POTENTIAL BILE-ACID METABOLITES .18. SYNTHESIS OF STEREOISOMERIC 3,6,12-ALPHA-TRIHYDROXY-5-BETA-CHOLANOIC ACIDS

Two new 6-hydroxylated bile acids, 3-beta, 6-alpha, 12-alpha- and 3-beta,6-beta,12-alpha-trihydroxy-5-beta-cholanoic acids, were synthesized from deoxycholic acid. In addition, their C-3 epimers, 3-alpha,6-alpha,12-alpha- and 3-alpha,6-beta,12-alpha-trihydroxy acids, were prepared by a new route. The principal reactions used were 1) 6-beta-hydroxylation of 3-methoxy-3,5-dienes with m-chloroperbenzoic acid in aqueous dioxane; 2) catalytic hydrogenation of the resulting 6-beta-hydroxy-3-oxo-4-enes to the 6-beta-hydroxy-3-oxo-5-beta compounds with palladium on calcium carbonate catalyst in ethanol; and 3) stereoselective reduction of appropriate 3-oxo derivatives with potassium tri-sec-butylborohydride and tert-butylamine-borane complex. The thin-layer chromatographic, gas-liquid chromatographic, and high performance liquid chromatographic mobilities, and H-1- and C-13-nuclear magnetic resonance spectroscopic data of the four stereoisomers are presented. With this work all the 6-hydroxylated derivatives of lithocholic, deoxycholic, chenode-oxycholic, ursodeoxycholic, and cholic acids in the 5-beta series are now know and have been synthesized.