Synthesis and structure-activity studies of 8α- and 9β-analogues of 14,17-ethanoestradiol

Synthetic routes to the title compounds are described, commencing with readily available 19-norsteroid precursors. The reaction of 3-methoxy-8 alpha-estra-1,3,5(10),14,16-pentaen-17-yl acetate 3 with phenyl vinyl sulfone at 150 degrees C proceeded in high yield, but with poor selectivity, to give a mixture of 14 alpha,17-cycloadducts, which underwent convergent functional group modification, to furnish 14 alpha,17 alpha-ethano-8 alpha-estradiol 13. The feasibility of performing similar cycloaddition chemistry on analogous 9 beta-precursors was demonstrated, but the preferred synthetic route entailed configurational inversion at C-9, of 14 alpha,17 alpha-ethanoestradiol 25, via moderately stereoselective hydrogenation of a 9,11-dehydro intermediate, leading to 14 alpha,17 alpha-ethano-9 beta-estradiol 32. The estrogen receptor binding affinities of 13 and 32 are reported, and discussed in terms of superimpositional modelling on estradiol.