229e230 Akuamma, 72e73 Akuammicine, 110e111 Akuammiline alkaloids, 130e131 Aldehyde, 31e34 Aldol reaction, 7 Alkaloid cimitrypazepine, 127 Alkaloid fargesine, 126 Alkaloid grandilodine B, 37e40 Alkaloid rhodomollein XXII, 45e47 Alkaloids, 6e7, 110 Alkylation reactions, 4 Alkyl bromide, 37 Allenes, 28e30, 367 Allosecurinine, 213e217 Allylamine, 121 Allylated carbamate, 37 Alsmaphorazine alkaloids, 110e111 Alsmaphorazine alkaloids, 110e111 Alstolactine A, 130e131 Alstomicine, 257e258 Alstonerine, 202e204 Alstonia macrophylla, 202e204, 252, 255e256 Alstonia scholaris, 232e233 Alstoscholarine alkaloids, 272e274 Alstoscholarisine H, 232e234 Amaryllidaceae, 136, 333e334 alkaloids, 337e338 Amide, 30e31, 40e42 Amino alcohols, 313 1-Amino-3-butyne hydrochloride, 194e196 Aminocarbonyl compounds, 153e154 Amino silyloxy diene, 30e31 Anatoxin-A, 311e312

Andranginine, 27e28 Apocynaceae, 26e27 Arborescidine B, 243 Arborescidine C, 240e241, 243 Arborisidine, 264e266 Artemisia rupestris, 139 Arylation, 108 Arylboronic acids, 248e250 a-Aryl ethylamine, 227 Aspergillus versicolor, 308 Aspidosperma, 158, 174e178, 237e238 Aspidosperma rhombeosignatum, 238 Aspidosperma subincanum, 243 Asymmetric allylic alkylation, 162 Asymmetric mannich reactions, 155e158 Asymmetric organocatalysis, 156e157 Axinella cylindratus, 247 Axinellamines, 205e208 AZADOL, 27e28 Azepino[5,4,3-cd]indoles, 125e126

B Benzene, 61 Benzoic acid, 173e174 Benzomorphans, 79 Benzyl ether, 90e92 Benzyl trans-1,3-butadiene-1-carbamate, 31e34 Berbanine, 365e366 Berberis empetrifolia Lam, 82 Berbidine, 365e366 Bicolorine, 335 Bioactive molecules, 2 Bioactive secondary metabolites, 193 BischlereNapieralski-type cyclization, 269e270 Bisdehydroneostemoninine, 84e87 Bisdehydrostemoninine, 84 2-Bromoacrolein, 37 2-Bromo-3,6-bis(methoxymethoxy) benzaldehyde, 302 Bromoisatin, 308e311

383

384 Index

C Calothrixins, 297e298, 330 Canthines, 230 Canthin-4-one alkaloids, 299e300 Carbazole, 119, 354e355 9H-carbazole, 24e26 b-Carboline, 229, 257e259, 266e267, 269 Carbon monoxide (CO), 61 Carbonylative spirolactonization, 85e87 Carboxylic acid moieties, 85e87 Carprofen, 361 Catalyzed debenzylation, 81e82 Catharanthine, 40e42 Caulibugula inermis, 301e302 Caulibugulones, 302 C-carbomethoxylation, 159 Cephalezomine G, 88, 90e92 Cephalotaxine, 209e211 Cephalotaxus alkaloids, 88 Cephalotaxus drupacea, 209e211 Cephalotaxus fortune, 209e211 Cephalotaxus harringtonii, 88 Chaetoglines, 275e277 Chemical warfare agents, 4e5 Chemistry, 1 Chemoselective furyl lithium, 30e31 Chloro(triphenylmethyl)disulfane (TrSSCl), 63 N-chlorosuccinimide (NCS), 69e70 Cimitrypazepine, 126 (E)-Cinnamyl alcohol, 89e90 Claisen condensation, 4 Clauszoline K, 357e359 Clavelina lepadiformis, 31e34 Claviceps fusiformis, 125e126 Conolidine, 271e272, 305e306 Cordatanine, 230e232 Craspidospermum verticillatum, 26e27 Creativity, 3 Crinasiadine, 334e335 b-Cuparenone, 193 Cyanuric chloride, 27e28 Cyclic enaminone, 165 Cyclin-dependent kinase, 194e196 Cycloaddition/nitrogen extrusion, 124 Cycloaddition reaction, 11e12 Cycloclavine, 28e30, 121 Cyclohexene, 31e34 Cyclopentenone, 205e207 a,b-Cyclopentenone, 191 Cyclopropanation, 28e31

