Catalytic Decision Points and Reaction Discovery

The ability to put together complex molecules, like piecing together a puzzle, is a challenging endeavor since the skills required to accomplish this are as much artistic as scientific.

My group enjoys thinking about and discovering new ways to assemble the atoms that complex molecules are made from. Once a new method has been identified in the laboratory, experiments are designed and performed to test and validate them for their robustness and utility.

We have demonstrated that transition metal catalyzed processes can be intercepted at various stages of the catalytic cycle �catalytic decision points� to provide structurally unique and different compounds depending upon the point of interception. This diverging strategy is not typically been exploited in the chemistry laboratory but is one that is adopted by nature in the assembly of secondary metabolites, more commonly referred to as natural products.

The new reactions are then used in our group to synthesize collections or libraries of previously unknown compounds. Once synthesized, the compounds are tested for their biological activity by researchers at the University of Pittsburgh and across the country. These compounds are designed on the premise that they may function as an important biological tool and may someday lead to the development of a new drug for diseases such as cancer or tuberculosis. The latter part of this project is done in collaboration with the University of Pittsburgh Chemical Methods and Library Development Center (UPCMLD). For more information see: http://ccc.chem.pitt.edu/.

In addition to preparing entirely new compounds, we also use the new methods discovered in our group to synthesize compounds in which their biological significance has already been established. The goal of these efforts is provide faster, more efficient and innovative means of accessing these structures. For example, these new methods have been successfully applied to the synthesis of HMAF, a potent anticancer compound currently in Phase III clinical trials and 15-deoxy-D^12,14 PGJ₂, a cyclopentenone prostaglandin that is a natural ligand for PPAR, a receptor linked to type II diabetes and obesity and FR901483, a compound possessing immunosuppressive activity. Ongoing projects include the synthesis of guanacastepene, isolated recently and shown to exhibit excellent activity against vancomycin resistant bacteria and suberosenone, possesses differential cytotoxicity in human tumor cell-lines.

The students involved with these projects are uniquely suited to go on to work in the pharmaceutical industry where they will strive to discover and develop new drugs.