Tetrahydrofuran-mediated radical processes: stereoselective synthesis of d,l-hexestrol

The highly stereoselective synthesis of d,l-hexestrol (1), an inhibitor of microtubule assembly, is developed by using, as a key step, an intermolecular coupling of Co2(CO)6-complexed propargyl radicals. The latter are generated by novel complementary processes involving an interaction of tetrahydrofuran with Co2(CO)6-complexed propargyl alcohols and cations. An isomerically pure d,l-μ-η2-[3,4-di(4-methoxyphenyl)-1,5-hexadiyne]-bis-dicobalthexacarbonyl (d,l-6) is isolated in 69–91% yield with intermolecular coupling reactions exhibiting an excellent chemo- (0.5–7%) and d,l-diastereoselectivity (90–94%). The structure of d,l-6 is determined by X-ray diffraction. The subsequent steps include BBr3-induced demethylation of 4-methoxyaryl groups, demetalation with cerium(IV) ammonium nitrate, and hydrogenation of acetylenic termini affording d,l-hexestrol (1).