Resolution of (+/-)-2-tetradecyloxiranecarboxylic acid. Absolute configuration and chiral synthesis of the hypoglycemic R enantiomer and biological activity of enantiomers.
The resolution of the hypoglycemic agent (+/-)-2-tetradecyloxiranecarboxylic acid (3) as its d- and l-ephedrine salts is presented. The active enantiomer (R)-(+)-3 was also synthesized by the Sharpless chiral epoxidation procedure and its methyl ester (R)-(+)-4 was shown to be identical with the corresponding ester from the resolved acid. Single-crystal X-ray structure analysis of the diastereomeric salt of (+)-3 and (-)-ephedrine allowed assignment of (+)-3 as the R configuration. The effects on fatty acid oxidation and glucose tolerance of the racemic and enantiomeric forms of 3, 4, and the CoA ester of 3 are presented. A postulated mechanism of action for the active enantiomer as an enantioselective, active-site-directed, irreversible inhibitor of carnitine palmitoyl transferase is suggested.
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors; D004852:Epoxy Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000138:chemical synthesis*; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008968:Molecular Conformation; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D002334:Carnitine O-Palmitoyltransferase; C021756:2-tetradecylglycidic acid