GOALI: Enantioselective Metal Carbene Transformations with Low Catalyst Loadings

Emory University, Atlanta GA

Investigators

Abstract

With the support of the Chemical Synthesis Program in the Division of Chemistry, Professor Huw M. L. Davies of Emory University is studying the development of practical methods to conduct synthetic transformations that will be of utility for the synthesis of next generation drug candidates. One of the major challenges in modern organic synthesis is how to achieve broadly useful reactions under safe and mild conditions with limited chemical waste. The application of new catalysts (additives that help a reaction to go faster or to increase its efficiency) has had a tremendous impact on organic synthesis but some of the best catalysts are often derived from very expensive and rare metals. To circumvent this challenge, the Davies program is examining how to conduct these catalyzed reactions with very low amounts of catalyst, so that each catalyst can conduct at least 100,000 cycles, greatly increasing the commercial viability of the processes. Under the optimized conditions, oxygen from the air in the only reagent needed beyond the substrates themselves and the only by-products are nitrogen and water. In addition to providing better catalysts, this program is aiding in the next generation of drug candidates and helping to train and mentor students to become better scientist including an awareness of how to develop truly practical synthetic methods. The Davies group has developed a series of rhodium and ruthenium catalysts, capable of a variety of synthetically useful reactions and of controlling the three-dimensional shape of the resulting products. These metals are expensive, but Davies has demonstrated they have the potential to be conducted with very low catalyst loadings. In this program, the Davies group is collaborating with the process group at AbbVie to determine how these catalysts can be applied under extremely low catalyst loading conditions in an industrial setting. The role of additives to enhance the catalyst performance are being examined with the goal of routinely achieving 100,000 catalyst turnovers and ideally up to 1 million turnovers. In addition, the precursors for the metal-catalyzed reactions are being generated under flow conditions, which greatly enhances the safety aspects of this chemistry. Under the optimized conditions, oxygen from the air in the only reagent needed beyond the substrates themselves in the two-step process and the only by-products are nitrogen and water. This program has the potential to broadly impact the utility of this chemistry in pharmaceutical applications and demonstrates that the use of extremely low catalyst loadings is of practical use in the battle to achieve synthetic sustainability. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.