K.C.NICOLAOU, E. J. SORENSEN CLASSICS IN TOTAL SYNTHESISClassics in Total Synthesis K.C. Nicolaou and E.J. SorensenOther successful books in organic chemistry from VCH IM. Lehn Supramolecular Che Concepts and Perspectives 1995, X, 271 pages with 51 figures. Hardcover. ISBN 3-527-29312-4. Softcover. ISBN 3-527-29311-6. J. Fuhthop, G. Penzl Organic Synthesis - Concepts, Methods, Starting Materials Second, Revised and Enlarged Edition With a Foreword by E.J. Corey 1994. XVI, 432 pages with 16 figures and 37 tables. Hardcover. ISBN 3-527-29086-9 Softcover. ISBN 3-527-29074-5. M. Nogradi Stereoselective Synthesis — A Practical Approach Second, Thoroughly Revised and Updated Edition With a Foreword by A.I. Meyers 1994. XVI, 452 pages with 171 figures and 23 tables. Hardcover. ISBN 3-527-29242-X. Softcover. ISBN 3-527-29243-8, D.P. Curran, N.A. Porter, B. Giese Stereochemistry of Radical Reactions — Concepts, Gt and Synthetic Applications 1995, XII, 280 pages with 31 figures and 2 tables. Hardcover. ISBN 3-527-29372-8. H. Waldmann (Ed.) Organic Synthesis Highlights II 1995. XIII, 407 pages with 318 figures and 3 tables. Hardcover. ISBN 3-527-29200-4, © VCH Verlagsgesellschalt mbH, D-60451 Weinheim (Federal Republic of Germany), 1996 oat 1 Distribution: VCH, P.O. Box 101161, D-6945) Weinheim, Federal Republic of Germany Switzerland: VCH, P.O. Box, CH-8020 Basel, Switzerland | United Kingdom and Kreland: VCH, 8 Wellington Court, Cambridge CBI 1HZ, United Kingdom USA and Canada: VCH, 220 Bast 25rd Street, New York, NY 10010-4606, USA. Japan: VCH, Eikow Building, 10-9 Hongo l-chome, Bunkyo-ku, Tokyo 113, Japan ISBN 3-527-29284-5 ISBN 3-527-20231-4Classics in Tota Synthesis Targets, Strategies, Methods With a Foreword by E.J. Corey (iL VCH"! K.C. Nicolaou and E.J. Sorensen Weinheim New York Basel Cambridge TokyoK.C, Nicolaou, Ph. D. Erik J, Sorensen, Ph. D. Department of Chemistry ‘and Department of Chemistry and Biochemistry The Scripps Research Institute University of California, San Diego 10666 North Torrey Pines Road 9500 Gilman Drive La Jolla, CA 92037 La Jolla, CA. 92093, USA USA ‘This book was carefully produced. Nevertheless, authors and publisher do not warrant the information contained therein to be free if errors. Readers are advised to Keep in mind that statements, data, illustrations, procedural details or other items may inadver tently be inaccurate Published jointly by VCH Verlagsgeselischaft mbH, Weinheim (Federal Republic of Germany) ‘CH Publishers, In., New York, NY (USA) Copy Editor: Dr. Rachel Schmidt-Radde Production Manager: Dipl.-Ing. (FH) Hans Jorg Maier Front cover: A red-tide incident that occurred on 8th May 1976, off Matsushima Istand, in Hyogo Prefecture, Japan, The structure ‘shown is that of brevetoxin B, a neurotoxin produced by algae that proliferate during red-tide incidents. Brevetoxin B is believed to have been responsible for massive fish killings and poisoning of humans who ate affected seafood. The total synthesis of brevetoxia Bis described in Chapter 37 of this book, Back cover: Structure of vitamin By. Library of Congress Card No. applied for ‘A catalogue record for this book is available from the British Library. Deutsche Bibliothek Cataloguing-in-Publication Data: Nicolaou, K.C. Classics in total synthesis / K.C. Nicolaou and Erik J. Sorensen, - Weinheim ; New York ; Basel ; Cambridge ; Tokyo VCH, 1996 ISBN 3-527-29284-5 Pp. ISBN 3-527-29231-4 brosch. NB: Sorensen, Erik J: © VCH Veriagsgeselschaft mbH, D-69451 Weinheim (Federal Republic of Germany), 1996 Printed on acid-free and chlorine-ree paper All rights reserved (including those of translation in other languages). No part of this book may be reproduced in any form ~ by photo. printing, microfilm, or any other means - nor transmitted or translated into machine language without writen permission from the Publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered “unprotected by law. Composition: Fa, Hagedornsatz GmbH, D.68519 Viemheim, Printing: Zechnersche Buchdruckerci, D-67346 Speyer. Bookbinding: Wilhelm Osswald & Co, D-67433 Neustadt. Printed in the Federal Republic of Germany.Foreword Ifa definitive history of twentieth century science is ever written, one of the highlights may well be a chapter on the chemical synthesis of complex molecules, especially the total synthesis of naturally occur- ring substances. I state this, while trying to be as objective as possible, because it is not easy to find an area of scientific work that encom- asses so many interesting elements. I shall name just a few: great com- plexity and variety; challenge verging on impossibility; demand for both mental and manipulative rigor, and for dedication, persistence, and hard work; never-ending frontiers for discovery and never-ending advances in sophistication; unlimited opportunities for intellectual excitement and satisfaction; strong coupling not only with all areas of chemistry, but also with biology and medicine: relevance, at a very fun- damental level to human well-being, health, and education As I read a prepublication draft of “Classics in Total Synthesis”, all of these general characteristics of synthetic research assumed a reality and sharpness that I had not expected, partly because 1 was already familiar with each of the thirty-seven classics in this collec- tion. It was a sheer delight to revisit each of these triumphs guided by the wise insights and analyses found throughout this book. There is a nice balance between the underlying historical material and the design and execution aspects of each synthesis. In addition, the broad perspectives on synthesis, supplemented in each section by detailed explanations of the key features of each synthesis, lead toa presentation that is both clear and stimulating. The pedagogy is effective As mentioned by the authors in their preface, the achievements in total synthesis have been so numerous and so important that it is Clearly impossible to include them all in a single volume. My hope is that “Classics in Total Synthesis” will be successful and that it will be followed by a continuing series. Such a colléction will add to our reading pleasure and further encourage and inspire new generations of chemists to dare the impossible (or even the unfashionable). There is much still to be leamed and to be discovered. Humanity will be enriched beyond measure if the twenty-first century is a period of continued vigorous development of synthetic chemistry. I would like to congratulate Professor Nicolaou and Dr, Sorensen on this fine addition to the literature of synthetic chemistry and to wish them well in their further work as scientists and as authors. May the joumey in total synthesis follow the Ithaca model (page 16) E.J. Corey Harvard University 30 October 1995Abbreviations Ac acetyl cae acetylacetonyl AD asymmetric dihydroxylation AIBN 2,2-azobisisobutyronitrile BBEDA N,N'-bis(benzylidene)ethylenediamine 9-BBN 9-borabicyclo[3.3.1}nonane BINAL-H 2,2-dihydroxy-1,1’-binaphthylaluminum. BINAP Bn benzyl BOC (-BOC)’ tert-butoxycarbonyl BOM benzyloxymethyl BTMSA bis(trimethylsilylacetylene Bz benzoyl 18-C-6 18-crown-6 Cbz benzyloxycarbonyl CHD coronary heart disease CoA cop Cp CSA Cy (Cy-Hex) DAIB DAST dba DBN DBs DBU DCBI pec D_Q de DEAD DEIPS DET DHP DHQ DHQD DIAD Dibal-H DIOP DiPAMP DIPT DMA 4-DMAP. (DMAP) DME DMF DMs DMSO DNA 1-DOPA, DPC DTBMS. EDC (EDCH e ee EE Et-DuPHOS Fmoe FPP coenzyme A 1,5-cyclooctadiene cyclopentadieny! 10-camphorsulfonic acid ceyclohexy? 3-ex0-(dimethylamino)isoborneo! diethylaminosulfur trifluoride trans, trans-dibenzy 1,5-diazabicyclo[4.3.0)non-5-ene S-dibenzosuberyl 1,8-diazabicyclo[5.4.0]undec-7-ene NN'-dicyclohexyl-O-benzylisourea 1,3-dicyclohexylcarbodiimide 2/3-dichloro-5,6-dicyano-1,4-benzoquinone diastereomeric excess diethyl azodicarboxylate diethylisopropylsily! diethy! tartrate 3.4-dihydro-2H-pyran dihydroquinine dibydroquinidine diisopropyl azodicarboxylate diisobutylaluminum hydride 2,3-O-isopropylidene-2,3-dihydroxy-1,4- bis(diphenylphosphino)butane 1,2-bis(o-anisylphenylphosphino)ethane diisopropy! tartrate N,N-dimethylacetamide 4-dimethylaminopyridine ethylene glycol dimethyl ether N.N-dimethylformamide dimethy! sulfide dimethyl sulfoxide deoxyribonucleic acid 3-(3,4-dihydroxyphenyl: dipyridine chromium(vi) oxide di(fert-buty!)methylsily! 1-(3-dimethylaminopropyl)-3-ethylearbodii- hydrochloride electron enantiomeric excess 1-ethoxyethy! 1,2-bis(2',5'-diethylphospholanoyethane 9-fluorenylmethoxycarbonyl farnesyl pyrophosphate Gc HETE hfe HMPA HMG HPLC HWE Im (imid.) IND Ipe KHMDS LDA LHMDS mCPBA MEM MOM Ms NaHMDS NB pNB NBS NCS NIS NMM NMO NMP PNNP PPTS psi pyr. (pyr, Py) PYR Ra-Ni Red-Al SAE SEM Sia TBAF TBAL TBS TEOC gas chromatography hydroxyeicosatetraenoic 3-{hepiafluoropropylhydroxymiethylene |v camphorato hexamethylphosphoramide hydroxymethylelutaryl high-pressure liquid chromatography Homer-Wadsworth-Emmons imidazole indoline isopinocamphey! potassium bis(trimethylsilylamide lithium diisopropylamide lithium bis(trimethylsilylamide 3-chloroperoxybenzoic acid 2-methoxyethoxymethyl methoxymethyl methanesulfanyl sodium bis(trimethylsily!)amide 2-nitrobenzy! 