Cyclopropane, 45e47 Cylindradine B, 247e249

D Daphane, 193 Daphlongamine H, 179e180, 217e219 Daphniphyllum, 136e137, 217e218, 343e345 Daphniphyllum longeracemosum, 213 Daphniphyllum macropodum, 178 Decalin, 118e119 Decursivine, 112 Demethoxyerythratidinone, 130 (+)-3-Demethoxyerythratidinone, 130 Demethoxypeharmaline A, 259e260 Dendrobine, 193e195 Denigrin A, 134 5-Deoxy-D-ribose, 31e34 Deoxyisocalyciphylline B, 217e219 Deoxyperaksine, 253e255 Deplancheine, 236 Desbromoarborescidine B, 241e242 Desbromoarborescidine C, 240e242 Desmethylflinderole, 120e121 DesseMartin periodinane, 265e266 Diazonium salt-mediated double-inversion approach, 85e87 Dicobalt octacarbonyl (Co2(CO)8)), 191 Dictyodendrins, 346e349 Dieckmann condensation, 202e204 Dieckmann cyclization protocol, 252e255 DielseAlder (DA) reaction, 4, 11e12 acetyl chloride, 16e17 alkaloids, 14e47 alkynyl amine, 20 alphayohimbine, 19e20 andranginine, 27e28 apocynaceae, 26e27 Aspidosperma alkaloids, 14e16 asymmetric aza-Diels-Alder reactions, 13e14 asymmetric DA (ADA), 13e14 asymmetric hetero DA (AHDA) reactions, 13e14 9H-carbazole, 24e26 chiral holmium complex, 16e17 cis-fused pyrrolidine, 17e19 Craspidospermum verticillatum, 26e27 diastereomers, 20e21 enone, 17e19 furfurylamine, 20 hetero-DielseAlder (HDA) reaction, 13

Index 1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA), 27e28 high-performance liquid chromatography (HPLC) analysis, 24e26 intramolecular [4 + 2] cycloaddition reaction (IMDA), 13e14 b-isocupreidine (b-ICD), 27e28 Kopsia arborea, 26e27 Lawesson’s reagent, 16e17 lowest unoccupied molecular orbital (LUMO), 13 mechanism, 13e14 methyl ester, 17e19 minovincine, 15e16 NOESY analysis, 24e26 opioid alkaloids, 22e23 oxazolidinone moiety, 16e17 oxo-DielseAlder reaction, 13e14 quebrachine, 19e20 secondary amine, 17e19 siloxyvinylindole, 16e17 Streptomyces ehimensis, 24e26 thioamide, 16e17 trifluoroacetic acid (TFA), 20e21 5-vinyl-2-pyridone, 27e28 X-ray crystallographic analysis, 16e17 Yohimbine, 19e20 Dienophiles, 12, 31e34, 37e40 Diethyl azodicarboxylate (DEAD), 82e84 Dihydromorphinone, 22e23 Dihydroperaksine, 253e255 Trans-dihydroxylation reactions, 90e92 Diisobutylaluminum hydride, 162 Diketopiperazine (DKP), 75 Dirhodium complex, 30e31 2,6-Di-tertbutyl-4-methylpyridine (DTBMP), 62e63 Drymaria cordata, 230 Drymaria diandra, 230

