Total Synthesis, Structure Determination, and Bioactive Stereostructure of Complex Macrolides
| Project/Area Number |
17K01941
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Biomolecular chemistry
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| Research Institution | Chuo University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 全合成 / 構造決定 / 立体配置 / NMR解析 / タンデム反応 / 閉環メタセシス / マクロリド / 類縁体 / 構造活性相関 / 細胞増殖阻害 / 立体配座 / 活性増強 / 構造改訂 / 絶対配置 / 相対配置 / 有機化学 / 天然有機化合物 / 立体構造決定 |
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| Outline of Final Research Achievements |
Total synthesis of the proposed structure of iriomoteolide-2a has been achieved. Our synthesis involved: 1) convergent assembly of important fragments via a Suzuki-Miyaura reaction and an esterification, and 2) forging the macrocyclic skeleton by means of a ring-closing metathesis. However, the NMR spectra of our synthetic material did not match those of natural iriomoteolide-2a. Synthesis/NMR analysis of model compounds and careful inspection of the NMR data of the authentic sample, followed by total syntheses of possible structures enabled us to determine the absolute configuration of iriomoteolide-2a.
Total synthesis of enigmazole A has been completed. The salient features of our synthesis include: 1) a stereoselective tandem synthesis of the tetrahydropyran ring, 2) a Au(I)-catalyzed Meyer-Schuster rearrangement of a propargylic benzoate, and 3) a macrocyclic ring-closing metathesis.
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| Academic Significance and Societal Importance of the Research Achievements |
海洋生物が生産する二次代謝産物（天然物）は、生物活性物質の構造多様性の源泉であり、新たな新薬の候補化合物の宝庫である。しかし、海洋天然物の多くは自然界には微量しか存在しないため、化学合成による化合物供給が天然物創薬には必須である。本研究では抗腫瘍性海洋天然物iriomoteolide-2aおよびenigmazole Aの完全化学合成（全合成）を達成した。これにより天然物および構造改変体の人工供給が可能となり、構造活性相関や活性発現機構の解析へと研究を展開するための基盤を確立した。
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Report
(4 results)
Research Products
(47 results)
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[Journal Article] Tetracyclic Truncated Analogue of the Marine Toxin Gambierol Modifies NMDA, Tau, and Amyloid β Expression in Mice Brains: Implications in AD Pathology2017
Author(s)
Eva Alonso, Andres C. Vieira, Ines Rodoriguez, Rebeca Alvarino, Sandra Gegunde, Haruhiko Fuwa, Yuto Suga, Makoto Sasaki, Amparo Alfonso, Jose Mannuel Cifuentes, Luis M. Botana
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Journal Title
ACS Chemical Neuroscience
Volume: 8
Issue: 6
Pages: 1358-1367
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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