4-nitrobenzyl N-bromosuccinimide N-chlorosuccinimide N-iodosuccinimide 4-methylmorpholine 4-methylmorphotine N-oxide I-methyl-2-pyrrolidinone nnclear magnetic resonance nucleophile pyridinium chlorochromate pyridinium dichromate prostaglandin pheny! phthalazine phthalimido pivaloy! 4-methoxybenzy! N,N’-bis(1-phenylethy)-N,N’-bis-(diphe- nylphosphino)ethylenediamine pyridinium 4-toluenesulfonate ‘pounds per square inch pyridine diphenyipyrimidine Raney nickel sodium bis(2-methoxyethoxy)aluminum hydride Sharpless Asymmetric Epoxidation 2-(trimethylsilyethoxymethy! siamyl tetra-n-butylammonium fluoride tetra-n-butylammonium iodide tert-butyldimethylsily! 2-(trimethylsilyethoxycarbonyl triethylsily! trifluoromethanesulfonyl trifluoroacetic acid trifluoroacetic anhydride tetrahydrofuran tetrahydropyranyl * triisopropylsilyl N.N.N’,N'-tetramethylethylenediamine trimethylsilyl tetra-n-propylammoniuim perruthenate tert-butyldiphenylsilyl triphenylmethy! 4-toluenesulfonylPreface This book is intended to be an historical record of some of the greatest total syntheses of all time. We also hope that it will serve as a teaching and learning tool for teachers, students, and practi- tioners of organic synthesis. In Chapter 1, the reader will find a dis- cussion on the philosophy, purpose, and use of total synthesi each of the remaining 36 chapters, we describe the total synthesis of a natural product. Through the examples chosen, an effort was made to trace the evolution of the science of total synthesis to its present state and to demonstrate the utility of important chemical reactions in the construction of target organic molecules. Despite the diversity of structures, each total synthesis is presented in a uni- fying pedagogical format, which hopefully distinguishes this book from any other. In the Introduction section of each chapter, the background and biological action of the target molecule is discussed, and the impor- tant synthetic reactions involved in the synthesis are presented. Following the introduction is the Retrosynthetic Analysis and Strategy section, in which the target molecule is analyzed retro- synthetically to show and explain the evolution of the synthetic strategy. In the Total Synthesis section, the execution of the syn- thesis is discussed, with special emphasis placed on tactics, effi- ciency, selectivity, stereochemistry, and synthetic maneuvering. The Conclusion section summarizes in a concise manner the main find- ings and impact of the total synthesis Throughout each chapter, clear structures, schemes, and figures accompany the text. Mechanism, reactivity, selectivity, and stereo- chemistry are especially addressed. Special emphasis is also placed on introducing both the logic of total synthesis and the rationale for the invention and use of important synthetic methods. In particular, we amplify the most important developments in asymmetric synthe- sis, catalysis, cyclization reactions, and organometallic chemistry. This volume is based partly on the lecture notes of K.C.N. that were used for teaching courses at the University of Pennsylvania, the University of California, San Diego, and The Scripps Research Institute. We apologize sincerely to those whose brilliant works have been left out owing to the inevitable closing of the curtain and hope that in the event of a second volume we can rectify these omissions. We also apologize in advance for the inevitable errors that a volume of this size may contain, and welcome constructive comments from our readers in order to correct such errors in future editions, It is our hope that this book will find its way into the hands of every student of organic synthesis and that it will serve both to edu-vill Preface cate and inspire. If we can excite and stimulate a new generation of chemists in the direction of organic synthesis, then we will be satis fied that a major part of our goal has been reached. We wish to thank Janise L. Petrey for her tenacity, skill, and patience in processing the many and fragmentary versions of this, book. We would also like to thank Alan Nadin for his thoughtful comments and useful suggestions on various aspects of the manu- script. We are grateful to Chris F. Claiborne, Otto Griither, R. Kip Guy, John |. Trujillo, and Eddy W. Yue for their assistance and for checking the references. We thank Professors Charlie L. Perrin, Jay S. Siegel, and Emmanuel A. Theodorakis for useful discussions and suggestions, and Vicky Nielsen for her managerial skills in keeping us all together, We owe our many thanks to Georgette, Colette, Alex, Chris, and P.J. Nicolaou and Karla Sorensen for their support and patience during this odyssey, and we offer our apologies for not being there when we should have been .. Our sincere appreciation goes to all the members of the K.C.N. group whose dedication, brilliance, and diverse ethnic background have made this group's contributions both possible and enjoyable, Finally, we would like to dedicate this book to Professor E.J. Corey, whose teachings and research have helped shape the science of organic synthesis and the art of total synthesis as we know it today. La Jolla K.C. Nicolaou October 1995 E.J. SorensenAbout the Authors K.C. Nicolaou was born in 1946 in Cyprus. He studied chemistry at the University of London (B.Sc., 1969; Ph.D., 1972), Columbia University (postdoctoral research) and Harvard University (postdoc- toral research), Between 1976 and 1989 he was a faculty member at the University of Pennsylvania. He currently holds joint appointments at The Scripps Research Institute, where he is the Darlene Shiley Professor of Chemistry and Chairman of the Department of ' Chemistry, and at the Univer- sity of California, San Diego, where he is Professor of Chem- istry. His research interests span the areas of synthetic organic chemistry, bioorganic chemistry, molecular design, and the chemistry and biology of natural products.x About the Authors Erik J. Sorensen was born in 1966 in Oneida, New York. He graduated from Syracuse Uni- versity with a B.A. in chemis- try. He received his Ph.D. degree in chemistry from the University of California, San Diego in 1995 working under the guidance of Professor K.C. Nicolaou. His research interests are in the areas of total syn- thesis and reaction engineeringContents Overview . Introduction: Constructing the Molecules of Nature 2. Strychnine (R. B. Woodward) (1954) 3. Penicillin V (J.C. Sheehan) (1957) 4, Reserpine (R. B. Woodward) (1958) 5, Prostaglandin Faq (PGF2q) and (E.J. Corey) (1969) Prostaglandin E> (PGE2) 6. Progesterone (W.S. Johnson) (1971) 7. Carpanone (O.L. Chapman) (971) 8. Vitamin B12 (R.B. Woodward and (1973) A. Eschenmoser) 9. Prostaglandin A> (PGA2) and (G. Stork) (1976, 1978) Prostaglandin Faq (PGF2a) 10, Estrone (K. P.C. Vollhardt) (1977) 11. Erythronolide B (E. J. Corey) (1978) 12. Monensin (¥. Kishi) (1979) 13. Periplanone B (W.C. Still) (1979) 14, Isocomene (M.C. Pirrung) (1979) 15. Monensin (W.C. Still) (1980) 16, Thienamycin (Merck) (1980) 17. Endiandric Acids (K.C. Nicolaou) (1982) 18. Biotin (Hoffmann-La Roche) (1982) 19. -Hexoses (S. Masamune and (1983) K.B. Sharpless) 20. Asteltoxin’ (S.L. Schreiber) (1983) 21. Periplanone B (S.L. Schreiber) (1984) 22. Menthol (Takasago) (1984) 23. Hirsutene and A%'2)-Capnellene (D. P. Curran) (1986) 24, Amphoteronolide B and (K.C. Nicolaou) (1987) Amphotericin B 25. Ginkgolide B (E.J. Corey) (1988) 26. Methyl Homosecodaphniphyllate —_ (C. H. Heathcock) (1988) 27. Indolizomycin (S.J. Danishefsky) (1990) 28. Cytovaricin (D.A. Evans) (1990) 29, Gilvocarcin M and Gilvocarcin V—_(K. Suzuki) (1992, 1994) 30. Calicheamicin y} (K.C. Nicolaou) (1992) 31, Rapamycin (K.C. Nicolaou) (1993) 32. Paconiflorigenin and Paeoniflorin (E.J. Corey) * (1993) 33. Strychnine (L.E. Overman) (1993) 34. Taxol (K.C. Nicolaou) (1994) 35, Zaragozic Acid A/Squalestatin $1 (K. C. Nicolaou) (1994) 36. Palytoxin (¥. Kishi) (1994) 37. Brevetoxin B (K.C. Nicolaou) (1995)Table of Contents Chapter 1 Introduction: Constructing the Molecules of Nature 1.1 Synthetic Chemistry and Total Synthesis .. . . 1.2 The Scope of Organic Synthetis.. 1.3. A Brief History of Organic Synthesis 1.4 The Practice of Total Synthesis 1.5. Target Molecules . : : 1.6 Natural Products as Synthetic Targets . 1.7 Designed Molecules as Synthetic Targets, 1.8 Synthetic Strategy gosneoeo 1.9 Retrosynthetic Analysis 1.10 Classics in Total Synthesis . .. Chapter 2 Strychnine R.B. Woodward (1954) 2.1. Introduction 22. Retrosynthetic Analysis and Strategy 2.3 Total Synthesis bees 24 Conclusion ....... Chapter 3 Penicillin V J.C. Sheehan (1957) 3.1. Introduction . 3.2 Retrosynthetic Analysis and Strategy... 3.3 Total Synthesis . . 3.4 Conclusion ... 