A SYNTHESIS OF 7-ALPHA-SUBSTITUTED ESTRADIOLS - SYNTHESIS AND BIOLOGICAL EVALUATION OF A 7-ALPHA-PENTYL SUBSTITUTED BODIPY FLUORESCENT CONJUGATE AND A F-18 LABELED 7-ALPHA-PENTYLESTRADIOL ANALOG

In an effort to assist in the preparation of ligands for the study of the estrogen receptor (ER), we have developed a new synthesis of 7alpha-substituted estradiols. The key step in the synthesis involves a copper-catalyzed, alpha-selective, 1,6-conjugate addition of 4-pentenyl magnesium bromide to a suitably protected 6-dehydrotestosterone derivative. Desaturation and then reductive aromatization of the resulting 7alpha-pentenyl androgen gave the 7alpha-pentenylestradiol in good yields. The alpha-stereoselectivity of this addition in the testosterone series, compared with the 19-nortestosterone series, is significantly improved by the presence of the C-19 methyl group, which shields the beta face from attack. A key intermediate was functionalized further by substitution with fluorine-18 to provide a potential imaging agent for positron emission tomography, and by conjugation with a BODIPY (Molecular Probes Inc., Eugene, OR, USA) fluorophore to make a fluorescent probe for the estrogen receptor. The synthesis and biological evaluation of these analogs is presented, as well as a discussion of the improvements in the synthetic procedure.