15 beta-hydroxysteroids (part I). Steroids of the human perinatal period: the synthesis of 3 beta,15 beta, 17 alpha-trihydroxy-5-pregnen-20-one.

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.