E Enantioselectivities, 157e158 Enone, 30e31 Epipolythiodiketopiperazine alkaloids, 62e63 Ergot alkaloids, 28e30, 121 Ericaceae, 44e45 Erythrina, 128e129 Ester moiety, 42e44 Ethylene glycol, 3 Ethyl ester, 94 Etoposide (VP-16), 193

385

F Fargesine, 82e84, 126 Fischer indole synthesis, 27e28 Flinderole AeC alkaloids, 119e120 Fontanesines, 269e270 FriedeleCrafts (FC) reactions, 93e95 acyl halides, 61 akuamma, 72e73 akuammiline-containing herbs, 72e73 applications, 62e95 benzene, 61 carbon monoxide (CO), 61 chloro(triphenylmethyl)disulfane (TrSSCl), 63 N-chlorosuccinimide (NCS), 69e70 diketopiperazine (DKP), 75 2,6-di-tertbutyl-4-methylpyridine (DTBMP), 62e63 epipolythiodiketopiperazine alkaloids, 62e63 gliocladin C, 75 (+)-haplophytine, 64e66 hexahydropyrroloindole alkaloids, 73 intermolecular FriedeleCrafts alkylation reactions, 62e79 isolated (+)-asperazine, 66 iso-pestalazine A, 66 Lewis acids, 60e61 (+)-luteoalbusin B, 63 mechanism, 59e60 (+)-pestalazine A, 70 Pestalotiopsis theae, 66 (+)-strictamine, 72e73 tropical endophytic fungi, 63e64 Furanoclausamine, 115e116

G Gliocladin C, 75 Glochidicine, 233e236 Glochidine, 233e235 Glycoborine, 357 Glyoxylic acid monohydrate, 268 Gram-scale batch synthesis, 230 Grandilodine B, 37e40 Grandilodines, 37e40 Grignard reaction, 4, 244 Grignard reagent, 45e47 Guaipyridine alkaloids, 139 Guaipyridine sesquiterpene alkaloids, 352

386 Index

H (+)-Haplophytine, 64e66 Heck reaction akuammicine, 110e111 akuammiline alkaloids, 130e131 alkaloids, 110 cimitrypazepine, 127 fargesine, 126 allylamine, 121 alsmaphorazine alkaloids, 110e111 Alsmaphorazine alkaloids, 110e111 alstolactine A, 130e131 amaryllidaceae, 136 arylation, 108 azepino[5,4,3-cd]indoles, 125e126 cimitrypazepine, 126 cycloaddition/nitrogen extrusion, 124 cycloclavine, 121 Daphniphyllum, 136e137 decalin, 118e119 decursivine, 112 definition, 107 demethoxyerythratidinone, 130 (+)-3-demethoxyerythratidinone, 130 denigrin A, 134 desmethylflinderole, 120e121 ergot alkaloids, 121 Erythrina, 128e129 fargesine, 126 flinderole AeC alkaloids, 119e120 furanoclausamine, 115e116 guaipyridine alkaloids, 139 hydridopalladium, 109e110 indole and substituted hydroindole derivatives, 128e129 indolosesquiterpenoids, 116e117 iodoaniline, 114e115 ketone, 138 lycorane, 128e129 Lycoris radiata, 136 mechanism, 109e110 methacryloyl chloride, 121 microwave irradiation (MWI), 128e129 oridamycins, 118e119 palladium (Pd), 107e108 Pd-catalyzed reductive N-heterocyclization, 127 Penicillium aurantiovirens, 125e126 ring-closing metathesis (RCM), 121 scholarisine K, 130e131 Scho¨llkopfeMagnuseBartoneZard (SMBZ) reaction, 114e115

