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| DC Field | Value | Language |
|---|---|---|
| dc.contributor.advisor | Hyoungsu Kim | - |
| dc.contributor.author | 곽수연 | - |
| dc.date.issued | 2024-02 | - |
| dc.identifier.other | 33760 | - |
| dc.identifier.uri | https://aurora.ajou.ac.kr/handle/2018.oak/38887 | - |
| dc.description | 학위논문(박사)--약학과,2024. 2 | - |
| dc.description.abstract | The total synthesis and structure confirmation of the potent cytotoxic agent (−)-asimitrin (1a), a C37 annonaceous acetogenin having a hydroxylated adjacent bis-tetrahydrofuran (THF) core, are described. The present synthesis features a highly stereoselective, chelate-controlled intramolecular amide enolate alkylation (IAEA) for the synthesis of key intermediate 17-hydroxy-16,17-erythro-16,19-trans-THF 6, our direct ketone synthesis/L-Selectride reduction protocol for stereoselective introduction of the C(21)−C(34) unit, Sharpless asymmetric dihydroxylation (SAD), and internal Williamson etherification for construction of the 20,23-trans-THF ring. This approach can be applied to three additional derivatives of the THF backbone, which exhibit trans/cis (1b), cis/cis (1c) and cis/trans (1d) conformations. Application of our modular strategy to the synthesis of other annonaceous acetogenins as well as analogues for medicinal chemistry studies provides access to a new area of natural products with potential for new drug development._x000D_ <br>_x000D_ <br>Keywords_x000D_ <br>intramolecular amide enolate alkylation · cyclization · bis-THF · natural products · total synthesis | - |
| dc.description.tableofcontents | I. Introduction 1_x000D_ <br> I.1. 3-Oxygenated Tetrahydrofuranoids Natural Products 2_x000D_ <br> I.1.1. Mono-THFs 2_x000D_ <br> I.1.2. Fused Bis-THFs 8_x000D_ <br> I.1.3. Adjacent Bis-THFs 10_x000D_ <br> I.1.4. THF-Containing Macrolides. 13_x000D_ <br> I.1.5. Mono-THF Fused with Medium-Sized Ether Ring 15_x000D_ <br> I.2. Previous Synthesis of Adjacent Bis-THF Acetogenins. 18_x000D_ <br> I.2.1. Marshall's Total Synthesis of (+)-Trilobin 18_x000D_ <br> I.2.2. Sinha and Keinan's Total Synthesis of (+)-Trilobacin 20_x000D_ <br> I.2.3. Sinha and Keinan's Total Synthesis of (+)-Asimicin 22_x000D_ <br> I.2.4. Borhan's Synthesis of 17-Hydroxy Annonaceous Acetogeinin Mucoxin 25_x000D_ <br>II. Results and Discussions 28_x000D_ <br> II.1. Previous Studies on Amide Enolate Alkylation 28_x000D_ <br> 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_x000D_ <br> II.1.2. Kim's Protecting Group-Dependent Intermolecular Amide Enolate Alkylation 31_x000D_ <br> II.2. Kim's Intramolecular Protecting Group-Dependent Amide Enolate Alkyation for Tetrahydrofuran 33_x000D_ <br> II.2.1. Substrate Scope for IAEA Reaction 34_x000D_ <br> II.2.2. Kim's Total Synthesis of C19 Nematocidal Tetrahydrofuranoids Oxylipids 38_x000D_ <br> II.2.3. Kim's Total Synthesis and Structure revision of (‒)-Bisezakyne A 47_x000D_ <br> II.2.4. Kim's Total Synthesis of (+)-Laurenidificin and (+)-Aplysiallene 52_x000D_ <br> II.3. Total Synthesis C37 Annonaceous Acetogenin (‒)-Asimitrin (1a) 58_x000D_ <br> II.3.A. (‒)-Asimitrin (1a) 58_x000D_ <br> II.3.B. Total Synthesis of C37 Annonaceous Acetogenin (‒)-Asimitrin (1a) 61_x000D_ <br> II.3.1. Retrosynthetic Plan 62_x000D_ <br> II.3.2. Construction of Key 17-Hydroxy-16,17-erythro-16,17-trans-THF 6 64_x000D_ <br> II.3.3. Construction of Key 17-Hydroxy-16,17-erythro-16,19-trans-THF 6 by Intramolecular Amide Enolate Alkylation 66_x000D_ <br> II.3.4. Construction of Key 17-Hydroxy-16,17-erythro-16,19-trans-20, 23-trans Adjacent Bis-THF 3a 67_x000D_ <br> II.3.5. Construction of Homoallylic Alcohol 2a by Keck Allylation 73_x000D_ <br> II.3.6. Keck Allylation of 17-OTIPS Bis-THF Alcohol II-3-21 75_x000D_ <br> II.3.7. Completion of the Total Synthesis of (−)-Asimitrin (1a) 80_x000D_ <br> 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_x000D_ <br> II.3.8. Construction of Key Intermediate 5b-5d 86_x000D_ <br> II.3.9. Construction of Key 17-Hydroxy-16,17-erythro-16,19-trans 20, 23-cis Adjacent Bis-THF 3b 88_x000D_ <br> II.3.10. Construction of Homoallylic Alcohol 2b by Keck Allylation 90_x000D_ <br> II.3.11. Completion of the Total Synthesis of 