Reeder A Y, Joannou G E
Department of Metabolic Mass Spectrometry, Royal Prince Alfred Hospital, Sydney, Australia.
Steroids. 1996 Feb;61(2):74-81. doi: 10.1016/0039-128x(95)00193-t.
15-Hydroxysteroids have long provided information about fetal well-being and fetal steroidogenesis. 3 beta,15 beta,-17 alpha-Trihydroxy-5-pregnen-20-one (1a) is a major 15 beta-hydroxylated metabolite unique to the human perinatal period. The synthesis of 3 beta, 15 beta, 17 alpha-trihydroxy-5-pregnen-20-one (1a) is reported here in the first of a series of publications on the chemical synthesis of 15 beta-hydroxylated steroids for use in the (a) development of new immunoassay techniques for application to newborn screening programs and fetal well-being; (b) development of new anti-androgenic drugs; and (c) study of androgen/estrogen interaction in late pregnancy. To this end, a method for the introduction of the 15 beta-hydroxy group onto the steroid nucleus was developed resulting in a nine-step stereoselective synthesis of 1a with an overall yield of 26%. A high yielding selenation-dehydroselenation procedure was developed for the synthesis of 3 beta-hydroxy-5,15-androstadien-17-one (8) which avoided the previously reported Baeyer-Villiger rearrangement. The introduction of the 15 beta-hydroxy group and the side chain was achieved by the addition of 2-lithio-2-methyl-1,3-dithiane to give 20,20-trimethylenedithio-5,15-pregnadien-3 beta, 17 beta-diol (9a) followed by its acid-catalyzed rearrangement to give 20,20-trimethylenedithio-5, 16-pregnadien-3 beta,15 beta-diol (10a). Acetylation and cleavage of the dithioacetal gave 3 beta,15 beta-diacetoxy-5,16-pregnadien-20-one (11b) which was hydrogenated to give 3 beta,15 beta-diacetoxy-5-pregnen-20-one (12b). Reaction of the ketone (12b) with oxygen and then basic hydrolysis gave the desired product 1a.
15-羟基类固醇长期以来一直为了解胎儿健康状况和胎儿类固醇生成提供信息。3β,15β,-17α-三羟基-5-孕烯-20-酮（1a）是人类围产期特有的一种主要的15β-羟基化代谢产物。本文报道了3β,15β,17α-三羟基-5-孕烯-20-酮（1a）的合成，这是关于15β-羟基化类固醇化学合成系列出版物中的第一篇，这些类固醇用于：（a）开发应用于新生儿筛查项目和胎儿健康状况的新型免疫测定技术；（b）开发新型抗雄激素药物；（c）研究妊娠晚期雄激素/雌激素的相互作用。为此，开发了一种将15β-羟基引入类固醇核的方法，由此实现了1a的九步立体选择性合成，总产率为26%。开发了一种高产率的硒化-脱氢硒化方法来合成3β-羟基-5,15-雄甾二烯-17-酮（8），该方法避免了先前报道的拜耳-维利格重排。通过添加2-锂代-2-甲基-1,3-二硫杂环戊烷来引入15β-羟基和侧链，得到20,20-三亚甲基二硫代-5,15-孕二烯-3β,17β-二醇（9a），随后其经酸催化重排得到20,20-三亚甲基二硫代-5,16-孕二烯-3β,15β-二醇（10a）。二硫缩醛的乙酰化和裂解得到3β,15β-二乙酰氧基-5,16-孕二烯-20-酮（11b），其经氢化得到3β,15β-二乙酰氧基-5-孕烯-20-酮（12b）。酮（12b）与氧气反应，然后进行碱性水解，得到所需产物1a。
