P-11 マイグラスタチンの合成研究(ポスター発表の部)

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Migrastatin (1) was isolated from two different strains of Streptomyces, inhibits human tumor cell migration. Migrastatin (1) has a 14-membered macrolactone, a characteristic glutarimide moiety, and a trisubstituted (Z)-alkene between two and three contiguous stereogenic centers. Recently, it was shown by Shen and co-workers that 1, 3 and 4 are shunt metabolites of Iso-migrastatin (2). Migrastatin (1) is unique because it displays a remarkable inhibitory effect on the migration of human tumor cells and it is not cytotoxicity. By envisioning intermediate 5 as a flexible building block to several members of these families including 1, we have planned total synthesis using an regio- and diastereoselective palladium-catalyzed nucleophilic addition of methoxide to alkenyloxiranes as a key reaction for constructing vicinal stereogenic centers C8 and C9. Indeed, palladium-catalyzed methoxylation of alkenyloxirane 15 was carried out with high stereospecificity by the use of B-MeO-9BBN (16) to give the alcohol 17 as a single stereoisomer. This key reaction was found to be applicable to 20 and enabled to accomplish the synthesis of intermediate 5. Another intermediate, the vinyl halide 7, was synthesized via proline-catalyzed enantioselective direct cross-aldol reaction of 22. Coupling reaction of 5 with 7 was under investigation. The coupling reaction 5 with 8 was successfully performed to give rise to 31 in 50% yield. After saponification of 31, the product was transformed into macrolactone 32 by Yamaguchi method. The total synthsis of 2 and determination of its stereochemistry are now under way.
2005-09-15

P-11 マイグラスタチンの合成研究(ポスター発表の部)

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