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Design and Strategy in Organic Synthesis

ISBN: 978-3-527-31964-0
822 pages
September 2013
Design and Strategy in Organic Synthesis (3527319646) cover image
This long-awaited graduate level book, written by one of the world's leading organic chemists in collaboration with two of his former and
present coworkers, adopts a refreshingly unique approach to synthesis planning and execution.

Following an introductory look at the concept of synthesis, the authors discuss the Why, What, and How of organic synthesis as they apply to natural products. Although emphasis is on the Chiron Approach utilizing amino-acids, carbohydrates, hydroxy acids, terpenes, lactones and other naturally occurring small molecules as starting materials, catalytic asymmetric methods are also included as a corollary whenever relevant. A must-have source of first class information for everyone working in organic synthesis, be it in academia or industry.

With a foreword by Larry E. Overman and David W. C. MacMillan
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Foreword XVII

Preface XIX

Acknowledgement XXIII

Abbreviations XXV

1 The Concept of Synthesis 1

1.1 Organic Synthesis as a Central Science 1

1.2 Organic Chemistry and the Public 3

1.3 The ‘‘Small Molecules’’ of life 6

1.4 Nature’s Rules 9

1.5 Organic Synthesis as a Mental and Visual Science 11

1.6 Art, Architecture, and Synthesis 12

1.7 Simplification of Complexity 13

1.8 Seeing Through the Mind’s Eye 15

1.9 Beauty is in the Eye of the Beholder 18

References 19

2 The ‘‘Why’’ of Synthesis 25

2.1 Nature the Provider, Healer, and Enticer 25

2.2 The Supply Problem 26

2.3 From Bench to Market 28

2.4 Thank you Nature! 30

2.5 Chasing Bugs with a Purpose 32

2.6 Structure-based Organic Synthesis 33

2.7 Almost There . . . or Just Arrived 34

2.8 The Futility of it All 35

2.9 Synthesis as a Seeker of the Truth 36

2.10 Nature as the Ultimate Synthesizer 42

2.11 A Brave New Chemical World 43

2.11.1 Beyond the molecule 43

2.11.2 Buckyballs and fullerenes 45

2.11.3 Dendrimers 45

2.11.4 Nanochemistry 45

2.11.5 Molecular machines 46

2.12 Exploring New Synthetic Methods 47

2.12.1 The Diels-Alder reaction 48

2.12.2 The direct aldol reaction 54

2.12.3 High impact catalytic oxidation and reduction reactions 57

2.12.4 High impact catalytic olefin-producing reactions 59

References 62

3 The ‘‘What’’ of Synthesis 73

3.1 Periods, Trends, and Incentives 73

3.2 A Century of Synthesis 74

3.3 We the ‘‘Synthesis People’’ 81

3.4 Complex and Therapeutic too! 82

3.5 Peptidomimetics and Unnatural Compounds 84

3.6 Diversity Through Complexity 89

References 90

4 The ‘‘How’’ of Synthesis 97

4.1 The Visual Dialogue 97

4.2 The Psychobiology of Synthesis Planning 98

4.2.1 ‘‘Psychosynthesis’’ 101

4.3 The Agony and Ecstasy of Synthesis 102

4.4 Rembrandt Meets Woodward 104

4.4.1 Cortisone 104

4.4.2 Strychnine 108

4.4.2.1 The Woodward Synthesis 109

4.4.2.2 The Overman synthesis 111

4.4.2.3 The Kuehne synthesis 113

4.4.2.4 The Bonjoch and Bosch synthesis 114

4.4.2.5 The Shibasaki synthesis 116

