Retrosynthetic Analysis and Synthesis of Natural Products 1 Synthetic Methods and Applications

For chemists, attempting to mimic nature by synthesizing complex natural products from raw material is a challenge that is fraught with pitfalls. To tackle this unique but potentially rewarding task, researchers can rely on well-established reactions and methods of practice, or apply their own synthesis methods to verify their potential. Whatever the goal and its complexity, there are multiple ways of achieving it. We must now establish a strategic and effective plan that requires the minimum number of steps, but lends itself to widespread use.

This book is structured around the study of a dozen target products (butyrolactone, macrolide, indole compound, cyclobutanic terpene, spiro- and polycyclic derivatives, etc.). For each product, the different disconnections are presented and the associated syntheses are analyzed step by step. The key reactions are described explicitly, followed by diagrams showing the range of impact of certain transformations. This set of data alone is conducive to understanding syntheses and indulging in this difficult, but worthwhile activity.

Olivier Piva is Professor of Organic Chemistry and Head of ICBMS at University Claude Bernard Lyon 1, France. His research interests encompass metathesis and photochemistry and their applications to the total synthesis of natural products.

Preface xi

Chapter 1. Total Synthesis: Some Elements to Contemplate 1

1.1. Total synthesis – why and for what purpose? 1

1.2. The different approaches 3

1.3. Efficiency, selectivity 7

1.4. The essential reactions 9

1.5. Towards a sustainable total synthesis 11

1.6. What about tomorrow? 12

1.7. References 12

Chapter 2. Squamostolide 21

2.1. Structure, isolation and properties 21

2.2. Bond disconnections 21

2.3. Approach according to M.J. Wu 23

2.3.1. Bond disconnections 23

2.3.2. Synthesis 24

2.3.3. Key reaction: Claisen–Ireland rearrangement 27

2.3.4. Key reaction: functionalization of true alkynes 29

2.3.5. Supporting synthetic transformations 31

2.4. Approach according to K.J. Quinn 33

2.4.1. Bond disconnections 33

2.4.2. Synthesis 34

2.4.3. Key reaction: alkene metathesis and tandem processes 37

2.4.4. Supporting synthetic transformations 43

2.5. References 44

Chapter 3. Rubrenolide 51

3.1. Structure, isolation and properties 51

3.2. Disconnections 52

3.3. Approach according to H. Fujioka 53

3.3.1. Disconnection 53

3.3.2. Synthesis, developed by the Fujioka group 54

3.3.3. Key reaction: iodoetherification 56

3.3.4. Key reaction: oxidation of aldehydes to carboxylic acids 57

3.3.5. Supporting synthetic transformations 58

3.4. Approach according to B. Zwanenburg 59

3.4.1. Retrosynthesis 59

3.4.2. Synthesis, Zwanenburg’s approach 60

3.4.3. Key reaction: Wolff rearrangement 62

3.4.4. Key reaction: dehydration of alcohols according to Grieco 63

3.4.5. Supporting synthetic transformations 64

3.5. Approach according to N. Kommu 65

3.5.1. Disconnections 65

3.5.2. Synthesis 66

3.5.3. Key reaction: diastereoselective alkylation of oxazolidinones 68

3.5.4. Key reaction: enantioselective reduction of ketones – CBS method 71

3.5.5. Key reaction: alkyne formation according to Ohira–Bestmann 73

3.5.6. Supporting synthetic transformations 74

3.6. References 75

Chapter 4. Bipinnatin J 81

4.1. Structure, isolation and properties 81

4.2. Disconnections 82

4.3. Approach according to D. Trauner (racemic synthesis) 83

4.3.1. Synthesis 83

4.3.2. Key reaction: ene reaction between alkynes and alkenes 86

4.3.3. Key reaction: Stille coupling 88

4.3.4. Key reaction: Nozaki–Hiyama–Kishi reaction 90

4.3.5. Supporting synthetic transformations 93

4.4. Approach according to V.H. Rawal 94

4.4.1. Synthesis 94

4.4.2. Key reaction: Negishi coupling 97

4.4.3. Supporting synthetic transformations 98

4.5. Enantioselective approach according to G. Pattenden 99

4.5.1. Synthesis 99

4.5.2. Supporting synthetic transformations 102

4.6. Approach according to D. Trauner – enantioselective version 102

4.6.1. Synthesis 102

4.6.2. Supporting synthetic transformations 105

4.7. Comparison of the four syntheses 106

4.8. References 107

Chapter 5. Tubingensin B 111

5.1. Structure, isolation and properties 111

5.2. Bond disconnections 112

5.3. Approach according to N.K. Garg 113

5.3.1. Bond disconnections 113

5.3.2. Synthesis 114

5.3.3. Key reaction: Sonogashira reaction 116

5.3.4. Key reaction: Suzuki coupling 118

