Development of Force Field Parameters for Predictions in Asymmetric Catalysis and a Foray into Mechanism Elucidation

The computational community has long promised predictive methods to accelerate experimental screening methods. Predicting stereochemical outcomes is of high importance due to the different biological and chemical properties of stereoisomers. The quantum-guided molecular mechanics (Q2MM) method allows the development of transition state force field (TSFF) parameters which can be used to realize this goal of predicting stereoisomer ratios. These TSFFs combine chemical accuracy with fast conformational sampling to describe diastereomeric TS ensembles. This thesis describes a new virtual screening procedure that brings predictive power closer to experimentalists. This virtual screening procedure is tested with two TSFFs that have been developed. The TSFF for the asymmetric redox-relay Heck reaction is shown to predict stereoselectivities of arylations of unbiased alkenes. Additionally, this TSFF also quantitatively shows advantages and limitations of the TSFF approach in asymmetric predictions. The second TSFF describes the asymmetric transfer hydrogenation of ketones using half-sandwich metal complexes. A theoretical comparative DFT study of Ru, Rh, and Ir complexes suggest a TSFF can be developed describing reactions of all three metals. Validation of a previously developed FF describing the ferrocene scaffold is presented here. Two mechanistic DFT studies are also described, where the first investigates the observed stereoretention of a cyclopropyl ketene rearrangment. The second study sheds light on the role of the catalyst and reactivity of key intermediates of a Rh-catalyzed asymmetric β-C-H functionalization of acceptor-substituted ketones. Lastly, kinetic studies were performed to elucidate the effects of different buffers on the reactivity of HMGCoA reductase.