| Project/Area Number |
08672450
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Tokyo University of Pharmacy & Life Science |
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Principal Investigator |
KIBAYASHI Chihiro Tokyo University of Pharmacy & Life Science, School of Pharmacy, Professor, 薬学部, 教授 (80057330)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAZAKI Naoki Tokyo University of Pharmacy & Life Science, School of Pharmacy, Assistant Profe, 薬学部, 講師 (30277264)
AOYAGI Sakae Tokyo University of Pharmacy & Life Science, School of Pharmacy, Associate Profe, 薬学部, 助教授 (30212385)
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| Project Period (FY) |
1996 – 1997
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| Project Status |
Completed (Fiscal Year 1997)
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| Budget Amount *help |
¥2,500,000 (Direct Cost: ¥2,500,000)
Fiscal Year 1997: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1996: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | lepadins A,B,C / marine alkaloids / tunicate / decahydroquinoline / cytotoxicity against human cancer cell lines / chiral hydroxamic acid / chiral acylnitroso compound / intramolecular hetero Diels-Alder reaction / 分子内ヘテロディールズ・アルダー反応 / 矢毒蛙アルカロイド / エピバチジン / 非オピオイド性鎮痛作用 / アシルニトロソ化合物 / 8-ナフチルメントール / ヘテロDiels-Alder反応 / π-スタッキング相互作用 / 不斉反応 |
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| Research Abstract |
Lepadins A,B,and C,isolated from tunicate Clavelina lepadiformis, are the first repoted example of marine natural products with a decahydroquinoline skeleton, and exhibit significant in vitro cytotoxixity against murine leukemia and human cancer cell lines. Although molecular structures and relative stereochemistry of these compounds have been assigned, their absolute stereochemistries still remain unknown. The present investigations were aimed at the first asymmetric total synthesis of lepadin alkaloids by utilizing intramolecular hetero Diels-Alder reaction as a basic strategy and also determining the absolute configuration of these alkaloids.
According to our previous findings, we envisioned the use of aqueous conditions for enhancement of stereoselectivity in intramolecular acylnitroso hetero Diels-Alder reaction. Thus, the chiral hydroxamic acid derived from L-malic acid was oxidized by the periodate salt to generate the acylnitroso compound, which spontaneously underwent cycloaddition to afford the trans-adduct with high stereoselectivity. Asymmetric hydroxylation with Davis reagent followed by aldol reaction resulted in the stereoselective construction of the decahydroquinoline frame work, which incorporates all functionalities and right stereostructure required for the synthesis of Lepadins A,B,and C,and thus, can be utilized as a common key synthetic intermediate for the target compounds.
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