| Project/Area Number |
07558088
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
Bioorganic chemistry
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| Research Institution | Tokyo Institute of Technology |
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Principal Investigator |
KUWAJIMA Isao Tokyo Institute of Technology Faculty of Science, Professor, 理学部, 教授 (50016086)
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| Co-Investigator(Kenkyū-buntansha) |
MORIHIRA Koichiro Yamanouti Pharmaceutical Co., Ltd Institute of Drug Discovery Research, Research, 第四創薬研究所, 研究員
HORIGUCHI Yoshiaki Tokyo Institute of Technology Faculty of Science, Associate Professor, 理学部, 助教授 (80209296)
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| Project Period (FY) |
1995 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥17,000,000 (Direct Cost: ¥17,000,000)
Fiscal Year 1997: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 1996: ¥5,100,000 (Direct Cost: ¥5,100,000)
Fiscal Year 1995: ¥8,500,000 (Direct Cost: ¥8,500,000)
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| Keywords | Taxane Diterpenoids / Total Synthesis / (+) -Taxusin / (-) -Taxol / Enantioselective / Biological Acticity / Taxinine / 不斉合成 / 制癌活性 / 抗癌剤 / 活性類縁体 |
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| Research Abstract |
Based on the methodology for construction of taxane tricarbocycles previously develop, total syntheses of taxane diterpenoids have been studied. Enantioselective total synthesis of (+)-taxusin has been performed by using the following transformations : (1)enantioselective conjugate addition isobutyric ester enolate to the enone, (2)construction of tricarbocycle, (3)cyclopropanation on DELTA^<3.8>-double bond, (4) reductive cleavage of cyclopropyl ketone to introduce 19-Me, (5)Introduction of 5-OH and methylenation of C-4 carbonyl group.
Enantioselective total synthesis of taxol, a more interesting and important target, has also been achieved as follows, By using 3-bromo-cyclohexadiene-2-carbacetal was used as a C fragment, and its coupling with optically pure A fragment afforded a tricarbocycle precursor. After B ring cyclization, diene moiety of C fragment was converted to the 4,7-diol via singlet oxygen oxygenation followed by cleavage of the 0-0 bond. After appropriate protection of 1,2-and 7,9-diol moieties, 19-methyl group was introduced via a similar way with taxusin synthesis, the resulting enol was converted to the desire ketone under basic conditions. Appropriate functional group manipulation including D ring construction led us to an efficient synthesis of (-)-taxol in enantioselective manner.
On the other hand, total synthesis of taxinine has been planed by using an anisole C fragment, and the tricarbocycle containing C enone fragment was synthesized. Conversion of this intermediate to taxinine is now in progress.
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