Development of Transition State Force Field Parameters for Asymmetric Reactions to Predict Stereoselectivity and to Gain Insight into the Interactions Dictating Stereoselectivity

In the pharmaceutical industry, the absolute configurations of chiral compounds need to be produced with high purity. Asymmetric catalysis has been used to generate products with high yields and high selectivities. To find the catalyst that gives the best selectivity and yield, a wide range of ligands needs to be tested. There has been immense interest in predictive methods that could search through ligand libraries and find which ligands could give the best selectivity rather than experimentally testing hundreds of ligands so just testing the 5-10 ligands give the best results. The Quantum-Guided Molecular Mechanics (Q2MM) method has been developed to tackle this problem by developing transition state force fields (TSFFs) as a method to predicting stereoselectivity. This thesis describes the process of developing TSFF and a virtual screening procedure that automates the process of calculating selectivity. There are two TSFF developed, for the Pd-catalyzed allylic amination and Pd-catalyzed 1,4-additon or arylboronic acids to enones, that have shown the predictive ability that can be useful for experimentalists. There are two additional TSFF that are still being developed for the Rh-catalyzed 1,4-addition of boronic acids to enones and Ir-catalyzed imine hydrogenation that are also presented here. Lastly, force field parameters for a ferrocene scaffold are verified and have shown how developed force field parameters can be combined and used to make selectivity predictions.