Synthesis of 24-nor-5 beta-cholan-23-oic acid derivatives: a convenient and efficient one-carbon degradation of the side chain of natural bile acids

C D Schteingart,A F Hofmann

doi:10.1016/s0022-2275(20)38445-5

Abstract

An efficient procedure for obtaining nor-bile acids from natural (C24) bile acids is described. Treatment of formylated bile acids with sodium nitrite in a mixture of trifluoroacetic anhydride with trifluoroacetic acid gives, through a "second order" Beckmann rearrangement, 24-nor-23-nitriles. These compounds, on alkaline hydrolysis, afford the corresponding nor-bile acids in high yields. The sequence was successfully applied to the synthesis of 3 alpha-hydroxy-24-nor-5 beta-cholan-23-oic (norlithocholic) acid, 3 alpha,6 alpha- (norhyodeoxycholic), 3 alpha,7 alpha- (norchenodeoxycholic), 3 alpha,7 beta- (norursodeoxycholic), and 3 alpha,12 alpha-dihydroxy-24-nor-5 beta-cholan-23-oic (nordeoxycholic) acids, as well as 3 alpha,7 alpha,12 alpha-trihydroxy-24-nor-5 beta-cholan-23-oic (norcholic) acid. 13C-NMR spectra of their methyl esters are reported. The procedure provides a more rapid alternative to the Barbier-Wieland degradation for shortening by one methylene group the side chain of natural (C24) bile acids.

Highlights

An efficient procedure for obtainingnor-bile acids from procedure that requires anhydrous conditions and gives natural (&) biIe acids is described
The a-hydroxylation of the methyl esters of tetrahydropyranyl (THP)-protected biJe acids with LDAloxidoperoxymolybdenum carbon degradation of the side chain of natural bile acids.J Lipid complex is known to proceed with good yields [14], the
We report here a modification of this method which has resulted in a new and efficient methodoIogyfor the one-carbondegradation of bile acids

Summary

RESULTS

In 1975, Smushkevich, Usorov, and Suvorov [15] reported the conversion of a carboxylic acid into its nornitrile. Though the model compounds described were very simple and the yields only moderate, we decided to try to apply the procedure to the synthesis of nor-bile acids, because its eventual success would result in a method far simpler than the Barbier-Wielanddegradation. In the method reported here, a suitable protected bile acid (Fig. 1) is transformed in one step into the nitrile of the lower homologue, which in turn is deprotected and hydrolyzed to the norbile acid in another simple operation

Hydroxyl group protection

Hyodeoxycholic acid

Side chain degradation

Hydmlysis of the nornitriles