期刊
AAPS JOURNAL
卷 7, 期 3, 页码 E752-E758出版社
SPRINGER
DOI: 10.1208/aapsj070375
关键词
Nicotiana alkaloids; tobacco; stereoselective synthesis
资金
- NIDA NIH HHS [U19DA017548] Funding Source: Medline
- NATIONAL INSTITUTE ON DRUG ABUSE [U19DA017548] Funding Source: NIH RePORTER
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 1 R, 2 R, 5R-(+)- or 1 S, 2 S, 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.
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