Research in my group is based broadly in methods development and chemical synthesis. Our early efforts have concentrated on the invention of new atom and group transfer-type reaction processes. The application of such methods to problems in natural product synthesis and chemical biology offers unique challenges in reaction design, and serves as the underlying motivation for our research. As one of our overarching goals, we wish to devise molecular systems for selective C-H amination and hydroxylation that integrate concepts in catalysis with those in molecular recognition. Such ideas are inspired by Nature and the metalloenzymes that perform hydrocarbon oxidation reactions with exquisite fidelity. A general interest in problems in molecular recognition and molecular design has stimulated our more recent work towards understanding the structure and physiology of ion channels. Altogether, projects in the group are intended to afford students expertise in synthetic chemistry while exposing them to problems in chemical kinetics and catalysis, physical organic and coordination chemistry, and structure design. Currently, we have four principal areas of concentration that include: 1. The elucidation of new reaction processes for carbon-heteroatom (C-N and C-O) bond formation through selective, metal-catalyzed C-H and s-bond functionalization. 2. Mechanistic analysis of Rh-promoted C-H amination; coordination chemistry and catalyst design. 3. Multi-step, asymmetric syntheses of complex, heterocyclic amine-derived natural products which include the manzacidins, tetrodotoxin, saxitoxin, aconitine, welwitindolinone, and agelastatin. 4. The development of guanidine toxin mimetics that function as tools for mapping the tertiary structure of the ion permeation pathway in voltage-gated Na+ and Ca2+ ion channel proteins.
REACTION DEVELOPMENT. We have delineated new strategies for the selective conversion of saturated C-H bonds to carbinolamine stereocenters. This methodology has general utility in synthesis and makes available large numbers of amine derivatives from inexpensive and easily prepared starting materials. Prior to our investigations, it was not possible to consider C-H bond amination in the retrosynthetic planning of a target molecule. We have shown, however, that such a reaction can indeed be accomplished with the aid of a dinuclear Rh catalyst and a commodity oxidant, using both simple and structurally diverse substrates. Currently, we seek to identify other catalyst structures that operate with efficiencies comparable to those of the Rh systems. Our ability to alter the ligand framework of the catalyst complex will enable us to influence chemo-, regio-, and stereoselectivities in the C-H bond amination event. Efforts in catalyst design are tied strongly to mechanistic studies that have attempted to identify key reactive intermediates on the pathway to C-H bond amination.
TARGET-DIRECTED SYNTHESIS AND MOLECULAR DESIGN. The development of novel synthetic strategies to complex target molecules such as tetrodotoxin, saxitoxin, aconitine, and the manzacidins serves to underscore the value of our reaction methods for simplifying problems in chemical synthesis. We have successfully completed the preparation of both tetrodotoxin and manzacidins A and C. The availability of these compounds through de novo synthesis affords us unique opportunities to craft structurally analogous molecular probes for exploring the structure and function of their respective protein targets. Current efforts are also aimed at the preparation of saxitoxin and aconitine, both of which are known to act on voltage-gated Na+ ion channels.
In combination with our progress towards a saxitoxin synthesis, we are preparing structural mimics of this target that maintain many of the key architectural elements thought to be essential for its bioactivity. The proposed compounds have been conceived through the aid of computer modeling, from which it has been possible to assess both molecular conformation and electrostatic surface potentials. Saxitoxin is known to block ion channel conductance by occluding the mouth of the channel pore. Analogs of this natural product can be used in combination with protein mutagenesis experiments to map the tertiary structure of the saxitoxin binding site. Through these studies, we hope to gain an understanding of the protein recognition features that impart selectivity for Na+ ions. Moreover, the availability of small molecules that disrupt the normal functioning of ion channels can be employed to study the mechanism by which ion flux across a membrane is coupled to downstream cellular signaling events. In all, our research program, which has at its core complex molecular synthesis and reaction development, positions us uniquely to address questions that are of relevance to understanding the neurophysiology of voltage-gated channel proteins.