Efficiency in Natural Product Total Synthesis

Pei-Qiang Huang, PhD, is Professor of Chemistry and former Dean of the College of Chemistry and Chemical Engineering at Xiamen University. Zhu-Jun Yao, PhD, is Cyrus Tang Chair Professor and University Distinguished Professor at Nanjing University. Richard P. Hsung, PhD, is Kremers Chair and Vials Distinguished Professor of Pharmaceutical Sciences at School of Pharmacy, University of Wisconsin–Madison.

• Contributors xiiiForeword xvPreface xviiIntroduction 1Pei‐Qiang Huang1 The Golden Age of the Total Synthesis of Natural Products: The Era as a Dominant Field 22 1991–2000: A Contrasting Decade 93 Total Synthesis in the Twenty‐First Century 104 The Challenges of the Efficiency in the Total Synthesis of Natural Products 125 The Renaissance of Natural Products as Drug Candidates 146 Recent Recognition of the Contribution of Natural Product‐Based Drugs to Society 16Acknowledgements 18References 181 Principles for Synthetic Efficiency and Expansion of the Field 27Pei‐Qiang Huang1.1 Concepts for Efficiency in the Total Synthesis of Natural Products 271.1.1 Ideal Synthesis 281.1.2 Selectivity 291.1.3 Green Synthesis 321.1.4 Atom Economy 321.1.5 E Factors 321.1.6 Step Economy 331.1.7 Pot Economy and PASE (Pot, Atom, and Step Economy) 341.1.8 Redox Economy 341.1.9 Protecting‐Group‐Free Synthesis 361.1.10 Multicomponent Reactions and One‐Pot Reactions 381.1.11 Scalability 401.1.12 Convergent Synthesis 411.2 Biomimetic Synthesis 411.2.1 Basic Logic of Biosynthesis 421.2.2 Tandem, Cascade, and Domino Reactions – One‐Pot Reactions 421.2.3 Site and Stereoselective Reactions 461.2.4 The C─H Bond Functionalization Strategy 461.2.5 The Building‐Block Strategy 471.2.6 The Collective Synthesis Strategy 491.2.7 The Oligomerization Tactic 501.3 The Expansion of the Field: Chemical Biology/Chemical Genetics 511.3.1 Diversity‐Oriented Synthesis (DOS) 511.3.2 Function‐Oriented Synthesis (FOS) 511.3.3 Biology‐Oriented Synthesis (BIOS) 521.3.4 Lead‐Oriented Synthesis (LOS) 521.4 Addressing the Threats that Humans May Face in the Near Future 531.4.1 A. G. Myers’ Endeavor 531.4.2 D. L. Boger’s Endeavor 55Acknowledgements 56References 562 Selected Procedure‐Economical Enantioselective Total Syntheses of Natural Products 67Pei‐Qiang Huang2.1 One‐Step/One‐Pot Enantioselective Total Synthesis of Natural Products/Drugs 682.1.1 Robinson’s One‐Step Synthesis of Tropinone 682.1.2 Hayashi’s One‐Pot Synthesis of (+)‐ABT‐341 692.2 Two‐Step/Two‐Pot Enantioselective Total Synthesis of Natural Products 692.2.1 Hayashi’s Two‐Pot Synthesis of (−)‐Oseltamivir 692.2.2 Ma’s Two‐Pot Synthesis of (−)‐Oseltamivir 702.2.3 Li’s Two‐Step Chemoenzymatic Total Synthesis of Aszonalenin 712.2.4 Ishikawa’s Two‐Step Total Syntheses of (+)‐WIN 64821 and (+)‐Naseseazine B 712.3 Three‐Step/Three‐Pot Enantioselective Total Synthesis of Natural