Synthesis of 14,17-propano analogues of estradiol

Stereocontrolled syntheses of the 14 alpha,17 alpha-propano and 14 beta,17 beta-propano analogues of estradiol are described, together with those of numerous derivatives in which additional functionality is incorporated into the bridged system, Intramolecular aldol condensation of 17 beta-acetoxy-3-methoxy-20-oxo-19-nor-17 alpha-pregna-1,3,5(10)-triene-14-carbaldehyde 1 furnishes 3-methoxy-17(1)-oxo-14,17 alpha-prop-17(2)-enoestra- 1,3,5(10)-trien-17 beta-yl acetate 2, which is transformed into 14,17 alpha-propanoestra-1,3,5(10)-triene-3,17 beta-diol 17. In the first of two synthetic approaches to the 14 beta,17 beta-propano series, cycloaddition of methyl propiolate to 3-methoxyestra-1,3,5(10),14,16-pentaen-17-yl acetate 25 gives a 14,17-bridged intermediate 26, in which the latent propyne equivalency of the dienophile is elaborated through selective functional group transformations to give 17-acetoxy-3-methoxy-20-oxo-19-nor-14 beta-pregna-1,3,5(10)-triene-14- carbaldehyde 50 and the derived product 52 of intramolecular aldol condensation. The second approach : entails regioselective functionalisation of 14-allyl-3-methoxy-14 beta-estra-1,3,5(10)-trien-17-one 54 at C-2' or C-3' to give intermediates for intramolecular closure between the chain terminus and C-17, leading to 14,17 beta-propano-14 beta-estra-1,3,5(10)-triene-3,17 alpha-diol 64. The results of competitive binding assays of the hormone analogues 17 and 64 toward the estradiol receptor are reported, and compared with those of bridge-functionalised derivatives.