Synthesis of 16-[carbamoyl(bromomethyl)alkyl]estradiol: a potential dual-action inhibitor designed to blockade estrogen action and biosynthesis

Abstract

The target compound 1, N-butyl-N-methyl-7-bromomethyl-9-[3′,17′β-dihydroxyestra-1′,3′,5′(10′)-trien-16′α-yl]nonanamide, possesses a bifunctionalized side chain at the 16α position of the steroidal D-ring, and is synthesized from commercially available estrone using a sequence of 13 steps. Two α-alkylations of lithium enolates are performed, yielding a general template that leads to the expected bifunctionalized compound. First, alkylation at position 16 of protected estrone requires an activated electrophile and produces mainly the desired 16α-isomer. Optimal conditions for the second α-alkylation of the resultant ester enolate are established to give mainly the monoalkylated ester. Finally, various functional group transformations can be carried out to generate interesting estradiol derivatives for structure–activity relationship studies.