Improved Chemical Synthesis, X-Ray Crystallographic Analysis, and NMR Characterization of (22R)-/(22S)-Hydroxy Epimers of Bile Acids

We report an improved synthesis of the (22R)- and (22S)-epimers of 3 alpha,7 alpha,12 alpha,22-tetrahydroxy-5 beta-cholan-24-oic acid and 3 alpha,7 alpha,22-trihydroxy-5 beta-cholan-24-oic acid from cholic acid (CA) and chenodeoxycholic acid (CDCA), respectively. The principal reactions involved were as follows: (1) oxidative decarboxylation of the bile acid peracetates with lead tetraacetate, and (2) subsequent Reformatsky reaction of the 23,24-dinor-22-aldehydes with ethyl bromoacetate in the presence of activated Zn as a catalyst with the reaction temperature maintained precisely at 75 A degrees C. The absolute configuration of the chiral center at C-22 of each epimer was established by single-crystal X-ray diffraction data using its ethyl ester-peracetate derivative. The H-1- and C-13-NMR spectra that permit the (22R)- and (22S)-epimers to be distinguished are reported as well as the specific H-1 shift effects induced by C5D5N. Bile acids having hydroxyl groups at C-22 are present in a variety of animal biles, previously have been difficult to identify, and are known to have distinctive physicochemical and biological properties.