A novel and stereoselective synthesis of 7α-alkynylestra-1,3,5(10)-triene-3,17β-estradiol

Different stereoselective synthetic routes for the preparation of 7α/β-substituted estradiol derivatives, that is, 7α-alkynylestra-1,3,5(10)-triene-3,17β-estradiol (13) and its 17β-acetate derivative (14), are explored. These steroids are key starting materials for Pd-catalyzed Sonogashira cross-coupling reactions to yield potential estrogen receptor (ER) antagonists, ER-based imaging ligands and other multi-functional agents. Initial preparation of 7α-alkynyl nortestosterone derivatives followed by various approaches to aromatize the A-ring, failed. Instead, stereoselective 7α-cyanation before A-ring aromatization, followed by 7α-cyano reduction to the 7α-aldehyde, dibromomethylenation and dehydrobromination of the aldehyde, gave the desired 7α-alkynyl derivatives 13 and 14 in good yield.