Efficiency in Natural Product Total Synthesis

Uniting the key organic topics of total synthesis and efficient synthetic methodologies, this book clearly overviews synthetic strategies and tactics applied in total synthesis, demonstrating how the total synthesis of natural products enables scientific and drug discovery.

• Focuses on efficiency, a fundamental and important issue in natural products synthesis that makes natural product synthesis a powerful tool in biological and pharmaceutical science
• Describes new methods like organocatalysis, multicomponent and cascade reactions, and biomimetic synthesis
• Appeals to graduate students with two sections at the end of each chapter illustrating key reactions, strategies, tactics, and concepts; and good but unfinished total synthesis (synthesis of core structure) before the last section
• Compiles examples of solid phase synthesis and continuing flow chemistry-based total synthesis which are very relevant and attractive to industry R&D professionals

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 xiii

Foreword xv

Preface xvii

Introduction 1
Pei‐Qiang Huang

1 The Golden Age of the Total Synthesis of Natural Products: The Era as a Dominant Field 2

2 1991–2000: A Contrasting Decade 9

3 Total Synthesis in the Twenty‐First 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 Product‐Based Drugs to Society 16

Acknowledgements 18

References 18

1 Principles for Synthetic Efficiency and Expansion of the Field 27
Pei‐Qiang 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 Protecting‐Group‐Free Synthesis 36