Products 732.3.1 Carreira’s Three‐Step Asymmetric Total Syntheses of (+)‐Aszonalenin and (−)‐Brevicompanine B 732.3.2 Husson’s Three‐Step Asymmetric Total Synthesis of (−)‐Sibirine 732.3.3 MacMillan’s Three‐Step Asymmetric Total Synthesis of (+)‐Frondosin B 752.3.4 Hayashi’s Three‐Pot Total Synthesis of (−)‐PGE1 Methyl Ester 752.3.5 Porco’s Three‐Pot Total Synthesis of (−)‐Hyperibone K 762.4 Four‐Step Enantioselective Total Synthesis of Natural Products 772.4.1 Lawrence’s Four‐Step Total Synthesis of (−)‐Angiopterlactone A 772.4.2 Maimone’s Four‐Step Synthesis of (+)‐Cardamom Peroxide 782.4.3 Xie, Lai, and Ma’s Four‐Step Total Synthesis of (−)‐Chimonanthine 792.4.4 Huang’s Four‐Step Total Synthesis of (−)‐Chaetominine 802.5 Five‐Step/Pot Enantioselective Total Synthesis of Natural Products 812.5.1 Carreira’s Five‐Step Total Syntheses of Δ9‐Tetrahydrocannabinols 812.5.2 Studer’s Five‐Step Total Syntheses of (+)‐Machaeriols B and D 832.5.3 Cook’s Five‐Pot Total Synthesis of (+)‐Artemisinin (Qinghaosu) 842.5.4 Corey’s Five‐Step Total Synthesis of Aflatoxin B2 852.6 Six‐Step Enantioselective Total Synthesis of Natural Products 862.6.1 Comins’ Six‐Step Total Synthesis of (S)‐Camptothecin 862.6.2 Krische’s Six‐Step Total Synthesis of (−)‐Cyanolide A 872.7 Seven‐Step Enantioselective Total Synthesis of Natural Products 892.7.1 Baran’s 7–10‐Step Total Syntheses of Hapalindole‐Type Natural Products 892.7.2 Aggarwal’s Seven‐Step Total Synthesis of (+)‐PGF2α 902.7.3 Echavarren’s Seven‐step Total Syntheses of Aromadendrane Sesquiterpenes 932.7.4 Zhu’s Seven‐Step Total Synthesis of Peganumine A 942.7.5 Rychnovsky’s Seven‐Step Synthesis of Lycopodium Alkaloid (+)‐Fastigiatine 962.8 Eight‐Step Enantioselective Total Synthesis of Natural Products 992.8.1 Overman’s Eight‐Step Synthesis of (+)‐Trans‐Clerodane Iterpenoid 992.8.2 Chain’s Eight‐Step Synthesis of (−)‐Englerin A 1002.8.3 Shenvi’s Eight‐Step Total Synthesis of (−)‐Jiadifenolide 1022.8.4 Maimone’s Eight‐Step Total Synthesis of (+)‐Chatancin 1032.8.5 Wipf ’s Eight‐Step Total Synthesis of (−)‐Cycloclavine 1052.8.6 Shenvi’s Eight‐Step Total Synthesis of (−)‐ Neothiobinupharidine 1082.9 Nine‐Step Enantioselective Total Synthesis of Natural Products 1102.9.1 Stoltz’s Nine‐Step Total Synthesis of (−)‐Cyanthiwigin F 1102.9.2 Maimone’s Nine‐Step Total Synthesis of (–)‐6‐Epi-Ophiobolin N 1122.9.3 MacMillan’s Nine‐Step Total Synthesis of (−)‐Vincorine 1142.9.4 Ramharter’s Nine‐Step Total Synthesis of (+)‐Lycoflexine 1162.9.5 Gao’s and Theodorakis’ Nine‐Step Total Syntheses of (+)‐Fusarisetin A 1182.10 Ten/Eleven‐Step Enantioselective Total Syntheses of Natural Products 1212.10.1 Lin’s 10‐Step Total Synthesis of (−)‐Huperzine A 1212.10.2 Trauner’s 10‐Step Total Synthesis of (+)‐Loline 1222.10.3 Zhai’s 10‐Step Total Synthesis of (+)‐Absinthin 1242.10.4 Baran’s 11‐Step Total Synthesis of (−)‐Maoecrystal V 1252.11 Fourteen/Fifteen‐Step Enantioselective Total Synthesis of Natural Products 1292.11.1 Baran’s 14‐Step Total Synthesis of (−)‐Ingenol 1292.11.2 Reisman’s 15‐Step Total Synthesis of (+)‐Ryanodol 1322.11.3 Johnson’s 15‐Step Total Synthesis of (+)‐Pactamycin 1342.12 Other Procedure‐Economical Enantioselective Total Syntheses of Natural Products 1372.13 Conclusion 137Acknowledgements 149References 1493 Diels–Alder Cascades in Natural Product Total Synthesis 159Richard P. Hsung, Zhi‐Xiong Ma, Lichao Fang, and John B. Feltenberger3.1 Introduction 1593.2 Cascades Initiated by Coupling of a Pre‐Formed Diene and Dienophile 1613.3 Simple Transformations to Diene/Dienophiles Followed by the Diels–Alder Cascade 1633.4 Rearrangement‐Initiated Diels–Alder Cascades 1703.5 Cyclization‐Initiated Diels–Alder Cascades 1753.6 Diels–Alder Initiated Cascades 1803.7 Concluding Remarks 185Acknowledgements 185References 1854 Organometallics‐Based Catalytic (Asymmetric) Synthesis of Natural Products 191Hongbin Zhai, Yun Li, Bin Cheng, Zhiqiang Ma, Peng Gao, Xin Chen, Weihe Zhang, Hanwei Hu, and Fang Fang4.1 Introduction 1914.2 Au‐Catalyzed Reactions in Total Synthesis 1914.3 Ag‐Catalyzed Reactions in Total Synthesis 1954.4 Pt‐Catalyzed Reactions in Total Synthesis 1994.4.1 Pt‐Catalyzed Enyne Cycloisomerization Reactions 1994.5 Co‐Catalyzed Pauson–Khand Reactions and Hetero‐Pauson–Khand Reactions in Total Synthesis 2024.6 Cu‐Catalyzed Reactions in Total Synthesis 2044.6.1 Asymmetric Conjugate Addition 2054.6.2 Arene Cyclopropanation 2084.7 Chromium‐Catalyzed Reactions in Total Synthesis 2094.8 Fe‐Mediated Coupling Reactions in Total Synthesis 2164.8.1 Reaction with Acid Chlorides 2174.8.2 Reaction with Alkenyl Electophiles 2174.8.3 Reaction with Aryl Halides 2184.8.4 Reaction with Alkyl Halides 2204.8.5 Related Iron‐Catalyzed C–C Bond Formations 2204.8.6 Iron‐Catalyzed C–O, C–S, and C–N Cross‐Coupling 2214.9 Mn‐Mediated Coupling Reactions in Total Synthesis 2214.10 Ni‐Catalyzed Reactions in Total Synthesis 2254.10.1 Ni‐Catalyzed Cycloadditions 2254.10.2 Ni‐Catalyzed Coupling Reactions 2254.11 Pd‐Catalyzed Cross‐Coupling Reactions in Total Synthesis 2284.11.1 Heck Reactions in Total Synthesis 2294.11.2 Suzuki Reactions in Total Synthesis 2314.11.3 Stille Reactions in Total Synthesis 2334.11.4 Tsuji–Trost Reactions in Total Synthesis 2354.11.5 Negishi Reactions in Total Synthesis 2374.11.6 Pd‐Catalyzed Domino Reactions in Total Synthesis 2384.12 Rh‐Catalyzed (C–H Functionalization by Metal Carbenoid and Nitrenoid Insertion) Reactions in Total Synthesis 2404.13 Ru‐Catalyzed RCM and RCAM in Total Synthesis 2444.14 Conclusion 252Acknowledgements 252References 2525 C–H Activation‐Based Strategy for Natural Product Synthesis 261Hongbin Zhai, Yun Li, and Fang Fang5.1 Introduction 2615.2 Recently Completed Total Syntheses of Natural Products via