From Biosynthesis to Total Synthesis

LIST OF CONTRIBUTORS xiii

PREFACE xv

1 From Biosyntheses to Total Syntheses: An Introduction 1
Bastien Nay and Xu-Wen Li

1.1 From Primary to Secondary Metabolism: the Key Building Blocks 1

1.1.1 Definitions 1

1.1.2 Energy Supply and Carbon Storing at the Early Stage of Metabolisms 1

1.1.3 Glucose as a Starting Material Toward Key Building Blocks of the Secondary Metabolism 1

1.1.4 Reactions Involved in the Construction of Secondary Metabolites 3

1.1.5 Secondary Metabolisms 4

1.2 From Biosynthesis to Total Synthesis: Strategies Toward the Natural Product Chemical Space 10

1.2.1 The Chemical Space of Natural Products 10

1.2.2 The Biosynthetic Pathways as an Inspiration for Synthetic Challenges 11

1.2.3 The Science of Total Synthesis 14

1.2.4 Conclusion: a Journey in the Future of Total Synthesis 16

References 16

SECTION I ACETATE BIOSYNTHETIC PATHWAY 19

2 Polyketides 21
Françoise Schaefers, Tobias A. M. Gulder, Cyril Bressy, Michael Smietana, Erica Benedetti, Stellios Arseniyadis, Markus Kalesse, and Martin Cordes

2.1 Polyketide Biosynthesis 21

2.1.1 Introduction 21

2.1.2 Assembly of Acetate/Malonate-Derived Metabolites 23

2.1.3 Classification of Polyketide Biosynthetic Machineries 23

2.1.4 Conclusion 39

References 40

2.2 Synthesis of Polyketides 44

2.2.1 Asymmetric Alkylation Reactions 44

2.2.2 Applications of Asymmetric Alkylation Reactions in Total Synthesis of Polyketides and Macrolides 60

References 83

2.3 Synthesis of Polyketides-Focus on Macrolides 87

2.3.1 Introduction 87

2.3.2 Stereoselective Synthesis of 1,3-Diols: Asymmetric Aldol Reactions 88

2.3.3 Stereoselective Synthesis of 1,3-Diols: Asymmetric Reductions 106

2.3.4 Application of Stereoselective Synthesis of 1,3-Diols in the Total Synthesis of Macrolides 117

2.3.5 Conclusion 126

References 126

3 Fatty Acids and their Derivatives 130
Anders Vik and Trond Vidar Hansen

3.1 Introduction 130

3.2 Biosynthesis 130

3.2.1 Fatty Acids and Lipids 130

3.2.2 Polyunsaturated Fatty Acids 134

3.2.3 Mediated Oxidations of ¿-3 and ¿-6 Polyunsaturated Fatty Acids 135

3.3 Synthesis of ¿-3 and ¿-6 All-Z Polyunsaturated Fatty Acids 140

3.3.1 Synthesis of Polyunsaturated Fatty Acids by the Wittig Reaction or by the Polyyne Semihydrogenation 140

3.3.2 Synthesis of Polyunsaturated Fatty Acids via Cross Coupling Reactions 143

3.4 A pplications in Total Synthesis of Polyunsaturated Fatty Acids 145

3.4.1 Palladium-Catalyzed Cross Coupling Reactions 145

3.4.2 Biomimetic Transformations of Polyunsaturated Fatty Acids 149

3.4.3 Landmark Total Syntheses 153

3.4.4 Synthesis of Leukotriene B5 158

3.5 Conclusion 160

Acknowledgments 160

References 160

4 Polyethers 162
Youwei Xie and Paul E. Floreancig

4.1 Introduction 162

4.2 Biosynthesis 162

4.2.1 Ionophore Antibiotics 162

4.2.2 Marine Ladder Toxins 165

4.2.3 A nnonaceous Acetogenins and Terpene Polyethers 165

4.3 Epoxide Reactivity and Stereoselective Synthesis 166

4.3.1 Regiocontrol in Epoxide-Opening Reactions 166

4.3.2 Stereoselective Epoxide Synthesis 172

4.4 A pplications to Total Synthesis 176

4.4.1 Acid-Mediated Transformations 176

4.4.2 Cascades via Epoxonium Ion Formation 179

4.4.3 Cyclizations under Basic Conditions 181

4.4.4 Cyclization in Water 182

4.5 Conclusions 183

References 184

SECTION II MEVALONATE BIOSYNTHETIC PATHWAY 187

5 From Acetate to Mevalonate and Deoxyxylulose Phosphate Biosynthetic Pathways: an Introduction to Terpenoids 189
Alexandros L. Zografos and Elissavet E. Anagnostaki

