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. 2005 Oct 31;7(3):E752–E758. doi: 10.1208/aapsj070375

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

Joshua T Ayers 1, Rui Xu 1, Linda P Dwoskin 1, Peter A Crooks 1,✉
PMCID: PMC2751277  PMID: 16353951

Abstract

The minor tobacco alkaloids nornicotine, anabasine, and anatabine fromNicotiana 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-pinanonewith3-(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, theR-(+)-andS-(−)-enantiomers of the above minor tobacco alkaloids were obtained in good overall chemical yield and excellent enantomeric excess.

Keywords: Nicotiana alkaloids, tobacco, stereoselective synthesis

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