21 22 21 40 4 44 45 50XIV Table of Contents Chapter 4 Reserpine R.B. Woodward (1958) 4.1. Introduction 4.2 *Retrosynthetic Analysis ‘and Suey : 4.3. Total Synthesis. 44 Conclusion .... Chapter 5 Prostaglandin F2q (PGF2q) and Prostaglandin Ez (PGE2) E.J. Corey (1969) Sl Introduction . 5.2 Retrosynthetic ‘Analysis ‘and I Sateey 5.3 Total Synthesis... 5.4 Conclusion Chapter 6 Progesterone W.S. Johnson (1971) 6.1 Introduction ..... 6.2 Retrosynthetic Anas ‘and Seategy 6.3 Total Synthesis 64 — Conclusion Chapter 7 Carpanone O.L. Chapman (1971) 7.1 Introduction . 72 Rewrosynthetic Analysis and. a Sitegy 7.3. Total Synthesis. 7.4 — Conclusion 65 67 a 81 83 85 88 92Table of Contents Chapier 8 Vitamin Bj2 R.B. Woodward and A. Eschenmoser (1973) 8.1 8.2 83 8.3.1 8.3.2 8.3.3 8.3.4 8.3.5 8.3.6 8.3.7 8.3.8 8.3.9 84 Introduction . Retrosynthetic Analysis and Strategy Total Synthesis... The Woodward Synthesis of Cyanobromide 6 . The Eschenmoser Synthesis of B-Ring Intermediate 8 . WS The Woodward Synthesis of C-Ring Intermediate 9 . The Eschenmoser Synthesis of C-Ring Intermediate 9 . - a7 ‘The Eschenmoser Synthesis of Thiodextrolin (7) . ‘The Woodward-Eschenmoser Mactocyclization Strategy ..... The Eschenmoser Synthesis of A-Ring Intermediate 24 and D-Ring Intermediate 25 ........ : The Eschenmoser Cyclization Strategy ne Completion of the Woodward-Eschenmoser Total Synthesis, of Coby. ‘Acid and Vitamin Biz . Conclusion paaeenee Chapter 9 Prostaglandin Az (PGA2) and Prostaglandin F2q (PGF 2a) G. Stork (1976, 1978) 9.1 Introduction oe 9.2 Retrosynthetic Analysis and Strategy for PGA2 9.3 Total Synthesis of PGA2... . oe 944 Retrosymthetc Analysis and Strategy f ‘for PGFs. i" 9.5 Total Synthesis of PGF2a - . 9.6 Conclusion ......... : Chapter 10 Estrone K.P.C. Vollhardt (1977) 10.1 Introduction . pee eee e eee 10.2 Retrosynthetic Amys a ‘and Sustepy 10.3 Total Synthesis . 10.4 Conclusion . 99 ‘100 105 - 105 113, us 121 123 126 130 . 134 . 137 138 140 144 146 151 . 153 160 © 162 - 165Table of Contents Chapter 11 Erythronolide B E.J. Corey (1978) I Introduction . a 11.2... Retrosynthetic Analysis and Suategy 5 11.3 Total Synthesis . . . il Conclusion . Chapter 12 Monensin ¥. Kishi (1979) 12.1 12.2 123 12.4 Introduction , Retrosynthetic Analysis: and Siategy Total Synthesis . Conclusion. . Chapter 13 Periplanone B WC. Still (1979) 13.1 13.2 13.3 13.4 Introduction . Retrosynthetic Analysis and Site Total Synthesis Conclusion . Chapter 14 Isocomene M.C. Pirrung (1979) 14.1 14.2 143 14.4 Introduction .. . . Retrosynthetic Analysis and Surteey Total Synthesis Conclusion 167 - 169 172 183 ~ 185 - 187 - 194 - 207 - 21 212 215 219 221 - 221 223 1. 225Table of Contents Chapter 15 Monensin W.G, Still (1980) 15.1 Introduction . 2207 15.2 Retrosynthetic Analysis and Siteay : 230 15.3. Total Synthesis. ......... » 238 15.4 Conclusion 246 Chapter 16 Thienamycin Merck (1980) 16.1 Introduction . . .. . 249 16.2 Retrosyntete Analysis and Strategy : 250 251 . 262 16.3 Total Synthesis 16.4 Conclusion . Chapter 17 Endiandric Acids A-D K.C. Nicolaou (1982) 265 267 17.1 Introduction... 06. eee 17.2 Retrosynthetic Analysis and Strategy 17.3. Total Synthesis ....... 270 17.3.1 Stepwise, Stereocontrolled Total Synthesis of Endiandric Acids A-D (and E-G).......-....- +. 270 17.3.2. “Biomimetic”, One-Step Total Synthesis of Endiandric Acids A- D (and E-G) pee eel 17.4 Conclusion eee 283 Chapter 18 Biotin Hoffmann-La Roche (1982) 18.1 Introduction . 5 veces 285 182 Retrosynthetic Analysis and Swateny ce eee esses ees 286 isaieeroml symbole ere eee) 18.4 Conclusion : 291 xviXVII Table of Contents Chapter 19 L-Hexoses S. Masamune and K.B. Sharpless (1983) 19.1 Introduction a wee eens 293 19.2 Retrosynthetic Analysis a ‘and | Seatey - cess. 298 19,3 Total Synthesis . wee 310 19.4 Conclusion ......... Chapter 20 Asteltoxin S.L. Schreiber (1983) 20.1 Introduction 20.2 Retrosynthetic Analys 20.3 Total Synthesis 204 Conclusion ..... 02... sees and Strategy... . Chapter 21 Periplanone B S.L. Schreiber (1984) 21.1 Introduction . . bese 333, 21.2 Retrosynthetic Analysis and Seay : 336 21.3 Total Synthesis ..... 2. 337 214 Conclusion 2... eeec cece. 340 Chapter 22 Menthol Takasago (1984) 22.1 Introduction... bee eeee eens 343 22.2 Retrosynthetic Analysis and: Suatey peer 354) 22.3. Total Synthesis... oe 355 22.4 Conclusion ...... 0... 357 22.5 Appendix: Catalytic Asymmetie Restos, an Overview ..... fee eeete access 388Table of Contents Chapter 23 Hirsutene and A%!2)_Capnellene D.P. Curran (1986) 23,1 Introduction 381 232 Retrosynthetic Analysis and Strategy. 409 23.3. Total Synthesis. 410 23.4 Conclusion. . 416 Chapter 24 Amphoteronolide B and Amphotericin B K.C. Nicolaou (1987) 24.1. Introduction . 421 24.1.1 Degradation Studies 421 24.2 Retrosynthetic Analysis and Strategy 425 24.3. Total Synthesis. 429 24.3.1 Construction of Building Blocks 16 and 19 429 24.3.2 Construction of Building Blocks 17 and 18: ‘The Carbohydrate Approach .... . 432 24.3.3 Construction of Building Blocks 17 and 18: The Sharpless Asymmetric Epoxidation Approach... 434 24.3.4 Completion of the Synthesis of Amphoteronolide B 438 24.3.5 Completion of the Synthesis of | Amphotericin B 444 24.4 Conclusion . 448 Chapter 25 Ginkgolide B E.J. Corey (1988) 25.1 Introduction... see eee cee cece eee . 451 25.2 Retrosynthetic Analysis and Strategy 452 25.3 Total Synthesi 456 25.4 Conclusion . 463 XIXTabie of Contents Chapter 26 Methyl Homosecodaphniphyllate C.H. Heathcock (1988) 26.1 Introduction 26.2 Retrosynthetic Analysis and sineay 26.3 Total Synthesis 264 Conclusion Chapter 27 Indolizomycin S.J. Danishefsky (1990) 27.1 Introduction... . 27.2 Retrosynthetic Analysis a and Seateey 27.3 Total Synthesis... 27.4 Conclusion Chapter 28 Cytovaricin D.A. Evans (1990) 28.1 Introduction ee 28.2. Retrosynthetic Analysis and Strategy 28.3 Total Synthesis... 28.3.1 Synthesis of Spiroketal Subunit 6. 28.3.2. Synthesis of Polyol Glycoside Subunit 28.3.3 Synthesis of Seco Acid 4 and Completion of the. Total Synthesis of Cytovaicin L 28.4 Conclusion . senna - 465 465 1. 467 469 .. 471 472 483 - 485 487 . 491 491 497, - 503 506Table of Contents Chapter 29 Gilvocarcin M and Gilvocarcin V K. Suzuki (1992, 1994) 29.1 Introduction... .. . 509 29.2 Retrosynthetic Aodyss and Sateey 510 29.3 Total Synthesis 512 29.4 Conclusion 519 Chapter 30 ; eee Calicheamicin y} K.C. Nicolaou (1992) 30.1, Introduction ..... beceveeee eee 523 30.2 Retrosynthetic Analysis and Sutey « wees 525 30.3 Total Synthesis ..... ». 535 30.3.1 Synthesis of Oligosaccharide 8 « - 535) 30.3.2 Synthesis of Aglycon 5 ..... 548 30.3.3. Coupling of Intermediates 8 and 9 and Completion of the Total Synthesis of Calicheamicin a a . 556 30.4 Conclusion ....... bec cee sees 562 Chapter 31 Rapamycin K.C. Nicolaou (1993) Sis] guinioductione re eee cree te 565 31.1.4 The Heck Reaction. bevee ees , 566 31.1.2 Palladium-Catalyzed Cycloisomerizations . . . ». 528 31.1.3 The Stephens-Castro and the Sonogashira Coupings - 582 31.1.4 The Suzuki Coupling » 586 31.1.5 The Stille Coupling 31.2 Retrosynthetic Analysis and Strategy 31.3. Total Synthesis ............... .. 591 . 599 607 31.3.1. Synthesis of Intermediates 147 and 158-160 » 607 31.3.2 Coupling of Key Intermediates 147 and 158-160... . 620 31.3.3 Final Stages and Cyclization to Rapamycin ........ ..624 31.4 Conclusion ....... 6.6.2 e cece eee «++ 626Table of Contents Chapter 32 Paeoniflorigenin and Paeoniflorin E.J. Corey (1993) B21 Introduction .... 00... ceeeeseeeveesee eee 633 32.3 Retrosynthetic Analysis and Strategy... te. 633 32.3. Total Synthesis ........ 636 32.4 Conclusion .. 640 Chapter 33 Strychnine LE. Overman (1993) 33.1 Introduction -... O41 33.2 Retrosynthetic Analysis and Strategy ..... «. 643 33.3. Total Synthesis. ven : - 646 33.4 Conclusion 652 Chapter 34 Taxol K.C. Nicolaou (1994) 34.1 Introduction... . bee +. 635 34.2 Retrosynthetic Analysis and Strategy... 2.2... 656 34.3. Total Synthesis ceeeees . vee 660 34.4 Conelusion 2.02... veeveeeee OTL Chapter 35 Zaragozic Acid A/ Squalestatin S1 K.C. Nicolaou (1994) 35.1 Introduction . 673 35.1.1 The Asymmetric Dihydroxylation .. . 675 35.2 Retrosynthetic Analysis and Strategy . 691 35.3. Total Synthesis... bees. 694 35.3.1 Degradation and Reconstitution Chemistry + 694 35.3.2 Synthesis of Key Intermediate Aldehyde 68 695 35.3.3 Model Studies ....... cette eee eee eee es 699Table of Contents 35.3.4. Synthesis of the Side Chains : - 702 35.35 Coupling of Key Intermediates and Completion ofthe Total Synthesis of Zaragozic Acid id A/Squaesain SI. 704 35.4 Conclusion ....... 0... 0eeereee ener ees » 707 Chapter 36 Palytoxin ¥, Kishi (1994) 36.1 Introduction . . . 7 36.1.1 The NiCl/CrCl Coupling Reaction viernes 2 36.2 Retrosynthetic Analysis and Strategy 17 36.3 Total Synthesis pegeoogd : 719 364 Conclusion ..........00seceeeeeeeeeeeeees 729 Chapter 37 Brevetoxin B K.C. Nicolaou (1995) 37.1 Introdu 21 371.1 The Invention and Development of New Synthetic Methods ........00000005 73 a, Tetrahydropyran Systems +. 