Synthesis of (3'R,5'S)-trans-3'-hydroxycotinine, a major metabolite of nicotine. Metabolic formation of 3'-hydroxycotinine in humans is highly stereoselective

J Med Chem. 1990 Jul;33(7):1888-91. doi: 10.1021/jm00169a009.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Biotransformation
  • Cotinine / analogs & derivatives
  • Cotinine / chemical synthesis*
  • Cotinine / isolation & purification
  • Cotinine / urine
  • Gas Chromatography-Mass Spectrometry
  • Humans
  • Indicators and Reagents
  • Nicotine / metabolism
  • Pyrrolidinones / chemical synthesis*
  • Smoking / urine
  • Stereoisomerism


  • Indicators and Reagents
  • Pyrrolidinones
  • hydroxycotinine
  • Nicotine
  • Cotinine