Contributors xiii
Foreword xv
Preface xvii
Introduction 1
PeiQiang Huang
1 The Golden Age of the Total Synthesis of Natural Products: The Era as a Dominant Field 2
2 19912000: A Contrasting Decade 9
3 Total Synthesis in the TwentyFirst Century 10
4 The Challenges of the Efficiency in the Total Synthesis of Natural Products 12
5 The Renaissance of Natural Products as Drug Candidates 14
6 Recent Recognition of the Contribution of Natural ProductBased Drugs to Society 16
Acknowledgements 18
References 18
1 Principles for Synthetic Efficiency and Expansion of the Field 27
PeiQiang Huang
1.1 Concepts for Efficiency in the Total Synthesis of Natural Products 27
1.1.1 Ideal Synthesis 28
1.1.2 Selectivity 29
1.1.3 Green Synthesis 32
1.1.4 Atom Economy 32
1.1.5 E Factors 32
1.1.6 Step Economy 33
1.1.7 Pot Economy and PASE (Pot, Atom, and Step Economy) 34
1.1.8 Redox Economy 34
1.1.9 ProtectingGroupFree Synthesis 36
1.1.10 Multicomponent Reactions and OnePot Reactions 38
1.1.11 Scalability 40
1.1.12 Convergent Synthesis 41
1.2 Biomimetic Synthesis 41
1.2.1 Basic Logic of Biosynthesis 42
1.2.2 Tandem, Cascade, and Domino Reactions OnePot Reactions 42
1.2.3 Site and Stereoselective Reactions 46
1.2.4 The CH Bond Functionalization Strategy 46
1.2.5 The BuildingBlock Strategy 47
1.2.6 The Collective Synthesis Strategy 49
1.2.7 The Oligomerization Tactic 50
1.3 The Expansion of the Field: Chemical Biology/Chemical Genetics 51
1.3.1 DiversityOriented Synthesis (DOS) 51
1.3.2 FunctionOriented Synthesis (FOS) 51
1.3.3 BiologyOriented Synthesis (BIOS) 52
1.3.4 LeadOriented Synthesis (LOS) 52
1.4 Addressing the Threats that Humans May Face in the Near Future 53
1.4.1 A. G. Myers Endeavor 53
1.4.2 D. L. Bogers Endeavor 55
Acknowledgements 56
References 56
2 Selected ProcedureEconomical Enantioselective Total Syntheses of Natural Products 67
PeiQiang Huang
2.1 OneStep/OnePot Enantioselective Total Synthesis of Natural Products/Drugs 68
2.1.1 Robinsons OneStep Synthesis of Tropinone 68
2.1.2 Hayashis OnePot Synthesis of (+)ABT341 69
2.2 TwoStep/TwoPot Enantioselective Total Synthesis of Natural Products 69
2.2.1 Hayashis TwoPot Synthesis of ()Oseltamivir 69
2.2.2 Mas TwoPot Synthesis of ()Oseltamivir 70
2.2.3 Lis TwoStep Chemoenzymatic Total Synthesis of Aszonalenin 71
2.2.4 Ishikawas TwoStep Total Syntheses of (+)WIN 64821 and (+)Naseseazine B 71
2.3 ThreeStep/ThreePot Enantioselective Total Synthesis of Natural Products 73
2.3.1 Carreiras ThreeStep Asymmetric Total Syntheses of (+)Aszonalenin and ()Brevicompanine B 73
2.3.2 Hussons ThreeStep Asymmetric Total Synthesis of ()Sibirine 73
2.3.3 MacMillans ThreeStep Asymmetric Total Synthesis of (+)Frondosin B 75
2.3.4 Hayashis ThreePot Total Synthesis of ()PGE1 Methyl Ester 75
2.3.5 Porcos ThreePot Total Synthesis of ()Hyperibone K 76
2.4 FourStep Enantioselective Total Synthesis of Natural Products 77
2.4.1 Lawrences FourStep Total Synthesis of ()Angiopterlactone A 77
2.4.2 Maimones FourStep Synthesis of (+)Cardamom Peroxide 78
2.4.3 Xie, Lai, and Mas FourStep Total Synthesis of ()Chimonanthine 79
2.4.4 Huangs FourStep Total Synthesis of ()Chaetominine 80
2.5 FiveStep/Pot Enantioselective Total Synthesis of Natural Products 81
2.5.1 Carreiras FiveStep Total Syntheses of 9Tetrahydrocannabinols 81
2.5.2 Studers FiveStep Total Syntheses of (+)Machaeriols B and D 83
2.5.3 Cooks FivePot Total Synthesis of (+)Artemisinin (Qinghaosu) 84
2.5.4 Coreys FiveStep Total Synthesis of Aflatoxin B2 85
