Synthesis of 5β-cholestane-3α, 7α, 12α, 25-tetrol and 5β-cholestane-3α, 7α, 12α, 24ξ, 25-pentol

Abstract

This paper describes syntheses of 5β-cholestane-3α, 7α, 12α, 25-tetrol and 5β-cholestane-3α, 7α, 12α, 24ξ, 25-pentol which give higher yields than previously published methods. In addition, 5β-cholestane-3α, 7α, 12α, 24ξ, 25-pentol was synthesized by a different procedure, namely via performic acid oxidation of the correspinding unsaturated triol, which gave a lower yield but avoided the formation of 5β-cholestane-3α, 7α, 12α, 25, 26-pentol, which normally tends to contaminate the final product. Structures were confirmed by gas-liquid chromatography, infrared-, proton magnetic resonance- and mass spectrometry, 5β-Cholestane-3α, 7α, 12α, 25-tetrol and 5β-cholestane-3α, 7α, 12α, 24ξ, 25-pentol were required for in vivo and in vitro studies of the (hypothetical) 25-hydroxylation pathway of cholic acid biosynthesis.Patients with the rare familial sterol storage disease, cerebrotendinous xanthomatosis (CTX) (1), secrete a number of C27 bile alcohols in bile and feces (2). One of the main components of the bile alcohol fraction was a tetrahydroxy bile alcohol, 5β-cholestane-3α,7α,12α,25-tetrol. A pentnhydroxy bile alcohol fraction consisted of two major and several minor components (3). One of the pentahydroxy bile alcohols was 5β-cholestane-3α7α,12α,24α,25-pentoiln dicating that in CTX subjects there existed a pathway of bile acid synthesis involving 25-hydroxylated intermediates, rather than 26-hydroxylated compounds, as previously reported for normal subjects.In order to investigate individual biochemical steps of the 25-hydroxylation pathway of cholic acid biosynthesis, it was necessary to prepare C27 bile alcohol derivatives, substituted in the 25-position. This paper describes the synthesis of 5β-cholestane-3α,7α,12α,25-tetrola nd 5β-cholestane-3α,7α,12α,- 24ξ,25-pentol from cholic acid. Certain modifications of the published procedures were required to improve the yield and purity of these substances.