Conformationally Constrained Nicotines. 1-Pyridinyl-7-azabicyclo[2.2.1]heptane and 1-Pyridinyl-8-azabicyclo[3.2.1]octane Analogues

Conformationally constrained bicyclo analogues of natural (−)-nicotine and unnatural (+)-nicotine have been synthesized from d - and l -glutamic acid, respectively. Regioselective addition of 3-lithiopyridine to the γ-carbonyl of a protected glutamate was followed by intramolecular imine formation and stereospecific catalytic hydrogenation of the resultant pyrroline to give cis -5-pyridinylproline. A sequence of transformations to convert the ester to bromide was followed by the key intramolecular anionic cyclization at the benzylic position to form the 1-pyridinyl-7-azabicyclo[2.2.1]heptane analogue. Alternatively, homologation of the ester of cis -5-pyridinylproline and conversion to bromide allowed cyclization to the 1-pyridinyl-7-azabicyclo[3.2.1]octane analogues.