5.1 Introduction 189

5.2 Mevalonic Acid Pathway 191

5.3 Mevalonate-Independent Pathway 192

5.4 Conclusion 194

References 194

6 Monoterpenes and Iridoids 196
Mario Waser and Uwe Rinner

6.1 Introduction 196

6.2 Biosynthesis 196

6.2.1 A cyclic Monoterpenes 197

6.2.2 Cyclic Monoterpenes 197

6.2.3 Iridoids 200

6.2.4 Irregular Monoterpenes 202

6.3 A symmetric Organocatalysis 203

6.3.1 Introduction and Historical Background 204

6.3.2 Enamine, Iminium, and Singly Occupied Molecular Orbital Activation 207

6.3.3 Chiral (Bronsted) Acids and H-Bonding Donors 213

6.3.4 Chiral Bronsted/Lewis Bases and Nucleophilic Catalysis 218

6.3.5 A symmetric Phase-Transfer Catalysis 220

6.4 O rganocatalysis in the Total Synthesis of Iridoids and Monoterpenoid Indole Alkaloids 225

6.4.1 (+)-Geniposide and 7-Deoxyloganin 226

6.4.2 (-)-Brasoside and (-)-Littoralisone 227

6.4.3 (+)-Mitsugashiwalactone 229

6.4.4 A lstoscholarine 229

6.4.5 (+)-Aspidospermidine and (+)-Vincadifformine 230

6.4.6 (+)-Yohimbine 230

6.5 Conclusion 231

References 231

7 Sesquiterpenes 236
Alexandros L. Zografos and Elissavet E. Anagnostaki

7.1 Biosynthesis 236

7.2 Cycloisomerization Reactions in Organic Synthesis 244

7.2.1 Enyne Cycloisomerization 245

7.2.2 Diene Cycloisomerization 257

7.3 Application of Cycloisomerizations in the Total Synthesis of Sesquiterpenoids 266

7.3.1 Picrotoxane Sesquiterpenes 266

7.3.2 A romadendrane Sesquiterpenes: Epiglobulol 267

7.3.3 Cubebol-Cubebenes Sesquiterpenes 267

7.3.4 Ventricos-7(13)-ene 270

7.3.5 Englerins 271

7.3.6 Echinopines 271

7.3.7 Cyperolone 273

7.3.8 Diverse Sesquiterpenoids 276

7.4 Conclusion 276

References 276

8 Diterpenes 279
Louis Barriault

8.1 Introduction 279

8.2 Biosynthesis of Diterpenes Based on Cationic Cyclizations 1,2-Shifts, and Transannular Processes 279

8.3 Pericyclic Reactions and their Application in the Synthesis of Selected Diterpenoids 284

8.3.1 Diels-Alder Reaction and Its Application in the Total Synthesis of Diterpenes 284

8.3.2 Cascade Pericyclic Reactions and their Application in the Total Synthesis of Diterpenes 291

8.4 Conclusion 293

References 294

9 Higher Terpenes and Steroids 296
Kazuaki Ishihara

9.1 Introduction 296

9.2 Biosynthesis 296

9.3 Cascade Polyene Cyclizations 303

9.3.1 Diastereoselective Polyene Cyclizations 303

9.3.2 "Chiral proton (H+)"-Induced Polyene Cyclizations 304

9.3.3 "Chiral Metal Ion"-Induced Polyene Cyclizations 308

9.3.4 "Chiral Halonium Ion (X+)"-Induced Polyene Cyclizations 313

9.3.5 "Chiral Carbocation"-Induced Polyene Cyclizations 319

9.3.6 Stereoselective Cyclizations of Homo(polyprenyl)arene Analogs 319

9.4 Biomimetic Total Synthesis of Terpenes and Steroids through Polyene Cyclization 319

9.5 Conclusion 328

References 328

SECTION III SHIKIMIC ACID BIOSYNTHETIC PATHWAY 331

10 Lignans, Lignins, and Resveratrols 333
Yu Peng

10.1 Biosynthesis 333

10.1.1 Primary Metabolism of Shikimic Acid and Aromatic Amino Acids 333

10.1.2 Lignans and Lignin 335

10.2 Auxiliary-Assisted C(sp3)-H Arylation Reactions in Organic Synthesis 336

10.3 Friedel-Crafts Reactions in Organic Synthesis 344

