7 抗腫瘍性抗生物質Fostriecin(CI-920)およびその類縁体の全合成(口頭発表の部)

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概要

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• Fostriecin (1, CI-920), produced by Streptomyces pulveraceus, is a promising antitumor antibiotic, which is known to inhibit DNA topoisomerase II by a unique, non-DNA-strand cleavage mechanism, and selectively inhibit protein phosphatase 2A and 4. We describe here synthesis of fostriecin and its analogue, 12,13,14,15,16,17-hexahydrofostriecin (2), via a convergent route involving a three-segment (A-C) coupling procedure (Figure 1). The segment B (4) was synthesized from (R)-malic acid by combination of Wittig reaction and Sharpless asymmetric dihydroxylation (Scheme 1). In the synthesis of hexahydrofostriecin 2 (Scheme 3), the segment C' was, at first, coupled with the segment B by taking account of the reactivity of the unsaturated lactone moiety. After the segment B-C' was coupled with the segment A 3c, the stereochemistry at C-5 position was successfully constructed by asymmetric reduction, and the resultant compound was transformed to hexahydrofostriecin 2. Total synthesis of fostriecin (1) was also achieved as follows (Scheme 4). In the case of fostriecin, the segment B was first coupled with the segment A rather than the segment C due to the labile property of triene moiety, then was transformed to the unsaturated lactone according to a similar procedure. Construction of the triene moiety was eventually achieved by combination of iodomethylenation and Stine coupling reaction. The phosphate moiety was introduced via two routes: (i) direct phosphorylation of the monohydroxyl derivative 35 in which other hydroxyl groups are protected; (ii) cyclic phosphorylation and selective cleavage of the cyclic phosphate derivative 38 (Scheme 5). Although the former is basically the same as those reported by other groups, the latter is novel and more effective than former one. The present total synthesis would serve as a versatile synthetic route to not only fostriecin and hexahydrofostriecin, but also its various analogues including stereoisomers.

• 2002-09-01

著者

• 今西 武

  大阪大学大学院薬学研究科

• 高橋 以都美

  Faculty Of Pharmaceutical Sciences Osaka University

• Imanishi Takeshi

  Graduate Shool Of Pharmaceutical Sciences Osaka University

• Imamura T

  Faculty Of Pharmaceutical Sciences Osaka University

• 宮下 和之

  阪大院薬

• 今西 武

  阪大院薬

• 宮下 和之

  大阪大学大学院薬学研究科

• 池尻 昌宏

  大阪大学大学院薬学研究科

• 池尻 昌宏

  阪大院薬

• 川崎 ひとみ

  阪大院薬

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