The main thrust of current research is directed toward the syntheses of natural and unnatural products that are of biological or structural interest. These investigations focus upon the design and development of general strategies that may be employed to assemble molecular subunits common to a number of alkaloids, terpenes, and acetogenins. A variety of new methods for effecting the regio- and stereoselective formation of carbon-carbon bonds as well as for the introduction and manipulation of functional groups are being explored. 

In a more biological arena, we are exploring the effects of preorganizing and varying the hydrophobicity of ligands upon protein-ligand interactions. It is commonly assumed that preorganizing a flexible ligand in the three dimensional shape it adopts when bound to a macromolecular receptor will provide a derivative having an increased binding affinity, primarily because the rigidified molecule is expected to benefit from a lesser entropic penalty. Over the years we have introduced conformational constraints into peptide-like ligands and never observed the increased binding affinities that were expected based upon the number of rotors being restricted. In order to understand the molecular basis of these observations, we began a series of detailed structural and energetic studies of complexes formed between constrained and flexible phosphotyrosine-derived pseudopeptides and selected SH2 domains. Contrary to the conventional wisdom, we discovered that the entropies of binding of preorganized ligands may be disfavored relative to less potent, flexible controls. We have also observed that energetic effects associated with changes in ligand hydrophobicity are not purely entropic and do not necessarily vary predictably.  These remarkable findings mandate reconsideration of current thinking about the effects of ligand preorganization in protein-ligand interactions, but more data are needed before new paradigms for the structure based design of biologically potent ligands can be formulated. Toward this goal, we are embarking on a more general study of the detailed effects of ligand preorganization and hydrophobicity upon energetics, kinetics, structure and dynamics in protein-ligand interactions.