A general procedure for the enantioselective synthesis of the minor tobacco alkaloids nornicotine, anabasine, and anatabine.
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.
Ayers
Joshua T
JT
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA.
Xu
Rui
R
Dwoskin
Linda P
LP
Crooks
Peter A
PA
D000470:Alkaloids / Q000138:chemical synthesis*; D000691:Anabasine / Q000138:chemical synthesis*; D009538:Nicotine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D011725:Pyridines / Q000138:chemical synthesis*; D013237:Stereoisomerism; D014026:Nicotiana
D000470:Alkaloids; D011725:Pyridines; C012737:anatabine; D009538:Nicotine; C005311:nornicotine; D000691:Anabasine