1.1.10 Multicomponent Reactions and One‐Pot 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 – One‐Pot Reactions 42

1.2.3 Site and Stereoselective Reactions 46

1.2.4 The C─H Bond Functionalization Strategy 46

1.2.5 The Building‐Block 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 Diversity‐Oriented Synthesis (DOS) 51

1.3.2 Function‐Oriented Synthesis (FOS) 51

1.3.3 Biology‐Oriented Synthesis (BIOS) 52

1.3.4 Lead‐Oriented 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. Boger’s Endeavor 55

Acknowledgements 56

References 56

2 Selected Procedure‐Economical Enantioselective Total Syntheses of Natural Products 67
Pei‐Qiang Huang

2.1 One‐Step/One‐Pot Enantioselective Total Synthesis of Natural Products/Drugs 68

2.1.1 Robinson’s One‐Step Synthesis of Tropinone 68

2.1.2 Hayashi’s One‐Pot Synthesis of (+)‐ABT‐341 69

2.2 Two‐Step/Two‐Pot Enantioselective Total Synthesis of Natural Products 69

2.2.1 Hayashi’s Two‐Pot Synthesis of (−)‐Oseltamivir 69

2.2.2 Ma’s Two‐Pot Synthesis of (−)‐Oseltamivir 70

2.2.3 Li’s Two‐Step Chemoenzymatic Total Synthesis of Aszonalenin 71

2.2.4 Ishikawa’s Two‐Step Total Syntheses of (+)‐WIN 64821 and (+)‐Naseseazine B 71

2.3 Three‐Step/Three‐Pot Enantioselective Total Synthesis of Natural Products 73

2.3.1 Carreira’s Three‐Step Asymmetric Total Syntheses of (+)‐Aszonalenin and (−)‐Brevicompanine B 73

2.3.2 Husson’s Three‐Step Asymmetric Total Synthesis of (−)‐Sibirine 73

2.3.3 MacMillan’s Three‐Step Asymmetric Total Synthesis of (+)‐Frondosin B 75

2.3.4 Hayashi’s Three‐Pot Total Synthesis of (−)‐PGE1 Methyl Ester 75

2.3.5 Porco’s Three‐Pot Total Synthesis of (−)‐Hyperibone K 76

2.4 Four‐Step Enantioselective Total Synthesis of Natural Products 77

2.4.1 Lawrence’s Four‐Step Total Synthesis of (−)‐Angiopterlactone A 77

2.4.2 Maimone’s Four‐Step Synthesis of (+)‐Cardamom Peroxide 78

2.4.3 Xie, Lai, and Ma’s Four‐Step Total Synthesis of (−)‐Chimonanthine 79

2.4.4 Huang’s Four‐Step Total Synthesis of (−)‐Chaetominine 80

2.5 Five‐Step/Pot Enantioselective Total Synthesis of Natural Products 81

2.5.1 Carreira’s Five‐Step Total Syntheses of Δ9‐Tetrahydrocannabinols 81

2.5.2 Studer’s Five‐Step Total Syntheses of (+)‐Machaeriols B and D 83

2.5.3 Cook’s Five‐Pot Total Synthesis of (+)‐Artemisinin (Qinghaosu) 84

2.5.4 Corey’s Five‐Step Total Synthesis of Aflatoxin B2 85

2.6 Six‐Step Enantioselective Total Synthesis of Natural Products 86

2.6.1 Comins’ Six‐Step Total Synthesis of (S)‐Camptothecin 86

2.6.2 Krische’s Six‐Step Total Synthesis of (−)‐Cyanolide A 87

2.7 Seven‐Step Enantioselective Total Synthesis of Natural Products 89

2.7.1 Baran’s 7–10‐Step Total Syntheses of Hapalindole‐Type Natural Products 89

2.7.2 Aggarwal’s Seven‐Step Total Synthesis of (+)‐PGF2α 90

2.7.3 Echavarren’s Seven‐step Total Syntheses of Aromadendrane Sesquiterpenes 93

2.7.4 Zhu’s Seven‐Step Total Synthesis of Peganumine A 94

2.7.5 Rychnovsky’s Seven‐Step Synthesis of Lycopodium Alkaloid (+)‐Fastigiatine 96

2.8 Eight‐Step Enantioselective Total Synthesis of Natural Products 99

2.8.1 Overman’s Eight‐Step Synthesis of (+)‐Trans‐Clerodane Iterpenoid 99

2.8.2 Chain’s Eight‐Step Synthesis of (−)‐Englerin A 100

2.8.3 Shenvi’s Eight‐Step Total Synthesis of (−)‐Jiadifenolide 102

2.8.4 Maimone’s Eight‐Step Total Synthesis of (+)‐Chatancin 103

2.8.5 Wipf ’s Eight‐Step Total Synthesis of (−)‐Cycloclavine 105

2.8.6 Shenvi’s Eight‐Step Total Synthesis of (−)‐ Neothiobinupharidine 108

2.9 Nine‐Step Enantioselective Total Synthesis of Natural Products 110

2.9.1 Stoltz’s Nine‐Step Total Synthesis of (−)‐Cyanthiwigin F 110

2.9.2 Maimone’s Nine‐Step Total Synthesis of (–)‐6‐Epi-Ophiobolin N 112

2.9.3 MacMillan’s Nine‐Step Total Synthesis of (−)‐Vincorine 114

2.9.4 Ramharter’s Nine‐Step Total Synthesis of (+)‐Lycoflexine 116

2.9.5 Gao’s and Theodorakis’ Nine‐Step Total Syntheses of (+)‐Fusarisetin A 118

2.10 Ten/Eleven‐Step Enantioselective Total Syntheses of Natural Products 121

2.10.1 Lin’s 10‐Step Total Synthesis of (−)‐Huperzine A 121

2.10.2 Trauner’s 10‐Step Total Synthesis of (+)‐Loline 122

2.10.3 Zhai’s 10‐Step Total Synthesis of (+)‐Absinthin 124

2.10.4 Baran’s 11‐Step Total Synthesis of (−)‐Maoecrystal V 125

2.11 Fourteen/Fifteen‐Step Enantioselective Total Synthesis of Natural Products 129

2.11.1 Baran’s 14‐Step Total Synthesis of (−)‐Ingenol 129

2.11.2 Reisman’s 15‐Step Total Synthesis of (+)‐Ryanodol 132

2.11.3 Johnson’s 15‐Step Total Synthesis of (+)‐Pactamycin 134

2.12 Other Procedure‐Economical Enantioselective Total Syntheses of Natural Products 137

2.13 Conclusion 137

Acknowledgements 149

References 149

3 Diels–Alder Cascades in Natural Product Total Synthesis 159
Richard P. Hsung, Zhi‐Xiong Ma, Lichao Fang, and John B. Feltenberger

3.1 Introduction 159

3.2 Cascades Initiated by Coupling of a Pre‐Formed Diene and Dienophile 161

3.3 Simple Transformations to Diene/Dienophiles Followed by the Diels–Alder Cascade 163

3.4 Rearrangement‐Initiated Diels–Alder Cascades 170

3.5 Cyclization‐Initiated Diels–Alder Cascades 175

3.6 Diels–Alder Initiated Cascades 180

3.7 Concluding Remarks 185

Acknowledgements 185

References 185

4 Organometallics‐Based 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 Au‐Catalyzed Reactions in Total Synthesis 191