4.4.2.6 The Fukuyama synthesis 118

4.4.2.7 The Mori synthesis 119

4.4.2.8 The MacMillan synthesis 121

4.4.2.9 Strychnine syntheses: Synopsis 122

4.5 The Post Woodwardian Era 123

4.5.1 The convergent template-based approach 123

4.5.2 Chiral auxiliary approach 125

4.5.3 Substrate control approach in cycloadditions 127

4.5.4 Biomimetic cyclization approach 129

4.6 Catalysis and Chirality in Total Synthesis 131

4.6.1 Applications of asymmetric catalysis to drug discovery 136

References 139

5 Sources of Enantiopure Compounds 145

5.1 Optical Resolution 146

5.2 Chemical Kinetic Resolution (KR) 147

5.2.1 Classical, natural, and parallel methods 147

5.2.2 Dynamic chemical kinetic resolution 147

5.3 Cell-free Enzyme-mediated Enantiopure Compounds 149

5.3.1 Hydrolases and ester formation 149

5.3.2 Nitrilases, amidases, and acylases 152

5.4 Cell-free Chemoenzymatic Methods 154

5.5 Metal-catalyzed Dynamic Kinetic Resolution (DKR) 154

5.6 Biocatalytic Methods for Enantiopure Compounds 155

5.6.1 Enzymatic reduction of ketones 155

5.6.2 Enzymatic hydroxylation and epoxidation 156

5.6.3 Enzymatic oxidation of alcohols 157

5.6.4 Enzymatic Baeyer-Villiger oxidation 157

5.7 Applications of Enzymatic and Chemoenzymatic Methods 158

5.8 Chemical Asymmetric Synthesis of Enantiopure Compounds 160

5.9 Enantiopure Compounds from Nature 164

References 165

6 The Chiron Approach 171

6.1 Living Through a Total Synthesis 171

6.2 Principles of the Chiron Approach 172

6.2.1 Definition 173

6.2.2 The Chiron Approach 175

6.2.3 Two philosophies, one goal 176

6.2.4 There is more than meets the eye 180

6.2.5 The flipside of molecules 183

6.2.6 Common root, different MO: chirons and synthons 184

6.2.7 To chiron or not to chiron 186

6.3 Anatomy of a Synthesis 186

References 189

7 Nature’s Chirons 193

7.1 α-Amino Acids 193

7.2 Carbohydrates 195

7.3 α-Hydroxy Acids 200

7.4 Terpenes 203

7.5 Cyclitols 206

References 208

8 From Target Molecule to Chiron 213

8.1 Where’s Waldo? 214

8.2 Apparent Chirons 217

8.3 Partially Hidden Chirons 220

8.4 Hidden Chirons 222

8.5 Chirons as ‘‘Sacrificial Lambs’’ 224

8.6 Locating α-Amino Acid-type Substructures 228

8.6.1 Apparent amino acids 229

8.6.2 Partially hidden amino acids 231

8.6.3 Hidden amino acids 232

8.7 Locating Carbohydrate-type Substructures 234

8.7.1 Patterns and shapes 235

8.7.2 The ‘‘Rule of Five’’ 236

8.7.3 Apparent carbohydrates 237

8.7.4 Partially hidden carbohydrates 239

8.7.5 Hidden carbohydrates 240

8.8 Locating Hydroxy Acid-type Substructures 243

8.8.1 Apparent hydroxy acids 243

8.8.2 Partially hidden hydroxy acids 245

8.8.3 Hidden hydroxy acids 248

8.8.4 The Roche acid − a unique C-Methyl chiron 251

8.9 Locating Terpene-type Substructures 254

8.9.1 Apparent terpenes 254

8.9.2 Partially hidden terpenes 258

8.9.3 Hidden terpenes 260

8.9.3.1 The terpene route to taxol 267

8.10 Locating Carbocyclic-type Substructures 270

8.10.1 Apparent carbocycles 271

8.10.2 Partially hidden carbocycles 272

8.10.3 Hidden carbocycles 275

8.10.4 Quinic acid, cyclitols, and other carbocycles as chirons 279

