Enantiospecific synthesis of annulated nicotine analogues from D- and L-glutamic acid. Pyridotropanes

The conformationally restricted nicotinoid 1-methyl-8-azabicyclo[3.2.1]octa no[2,3-c] pyridine[3,4-b]tropane, has been prepared enantiospecifically fro m both D- and L-glutamic acid. The method involved coupling of pyroglutamic acid derivatives with ortho-lithiated 4-chloropyridine, followed by intram olecular imine formation and reduction to generate the D- and L-5-substitut ed proline esters. Chloro-iodo exchange and side chain extension gave the p recursor for the [3.2.1] system. Construction of the 8-azabicyclo[3.2.1]oct ano-[2,3-c]pyridine framework was achieved by an intramolecular Heck reacti on. Subsequent ozonolysis gave the ketone which was reduced to the carbinol or methylene, yielding the fused nicotine analogues.