Enantiospecific Synthesis of Annulated Nicotine Analogues from d- and l-Glutamic Acid. Pyridotropanes

Abstract

The conformationally restricted nicotinoid 1-methyl-8-azabicyclo[3.2.1]octano[2,3-c]pyridine, pyrido[3,4-b]tropane, has been prepared enantiospecifically from both d- and l-glutamic acid. The method involved coupling of pyroglutamic acid derivatives with ortho-lithiated 4-chloropyridine, followed by intramolecular imine formation and reduction to generate the d- and l-5-substituted proline esters. Chloro-iodo exchange and side chain extension gave the precursor for the [3.2.1] system. Construction of the 8-azabicyclo[3.2.1]octano-[2,3-c]pyridine framework was achieved by an intramolecular Heck reaction. Subsequent ozonolysis gave the ketone which was reduced to the carbinol or methylene, yielding the fused nicotine analogues.