Classics in Total Synthesis III

K.C. Nicolaou holds joint appointments at The Scripps Research Institute, where he is the Chairman of the Department of Chemistry and holds the Darlene Shiley Chair in Chemistry and the Aline W. and L.S. Skaggs Professorship of Chemical Biology, and the University of California, San Diego, where he is Distinguished Professor of Chemistry. His impact on chemistry, biology and medicine flows from his research works in chemical synthesis and chemical biology described in numerous publications and patens. For his contributions to science and education, he was elected Fellow of the New York Academy of Sciences, Fellow of the American Academy of Arts and Sciences, Member of the National Academy of Sciences, USA, Member of the German Academy of Sciences Leopoldina, and Corresponding Member of the Academy of Athens, Greece. He is the recipient of many prizes, awards and honors. Jason S. Chen received his A.B. and A.M. degrees in Chemistry from Harvard University in 2001. After two years as a medicinal chemist at Enanta Pharmaceuticals, he began graduate studies at The Scripps Research Institute under the guidance of Professor K.C. Nicolaou. He received a National Defense Science and Engineering Graduate fellowship, and completed his Ph.D. studies in 2008. He currently is a post-doctoral fellow in Professor Nicolaou's laboratory.

• Chapter 1 Introduction: The Advancing Field of Total Synthesis1.1 Targets 21.2 Strategies and Methods 21.3 Classics in Total Synthesis III 10Chapter 2 TetrodotoxinY. Kishi; J. Du Bois (1972; 2003)2.1 Introduction 132.1.1 Aliphatic C–H Bond Functionalization 162.2 Kishi’s Retrosynthetic Analysis and Strategy 352.3 Kishi’s Total Synthesis 372.4 Du Bois’ Retrosynthetic Analysis and Strategy 432.5 Du Bois’ Total Synthesis 452.6 Conclusion 52Chapter 3 DiscodermolideNovartis: S. J. Mickel; I. Paterson; A. B. Smith, III (2004)3.1 Introduction 573.2 Retrosynthetic Analysis and Strategy 613.3 Total synthesis 653.3.1 Synthesis of the Common Precursor 653.3.2 Divergent Synthesis of the Fragments 673.3.3 Fragment Coupling and Completion of the Synthesis 723.4 Conclusion 79Chapter 4 Azaspiracid-1K. C. Nicolaou; D. A. Evans (2004, 2006; 2007)4.1 Introduction 834.2 Nicolaou’s Retrosynthetic Analysis and Strategy 924.3 Nicolaou’s Total Synthesis 954.3.1 Synthesis of the ABCDE Ring System 954.3.2 Synthesis of the FHI Ring System 1014.3.3 Fragment Coupling and Completion of the Synthesis 1054.4 Evans’ Retrosynthetic Analysis and Strategy 1074.5 Evans’ Total Synthesis 1084.5.1 Synthesis of the ABCD Ring System 1084.5.2 Synthesis of the EFGHI Ring System 1154.5.3 Fragment Coupling and Completion of the Synthesis 1214.6 Conclusion 121Chapter 5 ThiostreptonK. C. Nicolaou (2004)5.1 Introduction 1275.2 Retrosynthetic Analysis and Strategy 1355.3 Total Synthesis 1385.3.1 Synthesis of the Dehydropiperidine Fragment 1385.3.2 Synthesis of the Other Fragments 1445.3.3 Fragment Coupling and Completion of the Synthesis 1525.4 Conclusion 156Chapter 6 Pentacycloanammoxic Acid Methyl EsterE. J. Corey (2004, 2006)6.1 Introduction 1616.1.1 Synthesis of Ladderane Compounds 1646.2 First-Generation Retrosynthetic Analysis and Strategy 1716.3 First-Generation Total Synthesis 1726.4 Second-Generation Retrosynthetic Analysis and Strategy 1776.5 Second-Generation Total Synthesis 1796.6 Conclusion 182Chapter 7 Littoralisone, Oseltamivir (Tamiflur), and Hirsutellone BD. W. C. MacMillan; Y. Hayashi; K. C. Nicolaou (2005; 2009; 2009)7.1 Introduction 1877.1.1 Catalysis by Cinchona Alkaloids 1907.1.2 Enamine