Abstract
This report describes the chemical synthesis of six new bile acid analogs, namely, 3 alpha,7 alpha,12 alpha-trihydroxy-7 beta-methyl-5 beta-cholanoic acid (7 beta-methyl-cholic acid), 3 alpha,7 beta,12 alpha-trihydroxy-7 alpha-methyl-5 beta-cholanoic acid (7 alpha-methyl-ursocholic acid), 3 alpha,12 alpha-dihydroxy-7 xi-methyl-5 beta-cholanoic acid (7 xi-methyl-deoxycholic acid), 3 alpha,12 alpha-dihydroxy-7-methyl-5 beta-chol-7-en-24-oic acid, 3 alpha,12 alpha-dihydroxy-7-methyl-5 beta-chol-6-en-24-oic acid, and 3 alpha,12 alpha-dihydroxy-7-methylene-5 beta-cholan-24-oic acid. The carboxyl group of the starting material 3 alpha,12 alpha-dihydroxy-7-oxo-5 beta-cholanoic acid was protected by conversion to its oxazoline derivative. A Grignard reaction of the bile acid oxazoline with CH3MgI followed by acid hydrolysis gave two epimeric trihydroxy-7-methyl-cholanoic acids and three dehydration products. The latter were purified by silica gel column chromatography and silica gel-AgNO3 column chromatography of their methyl ester derivatives. Catalytic hydrogenation of 3 alpha,12 alpha-dihydroxy-7-methyl-5 beta-chol-6-en-24-oic acid and 3 alpha,12 alpha-dihydroxy-7-methylene-5 beta-cholan-24-oic acid gave 3 alpha,12 alpha-dihydroxy-7 xi-methyl-5 beta-cholanoic acid. The configuration of the 7-methyl groups and the position of the double bonds were assigned by proton nuclear magnetic resonance spectroscopy and the chromatographic and mass spectrometric properties of the new compounds. These compounds were synthesized for the purpose of exploring new and potentially more effective cholelitholytic agents. The hydrophilic bile acids 7 beta-methyl-cholic acid and 7 alpha-methyl-ursocholic acid are of particular interest because they should be resistant to bacterial 7-dehydroxylation.
Highlights
Position of the double bonds were assigned by proton nuclear magnetic resonance spectroscopy and the chromatographic and mass spectrometric properties of the new compounds.lThese compounds were synthesized for the purpose of exploring new prevented the formation of gallstones more effectively than Chenodeoxycholic acid (CDA)
The hydrophilic bile acids 7/3-methyl-cholicacid and 7a-methyl-ursocholic acid are of particular interest because they should be resistant to bacterial 7-dehydroxylation.-Kuroki, S., M
This report describes the synthesis of the following new formyl groups, we could purify the intermediate, bile acids: 3a,7a,12a-trihydroxy-7~-methyl-5P-cholan-242--(3a, 12a-dihydroxy-7-oxo-24-nor-5~-cholanyl)-4,4-dioic acid (7-Me-cholic acid (CA), VII), 3a,7P,12a-trihydroxy-7a-methyl- methyl-2-oxazoline (IVb), by recrystallizations from ethyl
Summary
The mixture of free acids (1.8 g), which showed three major spots on silica gel TLC (Table 1, solvent system A-1), was treated with diazomethane and the resulting methyl ester derivatives were placed on a column of silica gel (150 g, silica gel 60, 35-70 mesh, Merck, Darmstadt, West Germany) and eluted with increasing concentrations of acetone in benzene. Fifteen percent acetone in benzene (3 1) eluted a mixture of unsaturated dihydroxy compounds (VIIIa, IXa, and Xa, 2-(3a,7~,12a-Trihydroxy-7~-methyl-24-nor-5~-cholanyl)4,4-dimethyl-2-oxazoline(V, 2.5 g) was dissolved in a solution of concentrated HC1 (2 ml) and methanol (200 ml).
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