Martin Group Research Interests

In the area of alkaloid synthesis, we are developing and applying new tactics for constructing nitrogen heterocycles. Some problems of current interest involve the use of Diels-Alder and hetero Diels-Alder cycloadditions, dipolar cycloadditions, vinylogous Mannich reactions and other transformations of iminium ions, and ring closing metathesis as key steps to construct heterocyclic subunits common to different families of alkaloids. Some specific targets of interest include the lundurines, methyl lysergate, pinnamine, asparagamine, sarain A, hederacine A, actinophyllic acid, citrinadin A, haouamine A, acutumine, sieboldine A, carteramine A, and the welwitindolinones. The asymmetric syntheses of oxygenated natural products, especially C-aryl glycosides and glycoepitope mimetics, constitutes another important area of our research program. A new and general strategy for constructing C-aryl glycosides has been developed and is being applied to the total syntheses of pluramycin, kidamycin, 5-hydroxyaloin A, and medermycin. Other natural compounds of interest include the cortistatins and IB-00208. These targets have inspired novel variants of [4+3] cycloadditions and a new entry to angular polyaromatic systems. We have discovered a rhodium catalyst that complements the reactivity and selectivity of other known catalysts in allylic alkylations, and we are now exploring its use in cyclizations and a variety of cascade reactions to rapidly construct complex molecular architectures. Toward developing novel strategies for diversity oriented synthesis, we are developing four component reactions to prepare intermediates that may be readily elaborated in several facile steps to generate molecules having diverse heterocyclic scaffolds and functionality.


	Group Research Interests

	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 the area of alkaloid synthesis, we are developing and applying new tactics for constructing nitrogen heterocycles. Some problems of current interest involve the use of Diels-Alder and hetero Diels-Alder cycloadditions, dipolar cycloadditions, vinylogous Mannich reactions and other transformations of iminium ions, and ring closing metathesis as key steps to construct heterocyclic subunits common to different families of alkaloids. Some specific targets of interest include the lundurines, methyl lysergate, pinnamine, asparagamine, sarain A, hederacine A, actinophyllic acid, citrinadin A, haouamine A, acutumine, sieboldine A, carteramine A, and the welwitindolinones. The asymmetric syntheses of oxygenated natural products, especially C-aryl glycosides and glycoepitope mimetics, constitutes another important area of our research program. A new and general strategy for constructing C-aryl glycosides has been developed and is being applied to the total syntheses of pluramycin, kidamycin, 5-hydroxyaloin A, and medermycin. Other natural compounds of interest include the cortistatins and IB-00208. These targets have inspired novel variants of [4+3] cycloadditions and a new entry to angular polyaromatic systems. We have discovered a rhodium catalyst that complements the reactivity and selectivity of other known catalysts in allylic alkylations, and we are now exploring its use in cyclizations and a variety of cascade reactions to rapidly construct complex molecular architectures. Toward developing novel strategies for diversity oriented synthesis, we are developing four component reactions to prepare intermediates that may be readily elaborated in several facile steps to generate molecules having diverse heterocyclic scaffolds and functionality.

	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.