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).