Unsaturated steroids. Part 12. Synthesis of 1α,3β-dihydroxy-24-nor-9,10-secochola-5,7,10(19)trien-23-oic (calcitroic) acid and of the cholic-and 25-homocholic acid analogues

Abstract

The three title compounds have been synthesized by the same general method. Thus, methyl 3β-hydroxy-24-nor-5α-chol-7-en-23-oate (3; R = CO2Me), derived from 3β-acetoxypregn-7-ene-22-carbaldehyde (2), gave methyl 3-oxo-24-nor-5α-chol-7-en-23-oate (4; R = H,R′= CH3). Bromination of this to the 2ξ,4ξ-dibromo derivative (4; R = Br, R′= Me) followed by dehydrobromination formed the corresponding 1,4,7-triene-3-one (5). The corresponding enol acetate (6) was reduced to the 1,5,7-triene (7) which was converted into the adduct (8; R = H) with 4-phenyl-1,2,4-triazoline-3,5-dione; the 3β-dimethyl-t-butylsilyl ether of (8;R = H)gave the 1α,2α-epoxide(9; R = Me2ButSi). Removal of the silyl ether group with acid, and then of the triazoline residue with pyridine–1,5-diazabicyclo[4.3.0] non-5-ene gave methyl 3β-hydroxy-1α,2α-epoxy-24-norchola-5,7-dien-23-oate (10; R = Me). Reduction of the corresponding acid (10; R = H) gave 1α,3β-dihydroxy-24-norchola-5,7-dien-23-oic acid (11; R = H). Photolysis/thermolysis of the corresponding methyl ester (11; R = Me) followed by saponification gave 1α,3β-dihydroxy-24-nor-9,10-secochola-5,7,10(19)trien-23-oic acid (calcitroic acid)(1; R = H, n= 1). The analogous cholic (1; R = H, n= 2) and 25-homocholic acid (1; R = H, n= 3) derivatives were similarly synthesized.