Our research program involves studies in chemistry, biology, and medicine. A special emphasis is placed on training and research in complex molecule synthesis and inventing new reactions and on the utilization of this expertise in addressing problems of biochemical and medicinal significance. Our studies include: 1) the design and development of new reactions, methods, reagents, and strategies that introduce fundamentally novel ways of synthesizing complex molecules of biological or medicinal significance; 2) synthetic and mechanistic organometallic chemistry with an emphasis on new catalytic reactions; 3) elucidation of the molecular mode of action of biologically and medicinally important agents; 4) the molecular basis for tumor promotion; 5) drug delivery and novel mechanisms of transport into cells including the design and development of new transporters of drugs and probes; 6) the structure of biomacromolecules; 7) medicinal chemistry; and 8) computer modeling and molecular recognition.

The key to successful syntheses is the invention or discovery of new reactions. Our studies on organometallic chemistry are directed at the development of fundamentally new concepts, methods, reagents, and reactions for organic synthesis with the goal of moving the field of complex molecule synthesis closer to the ideal of short, safe, and efficient syntheses. Studies on new metal catalyzed reactions (e.g., 4+4, 4+2, 5+2, 6+2, 6+1, 5+2+1, 2+2+1, 5+1+2+1 cycloadditions) provide an exceptional opportunity to advance the frontiers of synthesis and focus on reactions that in the absence of metal catalysts would be impossible or difficult to achieve.

Another area of emphasis is on medicinal agents like bryostatin, currently in human clinical trials for the treatment of cancer. Bryostatin represents a remarkable synthetic challenge and a lead in an as yet unknown but novel mode of action that results in stimulation of the immune system. Bryostatin appears to enhance the efficacy of many anti-cancer agents. We have designed and synthesized analogues that are up to 3 order of magnitude better than bryostatin. Efforts on this lead continue along with several other problems of comparable synthetic challenge and medicinal importance. Related opportunities at the interface of synthesis, biology and medicine include studies on kirkine, gnidimacrin and apoptolidin, molecules that represent a formidable synthetic challenge and a unique opportunity in medicine.

One of the major problems in science is developing methods for breaching biological barriers. We are also involved in investigations on new molecular transporters that allow uptake of a wide range of molecules into cells, including small molecules, proteins, and anti-sense agents. This area opens new opportunities in chemotherapy including gene therapy and establishes a new tool of exceptional breadth for studying biochemical pathways.

Our studies on molecular carcinogenesis are directed at understanding the steps leading to the development of cancer, a necessary starting point for developing cancer-prevention strategies and chemotherapeutic agents. This project places a heavy emphasis on molecular modeling of enzyme activators and inhibitors, complex molecule synthesis, protein structure, and mode of action studies.

Organometallic Chemistry
1) J. Am. Chem. Soc. 2005, 2836; J. Am. Chem. Soc. 2004, 5948; J. Am. Chem. Soc. 2004, 9154; Angewandte Chemie Int. Ed., 2003, 1853; J. Am. Chem. Soc. 2002, 2876; J. Am. Chem. Soc. 2001, 179-180; J. Am. Chem. Soc. 2000, 7815-7816; J. Am. Chem. Soc., 1999, 10442.

Complex Molecule Total Synthesis
2) Proc. Natl. Acad. Sci. USA 2004, 8803; J. Am. Chem. Soc. 2002, 13648; J. Am. Chem. Soc. 2002, 4956; Organic Lett. 2000, 2323; Organic Lett., 1999, 137; J. Am. Chem. Soc.; 2002, 13648; J. Am. Chem. Soc., 1997, 12976.

Medicinal Chemistry, Drug Design, Biochemistry
3) Chemistry & Biology 2004, 1261; Organic Lett. 2005, 79; Current Drug Discovery Technologies 2004, 1; Proc. Natl. Acad. Sci. USA 2004, 8803; Pure Appl. Chem. 2003, 143; J. Am. Chem. Soc. 2002, 13648; Bioorganic and Medicinal Chemistry Letters, 2001, 719-722; Pure & Appl. Chem, 1998, 539; Medicinal Research Reviews, 1999, 388; Proc. Natl. Acad. Sci. USA, 1998, 6624.

Drug Delivery
4) J. Am. Chem. Soc. 2004, 9506; J. Am. Chem. Soc. 2004, 6850; Proc. Natl. Acad. Sci. USA , 2003, 14281; J. Med. Chem. 2002, 45, 3612-3618; J. Am. Chem. Soc. 2002, 13382; Natl. Acad. Sci. USA, 2000, 97, 13003-13008; Nature Medicine, 2000, 1253-1257.