31 有糸分裂阻害剤Curacin Aの合成研究(口頭発表の部)
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概要
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Curacin A(1) is a novel antimitotic agent isolated from a Caribbean cyanobacterium Lyngbya majuscula, and inhibits tubulin assembly by binding to the colchicine-binding site. Since curacin A has little structural similarity to the known natural and synthetic colchicine-site ligands, it is expected to play as an unique probe for this binding site and to show interesting bioactivity. First, we proposed the absolute configurations of three chiral centers in curacin A, to be 2R, 19R and 21S, by synthesizing the four stereoisomers, (+)- and (-)- 2a, 2b as the partial structure of curacin A. Next, we developed a versatile method for the synthesis of enantiomerically pure cis-2-ethylcyclopropanecarboxylic acid, (-)-(1R, 2S)-7, a component of curacin A, and its enantiomer, (+)-(1S, 2R)-7. Double-asymmetric Simmons-Smith cyclopropanations of dienes 11 and 15 derived from diethyl L-tartrate proceeded with excellent diastereofacial selectivity (>99% de) to give dicyclopropanes 12 and 16, and they were converted to the respective isomers of 7. Finally, we achieved the total synthesis of curacin A in a highly stereo-contolled manner. The key steps were (1) an asymmetric allylation using a chiral allyltitanium reagent and a double-asymmetric Simmons-Smith cyclopropanation to introduce three chiral centers, (2) Wittig and Wittig-Horner reactions to construct the C(3-4) and C(7-10) alkenes, and (3) a direct conversion of the thiazolidine to the thiazoline. The effects of the synthesized curacin A and related compounds on microtuble assembly were also examined.
- 1996-09-02
著者
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小磯 邦子
東大分生研
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岩崎 成夫
東大分生研
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岩崎 成夫
北里研究所:生物機能研究所
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白井 隆一
東大分生研
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白井 隆一
奈良先端科学技術大学院大学:物質科学教育研究センター
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小野田 俊彦
東大分生研
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