15 beta-hydroxysteroids (part II). Steroids of the human perinatal period: the synthesis of 3 alpha,15 beta, 17 alpha-trihydroxy-5 beta-pregnan-20-one.
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%.
Joannou
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GE
Department of Metabolic Mass Spectrometry, Royal Prince Alfred Hospital, Sydney, Australia.
Reeder
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AY
D006907:17-alpha-Hydroxypregnenolone / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D000312:Adrenal Hyperplasia, Congenital / Q000175:diagnosis*; D005314:Embryonic and Fetal Development / Q000502:physiology; D006801:Humans; D006914:Hydroxysteroids / Q000138:chemical synthesis*; D007231:Infant, Newborn / Q000378:metabolism*; D015394:Molecular Structure; D015997:Neonatal Screening / Q000379:methods*
D006914:Hydroxysteroids; D006907:17-alpha-Hydroxypregnenolone; C032092:3 beta,15 beta,17 alpha-trihydroxy-5-pregnen-20-one