A direct stereoselective synthesis of 7 beta-hydroxytestosterone.
Although 7 beta-hydroxytestosterone is a known product of hepatic androgen metabolism, there are no published methods for its chemical synthesis except from the equally difficult to obtain 7 beta-hydroxy-4-androstene-3,17-dione. We found that several seemingly straightforward routes for its synthesis failed. Consequently, we tried to produce 7 beta-hydroxytestosterone by enzymatic oxidation of 5-androstene-3 beta, 7 beta, 17 beta-triol with cholesterol oxidase (Brevibacterium sp.), a procedure previously used to synthesize 7 beta-hydroxy-4-cholesten-3-one from 3 beta, 7 beta-dihydroxycholesterol (Alexander and Fisher 1995). However, 5-androstene-3 beta, 7 beta, 17 beta-triol was, at best, a very poor substrate for the enzyme leading to the production of 7 beta-hydroxytestosterone in only trace amounts. Thus, we explored a strategy for the enzymatic synthesis in which a C8-ester at C-17 (5-androstene-3 beta, 7 beta, 17 beta-triol 17-caprylate) would serve to mimic the bulky and hydrophobic side chain of cholesterol and thus allow the C19-steroid to act as an effective substrate. When this ester was incubated with cholesterol oxidase, it was converted efficiently to 7 beta-hydroxytestosterone-17-caprylate. Attempts to remove the ester group by several mild hydrolytic procedures caused elimination of the 7 beta-hydroxyl group; we, therefore, obtained 7 beta-hydroxytestosterone by incubation of the intermediate ester with porcine lipase.
Labaree
D
D
Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Hoyte
R M
RM
Hochberg
R B
RB
D006915:Hydroxytestosterones / Q000138:chemical synthesis*; D013237:Stereoisomerism
D006915:Hydroxytestosterones; C107430:7-hydroxytestosterone