title: Synthesis of (3'R,5'S)-trans-3'-hydroxycotinine, a major metabolite of nicotine. Metabolic formation of 3'-hydroxycotinine in humans is highly stereoselective.
abstract: A method for the synthesis of (3'R,5'S-trans-3'-hydroxycotinine, a major metabolite of nicotine in humans, is described. The method involves deprotonation of (S)-cotinine with lithium diisopropylamide (LDA) followed by oxidation with the transition metal peroxide oxodiperoxymolybdenum(pyridine)(hexamethylphosphoric triamide) (MoOPH) to give an 80:20 mixture of trans-/cis-3'-hydroxycotinine. The pure (greater than 98%) trans isomer is obtained by conversion to the solid hexanoate ester, recrystallization, and cleavage of the ester by heating with n-butylamine. GC-MS analysis of urine extracts from several smokers indicated that in humans metabolic 3'-hydroxycotinine is 95-98% trans.
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Francisco.
authors.forename: P
authors.initials: P
authors.lastname: Jacob
authors.forename: A T
authors.initials: AT
authors.lastname: Shulgin
authors.forename: N L
authors.initials: NL
authors.lastname: Benowitz
mesh_terms: D001711:Biotransformation; D003367:Cotinine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000302:isolation & purification / Q000652:urine; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007202:Indicators and Reagents; D009538:Nicotine / Q000378:metabolism; D011760:Pyrrolidinones / Q000138:chemical synthesis*; D012907:Smoking / Q000652:urine; D013237:Stereoisomerism
chemical_list: D007202:Indicators and Reagents; D011760:Pyrrolidinones; C001381:hydroxycotinine; D009538:Nicotine; D003367:Cotinine