A NOVEL SYNTHESIS OF 14-ALPHA,15-ALPHA-METHYLENE ESTRADIOL (J-824)

A novel approach to the synthesis of the orally active estrogen 14 alp ha,15 alpha-methylene estradiol (8, J 824) is described, starting with 3-methoxy-estra-1,3,5(10),8,14-pentaen-17 alpha-ol (5). The 14 alpha, 15 alpha-methylene bridge was sonochemically introduced by regioselec tive and stereoselective Simmons-Smith methylenation of the 14-double bond. Birch reduction of the 8-double bond provided the desired 8 beta -H, 9 alpha-H steroid, whereas ionic hydrogenation afforded the 8 beta -H, 9 beta-H isomer, together with an epimerization of the 17 alpha-hy droxy group. Oxidation of the Birch product yielded the corresponding 17-oxo steroid, which gave the title compound by diborane reduction. F or radioimmunoassay development the 6-(O-carboxymethyl)-oximino deriva tive of 8 was prepared as hapten and the 2-hydroxy derivative of 8 was synthesized as a potential metabolite of 8, and 8 was tritium labeled as well.