Joannou G E, Reeder A Y
Department of Metabolic Mass Spectrometry, Royal Prince Alfred Hospital, Sydney, Australia.
Steroids. 1996 Feb;61(2):82-8. doi: 10.1016/0039-128x(95)00194-u.
Steroids hydroxylated at C-15 have long provided useful information about the well-being of the fetus and feto-placental unit in human pregnancy. In an attempt to develop a new and reliable immunoassay method for use in newborn screening programs for congenital adrenal hyperplasia, we report the chemical synthesis of 3 alpha,15 beta,17 alpha-trihydroxy-5 beta-pregnan-20-one (2) from 3 alpha-hydroxy-5 beta-androstan-17-one (4) in 9 steps. In brief, 3 alpha-hydroxy-5 beta-androst-15-en-17-one (6), was obtained from 4 by phenylselenation yielding 3 alpha-hydroxy-16 alpha-phenylseleno-5 beta- androstan-17-one (5a) which on dehydroselenation gave 6. Introduction of the 15 beta-hydroxy group and the side-chain was achieved by the addition of 2-lithio-2-methyl-1,3- dithiane followed by an acid-catalyzed rearrangement to give 20,20-trimethylenedithio-5 beta-pregn-16-en- 3 alpha,15 beta-diol (8a). Acetylation then cleavage of the dithioacetal gave 3 alpha,15 beta-diacetoxy-5 beta-pregn-16-en- 20-one (9) which on hydrogenation gave 3 alpha,15 beta-diacetoxy-5 beta-pregnan-20-one (10). Reaction of base and oxygenation of 10 gave a mixture of products which on basic hydrolysis gave 3 alpha,15 beta,17 alpha-trihydroxy-5 beta- pregnan-20-one (2) in an overall yield of 8.8%.
C-15位羟基化的甾体长期以来为了解人类妊娠中胎儿及胎儿-胎盘单位的健康状况提供了有用信息。为了开发一种用于先天性肾上腺皮质增生症新生儿筛查项目的新型可靠免疫分析方法，我们报告了以9步反应从3α-羟基-5β-雄甾烷-17-酮（4）化学合成3α,15β,17α-三羟基-5β-孕烷-20-酮（2）的过程。简而言之，通过苯硒化反应从4得到3α-羟基-5β-雄甾-15-烯-17-酮（6），生成3α-羟基-16α-苯硒基-5β-雄甾烷-17-酮（5a），后者经脱硒反应得到6。通过加入2-锂代-2-甲基-1,3-二硫杂环戊烷引入15β-羟基基团和侧链，随后经酸催化重排得到20,20-三亚甲基二硫代-5β-孕-16-烯-3α,15β-二醇（8a）。乙酰化后裂解二硫缩醛得到3α,15β-二乙酰氧基-5β-孕-16-烯-20-酮（9），其经氢化反应得到3α,15β-二乙酰氧基-5β-孕烷-20-酮（10）。10与碱反应并氧化得到产物混合物，经碱性水解得到3α,15β,17α-三羟基-5β-孕烷-20-酮（2），总产率为8.8%。
