Synthesis of 15,15-dialkylestradiols

Abstract

Conjugate alkylation of 3-methoxyestra-1,3,5(10),15-tetraen-17-one 1 leads to 15β-alkyl 17-ketones 2 (Me, Et or Prⁱ), which are converted, via palladium acetate-mediated dehydrosilylation of their derived silyl enol ethers, into the corresponding 15-alkyl Δ¹⁵-17-ketones 5. Conjugate alkylation of these intermediates results in formation of 15,15-dialkyl 17-ketones 10, which undergo stereoselective reduction with lithium aluminium hydride, and deprotection of C-3 to give 15,15-dialkyl analogues 12 of estradiol. Spectroscopic data are presented to demonstrate that substrates 1 and 5 undergo exclusive 15β-alkylation.