Abstracting Complementarity for the Design of Stereoselective Acid Catalysts

Complementarity is invoked to holistically characterize interactions between a catalyst and its substrate. Although the paradigm maintains utility across many fields of chemistry, it is challenging to proactively deploy, requiring post hoc analyses to demonstrate. Here, we report active site-based buried volume furnishes a quantitative and generalizable representation for complementarity by Brønsted acid organocatalysts. The low-dimensional, geometric abstraction helps construct analytical Gaussian models encoding complementarity. From these footholds, experimental validation realizes new stereoselective solutions across diverse structural motifs and functional modes. Unlike other heuristics for stereoinduction, active site-based buried volume guides the design of stereoselective solutions without requiring detailed attention to the mechanisms of stereoinduction. We anticipate the successful abstraction of high-dimensional, stereoselective interactions by complementarity into a single, low-dimensional descriptor will offer a systematic framework for future catalyst design.