Neighboring group participation: Part 16. Stereoselective synthesis and receptor-binding examination of the four stereoisomers of 16-bromomethyl-3,17-estradiols

Abstract

The four possible isomers of 3-benzyloxy-16-hydroxymethylestra-1,3,5(10)-trien-17-ol ( 1a– 4a) with proven configurations were converted into the corresponding 3-benzyloxy-16-bromomethylestra-1,3,5(10)-triene-3,17-diols ( 5e– 8e). Depending on the reaction conditions the cis isomers of 3-benzyloxy-16-hydroxymethylestra-1,3,5(10)-trien-17-ol ( 1a and 2a) were transformed into 3-benzyloxy-16-bromomethylestra-1,3,5(10)-trien-17-yl acetate ( 5b and 6b) or 16-bromomethyl-3-hydroxyestra-1,3,5(10)-trien-17-yl acetate ( 5c and 6c) on treatment with HBr and acetic acid. The mechanism of the process can be interpreted as involving front-side neighboring group participation. Under similar experimental conditions, the trans isomers ( 3a and 4a) yielded only 3-benzyloxy-16-acetoxymethylestra-1,3,5(10)-trien-17-yl acetates ( 3b and 4b) or 16-acetoxymethylestra-1,3,5(10)-triene-3,17-diyl diacetates ( 3d and 4d). Both the cis ( 1a and 2a) and the trans ( 3a, and 4a) isomers were transformed into 16-bromomethylestra-1,3,5(10)-trien-17-ol ( 5a– 8a) by the Appel reaction on treatment with CBr 4/Ph 3P. Debenzylation of 5a– 8a was carried out with HBr and acetic acid to yield 5e– 8e. The debenzylation process in the presence of acetic anhydride produces the diacetates 5d– 8d. The structures of the compounds were determined by means of MS, 1H NMR and 13C NMR spectroscopic methods. Compounds 5c– 8c and 5e– 8e were tested in a radioligand-binding assay. Except for the affinity of 7e for the estrogen receptor ( K i = 2.55 nM), the affinities of the eight compounds ( 5c– 8c and 5e– 8e) for the estrogen, androgen and progesterone receptors are low ( K i > 0.55, 0.52 and 0.21 μM, respectively).