733 b. Didehydrooxocane . . - 73S c. Oxepane Systems . Te 237 37.2. Retrosynthetic Analysis and Strategy . veces THB. 37.2.1 The Triply Convergent Approach The First-Generation Strategy vee 750 37.2.2 Stepwise Bis(oxepane) Synthesis Approach: ‘The Second-Generation Strategy seve neces 752 37.2.3. The Doubly Convergent Approach with Stepwise Formation of the Bis(oxepane) System: ‘The Third-Generation Strategy .......-+-++ . 155 37.3. Total Synthesis. palio060 762 37.3.1 Synthesis of IK Framework 86... beeen s 762 37.3.2. Synthesis of ABCDEFG Framework 87 ........... 768 37.3.3 Final Stages and Completion of the Total Synthesis of Brevetoxin B.......--00eceee 00ers wees TBI 374 Conclusion . 784 Author Index ............ Pees 787 Subject Index veces et ete eet ec ee ces 189 XxiIlIntroduction: Constructing the Molecules of Nature The world is made of two parts, the full (pleres, stereon) and the empty, the vacuum (cenon, manon). The fullness is divid- ed into small particles called atoms (atomon, that cannot be cut, indivisible), The atoms are infinite in number, eternal, absolutely simple; they are all alike in quality but differ in shape, order, and position. Every substance, every single object, is made up of those atoms, the possible combinations of which are infinite in an infinity of ways. The objects exist as long as the atoms constituting them remain together: they cease to exist when their atoms move away from one another. The endless changes of reality are due to the con- tinual ageregation and disaggregation of atoms. Democritus, fifth century B.C.! With remarkable accuracy, Democritus in the fifth century B.C. set the stage for modern chemistry. His atomic theory of matter, which he formulated without experimental verification, still stands, more or less intact, and encapsulates the profound truth that nature's stunning wealth boils down to atoms and molecules. As science uncovers the mysteries of the world around us, we stand ever more in awe of nature’s ingenious molecular designs and biological sys- tems: nucleic acids, saccharides, proteins, and secondary metabo- lites are four classes of wondrous molecules that nature synthesizes with remarkable ease, and uses with admirable precision in the assembly and function of living systems Me at Democritus1 Introduction: Constructing the Molecules of Nature The chemical synthesis of nature's molecules without the aid of enzymes often presents formidable challenges to human ingenuity and skill. While chemical processes for the synthesis of oligonu- cleotides and peptides are now well developed and quite routine, nature’s secondary metabolites, commonly known as natural pro- ducts, are not always easy to construct in the laboratory. Their structures exist in an almost infinite range of complexity and stabi- lity and, therefore, often present distinct synthetic problems which require unique strategies and tactics for their solution. It is this almost unlimited variation in structure and the constant discovery of new molecular constructs that keeps the field of natural products synthesis so attractive and vibrant. The dazzling biological proper- ties exhibited by many natural products and the attendant opportu- nities these molecules offer for probing biological questions also serve as major attractions in this field of investigation. The con- structing of nature’s molecules in the laboratory from atoms and/or simple molecules, a process often known as oral synthesis, is one of the most demanding human practices. For this reason, training in this field is considered highly valuable, attractive, and rewarding, particularly to those who enjoy challenge and those who wish to acquire the awesome power of creating new chemical entities. In order to put total synthesis into proper perspective, a brief overview of synthetic chemistry would be instructive, 1.1 Synthetic Chemistry and Total Synthesis Synthetic chemistry (from the Greek word synthesis = the process ‘of putting together) is the science of constructing molecules from atoms and/or (usually) simpler molecules. The discipline may be subdivided, according to the molecules involved, into synthetic organic chemistry and synthetic inorganic chemistry. The term organic synthesis is often used - maybe incorrectly in strict terms despite common usage and history? ~ to mean the same as synthetic organic chemistry. Even the phrase chemical synthesis is some- times used to designate the science of synthetic chemistry, although strictly speaking chemical synthesis is the process by which a parti- cular molecule is synthesized in the laboratory. Total synthesis is the chemical synthesis of a molecule, usually a natural product, from relatively simple starting materials and is to be distinguished from partial synthesis ot semisynthesis which designates the synthesis of a given molecule from an advanced pre- cursor related to it, which may or may not be a natural product itself. Again, the term total synthesis has evolved to commonly also mean the science of constructing molecules from simple frag- ments. For the purposes of this book we will use the broader mean- ings of these terms.1.2. The Scope of Organic Synthesis, 1.2. The Scope of Organic Synthesis “There is excitement, adventure, and challenge, and there can be great art in organic synthesis.” R.B. Woodward* “The organic chemist is more than a logician and strategist; he is an explorer strongly influenced to speculate, to imag- ine, and even to create, These added elements provide the touch of artistry which can be included in a cataloging of the basic principles of synthesis but they are very real and extremely important.” E.J. Corey* With these words, Woodward and Corey, arguably the two undis- puted masters of the art and science of organic synthesis, describe the heart and soul of the subject. The practice and advancement of the field of organic synthesis requires and cultivates some of the most sophisticated virtues and talents of human nature: knowledge, creativity, geometric and artistic perception, stamina, and courage. The centrality of the field of organic synthesis to chemistry in particular, and to the other sciences in general, lies not only in its capacity to deliver substances for further studies and usage, but more significantly in its capacity to create new entities that have not been seen before. The beneficial impact of this field on the health and welfare of society is beyond question, particularly when we make the connection between science and civil progress, as we know it, via technology. Several of the millions of organic com- pounds made over the last century and a half through chemical synthesis are directly linked to important applications in everyday life: pharmaceuticals that can cure or prevent diseases, antifertility agents for population control, insecticides, pesticides, plant and ani- mal hormones to increase food production and nutritional quali polymers, fabrics, dyes. cosmetics, detergents, photographic and electronic items, and other high-technology materials used in auto. mobile, aircraft, and computer industries, are but some examples of such marvelous inventions The impact of this science on biology and medicine in particular merits special mention and is becoming more evident as we approach the next century and as the power of organic synthesis increases with new advances in the field. The ultimate goal of organic synthesis is to assemble a given organic compound (targer molecule, usually a combination of atoms from the following group of elements: C. H. 0. N, S, P, halo- gens, and B) from readily available starting materials and reagents in the most efficient way. This process usually begins with the design of a synthetic plan (strategy, vide infra) which calls upon various synthetic reactions to address individual synthetic objec- tives in a certain sequence. Jf a transformation or a strategic mancu- ver required by the synthetic plan has not been demonstrated before, the plan must rely on the development of a suitable syn- R.B. Woodward4 1 Introduction: Constructing the Molecules of Nature thetic method or tactic to solve the particular problem at hand. Thus, the science of organic synthesis is constantly enriched by new inventions and discoveries pursued deliberately for their own sake or as subgoals within a program directed towards the synthesis of a target molecule. Despite great strides, organic synthesis should still be viewed as youthful science. It is also a powerful tool for several other disci- plines, including biology, physics, materials science, and medicine. As a field, organic synthesis can be divided into two major areas with further subdivisions as illustrated in Figure 1. The invention, discovery, and development of new synthetic reactions, reagents, and catalysts are grouped under the area of synthetic methodology, or methods-oriented