8.11 Locating Chirons Derived from Lactones 283

8.11.1 Apparent lactones 285

8.11.2 Partially hidden lactones 286

8.11.3 Hidden lactones 288

8.11.4 The replicating lactone strategy 292

References 294

9 Applications of the Chiron Approach 301

9.1 Category I Target Molecules 301

9.1.1 Streptolic acid 302

9.1.2 ent-Gelsedine 303

9.1.3 Vincamine 305

9.1.4 Peribysin E 307

9.2 Category II Target Molecules 308

9.2.1 FK-506 309

9.2.2 Okadaic acid 310

9.2.3 Phorboxazole A 312

9.2.4 Brevetoxin B 314

9.3 Category III Target Molecules 316

9.3.1 Neocarzinostatin 317

9.3.2 Idiospermuline 317

9.4 Prelude to Total Synthesis of Category I Molecules 320

References 320

10 Total Synthesis from α-Amino Acid Precursors 323

10.1 Actinobolin 323

10.2 Aspochalasin B 326

10.3 Cephalotaxine 329

10.4 α-Kainic Acid (W. Oppolzer) 332

10.5 α-Kainic Acid (P. T. Gallagher) 334

10.6 Croomine 336

10.7 Biotin 339

10.8 Salinosporamide A 342

10.9 Thienamycin 345

10.10 FR901483 348

10.10.1 The Sorensen synthesis 350

10.11 Tuberostemonine 353

10.12 Phyllanthine 358

10.13 Oscillarin 361

10.14 ent-Cyclizidine 364

10.15 Pactamycin 367

10.16 Miscellanea 371

References 373

11 Total Synthesis from Carbohydrate Precursors 377

11.1 Ajmalicine 377

11.2 ent-Actinobolin 381

11.3 Trehazolin and Trehazolamine 384

11.4 Fomannosin 390

11.5 9a-Desmethoxy Mitomycin A 394

11.6 Saxitoxin and β-Saxitoxinol 398

11.6.1 Second generation synthesis 400

11.7 ent-Decarbamoyl Saxitoxin 402

11.8 Zaragozic acid A 405

11.9 Hemibrevetoxin B 408

11.10 Carbohydrates in Synthesis and in Biology 416

11.11 Miscellanea 417

References 422

12 Total Synthesis from Hydroxy Acids 427

12.1 Griseoviridin 427

12.2 Halicholactone 431

12.3 Brasilenyne 435

12.4 Octalactin A 438

12.5 (3Z)-Dactomelyne 442

12.6 UCS1025A 446

12.7 Jerangolid A 449

12.8 Miscellanea 453

References 456

13 Total Synthesis from Terpenes 459

13.1 Picrotoxinin 459

13.2 Eucannabinolide 463

13.3 Trilobolide and Thapsivillosin F 467

13.4 Briarellin E and F 472

13.5 Samaderine Y 477

13.6 Ambiguine H and Hapalindole U 481

13.7 Platensimycin 484

13.7.1 The Nicolaou synthesis 485

13.7.2 The Ghosh synthesis 488

13.7.3 Nicolaou’s two asymmetric syntheses 491

13.7.4 Yamamoto’s organocatalytic asymmetric synthesis 494

13.7.5 Corey’s catalytic enantioselective synthesis 496

13.7.6 Platensimycin and the mind’s eye 496

13.8 Phomactin A 500

13.9 Pinnaic Acid 503

13.9.1 The Danishefsky and Zhao asymmetric syntheses 507

13.10 Fusicoauritone 510

13.11 Miscellanea 514

References 516

14 Total Synthesis from Carbocyclic Precursors 521

14.1 Punctatin A 521

14.2 Acanthoic Acid 524

14.3 Stachybocin Spirolactam 527

14.4 Scabronine G 529

14.5 Chapecoderin A 533

14.6 Dragmacidin F 533

14.7 Reserpine 538

14.7.1 The Woodward synthesis 539

14.7.2 The Stork synthesis 542

14.7.3 The Hanessian synthesis 545

14.8 Fawcettimine 548

14.8.1 Toste’s synthesis of fawcettimine 548

14.8.2 Heathcock’s synthesis of (±)-fawcettimine 551

14.9 Tamiflu 553

14.9.1 The Fang and Wong synthesis 553

14.9.2 The Hudlicky and Banwell syntheses 555

