Leveraging Main-Group Redox Catalysis for the Stereoselective Synthesis of Pharmaceutically-Relevant Saturated Heterocycles

With support of the Chemical Catalysis program in the Division of Chemistry, Professor Scott E. Denmark at the University of Illinois at Urbana-Champaign is studying the development of new methods for catalyzing the synthesis of high-value ring systems that are prominent in complex natural products, pharmaceutical and agrochemical compounds. The research aims to use selenium-based catalysts to anneal doubly functionalized reagents (featuring nitrogen, oxygen, and/or sulfur) onto readily available alkenes while controlling the orientation and three-dimensional arrangement of all elements. The research activities in organic and inorganic catalysis and synthesis are ideal for the intellectual and practical training of undergraduates, graduate students and postdoctoral coworkers. The actionable roadmap for the project is to construct the mechanistic / physical organic foundation for developing general and selective selenium-catalyzed alkene difunctionalization reactions. The overall project objective is divided into three Specific Aims: (1) catalytic, enantioselective syn-1,2-diamination to construct piperazines and tetrahydroquinazolines; (2) catalytic, enantioselective syn-1,2-oxyamination to construct morpholines and oxazolines; and (3) catalytic, enantioselective, intramolecular 1,2-oxyamination to construct polycyclic oxazolidin-2-ones. For each Aim, the project team will carry out detailed mechanistic (kinetic, spectroscopic, crystallographic, computational) investigations of the catalytic reactions to learn the rules for achieving high catalytic activity (TOF and TON) for the target reactions; design chiral catalysts that will impart high stereoselectivity and high chemical conversion for the introduction of new stereocenters; and demonstrate generality in a variety of substrate classes that represent broadly useful structural motifs. 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.