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

Joshua T. Ayers, Rui Xu, Linda P. Dwoskin, Peter A. Crooks

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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.

Original languageEnglish
Article number75
JournalAAPS Journal
Volume7
Issue number3
DOIs
StatePublished - Oct 31 2005

Bibliographical note

Funding Information:
This work was supported in part by National Institutes of Health (NIH), Bethesda, MD, grant U19DA017548. For the purpose of full disclosure, the University of Kentucky holds a patent on nornicotine, which has been licensed by Yaupon Therapeutics Inc (Lexington, KY). A potential royalty stream to P.A.C. and L.P.D. may occur consistent with University of Kentucky policy, and both P.A.C. and L.P.D. are founders of and have financial interest in Yaupon Therapeutics Inc.

Keywords

  • Nicotiana alkaloids
  • Stereoselective synthesis
  • Tobacco

ASJC Scopus subject areas

  • Pharmaceutical Science

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