16,19-trans-20,23-cis Adjacent Bis-THF Asimitrin Diastereomer (1b) 92_x000D_ <br> II.3.12. Construction of Key 17-Hydroxy-16,17-erythro-16,19-cis-20,23- cis Adjacent Bis-THF 3c 94 _x000D_ <br> II.3.13. Construction of Homoallylic Alcohol 2c by Keck Allylation 96_x000D_ <br> II.3.14. Completion of the Total Synthesis of 16,19-cis-20,23-cis Adjacent Bis-THF Asimitrin Diastereomer (1c) 98_x000D_ <br> II.3.15. Construction of Key 17-Hydroxy-16,17-erythro-16,19-cis- 20,23-trans Adjacent Bis-THF 3d 100_x000D_ <br> II.3.16. Construction of Homoallylic Alcohol 2d by Keck Allylation 102_x000D_ <br> II.3.17. Completion of the Total Synthesis of 16,19-cis-20,23-trans Adjacent Bis-THF Asimitrin Diastereomer (1d) 104_x000D_ <br> II.3.18. Improved Route to Key 17-Hydroxy-16,17-erythro-16,19-trans- 20,23-trans Adjacent Bis-THF 3a 106_x000D_ <br>III. Conclusion 110_x000D_ <br>IV. Experimentals 111_x000D_ <br> IV.1. Chelate-Controlled IAEA Reaction 112_x000D_ <br> IV.1.1. Construction of Intermediate 7 for IAEA Reaction 112_x000D_ <br> IV.1.2. Construction of 17-Hydroxy-16,17-erythro-16,19-trans-THF 6through Chelate-Controlled IAEA Reaction 117_x000D_ <br> IV.2. Initial Route for Total Synthesis C37 Annonaceous Acetogenin (‒)-Asimitrin (1a) 118_x000D_ <br> IV.2.1. Initial Construction of Key C(15)-C(34) Adjacent Bis-THF 3a Preparation of Ketone II-3-3 118_x000D_ <br> IV.2.2. Keck Allylation of 17-OPMB Bis-THF Aldehyde II-3-15 130_x000D_ <br> IV.3. Keck Allylation of 17-OTIPS Bis-THF Aldehyde II-3-21 136_x000D_ <br> IV.3.1. Keck Allylation of 17-OTIPS Aldehyde II-3-22 136_x000D_ <br> IV.3.2. Confirmation of C(15)/C(16)-threo Configuration in II-3-23 by Chemical Correlation Method 142_x000D_ <br> IV.4. Completion of Total Synthesis of (‒)-Asimitrin (1a) 145_x000D_ <br> IV.5. Initial Route for Total Synthesis C37 Annonaceous Acetogenin Asimitrin Diastereomer (1b) 152_x000D_ <br> IV.5.1. Synthesis of Intermediate of Asimitrin Diastereomers by Epimerization and Reduction 152_x000D_ <br> IV.5.2. Initial Construction of Key C(15)-C(34) Adjacent Bis-THF 3b 153_x000D_ <br> IV.5.3. Keck Allylation of 17-OPMB Bis-THF Aldehyde II-3-38 160_x000D_ <br> IV.5.4. Completion of Total Synthesis of Asimitrin (1b) 166_x000D_ <br> IV.6. Initial Route for Total Synthesis C37 Annonaceous Acetogenin Asimitrin Diastereomer (1c) 170_x000D_ <br> IV.6.1. Synthesis of Intermediate of Asimitrin Diastereomers by Epimerization and Reduction 170_x000D_ <br> IV.6.2. Construction of Key C(15)-C(34) Adjacent Bis-THF 3c 173_x000D_ <br> IV.6.3. Keck Allylation of 17-OPMB Bis-THF Aldehyde II-3-52 180_x000D_ <br> IV.6.4. Completion of Total Synthesis of Asimitrin (1c) 185_x000D_ <br> IV.7. Initial Route for Total Synthesis C37 Annonaceous Acetogenin Asimitrin Diastereomer (1d) 189_x000D_ <br> IV.7.1. Initial Construction of Key C(15)-C(34) Adjacent Bis-THF 3d 189_x000D_ <br> IV.7.2. Keck Allylation of 17-OPMB Bis-THF Aldehyde II-3-65 196_x000D_ <br> IV.7.3. Completion of Total Synthesis of Asimitrin (1d) 202_x000D_ <br> IV.8. Improved Route to Construction of 17-Hydoxy-16,19-trans- 20,23-trans Adjacent Bis-THF 3a 209_x000D_ <br> IV.8.1. Improved Route to Key C(15)-C(34) Adjacent Bis-THF 3a 209_x000D_ <br> IV.9. 1H NMR, 13C NMR Spectra 216_x000D_ <br>V. References 320_x000D_ | - |
| dc.language.iso | eng | - |
| dc.publisher | The Graduate School, Ajou University | - |
| dc.rights | 아주대학교 논문은 저작권에 의해 보호받습니다. | - |
| dc.title | First Total Synthesis and Structure Confirmation of (−)-Asimitrin, a C37 Annonaceous Acetogenin with a Hydroxylated Adjacent Bis-Tetrahydrofuran Core | - |
| dc.type | Thesis | - |
| dc.contributor.affiliation | 아주대학교 대학원 | - |
| dc.contributor.alternativeName | Soo Yeon Kwak | - |
| dc.contributor.department | 일반대학원 약학과 | - |
| dc.date.awarded | 2024-02 | - |
| dc.description.degree | Doctor | - |
| dc.identifier.url | https://dcoll.ajou.ac.kr/dcollection/common/orgView/000000033760 | - |
| dc.subject.keyword | bis-THF | - |
| dc.subject.keyword | cyclization | - |
| dc.subject.keyword | intramolecular amide enolate alkylation | - |
| dc.subject.keyword | natural products | - |
| dc.subject.keyword | total synthesis | - |
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