Synthetic study of 2-substituted vitamin D derivatives

点击翻译按钮获取中文摘要

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.