single-crystal X-ray analysis, 114e115 spiroindimicins, 114e115 transition-metal chemistry, 107e108 tuberculosis (TB), 133e134 vinylation, 108 xiamycin, 116e118 X-ray crystallographic analysis, 118e119 Zincke aldehyde, 110e111 Helicobacter pylori, 205e207 1,1,1,3,3,3-Hexafluoroisopropyl acrylate (HFIPA), 27e28 Hexahydropyrroloindole alkaloids, 73 2-Hexylfuran, 234e236 High-performance liquid chromatography (HPLC) analysis, 24e26 HornereWadswortheEmmons condensation, 260e262 Hybridaphniphylline B, 213, 215 Hydrazone amide, 27e28 Hydridopalladium, 109e110 Hydrogenolysis, 272e273 Hydroxyamine, 169e170 Hydroxycyclopropanol, 84 Hyellazole, 354 Hyrtiosulawesine, 267e268

I Iheyamine A, 171 Ileabethoxazole, 211e212 Imidazole alkaloids, 233e234 Indolenine alkaloids, 264 Indolosesquiterpenoids, 116e117 Indoxyl, 37e40 Inorganic chemistry, 2 Intermolecular FriedeleCrafts alkylation reactions, 62e79 Intramolecular nucleophilic substitution, 90e92 Intramolecular PausoneKhand reaction (IPKR), 191e192 2-Iodo aniline, 367 Ircinal A, 194e197 IrelandeClaisen rearrangement (ICR), 256 Iridomyrmecin, 193 Isocarbostyril alkaloids, 340, 342 b-Isocupreidine (b-ICD), 27e28 Isodaphlongamine H, 179e180, 218e220 Isoindolinone, 94 Isolated (+)-asperazine, 66 Isopavines, 248e251 Iso-pestalazine A, 66 Isoquinoline, 229

Index Isosolenopsin A, 162e164 Isoxazolidine, 37e40

J Jacobsen-type thiourea organocatalyst, 241e242

K Kalmanol, 193 Ketene equivalent approach, 40e42 Ketoepoxide, 45e47 Ketone, 30e34, 37e40 Kopsia arborea, 26e27 Kopsia hainanensis, 238 Kopsihainanine A, 238e240 Kumujian A, 231e232

L Lapidilectam, 37e40 Lapidilectines, 37e40 Lawesson reagent, 213 LemieuxeJohnson oxidative cleavage, 199e200 Lepadin, 31e34 Lewis acids, 60e61 Limaspermidine, 238e239 LivinghouseePagenkopf reaction, 194e196 Lobeline, 168 Lundurine A, 262e264 Lundurines, 37e40 (+)-Luteoalbusin B, 63 Lycopalhine A, 198e199, 201 Lycopodium magellanicum, 200 Lycopodium paniculatum, 200 Lycoposerramine-R, 42e44

M Macrocarpines A, 252e254 Macroline, 202e204, 256e258 Magallanesine, 93, 95 Magellanine, 200, 203 Magellaninone, 200, 203 Malaria, 119e120 Mannich reaction, 7 actinophyllic acid, 171e172 aminocarbonyl compounds, 153e154 applications, 158e180 Aspidosperma, 158, 174e178 asymmetric allylic alkylation, 162 asymmetric mannich reactions, 155e158

387

asymmetric organocatalysis, 156e157 benzoic acid, 173e174 C-carbomethoxylation, 159 cyclic enaminone, 165 daphlongamine H, 179e180 Daphniphyllum macropodum, 178 diisobutylaluminum hydride, 162 enantioselectivities, 157e158 hydroxyamine, 169e170 iheyamine A, 171 isodaphlongamine H, 179e180 isosolenopsin A, 162e164 lobeline, 168 mechanism, 154e155 methyl group, 162e164 nitrones, 168e169 nucleophiles, 155 piperidine alkaloids, 162e164 pseudotabersonine, 158 quinolizidine, 165 ring-closing metathesis (RCM), 158 solenopsin, 164 spirocyclic indolenine, 174e178 sulfonylmethyl carbamates, 162 tetracycles, 158e159 Vaccinium myrtillus, 165 vincadifformine, 174e178 Manzamine A, 194e197 Marine alkaloids, 31e34 Massadines, 205e208 Meloscine, 207e210 Menisporphine, 342e343 Metazocine, 82 Methyl group, 162e164 MizorokieHeck reaction. See Heck reaction Monoterpene indole alkaloids (MITAs), 237e238 Monoterpenoid indole alkaloids (MIAs), 232e233 Mukoeic acid, 355e356 Mukonine, 357

