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Synthetic study of 2-substituted vitamin D derivatives

2位取代维生素D衍生物的合成研究

基本信息

批准号：
06672102
负责人：
ANDO Kaori
金额：
$ 0.96万
依托单位：
University of the Ryukyus
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

1alpha, 25-Dihydroxyvitamin D_3 acts as one of the most potent regulators of calcium homeostasis and also induces differentiation in myeloid leukemia cells. In the course of our study of the modification at 2-position, we studied the asymmetric gamma-aldole reaction of several lithioenamines derived from alpha-alkyl beta-keto esters and chiral amines. Unfortunately, the formation of the dianion failed in the case of primary amine. When secondary amine was used, the aldole reaction occured cleanly but attempted purification and hydrolysis caused lactonization. Next we planed to use Evans' oxazolidone in order to get aldol product from propionate derivarite and alpha-bromoacrolein. The reaction worked well and 95% stereoselectivity was obtained. After protection of the hydroxy group by t-butyldimethylsilyl group, amide portion was transformed to benzyl ester. Reduction of this benzyl ester to the corresponding aldehyde followed by aldole reaction with acetic acid derivative, reduction of the above product to aldehyde followed by cis selective Horner-Emmons reaction, and finally Pd catalyzed cyclization will give the desired A-ring portion of 1alpha, 25-dihydroxy-2-methylvitamin D_3. We turned our attention to cis selective Horner-Emmons reaction. Conventional methods have some disadvantage (uneasy procedure, high cost of the reagents, low selectivity in some case). We felt the need of developing a practical way to the cis-unsaturated esters. After several trial, ethyl diphenylphosphonoacetate turned out to be a highly cis selective Horner-Emmons reagent. This new method provide simple and economical routes to a wide range of cis-unsaturated esters in almost quantitative yields.

1 α，25-二羟基维生素D_3是一种有效的钙稳态调节剂，也可诱导髓系白血病细胞分化。在2-位修饰的研究过程中，我们研究了由α-烷基β-酮酯衍生的几种锂烯胺与手性胺的不对称γ-羟醛反应。不幸的是，在伯胺的情况下，二价阴离子的形成失败。当使用仲胺时，羟醛反应干净地发生，但试图纯化和水解引起内酯化。下一步，我们计划利用Evans的恶唑烷酮，以丙酸酯衍生物和α-溴丙烯醛为原料合成羟醛缩合产物。反应进行得很好，立体选择性达到95%。在用叔丁基二甲基甲硅烷基保护羟基后，酰胺部分转化为苄基酯。该苄酯还原成相应的醛，然后与乙酸衍生物进行羟醛反应，再还原成醛，然后进行顺式选择性Horner-Emmons反应，最后在钯催化下环合，得到所需的1 α，25-二羟基-2-甲基维生素D_3的A环部分。我们将注意力转向顺式选择性Horner-Emmons反应。常规方法存在操作困难、试剂价格高、选择性差等缺点。我们认为有必要开发一种实用的方法来顺式不饱和酯。经过多次试验，二苯基膦酰基乙酸乙酯是一种高顺式选择性的Horner-Emmons试剂。这种新的方法提供了简单和经济的路线，以几乎定量的产率广泛的顺式不饱和酯。