Catalysis 1997.1.3 Iminium Catalysis and Enamine–Iminium Cascades 2097.1.4 Other Examples of Organocatalysis 2177.2 Introduction to Littoralisone 2257.2.1 Retrosynthetic Analysis of Littoralisone 2277.3 Total Synthesis of Littoralisone 2287.4 Introduction to Oseltamivir (Tamiflur) 2327.4.1 Retrosynthetic Analysis of Oseltamivir (Tamiflur) 2357.5 Total Synthesis of Oseltamivir (Tamiflur) 2367.6 Introduction to Hirsutellone B 2377.6.1 Retrosynthetic Analysis of Hirsutellone B 2407.7 Total Synthesis of Hirsutellone B 2427.8 Conclusion 248Chapter 8 Rubicordifolin and Rubioncolin BD. Trauner (2005, 2008)8.1 Introduction 2558.2 Retrosynthetic Analysis of Rubicordifolin 2588.3 Total Synthesis of Rubicordifolin 2598.4 Retrosynthetic Analysis of Rubioncolin B 2628.5 Total Synthesis of Rubioncolin B 2628.6 Conclusion 266Chapter 9 Cyanthiwigins U and FA. J. Phillips; B. M. Stoltz (2005; 2008)9.1 Introduction 2719.2 Phillips’ Retrosynthetic Analysis and Strategy 2769.3 Phillips’ Total Synthesis 2779.4 Stoltz’ Retrosynthetic Analysis and Strategy 2819.5 Stoltz’ Total Synthesis 2829.6 Conclusion 286Chapter 10 Stephacidin BA. G. Myers; P. S. Baran; R. M. Williams (2005; 2005; 2007)10.1 Introduction 29110.2 Myers’ Retrosynthetic Analysis and Strategy 29610.3 Myers’ Total Synthesis 29810.4 Baran’s Retrosynthetic Analysis and Strategy 30310.5 Baran’s Total Synthesis 30510.6 Williams’ Retrosynthetic Analysis and Strategy 31110.7 Williams’ Total Synthesis 31210.8 Conclusion 317Chapter 11 Abyssomicin C and atrop-Abyssomicin CE. J. Sorensen; K. C. Nicolaou (2005; 2006)11.1 Introduction 32111.2 Sorensen’s Retrosynthetic Analysis and Strategy 32411.3 Sorensen’s Total Synthesis of Abyssomicin c 32711.4 Nicolaou’s Retrosynthetic Analysis and Strategy 33111.5 Nicolaou’s Total Synthesis of Abyssomicin c and atrop-Abyssomicin c 33111.5.1 Chemistry and Biology of the Abyssomicins 33811.6 Conclusion 342Chapter 12 TetracyclineA. G. Myers (2005, 2007)12.1 Introduction 34512.1.1 Singlet Oxygen Ene Reactions 35612.2 Retrosynthetic Analysis and Strategy 36112.3 Total Synthesis 36412.4 Conclusion 373Chapter 13 Bisanthraquinone Natural ProductsK. C. Nicolaou (2005, 2009)13.1 Introduction 37713.2 Retrosynthetic Analysis and Strategy Toward2,2l-epi-Cytoskyrin A, Rugulosin, and Rugulin 38113.3 Total Synthesis of 2,2l-epi-Cytoskyrin A, Rugulosin, and Rugulin 38413.4 Retrosynthetic Analysis and Strategy Toward Antibiotic BE-43472B 39413.5 Total Synthesis of Antibiotic BE-43472B 39513.6 Conclusion 402Chapter 14 Garsubellin AM. Shibasaki, M. Kanai; S. J. Danishefsky (2005; 2006)14.1 Introduction 40714.2 Shibasaki and Kanai’s Retrosynthetic Analysis and Strategy 41314.3 Shibasaki and Kanai’s Total Synthesis 41314.4 Danishefsky’s Retrosynthetic Analysis and Strategy 42114.5 Danishefsky’s Total Synthesis 42314.6 Conclusion 429Chapter 15 Welwitindolinone AP. S. Baran; J. L. Wood (2005; 2006)15.1 Introduction 43315.2 Baran’s Retrosynthetic Analysis and Strategy 43515.3 Baran’s Total Synthesis 43515.4 Wood’s Retrosynthetic Analysis and Strategy 44015.5 Wood’s Total Synthesis 44015.6 Conclusion 446Chapter 16 Iejimalide BA. Fürstner (2006, 2007)16.1 Introduction 44916.2 Retrosynthetic Analysis and Strategy 45116.3 Total Synthesis 45416.3.1 Synthesis of the Fragments 45416.3.2 Fragment Coupling and Completion of the Synthesis 46216.3.3 Alternative Synthetic Approach 46416.4 Conclusion 466Chapter 17 Kedarcidin Chromophore and Maduropeptin ChromophoreA. G. Myers; M. Hirama, M. Inoue, I. Sato (2007; 2009)17.1 Introduction 46917.2 Retrosynthetic Analysis and Strategy