THE STRUCTURE AND FUNCTION OF ESTROGENS .11. SYNTHESIS OF (+/-)-7(8-]11-ALPHA)ABEO-ESTRADIOL AND ITS 9,11-DIDEHYDRO DERIVATIVE

Two approaches to the synthesis of (+/-)-7(8 --> 11-alpha)abeo-estra-1,3,5(10)-triene-3,17-beta-diol (2a) from (+/-)-1-beta-t-butoxy-7a-beta-methyl-2,3,3a-alpha,6,7,7a-hexahydro-1H-inden-5(4H)-one (11) were studied. A pathway involving 6-alkylation of (11) with 2-(3'-methoxyphenyl)ethyl halides or sulfonate esters was unsuccessful, but conjugate addition of 3-methoxybenzyl nucleophiles with (+/-)-beta-t-butoxy-7a-beta-methyl-6-methylene-2,3,3a-alpha,6,7,7a-hexahydro-1H-inden-5(4H)-one (18), prepared from (11), led to (+/-)-1-beta-t-butoxy-6-alpha-[2'-(3"-methoxyphenyl)ethyl]-7a-beta-methyl-2,3,3a-alpha,6,7,7a-hexahydro-1H-inden-5(4H)-one (10a). Acid-catalysed cyclization of (10a) afforded (+/-)-17-beta-t-butoxy-3-methoxy-7(8 --> 11)abeo-estra-1,3,5(10),9(11)-tetraene (29) which upon lithium/ammonia reduction in the presence of diphenylmethane gave (+/-)-17-beta-t-butoxy-3-methoxy-7(8 --> 11-alpha)abeo-estra-1,3,5(10)-triene (31). Deprotection of (31) and (29) afforded (+/-)-7(8 --> 11-alpha)abeo-estra-1,3,5(10)-tiene-3,17-beta-diol (2a) and (+/-)-7(8 --> 11)abeo-estra-1,3,5(10),9(11)-tetraene-3,17-beta-diol (32), respectively. Alternatively, reaction of (+/-)-1-beta-t-butoxy-7a-beta-methyl-6-methylene-2,3,3a-alpha,6,7,7a-hexahydro-1H-inden-5(4H)-one (18) with 3-methoxybenzyl phenyl sulfoxide (23a) gave (1RS,3'SR,2RS,-3a'SR,7a'SR)-3'-t-butoxy-2-(3"-methoxyphenyl)-3a'-methyl-2',3',3a',4',7',7a'-hexahydrospiro-[cyclopropane-1,5'-[5H]inden]-6'(1'H)-one (26), reductive cleavage of which with lithium/ammonia afforded (10a). The relative stereochemistries of (31) and of the spiro cyclopropyl ketone intermediate (26) were established unambiguously by X-ray crystallography.