Total synthesis of substituted (±)-6,6-dimethyl-B-norestra-1,3,5(10)-trien-17β-ols and their 9β-isomers

Abstract

Total syntheses of (±)-1,4-dimethoxy-6,6-dimethyl-B-norestra-1,3,5(10)-trien-17β-ol(11a), (±)-2,3-dimethoxy-6,6-dimethyl-B-norestra-1,3,5(10)-trien-17β-ol (11b), and (±)-3-methoxy-6,6-dimethyl-B-norestra-1,3,5(10)trien-17β-ol (11c), have been carried out starting from 4,7-dimethoxy-3,3-dimethylindan-1-one (1), 5,6-dimethoxy-3,3-dimethylindan-1-one (2), and 4′-methoxy-3-methylbut-2-enophenone (4), respectively. Generally, it is found that the intermediate 6,6-dimethyl-B-norestra-1,3,5(10),8-tetraen-17β-ols (10), on lithium–liquid ammonia reduction, yield a mixture of 8β,9α- and 8β,9β-trienols, (11) and (12) respectively, in the ratio 1 : 1. This is due to the comparable stabilities of these two isomers. However, the reduction carried out in presence of aniline affords a higher percentage of the 8β,9α-trienol (11). The assignment of configurations is made by chemical and 1H n.m.r. analysis. Catalytic hydrogenation of the tetraenols (10) is shown to proceed via initial isomerisation to the corresponding 6,6-dimethyl-B-norestra-1,3,5(10),9(11)-tetraen-17β-ols (26), followed by hydrogenation from the β-side to give, exclusively, the 8β,9β-trienols (12).