synthesis, whereas the synthetic pursuit of a defined molecule, natural or designed, is classified under sarger- oriented synthesis (total synthesis is included in this category). ORGANIC SYNTHESIS Methods Oriented } Natural Designed thetic ff} Synthet Products ] otezuies ] Reagents } Catatate ] Strategies | Fates ] Materials Science Biologically Theoretically Medically Interesting Interesting, Interesting Interesting Molecules. Molecules. Molecules Molecules. Figure 1. Organic synthesis in perspective.1.3. A Brief History of Organic Synthesis 1.3. A Brief History of Organic Synthesis Organic synthesis has a long history that can be traced back to ancient times, although at first it was not recognized as such, because it was practiced randomly and strictly heuristically. As a science, organic synthesis is relatively young, its beginning being marked by the rational synthesis of urea [CO(NH2)2) by Wohler in 1828° (see Figure 2). This synthesis was followed by other mile- stones such as the synthesis of acetic acid® (Kolbe, 1845), glucose? (Fischer, 1890), a-terpineol® (Perkin, 1904), camphor? (Komppa, 1903; Perkin, 1904), tropinone! (Robinson, 1917), haemin'! (Fischer, 1929), equilenin'? (Bachmann, 1939), pyridoxine hydro- chloride! (Folkers, 1939), and quinine'* (Woodward and Doering, 1944), ° wn " Me urea acetic acid lucose cxterpineo! (Wehier, 1828) (Kolbe, 1845) (Fischer, 1890) (Perkin, 1904) A, tropinone (Robinson, 1917) noe haemin (Fischer, 1929) Ho" Mo Me cequitonin pytidoxine hydrochloride Quinine (Bachmann, 1939) (Folkers, 1939) (Woodward & Doering, 1944) Figure 2. Selected landmark total syntheses of natural products from 1828 to 1944,6 1. Introduction: Constructing the Molecules of Nature ‘Table 1. Nobel Prize winners in organic synthesis and related fields.'5 Year Nobel Laureate(s) Work 1902. Emil Fischer sugars and purine syntheses 1905 Adolf von Baeyer advancement of organic chemistry and the chemical industry, through his work on organic dyes and hydroaromatic compounds 1910 Otto Wallach pioneering work in the field of alicyclic compounds, 1912 Victor Grignard and (V. G.) discovery of the Grignard reagent, (P. S.) hydrogenating Paul Sabatier organic compounds in the presence of finely disintegrated metals 1928 Adolf Windaus research into the constitution of the sterols and the connection with the vitamins 1930 Hans Fischer research into the constitution of haemin and chlorophyll and especially for his synthesis of haemin 1937 Walter Haworth and (W. H.) investigations on carbohydrates, vitamin C and (P.K,) Paul Kamer investigation of carotenoids, flavins, and vitamins A and Bz 1939 Leopold Ruzicka work on polymethylenes and higher terpenes 1947 Robert Robinson investigations on plant products of biological importance, especially the alkaloids 1950 Otto Diels and Kurt Alder discovery and development of the diene synthesis 1955 Vincent du Vigneaud work on biochemically important sulfur compounds, especially for the first synthesis of a polypeptide hormone 1963 Karl Ziegler and Giulio Natta discoveries in the field of the chemistry and technology of high polymers 1965 Robert Burns Woodward achievements in the art of organic synthesis 1968 H. Gobind Khorana (medicine) interpretations of the genetic code and its function in protein synthesis 1969 Derek H.R, Barton and development of the concept of conformation and its application Odd Hassel in chemistry 1975. Vladimir Prelog and (V. P) stereochemistry of organie molecules and reactions, John W. Comforth (J. C.) stereochemistry of enzyme-catalyzed reactions 1979 Herhert C. Brown and development of boron (H. C. B.) and phosphorus (G. W.) com- Georg Wittig pounds into important reagents in organic synthesis 1981 Roald Hoffmann and development of theories conceming the course of chemical Kenichi Fukui reactions 1984 R. Bruce Merrifield development of methodology for chemical synthesis on a solid matrix 1987 Donald J. Cram, Jean-Marie Lehn, development and use of molecules with structure-specific and Charles J. Pedersen interactions of high selectivity 1990 Elias J. Corey development of the theory and methodology of organic synthesis 1904 George A. Olah contributions to carbocation chemistry1.4 The Practice of Total Synthesis It was, however, after World War II that organic synthesis and the total synthesis of natural products, in particular, flourished, and many impressive achievements were recorded in rapid succession. With the arrival of R.B. Woodward and his foresight, complex structures fell one after another, total synthesis progressed enorm- ously, and the discipline enjoyed unparalleled respect among the sciences. The theme was taken to even higher levels of sophistica- tion and power by the Corey school. This was achieved by the introduction, on a systematic footing, of the concepts of retrosyn- thetic analysis (vide infra) and the emphasis on new synthetic technology as part of the synthetic program. The importance of organic synthesis to chemistry and its periph- eral sciences is clearly evidenced by the frequency with which Nobel Prizes have been awarded to practitioners of this and related fields (Table 1).'5 The drive towards higher levels of achievement in organic syn- thesis, both in terms of methodology and in terms of complexity of targets, remains unabated, The science is driven by the continuous discovery of novel and complex structures from nature that fasci- nate and challenge synthetic organic chemists, and by the need to improve our ability to synthesize organic molecules in more effi- cient and economical ways. Given the almost infinite molecular structures that chemists are likely to discover or imagine and the ever-increasing need for new chemical entities, these driving forces are likely to persist for some time to come. Refinements in analyti- cal, chromatographic, and spectroscopic techniques also contribute to and facilitate the advancement of the science of organic syn- thesis. Several texts, serial publications, treatises, and journals are dedicated to extensively monitoring the field and no doubt will continue to do so. 1.4 The Practice of Total Synthesis With its share of glorious moments, setbacks, and frustrations, total synthesis can be compared to the game of chess. The object of this game is to capture the opponent's king by a series of allowed moves played out in such a combination and order as to outmaneu- ver the opponent. Similarly, in total synthesis the object is to reach the target molecule by a series of reactions (allowed by nature) which have to be carried out in the right sequence to outmaneuver natural barriers. Studying and applying the moves (reactions) to capture the king (make the molecule) then becomes the object of total synthesis.|. Danishefsky 1 Introduction: Constructing the Molecules of Nature The practice and elegance of total synthesis involves and depends on the following stages 1. Selection of the target molecule; natural product, designed molecule 2. Design of the synthetic strategy: retrosynthetic analysis 3. Selection of the reagents and conditions: tactics 4. Experimental execution of the synthesis: dexterity, stamina Depending on the degree of difficulty encountered in the execution of the synthesis, there is often considerable interplay and readjust- ment of strategy and tactics before eventual success can be achieved. Thus, one should really add the often inevitable fifth stage ~ redesign of strategy and tactics — to the above four phases of total synthesis. The elegance and aesthetic appeal of the resulting total synthesis heavily depends on these five stages. 1.5 Target Molecules “There is no denying (nor should there be any need to deny!) that the sheer sense of challenge posed by a complex molecular target serves to stimulate the creative impulses of the synthetic chemist.” S.J. Danishefsky!