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

Abstract

Two approaches to the synthesis of (±)-7(8→11α)abeo-estra-1,3,5(10)-triene-3,17 β- diol (2a) from (±)-1 β-t-butoxy-7a β-methy1-2,3,3a α,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 (±)-1β-t-butoxy-7a β-methyl-6-methylene-2,3,3a,6,7,7a-hexahydro-1H-inden-5(4H)-one (18), prepared from (11), led to ( ±)-1β-t-butoxy-6 α-[2′-(3″-methoxyphenyl)ethy1]-7a β α,6,7,7a-hexahydro-1H-inden-5(4H-one (10a). Acid-catalysed cyclization of (10a) afforded (±)-17β-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 β- t-butoxy-3-methoxy-7(8 →11α)abeo-estra,1,3,5(10)- triene (31). Deprotection of (31) and (29) afforded (±)-7(8 →11 α)abeo-estra-1,3,5(10)-triene-3,17 β- diol (2a) and (±)-7(8 →1l)abeo-estra-1,3,5(10),9(11)-tetraene-3,17β-diol (32), respectively.

Alternatively, reaction of (±)-1β-t-butoxy-7a β-methyl-6-methylene-2,3,3a α,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.