10.4 Total Synthesis of Lignans by C(sp3)-H Arylation Reactions 353

10.5 Total Synthesis of Lignans and Polymeric Resveratrol by Friedel-Crafts Reactions 357

10.6 Conclusion 375

References 376

SECTION IV MIXED BIOSYNTHETIC PATHWAYS-THE STORY OF ALKALOIDS 381

11 Ornithine and Lysine Alkaloids 383
Sebastian Brauch, Wouter S. Veldmate, and Floris P. J. T. Rutjes

11.1 Biosynthesis of l-Ornithine and l-Lysine Alkaloids 383

11.1.1 Biosynthetic Formation of Alkaloids Derived from l-Ornithine 383

11.1.2 Biosynthetic Formation of Alkaloids Derived from l-Lysine 388

11.2 The Asymmetric Mannich Reaction in Organic Synthesis 392

11.2.1 Chiral Amines as Catalysts in Asymmetric Mannich Reactions 394

11.2.2 Chiral Bronsted Bases as Catalysts in Asymmetric Mannich Reactions 398

11.2.3 Chiral Bronsted Acids as Catalysts in Asymmetric Mannich Reactions 404

11.2.4 Organometallic Catalysts in Asymmetric Mannich Reactions 408

11.2.5 Biocatalytic Asymmetric Mannich Reactions 413

11.3 Mannich and Related Reactions in the Total Synthesis of l-Lysine- and l-Ornithine-Derived Alkaloids 414

11.4 Conclusion 426

References 427

12 Tyrosine Alkaloids 431
Uwe Rinner and Mario Waser

12.1 Introduction 431

12.2 Biosynthesis of Tyrosine-Derived Alkaloids 431

12.2.1 Phenylethylamines 431

12.2.2 Simple Tetrahydroisoquinoline Alkaloids 433

12.2.3 Modified Benzyltetrahydroisoquinoline Alkaloids 433

12.2.4 Phenethylisoquinoline Alkaloids 436

12.2.5 Amaryllidaceae Alkaloids 438

12.2.6 Biosynthetic Overview of Tyrosine-Derived Alkaloids 442

12.3 Aryl-Aryl Coupling Reactions 442

12.3.1 Copper-Mediated Aryl-Aryl Bond Forming Reactions 443

12.3.2 Nickel-Mediated Aryl-Aryl Bond Forming Reactions 446

12.3.3 Palladium-Mediated Aryl-Aryl Bond Forming Reactions 447

12.3.4 Transition Metal-Catalyzed Couplings of Nonactivated Aryl Compounds 450

12.4 Synthesis of Tyrosine-Derived Alkaloids 456

12.4.1 Synthesis of Modified Benzyltetrahydroisoquinoline Alkaloids 456

12.4.2 Synthesis of Phenethylisoquinoline Alkaloids 460

12.4.3 Synthesis of Amaryllidaceae Alkaloids 462

12.5 Conclusion 468

References 469

13 Histidine and Histidine-Like Alkaloids 473
Ian S. Young

13.1 Introduction 473

13.2 Biosynthesis 473

13.3 Atom Economy and Protecting-Group-Free Chemistry 480

13.4 Challenging the Boundaries of Synthesis: Pias 488

13.5 Conclusion 497

References 499

14 Anthranilic Acid-Tryptophan Alkaloids 502
Zhen-Yu Tang

14.1 Biosynthesis 502

14.2 Divergent Synthesis-Collective Total Synthesis 508

14.3 Collective Total Synthesis of Tryptophan-Derived Alkaloids 510

14.3.1 Monoterpene Indole Alkaloids 510

14.3.2 Bisindole Alkaloids 512

References 517

15 Future Directions of Modern Organic Synthesis 519
Jakob Pletz and Rolf Breinbauer

15.1 Introduction 519

15.2 Enzymes in Organic Synthesis: Merging Total Synthesis with Biosynthesis 520

15.3 Engineered Biosynthesis 526

15.4 Diversity-Oriented Synthesis, Biology-Oriented Synthesis, and Diverted Total Synthesis 533

15.4.1 Diversity-oriented Synthesis 535

15.4.2 Biology-oriented Synthesis 536

15.4.3 Diverted Total Synthesis 539

15.5 Conclusion 541

References 545

INDEX 548