Totally synthetic steroid heterocycles. Part 1. Synthesis of intermediate precursors of 16-oxa- and 16-thia-D-homoestrogens

Abstract

The total synthesis of 16-oxa- and 16-thia-D-homoestrogen derivatives is described. A straightforward synthesis of 16-thia- and 16-oxa-3-methoxy-D-homoestra-1,3,5(10),8,14-pentaen-17a-one (8a and b) and their 6-didehydro derivatives (24a and b) is achieved by condensation of 2-methyl-5-thia- and 5-oxacyclohexane-1,3-dione (1a and b) with 6-methoxy-1,2,3,4-tetrahydronaphthylidene-ethylisothiuronium acetate (5). The ethyl homologues (9a and b) are also prepared using the corresponding diones (2a and b). An alternative route to the estrapentaene (8a) starting with Michael addition of 6-m-methoxyphenylhex-1-en-3-one (25) to the dione (1a) also produces 3-methoxy-9,10-seco-16-thia-D-homoestra-1,3,5(10),8(14)-tetraene-9,17a-dione (29).