for Kedarcidin Chromophore 48317.3 Total Synthesis of Kedarcidin Chromophore 48717.3.1 Synthesis of the Fragments 48717.3.2 Fragment Coupling and Completion of the Synthesis 49617.4 Retrosynthetic Analysis and Strategy for Maduropeptin Chromophore 50217.5 Total Synthesis of Maduropeptin Chromophore 50517.5.1 Synthesis of the Fragments 50517.5.2 Fragment Coupling and Completion of the Synthesis 51117.6 Conclusion 518Chapter 18 Biyouyanagin AK. C. Nicolaou (2007)18.1 Introduction 52318.1.1 Photoinduced [2þ2] Cycloadditions 52618.2 Retrosynthetic Analysis and Strategy 53518.3 Total Synthesis 53718.4 Conclusion 541Chapter 19 AzadirachtinS. V. Ley (2007, 2009)19.1 Introduction 54519.1.1 Selected Strategies for the Construction of the Congested C8–C14 Bond 54719.2 Retrosynthetic Analysis and Strategy 55319.3 Synthesis 55519.4 Conclusion 562Chapter 20 Resveratrol-Derived Natural ProductsS. A. Snyder; K. C. Nicolaou, D. Y.-K. Chen (2007, 2009; 2009, 2010)20.1 Introduction 56720.2 Snyder’s Retrosynthetic Analysis and Strategy for a Collection of Resveratrol-Derived Natural Products 57120.3 Snyder’s Total Synthesis of a Collection of Resveratrol-Derived Natural Products 57420.4 Nicolaou and Chen’s Retrosynthetic Analysis and Strategy for Hopeahainol A and Hopeanol 58320.5 Nicolaou and Chen’s Total Synthesis of Hopeahainol A and Hopeanol 58520.6 Conclusion 592Chapter 21 Chlorosulfolipid CytotoxinE. M. Carreira (2009)21.1 Introduction 59521.1.1 Asymmetric Halogenation Reactions 60021.2 Retrosynthetic Analysis and Strategy 60821.3 Total Synthesis 60921.4 Conclusion 612Chapter 22 Sporolide BK. C. Nicolaou (2009)22.1 Introduction 61722.1.1 o-Quinone Diels–Alder Cycloadditions 62022.1.2 Transition Metal-Catalyzed [2þ2þ2] Cycloadditions 62422.2 Retrosynthetic Analysis and Strategy 62722.3 Total Synthesis 62922.4 Conclusion 635Chapter 23 11,11’-Dideoxyverticillin A and ChaetocinM. Movassaghi; M. Sodeoka (2009; 2010)23.1 Introduction 63923.2 Retrosynthetic Analysis and Strategy for 11,11l-Dideoxyverticillin A 64623.3 Total Synthesis of 11,11l-Dideoxyverticillin A 64823.4 Retrosynthetic Analysis and Strategy for Chaetocin 65123.5 Total Synthesis of Chaetocin 65323.6 Conclusion 655Chapter 24 Vannusal BK. C. Nicolaou (2009)24.1 Introduction 65924.1.1 SmI 2 -Mediated Ketyl–Olefin Cyclization 66224.2 Retrosynthetic Analysis and Strategy 67024.3 Total Synthesis 67224.3.1 Synthesis of the Left Domain 67224.3.2 Synthesis of the Right Domain 67524.3.3 Fragment Coupling, Completion of the Synthesis, and Structural Reassignment 678Chapter 25 HaplophytineT. Fukuyama, H. Tokuyama; K. C. Nicolaou, D.Y.-K. Chen (2009; 2009)25.1 Introduction 68925.2 Fukuyama and Tokuyama’s Retrosynthetic Analysis and Strategy 69125.3 Fukuyama and Tokuyama’s Total Synthesis 69525.3.1 Synthesis of the Left Domain 69525.3.2 Synthesis of the Right Domain 70025.3.3 Fragment Coupling and Completion of the Synthesis 70225.4 Nicolaou and Chen’s Retrosynthetic Analysis and Strategy 70625.5 Nicolaou and Chen’s Total Synthesis 70625.5.1 Synthesis of the Left Domain 70625.5.2 Synthesis of the Right Domain 70825.5.3 Fragment Coupling and Completion of the Synthesis 71125.6 Conclusion 716Chapter 26 Palau’amineP. S. Baran (2010)26.1 Introduction 71926.2 Retrosynthetic Analysis and Strategy 72226.3 Total Synthesis 72526.4 Conclusion 730Image / Photo Credits 733Author Index 735Subject Index 738

"Classics in Total Synthesis III will surely itself become a classic in the literature on the state of the art of contemporary organic synthetic chemistry." (Angewandte Chemie, 2011)