First Total Synthesis and Structure Confirmation of (?)-Asimitrin, a C37 Annonaceous Acetogenin with a Hydroxylated Adjacent Bis-Tetrahydrofuran Core

목차 (Table of Contents)

• I. Introduction 1
• I.1. 3-Oxygenated Tetrahydrofuranoids Natural Products 2
• I.1.1. Mono-THFs 2
• I.1.2. Fused Bis-THFs 8
• I.1.3. Adjacent Bis-THFs 10
• I.1.4. THF-Containing Macrolides. 13
• I.1.5. Mono-THF Fused with Medium-Sized Ether Ring 15
• I.2. Previous Synthesis of Adjacent Bis-THF Acetogenins. 18
• I.2.1. Marshall's Total Synthesis of (+)-Trilobin 18
• I.2.2. Sinha and Keinan's Total Synthesis of (+)-Trilobacin 20
• I.2.3. Sinha and Keinan's Total Synthesis of (+)-Asimicin 22
• I.2.4. Borhan's Synthesis of 17-Hydroxy Annonaceous Acetogeinin Mucoxin 25
• II. Results and Discussions 28
• II.1. Previous Studies on Amide Enolate Alkylation 28
• II.1.1. Kim's Divergent Construction of 2,5-cis- and 2,5-trans- Disubstituted THFs by Intramolecular Amide Enolate or Nitrile Anion 28
• II.1.2. Kim's Protecting Group-Dependent Intermolecular Amide Enolate Alkylation 31
• II.2. Kim's Intramolecular Protecting Group-Dependent Amide Enolate Alkyation for Tetrahydrofuran 33
• II.2.1. Substrate Scope for IAEA Reaction 34
• II.2.2. Kim's Total Synthesis of C19 Nematocidal Tetrahydrofuranoids Oxylipids 38
• II.2.3. Kim's Total Synthesis and Structure revision of (‒)-Bisezakyne A 47
• II.2.4. Kim's Total Synthesis of (+)-Laurenidificin and (+)-Aplysiallene 52
• II.3. Total Synthesis C37 Annonaceous Acetogenin (‒)-Asimitrin (1a) 58
• II.3.A. (‒)-Asimitrin (1a) 58
• II.3.B. Total Synthesis of C37 Annonaceous Acetogenin (‒)-Asimitrin (1a) 61
• II.3.1. Retrosynthetic Plan 62
• II.3.2. Construction of Key 17-Hydroxy-16,17-erythro-16,17-trans-THF 6 64
• II.3.3. Construction of Key 17-Hydroxy-16,17-erythro-16,19-trans-THF 6 by Intramolecular Amide Enolate Alkylation 66
• II.3.4. Construction of Key 17-Hydroxy-16,17-erythro-16,19-trans-20, 23-trans Adjacent Bis-THF 3a 67
• II.3.5. Construction of Homoallylic Alcohol 2a by Keck Allylation 73
• II.3.6. Keck Allylation of 17-OTIPS Bis-THF Alcohol II-3-21 75
• II.3.7. Completion of the Total Synthesis of (−)-Asimitrin (1a) 80
• II.3.C. Synthesis of 16,19-trans/20,23-cis, 16,19-cis/20,23-cis and 16,19-cis/ 20,23-trans Diastereomers of (‒)-Asimitrin (1a) 82
• II.3.8. Construction of Key Intermediate 5b-5d 86
• II.3.9. Construction of Key 17-Hydroxy-16,17-erythro-16,19-trans 20, 23-cis Adjacent Bis-THF 3b 88
• II.3.10. Construction of Homoallylic Alcohol 2b by Keck Allylation 90
• II.3.11. Completion of the Total Synthesis of 16,19-trans-20,23-cis Adjacent Bis-THF Asimitrin Diastereomer (1b) 92
• II.3.12. Construction of Key 17-Hydroxy-16,17-erythro-16,19-cis-20,23- cis Adjacent Bis-THF 3c 94