® Unless the target molecule is predefined, the selection of such a compound is not a trivial matter, for the selected molecule will determine and direct the path of discovery of new synthetic strate- gies and methods and new chemical entities. In other words, the target molecule defines to a large extent the research program that lies ahead and the opportunities to be encountered and exploited. Depending on the setting and specific goals of the synthetic chemist, different criteria are used for selecting target molecules. Thus, in academically oriented laboratories where the quest for basic science, competitiveness in the pursuit of excellence, and peer recognition are of primary concern, the target molecules are often selected for their potential to offer opportunities for the development of new synthetic technologies and strategies, to explore and probe biological questions, and to deliver interesting and impressive substances, In industrial laboratories, on the other hand, where emphasis is on commercial exploitation, the target molecules are selected for their potential to lead to practical and profitable applications. Synthetic targets are usually either natural products or designed molecules.1.6 Natural Products as Synthetic Targets 1.6 Natural Products as Synthetic Targets “The synthesis of substances occurring in Nature, perhaps in greater measure than activities in any other area of or- ganic chemistry, provides a measure of the condition and power of the science.” R.B. Woodward’? “Nature continues to be exceedingly generous to the synthet- ic chemist in providing ample opportunity for discovery and creative endeavor of highest magnitude and in surrounding him with an incredible variety of fascinating and complicat- ed structures.” |. Corey"® “Natural product synthesis poses the challenge to consider and develop new pathways of structural transformation. Natural products as targets for synthetic research possess a special fenility in this regard, because the structural chan- nels of biosynthesis are not necessarily the conduits of or- ganic synthesis.” A. Eschenmoser!? Ever since synthetic organic chemists realized their ability to assemble molecules from the elements and other simple starting materials, natural products served to fascinate and challenge them. In the classical era, the purpose of a total synthesis was to confirm the molecular structure of a natural product, but as powerful ana- lytical techniques emerged, especially X-ray crystallography and NMR spectroscopy, this is now rarely necessary. In the meantime, however, other reasons for total synthesis have evolved. Amongst the most important are: (a) the challenge, which is often irresistible to those who appreciate and practice the art of synthesizing a matt rally occurring substance of novel architecture; (b) the opportunity to discover and develop new synthetic chemistry that will solve, not only the problem under consideration, but also problems of broader interest; (c) the ability to make contributions in biology by providing not only the natural substance when supply is an issue, but also by making available designed molecules that may mimic or inhibit the action of the natural product; (d) the need to develop a process for the large-scale production of the natural product when utility and natural abundance dictate it; and (e) the sheer excitement of the endeavor! ‘There is wisdom and truth in the statement that natural products, and not designed molecules, provide the ultimate challenges to syn- thetic chemists. The designer can always adjust his designed targets to fit existing synthetic methods, whereas nature has no mercy on the synthetic chemist. If, for example, a methyl group is present in a molecule in a certain configuration, that group has to be installed in its proper place! Often a seemingly trivial structural feature forces the practitioner to imagine and create new science, for there are no compromises in the science of total synthesis. A, Eschenmoser10 D.H.R. Barton K.B. Sharpless 1 Introduction: Constructing the Molecules of Nature Since the syntheses of urea and acetic acid in 1828 and 1845, respectively, synthetic chemists have come a long way in terms of the complexity of the target molecules they can reach. Progress was at first steady, but became rather dramatic in the second half of the 20th century. Vitamin By, ginkgolide B, calicheamicin 74}, taxol, palytoxin, and brevetoxin B (Figure 3) are arguably six of the most impressive molecules to be synthesized to date. Such accomplishments prompt comments such as “given enough manpower and money, synthetic chemists can make any complex molecule”; with such statements, attempts are made to criticize research in this field by declaring it mature and even dead! How unwise these statements are, for one only has to compare our syn- thetic power with that of nature in order to recognize the rather pri- mitive state of the art. One message is clear: more expedient and economical processes are still needed to construct complex mole- cules, and this status will not change for some time to come. Asym- metric synthesis and catalysis are frontiers of enormous potential. Natural products provide wonderful opportunities for the develop- ment of new synthetic technologies and strategies for chemical synthesis. The following quotations from three masters of the science of inventing new reactions are appropriate here. “When we have been faced with a problem of effecting a chemical synthesis we have sought known methods. We have not paused to think why we do not invent a new method every time. If we adopt this philosophy we are going to be extremely busy till the end of the century (a) trying to equal the enzymes, and (b) thinking of new ways of synthesis.” Sir Derek H.R. Barton? “I believe that, for those who seek to discover new reac- tions, the most insightful lessons come from trying to trace important reactivity principles back to their origins.” K.B. Sharpless?! “In defining strategies and reactions to construct complex molecules we require synthetic methods that can (i) perform @ wanted structural change and none other (that is be chemoselective), (ii) orient the reacting partners in a correct fashion (be regioselective), (iii) create the correct orienta- tions of the various parts of the molecule with respect to each other (be diastereoselective), and (iv) enable the for- mation of a molecule of one handedness or a mirror image isomer (be enantioselective). Such extraordinary demands are exciting challenges.” B.M. Trost?1.6 Natural Products as Synthetic Targets ‘lnkgotide B (1988) Ho., Med ‘calicheamicin ;!(1992) Taxoi™ (1994) brevetoxin 8 (1995) Figure 3. Some of the most complex natural products synthesized to date. "112 1 Introduction: Constructing the Molecules of Nature Nonetheless, the standards and expectations for a total synthesis are different today than they were years ago, and an important new era for this field seems to be on the horizon. Thus, today we witness novel natural products providing unique opportunities for the devel- opment of new synthetic strategies and new synthetic technologies, and associated programs of molecular design, chemical synthesis, and biological investigation of synthetic molecules related to the natural products at hand. The interface of the chemistry and biology of natural products with chemical synthesis as the bridging tool between the two disciplines provides a major new area of research. Medicine will no doubt be a major beneficiary of this practice. 1.7 Designed Molecules as Synthetic Targets “This opens wide the door to the creative imagination of the chemist at the meeting point of chemistry with biology and physics, in order not only to discover but above all to invent, to create: the score of chemistry is not just to be played but 10 be composed! The essence of chemical science thus finds its full expression in the words of Leonardo da Vinci: ‘Where nature finishes producing its own species, man begins, using natural things and in harmony with this very nature, to create an infinity of species.’” J.-M, Lehn? The heart and the beauty of chemistry lies in its creative nature. On the basis of simple structural principles, the organic chemist is free to imagine and design unlimited numbers of new molecules never seen before either in nature or in the laboratory. This molecular design process is often guided by the particular interests of the chemist and can be aided by computer or manual molecular model- ing studies, Depending on the area, the designed molecules can be of theoretical, physical, materials science, or biological interest. These designed molecules then become potential targets for the synthetic chemist, and although some may look deceptively simple, they regularly present formidable challenges. Examples of designed molecules of theoretical interest (which may eventually attract a more practical interest depending on their properties) that have been synthesized in the laboratory are: tetrahedrane, prismane, cubane, dodecahedrane, [18]-annulene, heptahelicene, and various other “aesthetically pleasing molecular constructs. Undoubtedly, however, the most fertile area of molecular design for the organic chemist is that of biologically interesting molecules. The fascina- tion of biological action and of how living systems work, coupled with the potential for biomedical breakthroughs has prompted an avalanche of molecular design in academia and in the pharmaceuti-1.8 Synthetic Strategy cal industry, a trend that is continuously aided by the isolation and structural elucidation of both new biological receptors and of novel biologically active natural products. Frequently, the new molecular designs are based on the structures of bioactive natural products, or simply on principles of organic chemistry. It is thus hoped that their structure and chemical reactivity is translated into a specific biolog- ical action. Chemical synthesis followed by biological evaluation ‘may then confirm or disprove the design hypothesis thus leading to useful information for further studies. Today, the interplay of mole~ cular design, chemical synthesis, and biological evaluation is a powerful multidisciplinary approach to research at the chemistry- biology interface and to drug discovery and development. Numer- ous clinically useful drugs were discovered through this approach, including antibiotics, antiulcer drugs, and anticancer agents. Mole- cules for molecular recognition studies also fall into the category of designed: molecules. They include cryptands, spherands, self-repli- cating systems, self-assembling systems, DNA-binding molecules, nanotubes, and artificial molecular receptors. Combinatorial chemistry, a new chapter of organic synthesis, is now developing rapidly. This new approach to synthesizing large designed or random chemical libraries through application of solid phase synthetic methods, promises to revolutionize the process of drug discovery in the pharmaceutical industry.