5.3.5. Key reaction: cycloaddition [2+2] of arynes 120

5.3.6. Key reaction: radical cyclization and Baldwin’s rules 122

5.3.7. Key reaction: enantioselective hydrogenation of ketones 122

5.3.8. Supporting synthetic transformations 124

5.4. References 125

Chapter 6. Polygonatine A 127

6.1. Structure, isolation and properties 127

6.2. Disconnections 127

6.3. Synthesis according to S.M. Allin 128

6.3.1. Disconnection 128

6.3.2. Synthesis 129

6.3.3. Key reaction: radical cyclization of selenoesters 130

6.3.4. Supporting synthetic transformations 133

6.4. Synthesis by J.P. Michael 133

6.4.1. Disconnections 133

6.4.2. Synthesis 134

6.4.3. Key reaction: Vilsmeier–Haack–Arnold reaction 135

6.4.4. Supporting synthetic transformations 137

6.5. References 139

Chapter 7. (+)-Intricatetraol 143

7.1. Structure, isolation and properties 143

7.2. Disconnections 143

7.3. Approach according to Morimoto 145

7.3.1. Synthesis 145

7.3.2. Key reaction: epoxidation according to Katsuki–Sharpless 149

7.3.3. Key reaction: asymmetric epoxidation according to Shi 151

7.3.4. Supporting synthetic transformations 153

7.4. References 155

Chapter 8. Enigmazole A 159

8.1. Structure, isolation and properties 159

8.2. Disconnections 160

8.3. Approach according to T. Molinski 160

8.3.1. Disconnections 160

8.3.2. Synthesis 161

8.3.3. Key reaction: 1,2-enantioselective addition of dialkylzinc to aldehydes 166

8.3.4. Key reaction: reduction of β-aldols to 1,3-diols 168

8.3.5. Supporting synthetic transformations 169

8.4. Approach according to A. Fürstner 172

8.4.1. Disconnections 172

8.4.2. Synthesis 173

8.4.3. Key reaction: diastereoselective alkylation according to Myers 177

8.4.4. Key reaction: Yne-yne ring-closing metathesis (RCAM) 179

8.4.5. Key reaction: sigmatropic rearrangement [3,3] of propargyl esters 180

8.4.6. Supporting synthetic transformations 181

8.5. Approach according to A.B. Smith III 183

8.5.1. Disconnections 183

8.5.2. Synthesis 183

8.5.3. Key reaction: dithiane, umpolung and relayed reactions 189

8.5.4. Key reaction: Petasis–Ferrier rearrangement 191

8.5.5. Supporting synthetic transformations 191

8.6. Approach according to H. Fuwa 194

8.6.1. Disconnections 194

8.6.2. Synthesis 195

8.6.3. Key reaction: Tishchenko–Evans reaction 199

8.6.4. Key reaction: Meyer–Schuster and Rupe rearrangement 201

8.6.5. Supporting synthetic transformations 203

8.7. Comparative assessment of the different syntheses 205

8.8. References 206

Chapter 9. Biyouyanagin A 213

9.1. Structure, isolation and properties 213

9.2. Synthesis according to K.C. Nicolaou 214

9.2.1. Disconnections 214

9.2.2. Synthesis 215

9.2.3. Key reaction: 1,4-addition and organocatalysis 220

9.2.4. Shapiro reaction 222

9.2.5. Supporting synthetic transformations 225

9.3. References 229

Chapter 10. Elatol 233

10.1. Structure, isolation and properties 233

10.2. Disconnections 234

10.3. Approach according to B. Stoltz 234

10.3.1. Disconnections 234

10.3.2. Synthesis 235

10.3.3. Key reaction: Tsuji–Trost reaction 237

10.3.4. Key reaction: ring-closing metathesis of hindered olefins 241

10.3.5. Key reaction: reduction of enones according to Luche 242

10.3.6. Supporting synthetic diagrams 243

10.4. References 245

Chapter 11. Thiomarinol H 249

11.1. Structure, isolation and properties 249

11.2. Disconnections 250

11.3. Approach according to D.G. Hall 250

11.3.1. Disconnections 250

11.3.2. Synthesis 252

11.3.3. Key reaction: hetero-Diels–Alder enantioselective reaction 254

11.3.4. Supporting synthetic transformations 256

11.4. Approach according to S. Raghavan 258

11.4.1. Disconnections 258

11.4.2. Synthesis 260

11.4.3. Key reaction: Kirmse–Doyle rearrangement 262

11.4.4. Key reaction: Julia–Lythgoe and Julia–Kocienski reaction 264

11.4.5. Supporting synthetic transformations 268

11.5. References 270

Chapter 12. Oblongolides A and C 273

12.1. Structures, isolation and properties 273

12.2. Disconnections 274

12.3. Synthesis of oblongolide A according to Shing 275

12.3.1. Disconnections 275

12.3.2. Synthesis 275

12.3.3. Key reaction: intramolecular Diels–Alder reaction 278

12.3.4. Supporting synthetic transformations 280

12.4. Shishido’s approach to oblongolide C 281

12.4.1. Disconnections 281

12.4.2. Synthesis 283

12.4.3. Key reaction: intramolecular [3+2] cycloadditions 287

12.4.4. Supporting synthetic transformations 288

12.5. References 291

List of Abbreviations 295

Index 301

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