Enantiospecific synthesis of annulated nicotine analogues from D-Glutamic acid. 7-azabicyclo[2.2.1]heptano[2.3-c]pyridines

The conformationally restricted nicotinoid (1S,4S)-7-methyl-7-azabicyclo[2. 2.1]heptano[2,3-c]pyridine dihydrochloride has been prepared enantiospecifi cally from D-glutamic acid, The method involved a lithium cis-2,6-dimethylp iperidide-mediated intramolecular anionic cyclization of (2S,5R)-N-(tert-bu tyloxycarbonyl)-5-[3-(4-N-chloropyridinyl]proline methyl ester in tandem wi th a standard decarboxylation sequence. Reductive amination afforded the de sired N-methylated [2.2.1]bicyclonicotinoid. Cyclization of the correspondi ng iodopyridinylproline methyl ester, obtained via ultrasound-facilitated c hloro-iodo exchange, was also effected.