Synthesis and 29-14C-labeling of 3 alpha, 7 alpha, 12 alpha-trihydroxy-27-carboxymethyl-5 beta-cholestan-26-oic acid. A bile acid occurring in peroxisomal diseases.
The synthesis and 14C-labeling of 3 alpha, 7 alpha, 12 alpha-trihydroxy-27-carboxymethyl-5 beta-cholestan-26-oic acid by two different approaches is described. One of them involves chain elongation of cholic acid via Wittig-Horner condensation of its formylated 24-aldehyde with tetraethyl phosphonoglutarate. The resulting cholestenoate, on deprotection and hydrogenation, affords the unusual C29 bile acid in good yield. An alternative procedure consists in a malonic ester synthesis starting from the formylated 24-alcohol which, after conversion into a mesylate, is reacted with sodium salt of 2-carboethoxy-gamma-butyrolactone. Alkaline hydrolysis, decarboxylation, esterification with diazomethane and selective tosylation of the newly introduced primary hydroxyl function give a C28 precursor, which is easily chain-elongated into a labeled or unlabeled C29 bile acid by reaction with cyanide and hydrolysis. Due to the easy lactonization of some of the C28 intermediates, the latter method provides a better way for introducing a C-29 label than the sequence usually employed for carboxyl labeling of bile acids and consisting in a decarboxylative halogenation of the parent acid followed by substitution of the norhalogenide with [14C]cyanide and hydrolysis. The structure of the synthesized acid or its dimethyl ester is confirmed by 13C nuclear magnetic resonance spectroscopy and mass spectrometry, and is also shown by gas liquid chromatography to be identified with an authentic sample of biosynthetic C29 dioic bile acid extracted from body fluids of Zellweger patients.
Parmentier
G G
GG
Laboratory of Microbiology, Faculteit Geneeskunde, Katholieke, Universiteit Leuven, Belgium.
Busson
R H
RH
Janssen
G A
GA
Mannaerts
G P
GP
Eyssen
H J
HJ
D000447:Aldehydes / Q000737:chemistry; D002250:Carbon Radioisotopes; D019826:Cholic Acid; D002793:Cholic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D004951:Esterification; D006801:Humans; D006868:Hydrolysis; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy; D008314:Malonates / Q000737:chemistry; D008698:Mesylates / Q000737:chemistry; D008830:Microbodies / Q000378:metabolism*; D015394:Molecular Structure; D015211:Zellweger Syndrome / Q000378:metabolism
D000447:Aldehydes; D002250:Carbon Radioisotopes; D002793:Cholic Acids; D008314:Malonates; D008698:Mesylates; C003681:3,7,12-trihydroxycoprostanic acid; C030290:malonic acid; D019826:Cholic Acid