The Structure and Function of Estrogens. XI. Synthesis of (±)-7(8→11α) abeo -Estradiol and Its 9,11-Didehydro Derivative

Two approaches to the synthesis of (±)-7(8?11a)abeo-estra-1,3,5(10)-triene-3,17 ß- diol (2a) from (±)-1 ß-t-butoxy-7a ß-methy1-2,3,3a a,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 (±)-1ß-t-butoxy-7a ß-methyl-6-methylene-2,3,3a,6,7,7a-hexahydro-1H-inden-5(4H)-one (18), prepared from (11), led to ( ±)-1ß-t-butoxy-6 a-[2'-(3"-methoxyphenyl)ethy1]-7a ß a,6,7,7a-hexahydro-1H-inden-5(4H-one (10a). Acid-catalysed cyclization of (10a) afforded (±)-17ß-t-butoxy-3-methoxy-7(8 ?11)abeo-estra-l,3,5(10),9(11)-tetraene (29) which upon lithium/ammonia reduction in the presence of diphenylmethane gave ( ±)-17 ß- t-butoxy-3-methoxy-7(8 ?11a)abeo-estra,1,3,5(10)- triene (31). Deprotection of (31) and (29) afforded (±)-7(8 ?11 a)abeo-estra-1,3,5(10)-triene-3,17 ß- diol (2a) and (±)-7(8 ?1l)abeo-estra-1,3,5(10),9(11)-tetraene-3,17ß-diol (32), respectively. Alternatively, reaction of (±)-1ß-t-butoxy-7a ß-methyl-6-methylene-2,3,3a a,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.