a C–H Activation Approach 2615.3 Conclusion 270Acknowledgements 271References 2716 Recent Applications of Kagan’s Reagent (SmI2) in Natural Product Synthesis 273Erica Benedetti, Cyril Bressy, Michael Smietana, and Stellios Arseniyadis6.1 Background 2736.1.1 The Reformatsky Reaction 2746.1.2 Carbonyl/Alkene Reductive Reactions 2756.1.3 Pinacol‐Type Couplings 2766.1.4 Fragmentation Reactions 2776.2 SmI2‐Mediated Reactions in Natural Product Synthesis 2776.2.1 Synthesis of (+)‐Acutiphycin 2776.2.2 Synthesis of Brevetoxin B 2786.2.3 Synthesis of (±)‐Vigulariol 2806.2.4 Synthesis of Diazonamide A 2826.2.5 Synthesis of Epothilone A 2846.2.6 Synthesis of Strychnine 2846.2.7 Synthesis of the ABC Ring of Paclitaxel 2876.2.8 Miscellaneous 2886.3 Conclusion 290Acknowledgements 291References 2917 Asymmetric Organocatalysis in the Total Synthesis of Complex Natural Products 297Gang Zhao, Zheng Qing Ye, and Xiao Yu Wu7.1 Background 2977.2 Total Synthesis of Alkaloids 2987.2.1 Synthesis of (−)‐Flustramine B 2987.2.2 Enantioselective Total Synthesis of (+)‐Minfiensine 2997.2.3 Concise Synthesis of (−)‐Nakadomarin A 3007.2.4 Collective Total Synthesis of Strychnine, Akuammicine, Aspidospermidine, Vincadifformine, Kopsinine, and Kopsanone 3017.2.5 Asymmetric Synthesis of (−)‐Lycoramine, (−)‐Galanthamine, and (+)‐Lunarine 3037.2.6 Total Synthesis of the Galbulimima Alkaloid (−)‐GB17 3047.3 Total Synthesis of Terpenoids and Related Multicyclic Natural Products 3067.3.1 Total Synthesis of (+)‐Hirsutene 3067.3.2 Total Synthesis of (−)‐Brasoside and (−)‐Littoralisone 3067.3.3 Concise Synthesis of Ricciocarpin A 3077.3.4 Total Synthesis and Absolute Stereochemistry of Seragakinone A 3087.4 Total Synthesis of Macrolides (or Macrolactams) 3107.4.1 Total Synthesis and Structural Revision of Callipeltoside C 3107.4.2 Total Synthesis of (+)‐Cytotrienin A 3117.4.3 Total Synthesis of Diazonamide A 3127.5 Total Synthesis of Peptide Natural Products 3137.5.1 Total Synthesis of Chloptosin 3137.6 Summary of the Key Reactions and Tactics 314References 3158 Multicomponent Reactions in Natural Product Synthesis 319Michael Smietana, Erica Benedetti, Cyril Bressy, and Stellios Arseniyadis8.1 Background 3198.2 Multicomponent Reactions in Natural Product Synthesis 3208.2.1 Synthesis of Martinelline by Powell and Batey 3208.2.2 Synthesis of Eurystatin by Schmidt and Weinbrenner 3218.2.3 Synthesis of Motuporin by Bauer and Armstrong 3228.2.4 Synthesis of Thiomarinol H by Gao and Hall 3248.2.5 Synthesis of Minquartynoic Acid by Gung and Coworkers 3268.2.6 Synthesis of Spongistatin 2 by Smith and Coworkers 3288.2.7 Synthesis of Vannusal A and B by Nicolaou and Coworkers 3318.2.8 Synthesis of Calystegine B‐4 by Pyne and Coworkers 3338.2.9 Synthesis of Jerangolid D by Markó and Pospisil 3348.2.10 Synthesis of (−)‐Nakadomarin A by Young and Kerr 3358.3 Conclusion 338References 