A total synthesis of 4-cyano-1, 3-dimethoxy-2-azaestra-1, 3, 5 (10)-trien-17β-ol and its configuration assignment

Abstract

A total synthesis of 4-cyano-1,3-dimethoxy-2-azaestra-1,3,5(10)-trien-17β-ol(6a) has been achieved starting from 4-cyano-1,3-dimethoxy-5,6,7,8-tetrahydroisoquinoline(1a). Dichromate oxidation of 1a gave the 8-oxo derivative (1c) whose structure was confirmed unambiguously by the lan thanide induced chemical shift method. Grignard reaction of 1c with vinyl magnesium bromide followed by condensation of the vinyl-alcohol with 2-methyl-cyclopentane-1,3-dione resulted in the seco-dione(2) in 50% yield, which was cyclised with p-toluene sulfonic acid to the pentaenone(3a). Sodium borohydride reduction of 3a, stereoselective partial hydrogenation of the 14,15-double bond in 3b followed by isomerisation of the 8,9-double bond in 4 to 9,11-position and catalytic reduction of the 9,11-double bond gave the title compound(6a). The 14α, 8β, 9α-configuration in 6 was tentatively assigned on the basis of its NMR spectrum. The CMR spectra of the steroidal derivative and also the tetrahydroisoquinoline derivative(1b) have been studied and the configuration assigned to the steroid has also been supported by this study.