N Nakadomarin A, 194e197, 212e214 Name reactions, 3e4, 326 Natural products, 2, 4e5 Navelbine (vinorelbine), 193 Nitrones, 168e169 b-Nitrostyrenes, 248e250 Norisotuboflavine, 300e301 Norsecurinine, 213e217 Nucleophiles, 155

388 Index

O Opiate, 21e22 Opioids, 21e22 Organic chemistry, 1 Organic synthesis, 1 Organolithium, 37 Oridamycins, 118e119 Oxabicycle, 37 Oxidative aromatization reaction, 275 1-Oxoisoquinoline alkaloids, 365

P Palau’amine, 205e208 Palhinhaea cernua, 198e199 Palmanine, 82 Paniculatine, 200, 203 Papaver somniferum, 21e22 PausoneKhand reaction (PKR), 193 acid-catalyzed cyclization, 194 allosecurinine, 213e217 alstonerine, 202e204 applications, 193 axinellamines, 205e208 carbon-tethered enyne precursors, 191e192 cephalotaxine, 209e211 cyclopentenone, 205e207 a,b-cyclopentenone, 191 daphlongamine H, 217e219 dendrobine, 194e195 deoxyisocalyciphylline B, 217e219 dicobalt octacarbonyl (Co2(CO)8)), 191 disadvantages, 191e192 hybridaphniphylline B, 213, 215 ileabethoxazole, 211e212 ircinal A, 194e197 isodaphlongamine H, 218e220 LemieuxeJohnson oxidative cleavage, 199e200 lycopalhine A, 198e199, 201 macroline/sarpagine alkaloids, 202e204 magellanine, 200, 203 magellaninone, 200, 203 manzamine A, 194e197 massadines, 205e208 mechanism for, 192e193 meloscine, 207e210 nakadomarin A, 194e197, 212e214 negative electrospray collision testing, 192e193 norsecurinine, 213e217

palau’amine, 205e208 paniculatine, 200, 203 phenylacetylene-hexacarbonyldicobalt complex, 191 physostigmine, 197e199 regioselective intramolecular, 191e192 with no regioselectivity, 191e192 securinine, 213e217 a-skytanthine, 204e206 spiroaminoketone, 205e207 tecomanine, 196e197, 205 tecomine, 196 Pavines, 248e250 Pd-catalyzed CeC bond formation process, 295e296 Peharmaline A, 257e258, 260e261 Penicillium aurantiovirens, 125e126 Persistent total synthesis, 3 (+)-Pestalazine A, 70 Pestalotiopsis theae, 66 Phenanthridinone, 338e339 Phenylacetylene-hexacarbonyldicobalt complex, 191 Phenylhydrazine, 27e28 Phthalimide moiety, 278e279 Physostigma venenosum, 197e198 Physostigmine, 197e199 PicteteSpengler reaction (PSR), 202e204, 227e228 (S)-acetoxysuccinimide, 245e247 acidic reaction conditions, 228 ageladine A, 229e231 alstomicine, 257e258 alstoscholarine alkaloids, 272e274 alstoscholarisine H, 232e234 antiangionetic effects, 229e230 Apocynaceae family, 255e256 arborescidine B, 243 arborescidine C, 240e241, 243 arborisidine, 264e266 arylboronic acids, 248e250 a-aryl ethylamine, 227 asymmetric synthesis, 228e229, 245e246 Axinella cylindratus, 247 canthines, 230 b-carboline, 229, 257e259, 266e267, 269 catalytic asymmetric reaction, 248e250 chaetoglines, 275e277 chiral catalysts, 228 conolidine, 271e272 cordatanine, 230e232

