15-BETA-HYDROXYSTEROIDS .1. STEROIDS OF THE HUMAN PERINATAL-PERIOD - THE SYNTHESIS OF -BETA,15-BETA,17-ALPHA-TRIHYDROXY-5-PREGNEN-20-ONE

15-Hydroxysteroids have long provided information about fetal well-bei ng and fetal steroidogenesis. 3 beta,15 beta,17 alpha-Trihydroxy-5-pre gnen-20-one (la) 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 (la) is reported here in the first of a se ries 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 wa s developed resulting in a nine-step stereoselective synthesis of la w ith an overall yield of 26%. A high yielding selenation-dehydroselenat ion procedure was developed for the synthesis of 3 beta-hydroxy-5,15-a ndrostadien-17-one (8) which avoided the previously reported Baeyer-Vi lliger rearrangement. The introduction of the 15 beta-hydroxy group an d the side chain was achieved by the addition of 2-lithio-2-methyl-1,3 -dithiane to give 20,20-trimethylenedi-thio-5, 15-pregnadien-3 beta,17 beta-diol (9a) followed by its acid-catalyzed rearrangement to give 2 0,20-trimethylenedithio-5, 16-pregnadien-3 beta, 15 beta-diol (10a), A cetylation and cleavage of the dithioacetal gave 3 beta, 15 beta-diace toxy-5,16-pregnadien-20-one (11b) which was hydrogenated to give 3 bet a, 15 beta-diacetoxy-5-pregnen-20-one (12b), Reaction of the ketone (1 2b) with oxygen and then basic hydrolysis gave the desired product la.