™* 1.8 Synthetic Strategy Faced with a target molecule, how does a synthetic chemist go about devising a synthetic plan for its construction? For a chemist considering @ complex molecule containing many sensitive func- tional groups, rings, elements of stereochemistry, and unusual bond connectivities, this question presents a challenge requiring logical analysis and intellectual input of the highest order. In the early days of the science, when relatively simple targets were considered, the chemist would try to connect potential starting materials with the target molecule by known reactions. The starting materials were often closely related to the final products. As the target molecules became more complex, this process became impractical. Higher levels of intellectual planning and skill in execution were demanded. Synthetic chemists rose to the challenge by devising a new armory of methods and novel strategies. As the field of total synthesis developed and its intellectual demands were recognized, the science was received with much excitement and euphoria. The contributions of R.B, Woodward and the developments in the elec- tronic theory and mechanisms of organic reactions, conformational analysis, analytical and chromatographic techniques, crystallo- graphic and spectroscopic methods, and new synthetic technology that took place after World War II greatly facilitated this outburst of 1314 1 Introduction: Constructing the Molecules of Nature activity in the field and placed synthesis on center stage. As a strat- egist, the synthetic chemist quickly became a master of the art with formidable targets falling one after the other, and each new accomplishment pushing the envelope further and further in terms of complexity and efficiency. Landmark syntheses such as strych- nine (Woodward, 1954),25 reserpine (Woodward, 1956),”° penicillin V (Sheehan, 1957),27 colchicine (Eschenmoser, 1959),?* and chloro- phyll (Woodward, 1960)°° are monuments to the ingenuity and character of the chemists of this era. Thinking about synthetic strat- egy, however brilliant as it was, was not formulated into a system- atic and universal approach until E.J. Corey introduced retrosyn- thetic analysis in the 1960s. 1.9 Retrosynthetic Analysis “Retrosynthetic (or antithetic) analysis is a problem-solving technique for transforming the structure of a synthetic target (IGT) molecule 10 a sequence of progressively simpler structures along a pathway which ultimately leads to simple or commercially available starting materials for a chemical synthesis. The transformation of a molecule to a synthetic precursor is accomplished by the application of a transform, the exact reverse of a synthetic reaction, to a target struc- ture, Each structure derived antithetically from a TGT then itself becomes a TGT for further analysis. Repetition of this process eventually produces a tree of intermediates having chemical structures as nodes and pathways from bottom to top corresponding to possible synthetic routes to the TGT." E.J. Corey With these words, E.J. Corey defines for us the concept of retro- synthetic analysis for which he received the Nobel Prize in chemis- try in 1990, Nowadays, it has become routine to think about a tar- get molecule in terms of its retrosynthetic analysis. Furthermore, it is hard to imagine how chemists developed synthetic strategies prior to the formulation of these concepts in the 1960s, without thinking, at least subconsciously, in these terms about complex organic structures. Typically the synthetic strategist when faced with a new chal- lenge focuses on the target, pondering and analyzing the proposed structure and identifying strategic bonds that may be advanta- geously disconnected in the retrosynthetic sense. Several such bonds and disconnections may become apparent either as a sequence to simplify the structure, or as alternative approaches to such simplification. In a parallel mental process, the synthetic chemist also asks and attempts to answer the question of how to construct, in the synthetic direction, each bond broken by retro-1.9 Retrosynthetic Analysis synthesis, and how, if possible at all, to convert the simpler inter- mediates so generated to the more advanced targets in the retrosyn- thetic scheme. This can be an exhilarating experience, particularly at moments of brilliant flashes of inspiration, as perceived, of course, by the practitioner, The key to success at this stage is to be quite thorough and to uncover subtle features of the structure under consideration that may lead to elegant and efficient synthetic schemes, Hastiness and compromise have no place in such planning and should be avoided. Instead, forcing oneself to upgrade and refine the retrosynthetic analysis, always aiming to apply novel dis- connections and unprecedented maneuvers, frequently proves rewarding. Having exhausted all retrosynthetic possibilities, the strategist is then in a position to evaluate the possible paths uncovered and devise the most attractive synthetic strategy for the construction of the target molecule. The strategy may dictate the invention of new reactions, reagents, and tactics, and may require model studies before synthesis of the real target can start. This is usually a good practice, for it is destined, more often than not, to result in new synthetic technology, a vital feature of a novel total synthesis, and to pave the way for a projected total synthesis. Other attractive fea- tures of a planned synthetic strategy are: (a) efficient synthetic reac- tions; (b) brevity; (c) readily available and inexpensive starting materials; (d) practical and convenient conditions; (e) flexibility of modification in case of pitfalls; (f) adaptability to the synthesis of other members of the structural family, be they naturally occurring or designed molecules; and (g) novelty, elegance, and artistry! It is of paramount importance to recognize that in total synthesi the achievement itself is not always the prize or the most significant advance. Rather, it is the journey towards the target molecule that becomes the essence and significance of the exercise. The invention and development of new synthetic technology and strategies, and the molecular design, chemical synthesis, and biological investiga- tion of bioactive compounds structurally related to the target are two emerging and important aspects of modern total synthesis. Chemists and biologists will no doubt be busy for a long time har- vesting the benefits of this newly emerging field of investigation that combines the best of chemistry and biology. The following quotes from R.B. Woodward and C.P. Cavafy, a contemporary Greek poet, amplify the real essence of total syn- thesis in a chemical and more general sense, respectively. “Chemical synthesis always has some element of planning in it. But, the planning should never be too rigid. Because, in fact, the specific objective which the synthetic chemist uses as the excuse for his activity is often not of special importance in the general sense; rather, the important things are those that he finds out in the course of attempting to reach his objective.” R.B. Woodward"! 