Index cylindradine B, 247e249 dehydrogenation, 230 demethoxypeharmaline A, 259e260 deoxyperaksine, 253e255 deplancheine, 236 desbromoarborescidine B, 241e242 desbromoarborescidine C, 240e242 DesseMartin periodinane, 265e266 Dieckmann cyclization protocol, 252e255 dihydroperaksine, 253e255 fontanesines, 269e270 glochidicine, 233e236 glochidine, 233e235 glyoxylic acid monohydrate, 268 gram-scale batch synthesis, 230 Grignard reaction, 244 2-hexylfuran, 234e236 hydrogenolysis, 272e273 hyrtiosulawesine, 267e268 imidazole alkaloids, 233e234 indole and isoquinoline derivatives, 227 indolenine alkaloids, 264 intramolecular condensation, 259e260 intramolecular Schmidt reaction, 260e262 IrelandeClaisen rearrangement (ICR), 256 isopavines, 248e251 isoquinoline, 229 Jacobsen-type thiourea organocatalyst, 241e242 kopsihainanine A, 238e240 kumujian A, 231e232 limaspermidine, 238e239 lundurine A, 262e264 macrocarpines A, 252e254 macroline, 256e258 monoterpene indole alkaloids (MITAs), 237e238 monoterpenoid indole alkaloids (MIAs), 232e233 nitrogen heterocycles, 229, 233e234 b-nitrostyrenes, 248e250 oxidative aromatization reaction, 275 pavines, 248e250 peharmaline A, 257e258, 260e261 phthalimide moiety, 278e279 pityriacitrin, 267e269 polymer-bound triphenylphosphine, 239e240 pyrrole-imidazole alkaloid (PIA), 246 pyrrolidinone, 235 quinocarcin, 277, 279 secologanin, 229

389

silica gel chromatography, 252e253 spiroindolenine, 228 subincanadine E, 244e245, 247 Swern oxidation, 262e263 tangutorine, 236e237 tert-butyldimethylsilyl (TBS), 257 tetracyclic compounds, 233 tetracyclic indole alkaloids, 240e241 tetrahydro-b-carbolines alkaloids, 236 tetrahydroisoquinolines, 227, 229 tetra-n-butylammonium fluoride (TBAF), 257 trifluoroacetic acid (TFA), 247e248 trigonostemine A, 267e268 trigonostemine B, 267e268 tryptamine, 229 tryptophan, 274e275 tryptophan methyl ester, 265 tylophorine, 260e263 X-ray crystallographic analysis, 260e261 Piperidine alkaloids, 162e164 Pityriacitrin, 267e269 Polymer-bound triphenylphosphine, 239e240 Potassium azodicarboxylate (PAD), 24 Proaporphine alkaloids, 87e88 Protected functionality, 12 Protectionedeprotection process, 202e204 Pseudodistoma arborescenswas, 240e241 Pseudotabersonine, 158 Pyrrole-imidazole alkaloid (PIA), 246 Pyrrolidinone, 235

Q Quinocarcin, 277, 279 Quinolizidine, 165 Quinolones, 345

R Regioisomer, 357 Ring-closing metathesis (RCM), 121, 158 Rupestines, 139

S Secologanin, 229 Secondary metabolites, 4e5 Securinega suffruticosa, 213e217 Securinine, 213e217 Sexestobergsterol, 193 Seyferth Gilbert homologation, 213

