The research interests of our group include the total synthesis of biologically active natural products, the development of new synthetic methods, heterocyclic chemistry, bioorganic and medicinal chemistry, combinatorial chemistry, the study of DNA-agent interactions, and the chemistry of antitumor antibiotics. We place a special emphasis on investigations to define the structure-function relationships of natural or designed agents in efforts to understand the origin of their biological properties.
As the exploration of the properties of complex natural products becomes increasingly more sophisticated with the technological advances being made in their screening and evaluation and as structural details of their interaction with biological targets becomes more accessible, the importance and opportunities for providing unique solutions to complex biological problems has grown. A powerful complement to the examination of the naturally-derived agents themselves is the preparation and subsequent examination of key partial structures, agents containing deep-seated structural modifications, and the corresponding unnatural enantiomers of the natural products. Well conceived deep-seated structural modifications may be used to address the structural basis of the natural products interactions with biological targets and to define fundamental relationships between structure, functional reactivity, and properties. In these studies we address the challenging problem of understanding the beautiful solutions and subtle design elements that nature has provided in the form of a natural product and work to extend the solution through rational design elements to provide more selective, more efficacious, or more potent agents designed specifically for the problem or target under investigation.
Central to such studies is the development of dependable synthetic strategies and the advent of new synthetic methodology to permit the preparation of the natural products, key partial structures, and analogs incorporating deep-seated structural changes. The resulting efforts have reduced many difficult or intractable synthetic challenges to manageable problems providing an approach not only to the natural product but one capable of simple extrapolation to a series of structural analogs as well. In our own efforts this has provided the opportunity to fully explore the origin of the natural products properties and to devise agents with improved selectivity and efficacy.
Our ongoing investigations emphasize the development and application of hetero Diels-Alder reactions, the thermal reactions of cyclopropenone ketals, inter- and intramolecular acyl radical-alkene addition reactions, medium and large ring cyclization procedures, and the benzannulation reaction of arylchromium carbene complexes. In each instance, the methodology development represents the investigation of chemistry projected as a key step in the total synthesis of a natural or nonnatural product.