Synthesis of 14,17-propano analogues of estradiol

Abstract

Stereocontrolled syntheses of the 14α,17α-propano and 14β,17β-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 17β-acetoxy-3-methoxy-20-oxo-19-nor-17α -pregna-1,3,5(10)-triene-14-carbaldehyde 1 furnishes 3-methoxy-17¹-oxo-14,17α-prop-17² -enoestra-1,3,5(10)-trien-17β-yl acetate 2, which is transformed into 14,17α-propanoestra-1,3,5(10)-triene-3,17β-diol 17. In the first of two synthetic approaches to the 14β,17β-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-14β -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-14β-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 14,17β-propano-14β-estra-1,3,5(10)-triene-3,17α-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.

References

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