Chemical synthesis of 15β-hydroxytestosterone and its derivatives using a (4-methoxyphenyl)methyl protecting group

Reaction of 3β-hydroxyandrosta-5,15-dien-17-one with 4-methoxybenzyl alcohol followed by acetylation gave mainly 15β-[(4-methoxyphenyl)methoxy]-17-oxoandrost-5-en-3β-yl acetate. This product was transformed by borohydride reduction and organosilyl derivatization into the orthogonally protected 17β-(dimethylthexylsiloxy)-15β-[(4-methoxyphenyl)methoxy]androst-5-en-3β-yl acetate and 17β-(dimethylisopropylsiloxy)-15β-[4-methoxyphenyl)methoxy]androst-5-en-3β-yl acetate. After deacetylation, these intermediates were submitted to Oppenauer oxidation and both yielded testosterone derivatives 17β-(dimethylthexylsiloxy)-15β-[(4-methoxyphenyl)methoxy]adrost-4-en-3-one and 17β-(dimethylisopropylsiloxy)-15β-[(4-methoxyphenyl)-methoxy]androst-4-en-3-one. Removal of the (4-methoxyphenyl)methyl group from position 15 by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone treatment gave the partially protected derivatives 17β-(dimethylthexylsiloxy)-15β-hydroxyandrost-4-en-3-one and 17β-(dimethylisopropylsiloxy)-15β-hydroxyandrost-4-en-3-one. After acidic deprotection, the dimethylthexylsilyl derivative yielded 15β-hydroxytestosterone (15β,17β-dihydroxyandrost-4-en-3-one). Dimethylisopropylsilyl derivative was converted to the corresponding 15-hemisuccinate and 15-hemiglutarate (17β-hydroxy-3-oxoandrost-4-en-15β-yl 15-hemisuccinate and 15-hemiglutarate, respectively), which were designed as model haptens for immunoassay studies.