Totally synthetic steroid hormones—XX : Novel total syntheses of equilin and equilenin

Abstract

A series of novel total syntheses of equilin (Ia) and cognate compounds has been developed starting from estra-1,3,5(10),8-tetraenes of the general class II.† The key reactions in these syntheses are oxidation of a tetraene II with m-chloroperbenzoic acid, rearrangement of the resulting epoxide III with an acid of pKa 1·42–4·21 to an estra-1,3,5(10),9(11)-tetraen-8α-ol IV, catalytic hydrogenation of the 9(11)-olefinic bond to give an estra-1,3,5(10)-trien-8α-ol V, and dehydration of the latter with methanesulfonyl chloride or phosphorus oxychloride in dimethylformamide to an estra-1,3,5(10),7-tetraene. The most efficient synthesis of equilin so far developed proceeds from 3-methoxyestra-1,3,5(10),8-tetraen-17β-ol IIc to 3-methoxyestra-1,3,5(10),7-tetraen-17β-ol XIIIb (by the above methods) and finally by dimethylation and oxidation to equilin Ia in an overall yield of 37·7%. A novel route to equilenin and its derivatives is provided by the conversion of 8β,9α-epoxy-estra-1,3,5(10)-trienes IIIa–c and estra-1,3,5(10),9(11)-tetraen-8α-ols IVa–c with mineral acid to mixtures of estra-1,3,5(10),6,8-pentaenes of type XIX and estra-1,3,5 (10), 8,14-pentaenes of type XX. Fused MeMgI constitutes an excellent reagent for demethylating acid-labile steroids such as the estra-1,3,5(10),8-tetraenes II, the estra-1,3,5(10)-trien-8α-ols V and the estra-1,3,5(10), 7-tetraenes X. Methanesulfonyl chloride or phosphorus oxychloride in DMF provide useful reagents for the formylation of OH groups under mild conditions, the former being selective for alcoholic over phenolic hydroxyls. Some of these results have already been communicated in preliminary form.2