Synthesis of diastereomers of 3 alpha,7 alpha,12 alpha, 24-tetrahydroxy- and 3 alpha,7 alpha,24-trihydroxy-5 beta-cholestan- 26-oic acids and their structures

Abstract

Four stereoisomers of 3 alpha,7 alpha,12 alpha,24-tetrahydroxy-5 beta-cholestan-26-oic acids were synthesized as possible intermediates of the side-chain degradation step of bile acid biosynthesis. 3 alpha,7 alpha,12 alpha-Trihydroxy-5 beta-cholest-25-en-24-one prepared by thermolysis of beta-ketosulfoxide was reduced to the (24R)- and (24S)-allylic alcohols by reduction with sodium borohydride. Each isomeric alcohol was subjected to hydroboration and oxidation to give (25R)- and (25S)-3 alpha,7 alpha,12 alpha,24,26-pentahydroxy-5 beta-cholestanes. The separated four stereoisomers were converted into the corresponding 26-carboxylic acids. The stereoisomers of 3 alpha,7 alpha,24-trihydroxy-5 beta-cholestan-26-oic acids were synthesized in the same manner. To establish the stereochemistry of these carboxylic acids, the chemical transformation of methyl 3 alpha,7 alpha,12 alpha-trihydroxy- and 3 alpha,7 alpha-dihydroxy-5 beta-cholest-24-en-26-oates into the above stereoisomers and the reductive dehydroxylation of the 24-hydroxyl group into known 3 alpha,7 alpha,12 alpha,26-tetrahydroxy- and 3 alpha,7 alpha,26-trihydroxy-5 beta-cholestanes are described. The applications of spectroscopic methods (circular dichroism and 1H nuclear magnetic resonance) to elucidation of the stereochemistry are also discussed.