Presenter: Florence C.
Advisor(s): Daniel L. Comins
Author(s): Florence C. Fevrier, Daniel L. Comins
Graduate Program: Chemistry
Title: Recent Advances on Nicotine Chemistry at NC State University
Abstract: (S)-Nicotine, the most abundant alkaloid isolated from Nicotiana tabacum, has attracted much attention because of its important pharmacological effects on central nervous system disorders such as Parkinsonís or Alzheimerís diseases. Many groups of compounds have been isolated from natural sources or synthesized as ligands for the nicotinic acetylcholine receptors, of which nicotine and its analogs represent an important class. However, nicotine is not suitable for therapeutical use due to its undesirable side effects (potential for abuse, actions on the cardiovascular and gastrointestinal systems). As a consequence, pharmaceutical researchers are racing to synthesize a selective nAChR ligand for the development of neurodegenerative disorder drugs which possess the positive effect of nicotine without its harmful side effects. The development of new pharmaceuticals based on the core nicotine structure has been limited by the lack of synthetic methods for preparing derivatives directly from natural nicotine. In most previous studies, reagents other than nicotine were used as starting material. The use of non-chiral compounds as starting material often requires a low-yielding resolution to provide the desired enantiomer. In an attempt to avoid resolution steps, our attention was directed at the synthesis of nicotine derivatives using natural nicotine itself as an inexpensive starting material. A variety of novel nicotine derivatives were prepared. Addition of cuprate reagents to a N-acylpyridinium salt of nicotine, followed by aromatization, afforded C-4 substituted nicotines. The reductive disilylation of nicotine followed by addition of various carbonyl electrophiles and TBAF provided either C-5 substituted nicotines or 1,4-dihydronicotines. The synthesis and regioselective substitution of 2- and 6- halonicotine derivatives were performed in excellent yields. These methodologies allow the direct introduction of a plethora of functional groups anywhere onto the pyridine ring of nicotine.