Abstract
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 1H- and 13C-nuclear magnetic resonance spectroscopic data of the four stereoisomers are presented. With this work all the 6-hydroxylated derivatives of lithocholic, deoxycholic, chenodeoxycholic, ursodeoxycholic, and cholic acids in the 5 beta series are now known and have been synthesized.
Highlights
3a,6P,12a-trihydroxy acids, were prepared by a new route
As part of a program of synthesis of potential bile acid metabolites for use as authentic specimens, we have recently reported the preparation of new and uncommon 3, 6 - dihyd 1 ~(~9-), 3,6,7-trihyd1~~(l-o), and 3 ~, 6, 7, 1 2 ~ ~ tetrahydroxy-5/3-cholanoicacids [11]
In this report we describe the synthesis of the two remaining hitherto unreported stereoisomers (3/3,6a,12a[3] and 3/3,6/3,12a[4])of the four possible 3,6,12a-trihydroxy-5/3-cholanoiaccids (Chart 1)and, in addition, present an alternative route to the known two stereoisomers (3a,6a,12a[l] [12, 13] and 3a,6/3,12a[2] [14])
Summary
Melting points (mp) were determined on an electric micro hot stage and are uncorrected. 5/3-cholanoic), deoxycholic (3a,12a-dihydroxy-5/3-cholanoic), and cholic (3a,7a,12a-trihydroxy-5/3-cholanoic) acids are of substantiated interest in biosynthetic and metabolic studies of bile acids [1,2,3,4,5,6,7,8]. These bile acids, excreted in human biological fluids from patients with hepatobiliary diseases and in fetuses and newborn infants, have been exclusively identified by gas-liquid chromatographic and gas-liquid chromatographic-mass spectrometric analyses, their stereochemical configuration of hydroxyl groups often remains uncertain.
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