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Journal of Lipid Research, Vol. 45, 567-573, March 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Methods

Chemical synthesis of (22E)-3,6ß,7ß-trihydroxy-5ß-chol-22-en-24-oic acid and its taurine and glycine conjugates

Genta Kakiyama^*, Takashi Iida^1,*, Atsushi Yoshimoto^*, Takaaki Goto, Nariyasu Mano, Junichi Goto, Toshio Nambara, Lee R. Hagey and Alan F. Hofmann

^* Department of Chemistry, College of Humanities and Sciences, Nihon University, Sakurajousui, Setagaya, Tokyo 156-8550, Japan
Graduate School of Pharmaceutical Sciences, Tohoku University, Aobayama, Sendai 980-8578, Japan
Department of Medicine, University of California, San Diego, La Jolla, California 92093-0813

¹ To whom correspondence should be addressed. e-mail: takaiida{at}chs.nihon-u.ac.jp

A method for the synthesis of ²²-ß-muricholic acid (²²-ß-MCA), (22E)-3,6ß,7ß-trihydroxy-5ß-chol-22-en-24-oic acid, and its taurine and glycine conjugates (²²-ß-muricholyltaurine and ²²-ß-muricholylglycine) is described. The key intermediate, 3,6ß,7ß-triformyloxy-23,24-dinor-5ß-cholan-22-al, was prepared from ß-muricholic acid (ß-MCA) via the 24-nor-22-ene and 24-nor-22,23-diol derivatives. Wittig reaction of the aldehyde with (carbomethoxymethylene) triphenylphosphorane and subsequent hydrolysis gave (unconjugated) ²²-ß-MCA. Condensation reaction of the unconjugated acid with taurine or glycine methyl ester using diethylphosphorocyanide yielded the naturally occurring taurine or glycine conjugate (N-acylamidate) of ²²-ß-MCA.

These synthetic reference compounds are now available for investigation of the metabolism of ß-MCA by bacterial and hepatic enzymes in the rat and should also be useful as substrates for reductive deuteration or tritiation to give the 22,23-²H or ³H-ß-MCA.

Abbreviations: DEPC, diethylphosphorocyanide; EI, electron ionization; ESI, electrospray ionization; EtOAc, ethyl acetate; HR-MS, high-resolution mass spectra; IR, infrared; LR-MS, low-resolution mass spectra; ß-MCA, ß-muricholic acid; ²²-ß-MCA, ²²-ß-muricholic acid; NIM, negative ion mode; PIM, positive ion mode; UDCA, ursodeoxycholic acid; ²²-UDCA, ²²-ursodeoxycholic acid

Supplementary key words unsaturated bile acid • tauro-²²-ß-muricholic acid • ²²-ß-muricholyltaurine • glyco-²²-ß-muricholic acid • ²²-ß-muricholylglycine

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