Throughout my doctoral studies, I have endeavored to address the question of how to rationally design chiral catalysts to control enantioselectivity in a predictable fashion. To approach this problem, I have focused on the strategic implementation of attractive non-covalent interactions between catalysts and their substrates at the enantiodetermining transition state. A significant portion of this work involved the development of an approach to elucidating the structural origins of selectivity in complex data sets, with an eye towards rational catalyst design. The insights gained from these studies constitute the subject matter of this dissertation.

Chapter 1 provides an overview of a subset of attractive non-covalent interactions involving aromatic rings. Examples are highlighted in which these interactions have been characterized in the ground state with the explicit intention of quantifying their strengths and geometric requirements. Using the lessons learned from these reports, case studies are presented in which the interactions under discussion have been leveraged to catalyze chemical reactions via the paradigm of transition state stabilization. The insight gleaned from this literature survey is intended to provide a framework for the discussion of the catalyst design concepts outlined in the following chapters.

Chapter 2 describes the development of a novel class of axially chiral triazole containing phosphoric acid catalysts designed to impart enantioselectivity via attractive non-covalent interactions with a substrate at the enantiodetermining TS. This strategy stands in contrast to that typically discussed in the literature in which catalyst steric bulk is frequently invoked to rationalize asymmetric induction. Using this newly prepared catalyst library, an enantioselective cross dehydrogenative coupling was developed within the conceptual framework of the Toste group’s strategy of chiral anion phase transfer catalysis. Preliminary experiments suggested that the triazole substituents played a role in the determination of asymmetric induction beyond steric bulk, as initially hypothesized.

The third chapter describes our efforts to elucidate the structural origins of enantioselectivity in the oxidative coupling reaction presented in Chapter 2. By obtaining an enantioselectivity data set based on strategically modulated catalysts and substrates, we applied linear regression techniques to correlate our experimental data with molecular descriptors describing the structural variation throughout the data set. The resulting models, along with the overall enantioselectivity trends, were used to develop intuitively sensible mechanistic hypotheses that were subsequently tested through the application of new catalysts specifically tailored to address them. Based on the hypothesis that the triazole catalysts were engaged in enantiodetermining  interactions with the substrates at the TS, we rationally designed catalysts that afforded the products with the highest enantiomeric excesses reported to date.

Chapter 4 builds on the strategy outlined in Chapter 3 in the context of a boronic acid-directed phosphoric acid catalyzed enantioselective fluorination of allylic alcohols. Specifically, the logic developed in this chapter allows for the generalization of our data intensive strategy to scenarios in which the mechanism for selectivity determination changes throughout a data set. Through the careful organization of enantioselectivity data and strategically implemented mechanistic experiments, we identified a region of structural space in which we propose that a lone pair- interaction governs enantioselectivity. Based on this hypothesis, we rationally designed a catalyst system capable of producing either enantiomer of a chiral fluorinated building block in high enantiomeric excess using the same chiral catalyst.