Synthesis of 4- and 16α-hydroxylated equine estrogens

Abstract 4-Hydroxyequilin, 4-hydroxyequilenin, and 16α-hydroxyequilenin were synthesized as authentic specimens for the metabolic studies of equine estrogens. The synthetic route leading to the 4-hydroxylated compounds was started from o-vanillin, which was transformed into the β-ketosulfoxide (2b) by sequential multistep reactions. This was converted to the α,β-unsaturated ketone (3) as Michael acceptor. Condensation of 3 with 2-methylcyclopentane-1,3-dione, followed by ring closure with methanesulfonic acid provided the cyclized estrapentaene (5) . Several oxidoreduction reactions were then performed to give the desired compounds. Preparation of 16α-hydroxyequilenin was attained by reductive cleavage of the 16α,17α-epoxide formed from equilenin.