390 Index Silica gel chromatography, 252e253 Silyl dienol ether, 45e47 a-Skytanthine, 204e206 Solenopsin, 164 Sonogashira reaction acridone alkaloids, 303e304 amino alcohols, 313 anatoxin-A, 311e312 applications, 297e316 Aspergillus versicolor, 308 2-bromo-3,6-bis(methoxymethoxy) benzaldehyde, 302 bromoisatin, 308e311 calothrixins, 297e298 canthin-4-one alkaloids, 299e300 Caulibugula inermis, 301e302 conolidine, 305e306 mechanism, 296e297 norisotuboflavine, 300e301 optimization, 309t Pd-catalyzed CeC bond formation process, 295e296 Tabernaemontana divaricata, 305e306 tetrahydrofuran (THF), 298e299 trifluoroacetic acid (TFA), 304e305 trimethylsilyl enynes, 313e314 Spatane, 193 Spiroaminoketone, 205e207 Spirocyclic indolenine, 174e178 Spiroindolenine, 228 Stemona alkaloids, 84e87 Stemonaceae plants, 84 Streptomyces ehimensis, 24e26 (+)-Strictamine, 72e73 Stypopodium zonale, 78 Subincanadine E, 244e245, 247 Substrate, 37e40 Sulfonylmethyl carbamates, 162 Suzuki cross-coupling reaction (SCCR) allenes, 367 amaryllidaceae alkaloids, 337e338 amaryllidaceae family, 333e334 applications, 329e369 berbanine, 365e366 berbidine, 365e366 bicolorine, 335 calothrixins, 330 carbazole, 354e355 carprofen, 361 clauszoline K, 357e359 crinasiadine, 334e335 Daphniphyllum alkaloids, 343e345

dictyodendrins, 346e349 glycoborine, 357 guaipyridine sesquiterpene alkaloids, 352 hyellazole, 354 2-iodo aniline, 367 isocarbostyril alkaloids, 340, 342 mechanism, 327e328 menisporphine, 342e343 mukoeic acid, 355e356 mukonine, 357 name reaction, 326 1-oxoisoquinoline alkaloids, 365 phenanthridinone, 338e339 quinolones, 345 regioisomer, 357 Swern oxidation, 213, 262e263

T Tabernaemontana divaricata, 270e271, 305e306 Tangutorine, 236e237 (+)-Taondiol, 78e79 Taonia atomaria, 78 Taxol (paclitaxel), 193 Taxotere (docetaxel), 193 Tecomanine, 196e197, 205 Tecomine, 196 Teniposide (VM-26), 193 Tert-butyldimethylsilyl (TBS), 257 Tertiary allylic alcohol, 30e31 Tetracycles, 158e159 Tetracyclic indole alkaloids, 240e241 Tetrahydro-b-carbolines alkaloids, 236 Tetrahydro benzoazocine, 94 Tetrahydrofuran (THF), 298e299 Tetrahydroisoquinolines, 227, 229 2,2,6,6-Tetramethyl-1-piperidinyloxy (TEMPO), 28e30 Tetra-n-butylammonium fluoride (TBAF), 257 Topotecan (Hycamtin), 193 Total synthesis, 3 Traditional medicine, 5 Trifluoroacetic acid (TFA), 247e248, 304e305 Trigonostemine A, 267e268 Trigonostemine B, 267e268 Trimethylsilyl enynes, 313e314 Triol, 31e34 Trisubstituted cyclohexene, 31e34 Trisubstituted olefin, 31e34 Tropical endophytic fungi, 63e64

Index Tryptamine, 229 Tryptophan, 274e275 Tryptophan methyl ester, 265 Tylophorine, 260e263

U

a,b-unsaturated ketone, 31e34

V Vaccinium myrtillus, 165 Verongula rigida, 240e241 VilsmeiereHaack reaction, 79 Vincadifformine, 174e178 Vincristine (Oncovin), 193

5-vinyl-2-pyridone, 27e28 Virosaine A, 35e36

W Wittig reaction, 4, 7

X Xiamycin, 116e117 X-ray crystallographic analysis, 118e119, 260e261

Z Zincke aldehyde, 110e111

391

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