14.9.3 The Shibasaki catalytic asymmetric Diels-Alder synthesis 557

14.9.4 Tamiflu synthesis in the age of catalysis: Synopsis 558

14.10 Miscellanea 560

References 563

15 Total Synthesis with Lactones as Precursors 567

15.1 Megaphone 567

15.2 Dihydromevinolin 569

15.3 Mannostatin A 572

15.4 Furaquinocin C 577

15.5 Miscellanea 577

References 580

16 Single Target Molecule-oriented Synthesis 583

16.1 Synchronicity 583

16.2 Joining Forces 584

16.3 Back-to-back Publishing 586

16.3.1 Veratramine (1967) 587

16.3.2 (±)-Lycopodine (1968) 588

16.3.3 Ionomycin (1990) 589

16.3.4 Vancomycin aglycone (1998) 591

16.4 Same Year Publications 593

16.4.1 (±)-Colchicine (1959) 594

16.4.2 (±)-Catharanthine (1970) 595

16.4.3 (±)-Cephalotaxine (1972) 596

16.4.4 Bleomycin A2 (1982) 597

16.4.5 Kopsinine (1985) 598

16.4.6 Rapamycin (1993) 600

16.4.7 Phomoidrides (CP molecules) (2000) 604

16.4.7.1 The Nicolaou Synthesis 604

16.4.7.2 The Shair synthesis 606

16.4.7.3 The Fukuyama synthesis 608

16.4.7.4 The Danishefsky synthesis 609

16.4.7.5 What is in a drawing? 611

16.4.8 Borrelidin (2003–2004) 612

16.4.8.1 The Morken synthesis 612

16.4.8.2 The Hanessian synthesis 614

16.4.8.3 The O˜mura and Theodorakis syntheses 615

16.4.9 Amphidinolide E (2006) 618

16.5 Single Target Molecules with Special Relevance 620

16.6 Quinine 621

16.6.1 The Stork synthesis 621

16.6.2 Quinine: The Woodward and Doering formal vs total syntheses issue 624

16.6.3 Quinine: Apr´es Woodward and Doering 627

16.6.3.1 The Uskokovi´c synthesis 627

16.6.3.2 The Gates synthesis 630

16.6.3.3 The Taylor and Martin synthesis 631

16.6.4 Quinine: Total synthesis in the modern age of catalysis 631

16.6.4.1 The Jacobsen synthesis 631

16.6.4.2 The Kobayashi synthesis 633

16.6.4.3 The Williams and Krische syntheses of 7-hydroxyquinine 635

16.6.5 The total synthesis of quinine in the mind’s eye 637

16.7 Lactacystin 641

16.7.1 The first Corey synthesis 642

16.7.2 The second Corey synthesis 643

16.7.3 The Baldwin synthesis 645

16.7.4 The Chida Synthesis 647

16.7.5 The O˜mura-Smith synthesis 648

16.7.6 The Panek synthesis 650

16.7.7 The Jacobsen synthesis 651

16.7.8 The Shibasaki synthesis 654

16.7.9 Lactacystin and omuralide: Alternative methods and synthetic approaches 656

16.7.10 The Kang approach 656

16.7.11 The Adams synthesis of omuralide 657

16.7.12 The Ohfune approach 658

16.7.13 The Pattenden approach 659

16.7.14 The Hatekayama approach 659

16.7.15 The Donohue synthesis of (±)-omuralide 660

16.7.16 The Wardrop approach 661

16.7.17 The Hayes synthesis of lactacystin 662

16.7.18 Total synthesis of lactacystin: Synopsis 663

16.8 Taxol 665

16.8.1 What mad pursuit 666

16.8.2 The Holton synthesis of taxol 666

16.8.3 The Nicolaou synthesis of taxol 670

16.8.4 The Danishefsky synthesis of taxol 673

16.8.5 The Wender synthesis of taxol 676

16.8.6 The Kuwajima synthesis of taxol 679

16.8.7 The Mukaiyama synthesis of taxol 682

16.8.8 The six total syntheses of taxol: The calm after the storm 685

16.8.9 Total syntheses of taxol in the mind’s eye 686

References 690

17 Man, Machine, and Visual Imagery in Synthesis Planning 699

