Improved Chemical Synthesis,X-Ray Crystallographic Analysis,and NMR Characterization of (22R)-/(22S)-Hydroxy Epimers of Bile Acids |
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Authors: | Kaoru Omura Ayumi Ohsaki Biao Zhou Manaka Kushida Takashi Mitsuma Akiko Kobayashi Lee R Hagey Alan F Hofmann Takashi Iida |
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Affiliation: | 1. Department of Chemistry, College of Humanities and Sciences, Nihon University, Sakurajousui, Setagaya, Tokyo, 156-8550, Japan 2. Department of Applied Chemistry, Graduate School of Advanced Science and Engineering, Waseda University, Shinjuku, Tokyo, 169-8555, Japan 3. Department of Medicine, University of California, La Jolla, San Diego, CA, 92093-0063, USA
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Abstract: | We report an improved synthesis of the (22R)- and (22S)-epimers of 3α,7α,12α,22-tetrahydroxy-5β-cholan-24-oic acid and 3α,7α,22-trihydroxy-5β-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 °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 1H- and 13C-NMR spectra that permit the (22R)- and (22S)-epimers to be distinguished are reported as well as the specific 1H 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. |
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Keywords: | (22R)‐Hydroxy‐bile acids (22S)‐Hydroxy‐bile acids Oxidative decarboxylation Reformatosky reaction X‐ray crystallography NMR |
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