3389 Renewable Resource‐Based Building Blocks/Chirons for the Total Synthesis of Natural Products 345Wai‐Lung Ng, Anthony W. H. Wong, and Tony K. M. Shing9.1 Introduction 3459.1.1 The Chiron Approach Toward the Total Synthesis of Natural Products 3459.1.2 General Survey of Natural Chirons 3459.2 Total Synthesis of Alkaloids 3479.2.1 Amino Acids as Starting Chirons 3479.2.2 Carbohydrates as Starting Chirons 3619.2.3 Terpene and α‐Hydroxyl Acid as Starting Chirons 3709.3 Total Synthesis of Terpenoids 3719.3.1 Terpene as a Starting Chiron 3719.4 Total Synthesis of Miscellaneous Natural Products 3829.4.1 Amino Acids as Starting Chirons 3829.5 Conclusions and Perspectives 387References 38910 Natural Product Synthesis for Drug Discovery and Chemical Biology 395Zhu‐Jun Yao and Wan‐Guo Wei10.1 The Importance of Bioactive Natural Products in Biological Investigation 39510.2 Bioactive Natural‐Product‐Inspired Chemical Biology 39710.3 Natural Products in Drug Discovery 40110.3.1 Natural Products as Antibody‐Drug Conjugate (ADC) Payloads 40710.4 TOS, DOS, FOS, and BOS in Natural Product Synthesis 41010.4.1 Target‐Oriented Synthesis (TOS) 41010.4.2 Diversity‐Oriented Synthesis (DOS) 41110.4.3 Function‐Oriented Synthesis (FOS) 41810.4.4 Biology‐Oriented Synthesis (BIOS) 42010.5 Semisynthesis 42310.6 Representative Natural‐Product Drugs and Their Synthesis 42710.6.1 Nicolaou and Yang’s Synthesis of Taxol 42710.6.2 Danishefsky’s Synthesis of Epothilone A 42910.6.3 Smith’s Synthesis of Kendomycin 42910.6.4 Yao’s Synthesis of Camptothecin 43010.6.5 Nicolaou and Li’s Synthesis of Platensimycin 43210.6.6 Shasun Pharma Solutions Ltd’s Synthesis of (−)‐Huperzine A 43410.6.7 Baran’s Synthesis of Ingenol 43510.7 Overview and Perspective 436Acknowledgements 436References 43611 Modern Technologies in Natural Product Synthesis 447Zhu‐Jun Yao and Shouyun Yu11.1 Visible‐Light Photochemistry 44711.2 Electrochemistry 45211.3 Flow Chemistry 45711.4 Flow Photochemistry 46011.5 Flow Electrochemistry 46211.6 Overview and Perspective 462Acknowledgements 463References 46312 Concluding Remarks and Perspectives 465Pei‐Qiang Huang, Richard P. Hsung, Zhi‐Xiong Ma, and Zhu‐Jun Yao12.1 The Enantioselective Total Synthesis of Natural Products 46712.2 A Novel Model of Total Synthesis: The Combination of Chemical Synthesis with Synthetic Biology 46712.2.1 Seeberger’s One‐Pot Photochemical Continuous‐Flow Strategy 46812.2.2 Wu’s “Dark Singlet Oxygen” Strategy 46812.2.3 George’s “Green” Photochemical Strategies 46912.2.4 A Novel Strategy Merging Synthetic Biology with Chemistry 46912.2.5 Zhang’s Two‐Step Catalytic Transformation of AA to Artemisinin: The End‐Game? 47012.3 The Robot Chemist and the Generalized Automation of Small‐Molecule Synthesis 47112.4 A Synergistic Future with Academia and Industry Coming to the Same Table 471Acknowledgements 475References 475Index 479