Absolute structure determination of the highly biologically active bisdehydrodoisynolic acids

In a project designed to relate the unexpected in vivo and in vitro propert ies exhibited by (+)- and (-)-bisdehydrodoisynolic acid with their absolute stereochemical structure, an X-ray crystal-structure analysis was:undertak en of the highly estrogenic, poorly binding (-) enantiomer. H-1 and C-13 NM R spectra are also reported for the first time. The crystal structure shows the cis juxtaposition of the carboxyl and ethyl groups, which are separate d by a large torsion angle, and that only the carbon atom holding the carbo xyl group is out of the plane in which the remainder of the fused three-rin g moiety lies. The crystal structure, which unequivocally characterizes the (-) enantiomer as cis-13(S),14(R) and, implicitly, the (+) enantiomer as c is-13(R),14(S), will be useful in continued studies aimed at explaining the selective estrogen receptor modulation (SERM) of these enantiomers which, in some cases, produces significantly different end-organ effects compared to those of estradiol, in both males and females, affording the promise of a variety of therapeutic and pharmacologic applications. (C) 2000 Wiley-Lis s, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 513-518 , 2000.