1516 1. Introduction: Constructing the Molecules of Nature Ithaca When you start on your journey to ithaca, Then pray that the road is long, Full of adventure, full of knowledge, Do not fear the Lestrygonians And the Cyclopes and the angry Poseidon. You will never meet such as these on your path, If your thoughts remain lofty, if @ fine Emotion touches your body and your spirit. You will never meet the Lestrygorians, The Cyclopes and the fierce Poseidon, Wf you do not carry them within your soul, 1f your soul does not raise them up before you. Then pray the road is long. That the summer mornings are many, That you will enter ports seen for the first time With such pleasure, with such joy! Stop at Phoenician markets, And purchase fine merchandise, Mother-of-pear! and corals, amber and ebony, And pleasurable perfumes of all kinds, Buy as many pleasurable perfumes as you can; r Visit hosts of Egyptian cities, To lear and learn from those who have knowledge. i Always keep Ithaca fixed in your mind. To arrive there is your ultimate goal. But do not hurry the voyage at all. It is better to let it last for long years; ‘And even to anchor at the isle when you are old, Rich withal that you have gained on the way, Not expecting that Ithaca will offer you riches. Ithaca has given you the beautiful voyage. Without her you would never have taken the road. But she has nothing more to give you. CP. Cavafy And if you find her poor, Ithaca has not defrauded you. With the Great Wisdom you have gained, with so much experience, You must surely have understood by then what Ithacas mean. C.P. Cavaty%?4.10 Classics in Total Synthesis 1.10 Classics in Total Synthesis ‘One of the most difficult tasks we faced in writing this book was the selection of what we considered to be “classics” in the art of total synthesis, particularly under the pressure of space and time. With so much wealth and so many brilliant accomplishments it was hard 10 come to the inevitable close, We sincerely apologize to those whose elegant work could not be included owing to the limitations of this undertaking; and we can offer the hope, that in the event of a second volume, their masterpieces will be there. The chosen syntheses repre- sent both the Woodward and Corey eras, and project into the future in terms of the new criteria for target selection and expectations of the exercises. Each following chapter in this book describes a total syn- thesis of a natural product and is divided into the following sections: Introduction, Retrosynthetic Analysis and Strategy, Total Synthesis, and Conclusion; references are given separately in each chapter. Even though the natural products discussed are structurally distinct, the discussions of their syntheses revolve around similar themes: nat- ural origin and biological activity of the molecules, the concept of retrosynthetic analysis and the evolution of the synthetic strategy, important synthetic reactions and reagents, mechanistic concepts behind the reactions and stereoselectivities, and conclusions drawn from the experience of the syntheses are all presented in a unified approach. This presentation style reflects not only today’s systematic approach to total synthesis but also facilitates understanding of the basic principles involved in the synthesis of complex molecules. It is hoped that this approach will well serve those who wish to pursue the art of total synthesis and those who are destined to go beyond the boundaries set by the examples included in this book. An important objective of our undertaking was identifying and pro- jecting the important synthetic reactions in each total synthesis dis- cussed. Thus, considerable space has been devoted to presenting and analyzing important methodology. Amongst the reactions and con- cepts discussed are: the Woodward-Hoffmann rules, the cation-1 cyclization, the Diels-Alder reaction, the intramolecular nitrone and nitrile oxide/olefin cyclization, the Cope, oxy-Cope, aza-Cope, and Claisen [3,3] sigmatropic rearrangements, radicals in organic synthe- sis, the cobalt-mediated cyclization of acetylenic compounds, macro- lactonization reactions, Wittig and Homer-Wadsworth-Emmons reac- tions, the Evans aldol reaction, chelation-controlled carbonyl addition reactions, the Sharpless asymmetric epoxidation and asymmetric di- hydroxylation reactions, other catalytic asymmetric reactions, the Bergman cycloaromatization reaction of conjugated enediynes, the McMurry and Shapiro reactions, the Stille and related palladium-catal- yzed C-C bond forming reactions, the hydroxyepoxide-opening reac- tions for cyclic ether formation, [2+2] photo- and thermal cycloaddi- tions, NiCl;/CrCl-mediated C-C bond forming reaction, the bridging of macrocycles to bicycles, glycoside bond forming reactions, and a variety of novel cascade sequences and rearrangement reactions. 71 Introduction: Constructing the Molecules of Nature It should be emphasized that, for pedagogic purposes and in order to avoid long discussions and possible confusion, the Retro- and Strategy sections do not always present the original analysis and thoughts of the synthetic strategists involved. Rather, the final plan for the total synthesis is used to illustrate the retrosynthetic analysis. On occasion, mechanistic interpretations are offered, which are not found in the original papers and are, there- fore, speculations on our part. These are solely our responsibility, and we apologize in advance to the original authors for any misin- terpretations of their results. ‘We will now begin our journey in total synthesis from the 1950s to the 1990s. As you read through these pages we hope your jour- ney to “Ithaca” will be as adventurous, educational, and enjoyable as was our odyssey of putting together this book on “Classics in ion of the state of the art should serve to put total synthesis in perspective as the 20th century draws to a 18 synthetic Analy: Total Synthesis” This forty-year expo: close. References 10, u 12, Sarton, G. In Ancient Science Through the Golden Age of Greece, Dover Publications: New York, 1980, p. 253. - Corey, E.J.; Cheng, X.-M. The Logic of Chemical Synthesis, John Wiley & Sons: New York, 1989. Woodward, R.B. In Perspectives in Organic Chem istry, Todd, A.R., Ed., Interscience: New York, 1956, pp. 155-184 Corey, E.J. Pure & Appl. Chem. 1967, 14,19. . Wohier, F. Ann. Phys. Chem, 1828, 12, 253 Kolbe, H. Ann. Chem. Pharm. 1845, 54, 145. Fischer, E. Ber. Dtsch. Chem. Ges. 1890, 23, 799. (a) Perkin, W.H. J. Chem. Soc. 1904, 654; (b) See also, Fleming, I. Selected Organic Syntheses, John Wiley & Sons: New York, 1973. See, Thomas, A.F. In The Total Synthesis of Natural Products, ApSimon, J.. Ed., John Wiley & Sons: New York, 1973. Vol. 2. pp. 149-154. Robinson, R. J. Chem. Soe. 1917, 762. (a) Fischer, H.; Kirstahler, A. Justus Liebigs Ann. Chem, 1928, 466, 178: (b) Fischer, H.; Zeile, K. ibid. 1929, 468. 98. Bachmann, W.E.; Cole, W. Wilds, A.L. J. Am. Chem, Soc. 1939, 61, 974 16. 17, 20. 21 22, Harris, $.A.; Stiller, E.T. Folkers, K. J. Am. Chem. Soc. 1939, 6], 1243; Hartis, S.A.; Folkers, K. ibid. 1939, 61, 1245; Haris, S.A.; Folkers, K. ibid. 1939, 61, 3307. (a) Woodward, R.B.; Doering, W.E. J. Am, Chem. Soc. 1944, 66, 849: (b) Woodward, R.B.; Doering, W.E. ibid. 1945, 67, 860. See brochure of Nobel Committees for Physics and Chemistry, The Royal Swedish Academy of Sciences, List of the Nobel Prize Laureates 1901-1994, Alm- quist & Wiksell Tryckeri: Uppsala, Sweden, 1995. Danishefsky, S.J. Aldrichimica Acta 1986, 19. 59. Woodward, R.B. In Perspectives in Organic Chem- istry, Todd, A.R., Ed., Interscience: New York, 1956, p. 155: . Corey, E.J. In Bindra, J.S.; Bindra, R. Creativity in Organic Synthesis, Academic Press: San Francisco, 1975, Vol. I. vii. Eschenmoser, A.; Wintner, C.E, Science (Washing- ton, D.C.) 1977, 196, 1410. Barton, D.H.R. Chem. Br. 1973, 9, 149. Sharpless, K.B. Proc. Robert A. Welch Foundation Conf. Chem. Res. 1983, 27, 59. Trost, B.M. Science (Washington, D.C.) 1988, 227, 908.23, 24, 25. 26. 20 Lehn, JM. Angew. Chem. Int. Ed. Engl. 1999, 29, 1304; Lehn, J.-M. Supramolecular Chemistry, VCH: Weinheim, 1996. . Nicolaou, K.C.; Xiao, X.-Y.; Parandoosh, Z.; Senyel, ‘Az Nova, M.P. Angew: Chem. Int. Ed. Engl. 1995, 34, 2289 and references cited therein (@) Woodward, R.B.; Cava, M.P; Ollis, W.D.; Hun- get, A. Daeniker, H.U.; Schenker, K. J. Am. Chem Soc. 1984, 76, 4749; (b) Woodward, R.B.; Cava, M.P; Ollis, W.D.; Hunger, A.; Daeniker, H.U. Schenker, K. Tetrahedron 1963, 19, 247. (a) Woodward, R.B.; Bader, F.E.; Bickel, H.; Frey, A.J; Kierstead, R.W. J. Am. Chem. Soc. 1986, 78, 2023, 2657, (b) Woodward, R.B.; Bader, F, Bickel, H.; Frey, A.J. Kierstead, R.W. Tetrahedron 1958, 2, 1 Sheehan, J.C.; Henery-Logan, K.R. J. Am. Chem. Soc. 1957, 79, 1262; (b) Sheehan, J.C; Henery- Logan, K.R. ibid. 1959, 81, 3089. 28, 29, 30, 31 32 References 19 Schreiber, 1.; Leimgruber, W.; Pesaro, M.; Schudel, P;, Threlfall, T.; Eschenmoser, A. Heli. Chim. Acta 1961, 44, 540, (a) Woodward, R.B. Pure & Appl. Chem. 1961, 2, 383; (b) Woodward, R.B.; Ayer, W. A. Beaton, J.M.; Bickelhaupt, F; Bonnett, R.; Buchschacher, P Closs, G.L Dutler, H.: Hannah, J.; Hauck, FP: 10, Ss Langemann, A LeGoff, Leimgruber, | W.: Lwowski, W.; Sauer, J.; Valenta, Z.; Volz, H. J. Am. Chem. Soc. 1960, 82, 3800; (c) Woodward, R.B.: Ayer. W.A.; Beaton, J.M.; Bickelhaupt, F; Bonnet, R.; Buchschacher, P; Le Goff, E.; Leimgruber, W.: Lwowski, Ws Sauer, Ji: Valenta, Z.; Volz, H. Tetrahedron 1990, 46, 7599. Reference 2, p. 6. Woodward, R.B. Proc. Robert A. Welch Foundation Conf. Chem, Res. 1969, 12,3. Cavaly, CP In The Complete Poems of Cavafy, Translated by Rae Dalven, Harcourt, Brace & World: New York, 1961, p. 36.