The objective of this research program is to develop new tactics and strategies to synthesize alkaloid natural products and other biologically-active nitrogen containing compounds. Within this context, there are a number of specific objectives that fall into the two main categories of methodological studies and total synthesis. On the methodological front, the specific goals are to: (1) Explore and develop a novel cascade of reactions involving tandem cyclizations of imines and iminium ions that allows for the rapid, convergent and stereoselective synthesis of fused nitrogen heterocycles; (2) Develop a synthetic method for the homologation of carboxylic acids into alpha, beta-unsaturated ketones; and (3) Develop an efficient, stereoselective procedure for the synthesis of cis-2,5-pyrrolidines having unsaturated substituents. In the arena of total synthesis, the specific goals are to: (1) Apply biogenetically-inspired transformations to the syntheses of the indole alkaloids condylocarpine and akuammidine, an anesthetic agent; (2) Apply ring-closing metathesis as a key step in the concise syntheses of the potent nicotinic acetylcholine receptor agonists anatoxin-a and pinnamine and the anticancer alkaloid peduncularine; (3) Apply a novel, intramolecular variant of the vinylogous Mannich reaction as a key construction in a short synthesis of the potent immunosuppressive agent FR9O1483; (4) Apply cascade imine/iminium ion cyclizations to the concise syntheses of the complex spirocyclic alkaloids halichlorine, a selective inhibitor of the induced vascular cell adhesion molecule-1, and pinnaic acid, a specific inhibitor of cytosolic phospholipase A2 and (5) Submit selected intermediates to Eli Lilly, Merck Research Laboratories, Pfizer, Inc., and Abbott Laboratories for biological evaluation.
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