2.6 SixStep Enantioselective Total Synthesis of Natural Products 86
2.6.1 Comins SixStep Total Synthesis of (S)Camptothecin 86
2.6.2 Krisches SixStep Total Synthesis of ()Cyanolide A 87
2.7 SevenStep Enantioselective Total Synthesis of Natural Products 89
2.7.1 Barans 710Step Total Syntheses of HapalindoleType Natural Products 89
2.7.2 Aggarwals SevenStep Total Synthesis of (+)PGF2 90
2.7.3 Echavarrens Sevenstep Total Syntheses of Aromadendrane Sesquiterpenes 93
2.7.4 Zhus SevenStep Total Synthesis of Peganumine A 94
2.7.5 Rychnovskys SevenStep Synthesis ofLycopodium Alkaloid (+)Fastigiatine 96
2.8 EightStep Enantioselective Total Synthesis of Natural Products 99
2.8.1 Overmans EightStep Synthesis of (+)TransClerodane Iterpenoid 99
2.8.2 Chains EightStep Synthesis of ()Englerin A 100
2.8.3 Shenvis EightStep Total Synthesis of ()Jiadifenolide 102
2.8.4 Maimones EightStep Total Synthesis of (+)Chatancin 103
2.8.5 Wipf s EightStep Total Synthesis of ()Cycloclavine 105
2.8.6 Shenvis EightStep Total Synthesis of () Neothiobinupharidine 108
2.9 NineStep Enantioselective Total Synthesis of Natural Products 110
2.9.1 Stoltzs NineStep Total Synthesis of ()Cyanthiwigin F 110
2.9.2 Maimones NineStep Total Synthesis of ()6Epi-Ophiobolin N 112
2.9.3 MacMillans NineStep Total Synthesis of ()Vincorine 114
2.9.4 Ramharters NineStep Total Synthesis of (+)Lycoflexine 116
2.9.5 Gaos and Theodorakis NineStep Total Syntheses of (+)Fusarisetin A 118
2.10 Ten/ElevenStep Enantioselective Total Syntheses of Natural Products 121
2.10.1 Lins 10Step Total Synthesis of ()Huperzine A 121
2.10.2 Trauners 10Step Total Synthesis of (+)Loline 122
2.10.3 Zhais 10Step Total Synthesis of (+)Absinthin 124
2.10.4 Barans 11Step Total Synthesis of ()Maoecrystal V 125
2.11 Fourteen/FifteenStep Enantioselective Total Synthesis of Natural Products 129
2.11.1 Barans 14Step Total Synthesis of ()Ingenol 129
2.11.2 Reismans 15Step Total Synthesis of (+)Ryanodol 132
2.11.3 Johnsons 15Step Total Synthesis of (+)Pactamycin 134
2.12 Other ProcedureEconomical Enantioselective Total Syntheses of Natural Products 137
2.13 Conclusion 137
Acknowledgements 149
References 149
3 DielsAlder Cascades in Natural Product Total Synthesis 159
Richard P. Hsung, ZhiXiong Ma, Lichao Fang, and John B. Feltenberger
3.1 Introduction 159
3.2 Cascades Initiated by Coupling of a PreFormed Diene and Dienophile 161
3.3 Simple Transformations to Diene/Dienophiles Followed by the DielsAlder Cascade 163
3.4 RearrangementInitiated DielsAlder Cascades 170
3.5 CyclizationInitiated DielsAlder Cascades 175
3.6 DielsAlder Initiated Cascades 180
3.7 Concluding Remarks 185
Acknowledgements 185
References 185
4 OrganometallicsBased Catalytic (Asymmetric) Synthesis of Natural Products 191
Hongbin Zhai, Yun Li, Bin Cheng, Zhiqiang Ma, Peng Gao, Xin Chen, Weihe Zhang, Hanwei Hu, and Fang Fang
4.1 Introduction 191
4.2 AuCatalyzed Reactions in Total Synthesis 191
4.3 AgCatalyzed Reactions in Total Synthesis 195
4.4 PtCatalyzed Reactions in Total Synthesis 199
4.4.1 PtCatalyzed Enyne Cycloisomerization Reactions 199
4.5 CoCatalyzed PausonKhand Reactions and HeteroPausonKhand Reactions in Total Synthesis 202
4.6 CuCatalyzed Reactions in Total Synthesis 204
4.6.1 Asymmetric Conjugate Addition 205
4.6.2 Arene Cyclopropanation 208
4.7 ChromiumCatalyzed Reactions in Total Synthesis 209
4.8 FeMediated Coupling Reactions in Total Synthesis 216
4.8.1 Reaction with Acid Chlorides 217
4.8.2 Reaction with Alkenyl Electophiles 217
