SYNTHESIS OF (3'R,5'S)-TRANS-3'-HYDROXYCOTININE, A MAJOR METABOLITE OF NICOTINE - METABOLIC FORMATION OF 3'-HYDROXYCOTININE IN HUMANS IS HIGHLY STEREOSELECTIVE

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 '-hydroxycotinine. The pure (>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. © 1990, American Chemical Society. All rights reserved.