A direct stereoselective synthesis of 7β-hydroxytestosterone

Article abstract of DOI:10.1016/S0039-128X(97)00018-4

Although 7β-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 7β-hydroxy-4-androstene-3,17-dione. We found that several seemingly straightforward routes for its synthesis failed. Consequently, we tried to produce 7β-hydroxytestosterone by enzymatic oxidation of 5-androstene-3β,7β,17β-triol with cholesterol oxidase (Brevibacterium sp.), a procedure previously used to synthesize 7β-hydroxy- 4-cholesten-3-one from 3β,7β-dihydroxycholesterol (Alexander and Fisher 1995). However, 5-androstene-3β,7β,17β-triol was, at best, a very poor substrate for the enzyme leading to the production of 7β- hydroxytestosterone in only trace amounts. Thus, we explored a strategy for the enzymatic synthesis in which a C₈-ester at C-17 (5-androstene- 3β,7β,17β-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 7β-hydroxytestosterone-17- caprylate. Attempts to remove the ester group by several mild hydrolytic procedures caused elimination of the 7β-hydroxyl group: we, therefore, obtained 7β-hydroxy-testosterone by incubation of the intermediate ester with porcine lipase.