Professor Paul J. Chirik of Princeton University is supported by the Chemical Catalysis program in the Division of Chemistry to develop efficient catalysts from Earth-abundant metals for the sustainable synthesis of single enantiomer drug-like molecules. This Grant Opportunities for Academic Liaisons with Industry (GOALI) project is conducted in collaboration with Dr. Rebecca T Ruck of Merck & Co., Inc. Single enantiomer compounds, those that can be distinguished from their mirror image counterparts much like a pair of hands often exhibit unique biological function and constituted two-thirds of FDA drugs approved in 2015. Preparing these chiral compounds as single enantiomers, or hands, is often challenging but transition metal catalysis has revolutionized the field by providing direct routes to these compounds from abundant precursors. Traditional catalysts often rely on the rarest elements on Earth and raise concerns about the overall sustainability, carbon dioxide (CO2) footprint and toxicity of these processes. The research team focuses on new reactions unique to Earth abundant transition metals that are desirable for sustainable reactions. Interfacing with the Merck team provides access to high throughput experimentation, a technique that enables rapid evaluation of numerous chemical reactions in parallel. This approach, coupled with molecular understanding developed at Princeton, enables rational catalyst design and generates insights that enables new sustainable synthetic methods as well as diagnostics to probe drug safety and efficacy within the pharmaceutical industry. Through an industrial-academic partnership advances are possible that would not be had the two group acted independently. These studies also provide fundamental catalyst design principles that may ultimately translate to other areas of catalysis beyond of the pharmaceutical industry. In addition, students and postdocs involved in the project gain unique experience working with industrial chemists and gain invaluable career advice and mentorship not typically found in traditional graduate programs.
Transition metal catalysis has revolutionized chemical synthesis and is a key component of sustainable chemistry. Use of Earth-abundant rather than precious metals is not only economically and environmentally advantageous but the variable electronic structures, density of states, and coordination geometries that are available with first row transition metals open pathways for new chemical reactivity. The intellectual merit of this proposal lies in the rational application of electronic structure control to address long-standing challenges in base metal catalysis with applications in the pharmaceutical industry. Sustainable methods for the preparation of single enantiomer compounds and the reduction of heterocycles are described. Hydrogenation catalysts that operate by 3 distinct mechanisms, differentiated by the method of electron flow during catalytic turnover, are investigated. Access to distinct reaction channels involving both homolytic and heterolytic bond activation from similar catalyst platforms is unique to base metals and improves the likelihood for success to overcome long-standing challenges such as enantioselective heteroarene hydrogenation and reduction of substrates lacking coordinating functionality. High throughput experimentation (HTE) coupled with physical inorganic spectroscopy, structural chemistry and magnetism provide a unique opportunity to solve fundamental and applied problems in chemical catalysis. Guided by pharmaceutically relevant targets, focus is devoted to Earth-abundant metal catalysts that improve the speed, diversity, complexity and sustainability of transformations used in drug discovery.
