Comprehensive Stereochemical Models for Selectivity Prediction in Diverse Chiral Phosphate-Catalyzed Reaction Space

The reactivity landscape of chiral phosphate catalysis is rapidly expanding and currently ranges from the hydrogenation of enals to the electrophilic activation of allenamides. Despite the importance of such transformations for the stereocontrolled synthesis of a diverse array of organic compounds, the preferred pathway and reasons for stereocontrol have not been firmly established, making it difficult to develop new reactions more generally. Here, we address this challenge by integrating traditional transition state calculations with statistical tools to rapidly connect and analyze several types of chiral phosphate-catalyzed enantioselective transformations. Detailed density functional theory (DFT) calculations of carefully selected case studies reveal that this set of superficially unrelated reactions operate, in many cases, through a single mechanism involving two hydrogen-bonding interactions from the iminium intermediate and nucleophile to the catalyst. From the transition state structures, we rationalize the different factors on which the enantioselectivity depends, focusing on the orientation of the reactants with respect to the catalyst. These theoretical analyses led to the construction of stereochemical models that correlate the magnitude and explain the sense of enantioselectivity for over 200 chemical reactions. We demonstrate how the resulting models can be used to assist reaction application to include additional substrates and develop related transformations. Ultimately, our findings represent a framework for formulating mechanistically relevant correlations driven by high-level transition state analysis, and this strategy should be broadly applicable to other catalytic systems widely applied in asymmetric synthesis.