# Stereoselective Generalizations over Diverse Sets of Chiral Acids Enabled by Buried Volume

## TL;DR

This paper introduces a new way to model stereoselectivity in Brønsted acid catalysis using buried volume in the active site, simplifying predictions across diverse catalysts.

## Contribution

Active site-based buried volume is shown to generalize stereoselectivity across diverse Brønsted acid catalysts with high accuracy.

## Key findings

- Buried volume is an effective descriptor for stereoselectivity across 50+ data sets and nearly 200 catalysts.
- The descriptor captures both structural and functional diversity, including stereoelectronic effects.
- It simplifies modeling by reducing the need for high-dimensional or bespoke representations.

## Abstract

Stereoselective catalysis
is a paradigm of complexity, navigating
arrays of specific, yet weak, noncovalent interactions to achieve
asymmetric induction. Accordingly, structure–activity relationships
modeling stereoselectivity have required bespoke representations,
high dimensionality, and/or large data sets to furnish productive
trends, hampering their subsequent interpretability and utility. Here,
we report that active site-based buried volume is a uniquely advantageous
descriptor for the construction of models to stereoselectivity by
Brønsted acid organocatalysts. Through statistical analyses of
50+ data sets across nearly 200 distinct catalysts, we realize active
site-based buried volume is an exceptional representation, accommodating
both extensive structural diversity (within data sets) and functional
diversity (across data sets). We show that the descriptor’s
value likely relates to its surprising capacity to generalize beyond
simple steric interactions and account for diverse stereoelectronic
effects consequential to reported stereoselectivity. As such, we anticipate
future modeling of stereoselectivity by Brønsted acid is greatly
simplified via the concise representation, active site-based buried
volume.