The Structure and Function of Estrogens .10. Synthesis of 5,5-Dimethyl-Cis-4b,5,6,10b,11,12-Hexahydrochrysene-2,8-Diol - the Estrogenic Activity of This and of Related C-Methylated Hydrochrysenediols

Abstract

Reaction of 6-methoxy-2-(p- methoxyphenyl )-3,4-dihydronaphthalen-1(2H)- one (9) with dimethylketene ethyl trimethylsilyl acetal (10) in the presence of titanium tetrachloride gave ethyl 2-methyl-2-[6?-methoxy- 2?-(p- methoxyphenyl )-3?,4?-dihydronaphthalen-1?-yl] propanoate (11) which upon treatment with methanesulfonic acid afforded the lactone (13). Reduction of (11) with lithium/ammonia yielded mainly 6-methoxy- 2-(p- methoxyphenyl )-1,2,3,4-tetrahydronaphthalene (16), but hydrogenation of (11) over palladium/charcoal gave 61% of ethyl (1?RS,2?RS)-2-methyl-2-[6?-methoxy-2?-(p- methoxyphenyl )-1?,2?,3?,4?- (tetrahydronaphthalen-1?-yl] propanoate (21a). Alternatively, the ester (21a) was prepared in three steps from the ketone (9) by reaction of the derived 1ξ-acetoxy-6-methoxy-2ξ-(p- methoxyphenyl )-1,2,3,4- tetrahydronaphthalene (20b) with the ketene silyl acetal (10) in the presence of zinc iodide. Treatment of the ester (21a) with methanesulfonic acid afforded 72% of 2,8-dimethoxy-5,5-dimethyl-cis-4b, 10b,11,12-tetrahydrochrysen-6(5H)-one (22) which was converted into 2,8-dimethoxy-5,5-dimethyl-cis-4b,5,6,10b,11,12-hexahydrochrysene (23) in 63% yield via the dithiolan (24). Demethylation of (23) gave 5,5- dimethyl-cis-4b,5,6,10b,11,12-hexahydrochrysene-2,8-diol (3a).     Assays of the oestrogenic activity of compound (3a), and of related hydrochrysenediols are reported.