4.3 Ag‐Catalyzed Reactions in Total Synthesis 195

4.4 Pt‐Catalyzed Reactions in Total Synthesis 199

4.4.1 Pt‐Catalyzed Enyne Cycloisomerization Reactions 199

4.5 Co‐Catalyzed Pauson–Khand Reactions and Hetero‐Pauson–Khand Reactions in Total Synthesis 202

4.6 Cu‐Catalyzed Reactions in Total Synthesis 204

4.6.1 Asymmetric Conjugate Addition 205

4.6.2 Arene Cyclopropanation 208

4.7 Chromium‐Catalyzed Reactions in Total Synthesis 209

4.8 Fe‐Mediated 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 Iron‐Catalyzed C–C Bond Formations 220

4.8.6 Iron‐Catalyzed C–O, C–S, and C–N Cross‐Coupling 221

4.9 Mn‐Mediated Coupling Reactions in Total Synthesis 221

4.10 Ni‐Catalyzed Reactions in Total Synthesis 225

4.10.1 Ni‐Catalyzed Cycloadditions 225

4.10.2 Ni‐Catalyzed Coupling Reactions 225

4.11 Pd‐Catalyzed Cross‐Coupling 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 Tsuji–Trost Reactions in Total Synthesis 235

4.11.5 Negishi Reactions in Total Synthesis 237

4.11.6 Pd‐Catalyzed Domino Reactions in Total Synthesis 238

4.12 Rh‐Catalyzed (C–H Functionalization by Metal Carbenoid and Nitrenoid Insertion) Reactions in Total Synthesis 240

4.13 Ru‐Catalyzed RCM and RCAM in Total Synthesis 244

4.14 Conclusion 252

Acknowledgements 252

References 252

5 C–H Activation‐Based 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 C–H Activation Approach 261

5.3 Conclusion 270

Acknowledgements 271

References 271

6 Recent Applications of Kagan’s 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 Pinacol‐Type Couplings 276

6.1.4 Fragmentation Reactions 277

6.2 SmI2‐Mediated 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 B‐4 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 Resource‐Based Building Blocks/Chirons for the Total Synthesis of Natural Products 345
Wai‐Lung 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 α‐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
Zhu‐Jun Yao and Wan‐Guo Wei

10.1 The Importance of Bioactive Natural Products in Biological Investigation 395

10.2 Bioactive Natural‐Product‐Inspired Chemical Biology 397

10.3 Natural Products in Drug Discovery 401

10.3.1 Natural Products as Antibody‐Drug Conjugate (ADC) Payloads 407

10.4 TOS, DOS, FOS, and BOS in Natural Product Synthesis 410

10.4.1 Target‐Oriented Synthesis (TOS) 410

10.4.2 Diversity‐Oriented Synthesis (DOS) 411

10.4.3 Function‐Oriented Synthesis (FOS) 418

10.4.4 Biology‐Oriented Synthesis (BIOS) 420

10.5 Semisynthesis 423

10.6 Representative Natural‐Product Drugs and Their Synthesis 427

10.6.1 Nicolaou and Yang’s Synthesis of Taxol 427

10.6.2 Danishefsky’s Synthesis of Epothilone A 429

10.6.3 Smith’s Synthesis of Kendomycin 429

10.6.4 Yao’s Synthesis of Camptothecin 430

10.6.5 Nicolaou and Li’s Synthesis of Platensimycin 432

10.6.6 Shasun Pharma Solutions Ltd’s Synthesis of (−)‐Huperzine A 434

10.6.7 Baran’s Synthesis of Ingenol 435

10.7 Overview and Perspective 436

Acknowledgements 436

References 436

11 Modern Technologies in Natural Product Synthesis 447
Zhu‐Jun Yao and Shouyun Yu

11.1 Visible‐Light 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
Pei‐Qiang Huang, Richard P. Hsung, Zhi‐Xiong Ma, and Zhu‐Jun 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 Seeberger’s One‐Pot Photochemical Continuous‐Flow Strategy 468

12.2.2 Wu’s “Dark Singlet Oxygen” Strategy 468

12.2.3 George’s “Green” Photochemical Strategies 469

12.2.4 A Novel Strategy Merging Synthetic Biology with Chemistry 469

12.2.5 Zhang’s Two‐Step Catalytic Transformation of AA to Artemisinin: The End‐Game? 470

12.3 The Robot Chemist and the Generalized Automation of Small‐Molecule Synthesis 471

12.4 A Synergistic Future with Academia and Industry Coming to the Same Table 471

Acknowledgements 475

References 475

Index 479

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