4.8.3 Reaction with Aryl Halides 218
4.8.4 Reaction with Alkyl Halides 220
4.8.5 Related IronCatalyzed CC Bond Formations 220
4.8.6 IronCatalyzed CO, CS, and CN CrossCoupling 221
4.9 MnMediated Coupling Reactions in Total Synthesis 221
4.10 NiCatalyzed Reactions in Total Synthesis 225
4.10.1 NiCatalyzed Cycloadditions 225
4.10.2 NiCatalyzed Coupling Reactions 225
4.11 PdCatalyzed CrossCoupling Reactions in Total Synthesis 228
4.11.1 Heck Reactions in Total Synthesis 229
4.11.2 Suzuki Reactions in Total Synthesis 231
4.11.3 Stille Reactions in Total Synthesis 233
4.11.4 TsujiTrost Reactions in Total Synthesis 235
4.11.5 Negishi Reactions in Total Synthesis 237
4.11.6 PdCatalyzed Domino Reactions in Total Synthesis 238
4.12 RhCatalyzed (CH Functionalization by Metal Carbenoid and Nitrenoid Insertion) Reactions in Total Synthesis 240
4.13 RuCatalyzed RCM and RCAM in Total Synthesis 244
4.14 Conclusion 252
Acknowledgements 252
References 252
5 CH ActivationBased Strategy for Natural Product Synthesis 261
Hongbin Zhai, Yun Li, and Fang Fang
5.1 Introduction 261
5.2 Recently Completed Total Syntheses of Natural Products via a CH Activation Approach 261
5.3 Conclusion 270
Acknowledgements 271
References 271
6 Recent Applications of Kagans Reagent (SmI2) in Natural Product Synthesis 273
Erica Benedetti, Cyril Bressy, Michael Smietana, and Stellios Arseniyadis
6.1 Background 273
6.1.1 The Reformatsky Reaction 274
6.1.2 Carbonyl/Alkene Reductive Reactions 275
6.1.3 PinacolType Couplings 276
6.1.4 Fragmentation Reactions 277
6.2 SmI2Mediated Reactions in Natural Product Synthesis 277
6.2.1 Synthesis of (+)Acutiphycin 277
6.2.2 Synthesis of Brevetoxin B 278
6.2.3 Synthesis of (±)Vigulariol 280
6.2.4 Synthesis of Diazonamide A 282
6.2.5 Synthesis of Epothilone A 284
6.2.6 Synthesis of Strychnine 284
6.2.7 Synthesis of the ABC Ring of Paclitaxel 287
6.2.8 Miscellaneous 288
6.3 Conclusion 290
Acknowledgements 291
References 291
7 Asymmetric Organocatalysis in the Total Synthesis of Complex Natural Products 297
Gang Zhao, Zheng Qing Ye, and Xiao Yu Wu
7.1 Background 297
7.2 Total Synthesis of Alkaloids 298
7.2.1 Synthesis of ()Flustramine B 298
7.2.2 Enantioselective Total Synthesis of (+)Minfiensine 299
7.2.3 Concise Synthesis of ()Nakadomarin A 300
7.2.4 Collective Total Synthesis of Strychnine, Akuammicine, Aspidospermidine, Vincadifformine, Kopsinine, and Kopsanone 301
7.2.5 Asymmetric Synthesis of ()Lycoramine, ()Galanthamine, and (+)Lunarine 303
7.2.6 Total Synthesis of the Galbulimima Alkaloid ()GB17 304
7.3 Total Synthesis of Terpenoids and Related Multicyclic Natural Products 306
7.3.1 Total Synthesis of (+)Hirsutene 306
7.3.2 Total Synthesis of ()Brasoside and ()Littoralisone 306
7.3.3 Concise Synthesis of Ricciocarpin A 307
7.3.4 Total Synthesis and Absolute Stereochemistry of Seragakinone A 308
7.4 Total Synthesis of Macrolides (or Macrolactams) 310
7.4.1 Total Synthesis and Structural Revision of Callipeltoside C 310
7.4.2 Total Synthesis of (+)Cytotrienin A 311
7.4.3 Total Synthesis of Diazonamide A 312
7.5 Total Synthesis of Peptide Natural Products 313
7.5.1 Total Synthesis of Chloptosin 313
7.6 Summary of the Key Reactions and Tactics 314
References 315
8 Multicomponent Reactions in Natural Product Synthesis 319
Michael Smietana, Erica Benedetti, Cyril Bressy, and Stellios Arseniyadis
8.1 Background 319
8.2 Multicomponent Reactions in Natural Product Synthesis 320
8.2.1 Synthesis of Martinelline by Powell and Batey 320
