Synthesis of Nicotine Derivatives from Natural Nicotine, Total Synthesis of (S)-Brevicolline, and Advances towards the Synthesis of Dihydrolycolucine.

Abstract

Nicotine and its derivatives are currently being synthesized and tested to explore their pharmaceutical capabilities in the treatment of Alzheimer's disease, Parkinson's disease, and other central nervous system disorders. One area of research the Comins group has been undertaking is the development of methodologies for the synthesis of nicotine derivatives from natural nicotine. Herein, regioselective substitutions of the pyridine ring of (S)-nicotine will be described. Efforts are underway to expand the scope of these methods and to apply them to the preparation of potential pharmaceuticals, insecticides, synthetic intermediates, and novel ligands for catalytic asymmetric synthesis. Nicotine was used as a building block for the syntheses of SIB-1508Y, a potential anti-Parkinson's drug, which was successfully synthesized enantiomerically pure in only five steps. (S)-Brevicolline, a natural product of the -carboline family was synthesized from nicotine in only six steps. Our goal is to transform inexpensive, commercially available (S)-nicotine from an underutilized natural product to a useful member of the chiral pool.

Our group previously reported the intramolecular Diels-Alder reaction of 1-acyl-2-alkenyl-1,2-dihydropyridines. A derivative of a dihydropyridine Diels-Alder product could be ring-opened via a Retro-Mannich reaction to give a cis-decahydroquinoline derivative. The potential of this methodology for the synthesis of dihydrolycolucine, natural product from the Lycopodium family, prompted us to carry the model studies described in Chapter IV.