A general procedure for the enantioselective synthesis of the minor tobacco alkaloids nornicotine, anabasine, and anatabine

AAPS J. 2005 Oct 31;7(3):E752-8. doi: 10.1208/aapsj070375.

Abstract

The minor tobacco alkaloids nornicotine, anabasine, and anatabine from Nicotiana tobacum are known to possess nicotinic receptor agonist activity, although they are relatively less potent than S-(-)-nicotine, the principal tobacco alkaloid. Previous pharmacological investigations and structure-activity studies have been limited owing to the lack of availability of the optically pure forms of these minor alkaloids. We now report a 2-step synthetic procedure for the enantioselective synthesis of the optical isomers of nornicotine and anabasine, and a modified procedure for the synthesis of anatabine enantiomers. These procedures involve initial formation of the chiral ketimine resulting from the condensation of either 1R, 2R, 5R-(+)- or 1S, 2S, 5S-(-)-2-hydroxy-3-pinanone with 3-(aminomethyl)pyridine followed by enantioselective C-alkylation with an appropriate halogenoalkane or halogenoalkene species, N-deprotection, and base-catalyzed intramolecular ring closure, to form the appropriate, chirally pure minor tobacco alkaloid. Using this approach, the R-(+)- and S-(-)-enantiomers of the above minor tobacco alkaloids were obtained in good overall chemical yield and excellent enantomeric excess.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alkaloids / chemical synthesis*
  • Anabasine / chemical synthesis*
  • Nicotiana*
  • Nicotine / analogs & derivatives*
  • Nicotine / chemical synthesis
  • Pyridines / chemical synthesis*
  • Stereoisomerism

Substances

  • Alkaloids
  • Pyridines
  • anatabine
  • Nicotine
  • nornicotine
  • Anabasine