8.2.2 Synthesis of Eurystatin by Schmidt and Weinbrenner 321
8.2.3 Synthesis of Motuporin by Bauer and Armstrong 322
8.2.4 Synthesis of Thiomarinol H by Gao and Hall 324
8.2.5 Synthesis of Minquartynoic Acid by Gung and Coworkers 326
8.2.6 Synthesis of Spongistatin 2 by Smith and Coworkers 328
8.2.7 Synthesis of Vannusal A and B by Nicolaou and Coworkers 331
8.2.8 Synthesis of Calystegine B4 by Pyne and Coworkers 333
8.2.9 Synthesis of Jerangolid D by Markó and Pospisil 334
8.2.10 Synthesis of ()Nakadomarin A by Young and Kerr 335
8.3 Conclusion 338
References 338
9 Renewable ResourceBased Building Blocks/Chirons for the Total Synthesis of Natural Products 345
WaiLung Ng, Anthony W. H. Wong, and Tony K. M. Shing
9.1 Introduction 345
9.1.1 The Chiron Approach Toward the Total Synthesis of Natural Products 345
9.1.2 General Survey of Natural Chirons 345
9.2 Total Synthesis of Alkaloids 347
9.2.1 Amino Acids as Starting Chirons 347
9.2.2 Carbohydrates as Starting Chirons 361
9.2.3 Terpene and Hydroxyl Acid as Starting Chirons 370
9.3 Total Synthesis of Terpenoids 371
9.3.1 Terpene as a Starting Chiron 371
9.4 Total Synthesis of Miscellaneous Natural Products 382
9.4.1 Amino Acids as Starting Chirons 382
9.5 Conclusions and Perspectives 387
References 389
10 Natural Product Synthesis for Drug Discovery and Chemical Biology 395
ZhuJun Yao and WanGuo Wei
10.1 The Importance of Bioactive Natural Products in Biological Investigation 395
10.2 Bioactive NaturalProductInspired Chemical Biology 397
10.3 Natural Products in Drug Discovery 401
10.3.1 Natural Products as AntibodyDrug Conjugate (ADC) Payloads 407
10.4 TOS, DOS, FOS, and BOS in Natural Product Synthesis 410
10.4.1 TargetOriented Synthesis (TOS) 410
10.4.2 DiversityOriented Synthesis (DOS) 411
10.4.3 FunctionOriented Synthesis (FOS) 418
10.4.4 BiologyOriented Synthesis (BIOS) 420
10.5 Semisynthesis 423
10.6 Representative NaturalProduct Drugs and Their Synthesis 427
10.6.1 Nicolaou and Yangs Synthesis of Taxol 427
10.6.2 Danishefskys Synthesis of Epothilone A 429
10.6.3 Smiths Synthesis of Kendomycin 429
10.6.4 Yaos Synthesis of Camptothecin 430
10.6.5 Nicolaou and Lis Synthesis of Platensimycin 432
10.6.6 Shasun Pharma Solutions Ltds Synthesis of ()Huperzine A 434
10.6.7 Barans Synthesis of Ingenol 435
10.7 Overview and Perspective 436
Acknowledgements 436
References 436
11 Modern Technologies in Natural Product Synthesis 447
ZhuJun Yao and Shouyun Yu
11.1 VisibleLight Photochemistry 447
11.2 Electrochemistry 452
11.3 Flow Chemistry 457
11.4 Flow Photochemistry 460
11.5 Flow Electrochemistry 462
11.6 Overview and Perspective 462
Acknowledgements 463
References 463
12 Concluding Remarks and Perspectives 465
PeiQiang Huang, Richard P. Hsung, ZhiXiong Ma, and ZhuJun Yao
12.1 The Enantioselective Total Synthesis of Natural Products 467
12.2 A Novel Model of Total Synthesis: The Combination of Chemical Synthesis with Synthetic Biology 467
12.2.1 Seebergers OnePot Photochemical ContinuousFlow Strategy 468
12.2.2 Wus Dark Singlet Oxygen Strategy 468
12.2.3 Georges Green Photochemical Strategies 469
12.2.4 A Novel Strategy Merging Synthetic Biology with Chemistry 469
12.2.5 Zhangs TwoStep Catalytic Transformation of AA to Artemisinin: The EndGame? 470
12.3 The Robot Chemist and the Generalized Automation of SmallMolecule Synthesis 471
12.4 A Synergistic Future with Academia and Industry Coming to the Same Table 471
Acknowledgements 475
References 475
Index 479
