Computational Prediction of Enantioselectivity in Metal-Catalyzed Reactions

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In this project funded by the Chemical Catalysis Program of the Chemistry Division, Paul Helquist and Olaf Wiest of the University of Notre Dame will develop computational methods to predict hydrogenation enantioselectivity of any combination of chiral catalyst plus substrate. The approach is to calculate the pertinent transition structures for a given transition metal-catalyzed hydrogenation reaction using quantum mechanical methods; to parameterize and validate the ground and transition state force fields (TSFF) using the quantum mechanics-guided molecular mechanics (Q2MM) approach; to calculate the differences in free energy of activation of the relevant diastereomeric transition structures using the TSFFs; to use the force fields for rapid prediction of enantioselectivities for virtual ligand libraries; and finally to validate the top ligand candidates using experimental methods. The broader impacts involve training undergraduate and graduate students, outreach to local high school students through a summer research laboratory experience, broad dissemination of research results and Q2MM software, a general public science exhibit on the importance of catalysis on everyday life, and the scientific and technological impacts of the ability to predict stereochemical outcomes of catalytic reactions without having to perform experimental screening.This work will deepen our understanding of how catalysts can make one molecule selectively of a pair that are mirror images and advance our ability to predict the outcomes of such catalytic reactions using computational methods. Such knowledge would benefit the fine chemical and pharmaceutical industries and potentially lead to faster, more efficient methods to synthesize drugs and other types of bioactive compounds.