• II.3.13. Construction of Homoallylic Alcohol 2c by Keck Allylation 96
• II.3.14. Completion of the Total Synthesis of 16,19-cis-20,23-cis Adjacent Bis-THF Asimitrin Diastereomer (1c) 98
• II.3.15. Construction of Key 17-Hydroxy-16,17-erythro-16,19-cis- 20,23-trans Adjacent Bis-THF 3d 100
• II.3.16. Construction of Homoallylic Alcohol 2d by Keck Allylation 102
• II.3.17. Completion of the Total Synthesis of 16,19-cis-20,23-trans Adjacent Bis-THF Asimitrin Diastereomer (1d) 104
• II.3.18. Improved Route to Key 17-Hydroxy-16,17-erythro-16,19-trans- 20,23-trans Adjacent Bis-THF 3a 106
• III. Conclusion 110
• IV. Experimentals 111
• IV.1. Chelate-Controlled IAEA Reaction 112
• IV.1.1. Construction of Intermediate 7 for IAEA Reaction 112
• IV.1.2. Construction of 17-Hydroxy-16,17-erythro-16,19-trans-THF 6through Chelate-Controlled IAEA Reaction 117
• IV.2. Initial Route for Total Synthesis C37 Annonaceous Acetogenin (‒)-Asimitrin (1a) 118
• IV.2.1. Initial Construction of Key C(15)-C(34) Adjacent Bis-THF 3a Preparation of Ketone II-3-3 118
• IV.2.2. Keck Allylation of 17-OPMB Bis-THF Aldehyde II-3-15 130
• IV.3. Keck Allylation of 17-OTIPS Bis-THF Aldehyde II-3-21 136
• IV.3.1. Keck Allylation of 17-OTIPS Aldehyde II-3-22 136
• IV.3.2. Confirmation of C(15)/C(16)-threo Configuration in II-3-23 by Chemical Correlation Method 142
• IV.4. Completion of Total Synthesis of (‒)-Asimitrin (1a) 145
• IV.5. Initial Route for Total Synthesis C37 Annonaceous Acetogenin Asimitrin Diastereomer (1b) 152
• IV.5.1. Synthesis of Intermediate of Asimitrin Diastereomers by Epimerization and Reduction 152
• IV.5.2. Initial Construction of Key C(15)-C(34) Adjacent Bis-THF 3b 153
• IV.5.3. Keck Allylation of 17-OPMB Bis-THF Aldehyde II-3-38 160
• IV.5.4. Completion of Total Synthesis of Asimitrin (1b) 166
• IV.6. Initial Route for Total Synthesis C37 Annonaceous Acetogenin Asimitrin Diastereomer (1c) 170
• IV.6.1. Synthesis of Intermediate of Asimitrin Diastereomers by Epimerization and Reduction 170
• IV.6.2. Construction of Key C(15)-C(34) Adjacent Bis-THF 3c 173
• IV.6.3. Keck Allylation of 17-OPMB Bis-THF Aldehyde II-3-52 180
• IV.6.4. Completion of Total Synthesis of Asimitrin (1c) 185
• IV.7. Initial Route for Total Synthesis C37 Annonaceous Acetogenin Asimitrin Diastereomer (1d) 189
• IV.7.1. Initial Construction of Key C(15)-C(34) Adjacent Bis-THF 3d 189
• IV.7.2. Keck Allylation of 17-OPMB Bis-THF Aldehyde II-3-65 196
• IV.7.3. Completion of Total Synthesis of Asimitrin (1d) 202
• IV.8. Improved Route to Construction of 17-Hydoxy-16,19-trans- 20,23-trans Adjacent Bis-THF 3a 209
• IV.8.1. Improved Route to Key C(15)-C(34) Adjacent Bis-THF 3a 209
• IV.9. 1H NMR, 13C NMR Spectra 216
• V. References 320