| Project/Area Number |
04557096
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| Research Category |
Grant-in-Aid for Developmental Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Chemical pharmacy
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| Research Institution | Okayama University of Science (1994)
Hokkaido University (1992-1993) |
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Principal Investigator |
YONEMITSU Osamu Okayama University of Science, Faculty of Science Professor, 理学部, 教授 (60001038)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAJIMA Noriyuki Hokkaido University, Faculty of Pharmaceutical Sciences Instructor, 薬学部, 助手 (40188959)
HORITA Kiyoshi Hokkaido University, Faculty of Pharmaceutical Sciences Instructor, 薬学部, 助手 (50181540)
HAMADA Tatsuo Hokkaido University, Faculty of Pharmaceutical Sciences Associate Professor, 薬学部, 助教授 (40001979)
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| Project Period (FY) |
1992 – 1994
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| Project Status |
Completed (Fiscal Year 1994)
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| Budget Amount *help |
¥11,800,000 (Direct Cost: ¥11,800,000)
Fiscal Year 1994: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1993: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1992: ¥5,300,000 (Direct Cost: ¥5,300,000)
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| Keywords | macrolide antibiotic / polyether antibiotic / polyether-macrolide / lactonization / stereoselective reaction / computer chemistry / conformational control / protective group / ポリエ-フルマクロリド / 立体選択的反応 / 立体選択的合成 / マクロラクトン化反応 / 酸化 / 還元 / マクロリド / ポリエーテル / 立体制御 / コンホメーション / 全合成 / NMR |
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| Research Abstract |
The purpose of this research was to contribute to the progress of modern fine organic synthetic chemistry as a basis of the creation of new medicines throrgh the development of a new methodology for selective and efficient syntheses of very complex molecules such as macroide, polyether antilbiotics and marine polyether-macrolides. During the past three years research the following three results were mainly obtained.
1. Synthsis of macrolides : A new stereoselective syntheses of erythromolide A,the most important aglycon, was completed via an extremely efficient macrolactionization with the aid of MM2-CONFLEX3 calculation and NMR analysis of seco-acid derivatives. The representative aglycons in carbomycin series such as carbonolide A,leuconolides, and maridonolides were also synthesized completely stereoselectively from carbonolide B through conformational control of 16-membered macro-rings. Computer-aided conformational analysis and structural design of key intermediates for the stereoselective synthesis of tedanolide, an anti-tumor marine macrolide, were successfully applied, and an 18-membered lactone was synthesized highly efficiently.
2. Synthesis of polyethers : Highly stereoselective syntheses of complex isolasalocid A,lasalocid A,salinomycin, and lysocellin by a common methodology using a new method for the construction of substituted tetrahydofuran and tetrahydropyran rings and MPM type protective groups were completed.
3. Synthesis of polyether-macrolides : Four fragments (I : C1-C15, II : C16-C26, III : C27-C36, IV : C37-C54) of halichondrin B were stereoselectively synthesized, and couplings among the fragments were completed to give C1-C36 and C16-C54 intermediates. In order to complete the total synthesis of halichondrin B final couplings are now in progress.
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