17.1 The LHASA Program 701

17.2 SYNGEN 702

17.3 WODCA 703

17.4 The CHIRON Program 704

17.4.1 CASA (Computer-assisted stereochemical analysis) 704

17.4.2 CAPS (Computer-assisted precursor selection) 705

17.5 Computer-aided synthesis planning 710

References 711

18 The Essence of Synthesis – A Retrospective 713

18.1 Lest we Forget 714

18.2 The Corey and Stork Schools 714

18.3 The Visual Dialogue with Molecules 716

18.4 Total Synthesis: From whence we came. . . 717

18.5 In Pursuit of the ‘‘Ideal Synthesis’’ 722

18.5.1 The problem with protecting groups – blessing or curse? 724

18.5.1.1 Protecting-group-free synthesis? 725

18.5.2 The ‘‘redox economy’’ problem 725

18.5.3 The ‘‘functional group adjustment’’ problem 726

18.5.4 ‘‘Chiral economy’’ 727

18.6 For the Love of Synthesis (Synthephilia) 730

18.6.1 Reaching the summit 731

18.7 Organic Synthesis: To where we are going 732

18.8 Synthesis at the Service of Humankind 734

18.9 From the Chiron Approach to Catalysis 736

18.9.1 The young, the brave, and the bold: Passing the baton 740

18.9.1.1 Himandrine 740

18.9.1.2 Palau’amine 743

18.9.1.3 Minfiensine 745

18.9.1.4 Maoecrystal Z 747

18.9.2 Parting thoughts 749

18.10 A Salute to the Vanguards of Synthesis 749

References 750

Author Index [Natural product/Target] 757

Chiron/Starting Material to Natural Product/Target Index 771

Natural product/Target [Chiron] 781

Key (Named) Reactions Index 791

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Stephen Hanessian holds the Isis Pharmaceutical Research Chair at the University of Montreal and is also on the faculty of the Departments of Chemistry, Pharmaceutical Sciences and Pharmacology at the University of California, Irvine. He has received numerous awards and distinctions, the latest being the 2012 Ernest Guenther Award in the Chemistry of Natural Products from the American Chemical Society, and the IUPAC-Richter-Preis in Medicinal Chemistry.

Simon Giroux was born and raised in Montreal, Canada. He received his PhD in 2006 with Prof. Stephen Hanessian and subsequently spent 2 years in the laboratory of Prof. E. J. Corey at Harvard University, as an NSERC postdoctoral fellow. He is currently working as a medicinal chemist at Vertex Pharmaceuticals in Cambridge, Massachusetts.

Bradley L. Merner is a native of St. John's, Newfoundland, Canada. He completed is PhD degree under the direction of Prof. Graham J. Bodwell at Memorial University in 2010, and then moved to the University of Montreal as postdoctoral research associate in the laboratories of Prof. Stephen Hanessian. In the fall of 2013 he will join the Department of Chemistry and Biochemistry at Auburn University as an Assistant Professor.
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2012 IUPAC-Richter Prize Professor Stephen Hanessian has been awarded the 2012 IUPAC-Richter Prize. Read the announcement...
2012 Ernest Guenther Award Professor Stephen Hanessian has won the 2012 Ernest Guenther Award in Natural Products Chemistry from the American Chemical Society (ACS). Find out more...
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