Project Summary Pharmaceutical production is driven by the development of novel chemical transformations as they can allow for the expedient synthesis of drug molecules. Reactions that proceed through simple disconnections and which set important stereochemical information in the presence of a chiral catalyst are particularly valuable. A plethora of BINOL-derived phosphoric acid catalyzed reactions to form carbon-carbon bonds have been developed and used in these contexts, however identifying the best chiral catalyst can be challenging as the optimal choice is often substrate dependent. Since the underlying mechanisms that result in the transfer of chiral information from the catalyst to the product are poorly understood, making informed decisions regarding catalyst design in the development of new reactions is difficult. One particular phosphoric acid class that has received little mechanistic study, partially due to its increased complexity, are doubly axially chiral phosphoric acids (DAP). These catalysts, which contain a second chiral axis, have been shown to effectively catalyze intramolecular allylic substitution reactions for the synthesis of enantioenriched heterocycles, however the optimized reaction conditions are difficult to translate to other heterocyclic systems. The primary objective of this project is to develop a combined experimental and computational model that explains how substitution on the DAP catalyst affects the observed selectivity of allylic substitution reactions for the synthesis of enantioenriched heterocycles. To address this objective, two specific aims are proposed: 1) investigate the mechanism of chiral DAP-catalyzed allylic substitution reactions, and 2) probe DAP catalyst flexibility across a broad set of reaction classes. The DAP catalysts will be parameterized by analyzing linear free energy relationships from correlated experimental data and computed molecular fragments that probe for the presence of non-covalent interactions. This model will then be used to predict a more selective catalyst that will expand the targeted reaction scope through the inclusion of previously inaccessible substrates. A comprehensive model that can predict chiral DAP catalysts for novel transformations will then be developed. This meta-analytical approach will incorporate the study of numerous transformations previously reported with BINOL-derived phosphoric acids in order to effectively parameterize the DAP scaffold to achieve better catalyst predictions. In summary, these studies determine how catalyst flexibility and the resulting non-covalent interactions affect the stability of reaction transition states affording highly enantioselective products, particularly those for chiral heterocycle formation. The optimization and development of these methods will ultimately allow synthetic access to a broad range of pharmaceutical agents.