PREPARATION OF 16-FORMYLESTRADIOL AND THE 16-(ALPHA-METHYLENEBUTANOLIDE) DERIVATIVE

Routes to the preparation of 16-formylestradiol are described. Estrone was converted to (E)-16-methoxymethylene estrone via the 16-hydroxyme thylene estrone. Reduction of the methoxymethylene estrone with NaBH4 in the presence of CeCl3 gave 16-methoxymethylene estradiol. Deprotect ion by acid afforded the desired 16-formylestradiol. Attempts to prepa re the 16- formylestradiol via the 16-butylthiomethylene derivative ga ve only 16-formylestra-1,3,5(10),16-tetraen-3-ol, and a route through the 16-dimethoxymethyl derivative gave a mixture of the 16-formyltetra en-3-ol and the 16-formylestradiol in low yield. The 16-formylestradio l was subsequently converted to the alpha-methylene lactone conjugate, stra-1,3,5(10)trien-16-yl)-2-methylene4-butanolide by reaction with m ethyl alpha-(bromomethyl) acrylate and zinc.