Synthetic study of 2-substituted vitamin D derivatives

1 α， 25-二羟基维生素D_3是钙稳态最有效的调节因子之一，也可诱导髓性白血病细胞分化。在我们研究2位修饰的过程中，我们研究了几种由α -烷基-酮酯和手性胺衍生的锂胺的不对称γ -醛酮反应。不幸的是，在伯胺的情况下，离子的形成失败了。当使用仲胺时，醛醇反应发生干净，但试图纯化和水解引起内酯化。接下来我们计划用Evans的恶唑酮从丙酸衍生物和-溴丙烯醛中得到醛醇产品。反应效果良好，立体选择性达95%。羟基被丁基二甲基硅基保护后，酰胺部分转化为苄酯。将该苯酯还原为相应的醛，然后与乙酸衍生物醛缩反应，将上述产物还原为醛，然后进行顺式选择性霍纳-埃蒙斯反应，最后Pd催化环化将得到所需的1 α， 25-二羟基-2-甲基维生素D_3的a环部分。我们把注意力转向顺式选择性霍纳-埃蒙斯反应。常规方法存在一些缺点（操作简便、试剂成本高、某些情况下选择性低）。我们觉得有必要开发一种实用的方法来制备顺式不饱和酯。经过多次试验，二苯基膦乙酸乙酯被证明是一种高度顺式选择性的霍纳-埃蒙斯试剂。这种新方法提供了一条简单、经济的路线，以几乎定量的收率制备范围广泛的顺式不饱和酯。

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.