Mechanism-Guided Catalyst Development through Reaction Discovery Simulation

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Project Summary Advances in chemical synthesis provide access to complex biologically active structures that are highly relevant as pharmaceuticals and analysis tools. High performance reactions that allow selective formation of specific covalent bonds are usually achieved by first uncovering their fundamental chemical reaction mechanisms, as these mechanistic details pave the way for further experimentation. Especially in the areas of C-H functionalization, Lewis acid/base chemistries, and stereoselective transformations, the discovery of mechanism is vital due to the high difficultly level in achieving these reaction steps. Further development of these reaction types will enable efficient construction of a wide variety of powerful therapeutics, signaling probes, and natural products. The proposed research will leverage first principles simulations to greatly accelerate catalyst development for novel synthetic reactions. The Zimmerman group's recently developed reaction pathway discovery tools are especially well-positioned for this task, being able to reveal unexpected reaction pathways as well as intuitive paths, giving deep insight into the atomistic details of reactivity. In collaboration with numerous reaction development groups, these tools have already been used to reveal principles for several classes of catalysts, and have even allowed new catalyst structures to be designed. Application of these methods to the proposed transformations (Ni-based C-H functionalization, macrolide glycosylation by chiral organocatalysts, Lewis-acid catalyzed carbonyl-olefin metathesis, and oxidative enzymatic transformations) will give the basic scientific insight needed to enable challenging synthetic steps. In summary, the proposed development of catalysts for highly selective transformations will enable synthesis of a variety of scientifically and therapeutically relevant molecules, with profound implications for the treatment and study of human health.