89 活性酸素産生阻害物質OPC-15161の全合成(ポスター発表の部)

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The first total synthesis of OPC-15161, a novel inhibitor of superoxide generation by guinea pig macrophages, is presented. The synthetic strategy we employed exploits the coupling of the fully functionalized pyrazine part with the indolyl group. The framework of the pyrazine moiety was assembled from 2-hydroxyimino-4-methylpentanoic acid (2) and ethyl aminocyanoacetate (3). Condensation using DCC and the following intramolecular cyclization between the oxime and cyano groups afforded pyrazinone N-oxide 5. O-Benzylation followed by reduction of the ethoxycarbonyl group by DIBAL gave the amino pyrazine alcohol 8. The aryl chloride 9 was obtained by the direct substitutive deamination using isoamyl nitrite and CuCl-CuCl_2. After protection of the primary hydroxyl group as tetrahydropyranyl ether, the methoxy group was introduced at the 5-position by treatment of 2,5-dibenzyloxypyrazine 4-oxide 13 with methoxide. The methoxy compound 14, which has been fully functionalized, was converted to benzylic iodide 17 through deprotection, mesylation, and iodination to facilitate a coupling with the indolyl group. The functionalized pyrazine 17 was efficiently coupled with the zinc salt of indole to produce 18 which upon catalytic hydrogenolysis afforded OPC-15161. The first convergent synthesis established the versatile and flexible synthetic pathway for the preparation of OPC-15161. Hence, this strategy will for the first time allow practical and efficient access to OPC-15161 analogues offering the opportunity for evaluating their inhibitory activity against superoxide anion generation.
天然有機化合物討論会の論文
1992-09-10

89 活性酸素産生阻害物質OPC-15161の全合成(ポスター発表の部)

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