A synthesis of 7 alpha-substituted estradiols: synthesis and biological evaluation of a 7 alpha-pentyl-substituted BODIPY fluorescent conjugate and a fluorine-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 7 alpha-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 7 alpha-pentenyl androgen gave the 7 alpha-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.