Natural Product Synthesis

The focus of current research is upon inventing and developing general tactics and strategies for the synthesis of natural and unnatural products of biological or structural interest. A variety of architecturally complex alkaloids, acetogenins, and terpenes serve as targets of opportunity to discover novel chemistry. For example, we are developing and applying new aspects of Diels-Alder and hetero Diels-Alder cycloadditions as well as vinylogous Mannich and ring closing metathesis reactions to elaborate functionalized nitrogen and oxygen heterocycles as key steps in formulating approaches to a diverse array of natural products. In addition to these strategy level constructions, useful synthetic processes, including domino and multicomponent reactions, are being developed to fill voids in available methodology.

Protein-Ligand Interactions and Enzyme Mechanism

The design and synthesis of small molecules that exhibit high affinities for biomacromolecules is critical to the study of enzyme mechanism and specificity and to correlating structure and function. Toward these objectives, a novel class of rigid dipeptide replacements derived from cyclopropanes has been invented, and these have been incorporated in pseudopeptides that serve as structural probes and enzyme inhibitors. Of particular interest is a critical evaluation of the effects of ligand preorganization upon energetics, kinetics, structure, and dynamics in protein-ligand interactions.