A DIRECT STEREOSELECTIVE SYNTHESIS OF 7-BETA-HYDROXYTESTOSTERONE

Although 7 beta-hydroxytestosterone is a known product androgen metabo lism, 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-hydroxytes tosterone by enzymatic oxidation of 5-androstene-3 beta,7 beta,17 beta -triol with cholesterol oxidase (Brevibacterium sp.), a procedure prev iously used to synthesize 7 beta-hydroxy-4-cholesten-3-one from 3 beta ,7 beta-dihydroxycholesterol (Alexander and Fisher 1995). However, 5-a ndrostene-3 beta,7 beta,17 beta-triol was, at best, a very poor substr ate for the enzyme leading to the production of 7 beta-hydroxytestoste rone in only trace amounts. Thus, we explored a strategy for the enzym atic synthesis in which a C-8-ester at C-17 (5-androstene-3 beta,7 bet a,17 beta-triol 17-caprylate) would serve to mimic the bulky and hydro phobic side chain of cholesterol and thus allow the C-19-steroid to ac t as an effective substrate. When this ester was incubated with choles terol oxidase, it was converted efficiently to 7 beta-hydroxytestoster one-17-caprylate. Attempts to remove the ester group by several mild h ydrolytic procedures caused elimination of the 7 beta-hydroxyl group; we, therefore, obtained 7 beta-hydroxy-testosterone by incubation of t he intermediate ester with porcine lipase. (C) 1997 by Elsevier Scienc e Inc.