Toward De Novo Catalyst Discovery: Fast Identification of New Catalyst Candidates for Alcohol‐Mediated Morita–Baylis–Hillman Reactions**

Abstract

AbstractRecently we have demonstrated how a genetic algorithm (GA) starting from random tertiary amines can be used to discover a new and efficient catalyst for the alcohol‐mediated Morita–Baylis–Hillman (MBH) reaction. In particular, the discovered catalyst was shown experimentally to be eight times more active than DABCO, commonly used to catalyze the MBH reaction. This represents a breakthrough in using generative models for catalyst optimization. However, the GA procedure, and hence discovery, relied on two important pieces of information; 1) the knowledge that tertiary amines catalyze the reaction and 2) the mechanism and reaction profile for the catalyzed reaction, in particular the transition state structure of the rate‐determining step. Thus, truly de novo catalyst discovery must include these steps. Here we present such a method for discovering catalyst candidates for a specific reaction while simultaneously proposing a mechanism for the catalyzed reaction. We show that tertiary amines and phosphines are potential catalysts for the MBH reaction by screening 11 molecular templates representing common functional groups. The method relies on an automated reaction discovery workflow using meta‐dynamics calculations. Combining this method for catalyst candidate discovery with our GA‐based catalyst optimization method results in an algorithm for truly de novo catalyst discovery.