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Studies on the synthesis of extremely potent antitumor hybride steroidal dimer

极强抗肿瘤杂合甾体二聚体的合成研究

基本信息

批准号：
16590018
负责人：
TSUBUKI Masayoshi
金额：
$ 2.18万
依托单位：
Hoshi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

Wittig rearrangement has been established as one of the most useful synthetic tools in organic synthesis. Considerable variation in Wittig rearrangement has been explored and widely applied to natural product synthesis. In a continuation of these efforts, we were interested in the development of Wittig rearrangement under neutral condition. We considered the possibility that a-allyloxymalonates undergo [2,3]-sigmatropic rearrangement under the Krapcho reaction condition. Treatment of dimethyl a-allyloxymalonates with lithium chloride in HMPA at 130-140℃ for 5-30 min resulted in sequential Wittig rearrangement and demethoxycarbonylation. This afforded methyl 2-hydroxy-4-pentenoate derivatives in 55-96% yields with high E selectivity. Its application to steroidal side chain synthesis was also carried out. Sequential Wittig rearrangement and demethoxycarbonylation of (E)-17(20)-pregnen-16a-yloxymalonate furnished (20S,22S)-and (20S,20R)-22-hydroxy steroids in a ratio of 76:24, respectively. Major isomer, (20S,22S)-steroid, could be a key intermediate for the synthesis of biologically active ecdysteroid, withanolide, OSW-1, and cephalostatin.We have accomplished the synthesis of an extremely potent antitumor saponin OSW-1 and its analogues by means of the Wittig rearrangement of allylic thiophenemethyl ether for the construction of (20S)-22-hydroxy steroidal side chain. Thus, Wittig rearrangement of 17E(20)-ethylidene-16α-thiophenemethyloxy steroid, prepared from commercially available epoxy ketone, afforded (20S)-22-hydroxy steroid in 59% yield. Introduction of trans diol functionality at the C(16) and C(17) positions was carried out by usual methods to give 16β,17α-diol. Glycosylation of the accepter with disaccharide imidate, synthesized by the known protocol, proceeded smoothly under the promotion of TMSOTf to give the desired β-glycoside. Removal of all protecting groups followed by desulphurization furnished OSW-1.

维蒂格重排已成为有机合成中最有用的合成工具之一。Wittig重排的大量变异已被探索并广泛应用于天然产物的合成。在这些努力的延续中，我们对中性条件下Wittig重排的发展感兴趣。我们考虑了a-烯丙基丙二酸盐在Krapcho反应条件下发生[2,3]-异位重排的可能性。二甲基a-烯丙氧基丙二酸酯在130 ~ 140℃下用氯化锂处理5 ~ 30 min，得到了连续的Wittig重排和去甲氧基羰基化反应。这提供了2-羟基-4-戊酸甲酯衍生物，收率为55-96%，具有高E选择性。并将其应用于甾体侧链的合成。(E)-17(20)-孕酮-16a-羟丙二酸酯的顺序Wittig重排和去甲氧基羰基化分别以76:24的比例提供（20S,22S）和(20S,20R)-22羟基类固醇。主要同分异构体(20S,22S)-甾体可能是合成具有生物活性的表皮甾体、威纳醇内酯、OSW-1和头孢司他汀的关键中间体。本文通过烯丙基噻吩甲醚的Wittig重排，构建了(20S)-22羟基甾体侧链，合成了极有效的抗肿瘤皂苷OSW-1及其类似物。由此，以市售环氧酮为原料制备的17E(20)-乙基-16α-噻吩甲氧基甾体，通过Wittig重排得到(20S)-22-羟基甾体，收率为59%。采用常规方法在C（16）和C（17）位置引入反式二醇官能团，得到16β，17α-二醇。在TMSOTf的促进下，根据已知方案合成的受体与酰二糖的糖基化过程顺利进行，得到所需的β-糖苷。去除所有保护基团，然后脱硫提供OSW-1。