Regio-MPNN: predicting regioselectivity for general metal-catalyzed cross-coupling reactions using a chemical knowledge informed message passing neural network†

As a fundamental problem in organic chemistry, synthesis planning aims at designing energy and cost-efficient reaction pathways for target compounds. In synthesis planning, it is crucial to understand regioselectivity, or the preference of a reaction over competing reaction sites. Precisely predicting regioselectivity enables early exclusion of unproductive reactions and paves the way to designing high-yielding synthetic routes with minimal separation and material costs. However, it is still at the emerging state to combine chemical knowledge and data-driven methods to make practical predictions for regioselectivity. At the same time, metal-catalyzed cross-coupling reactions have profoundly transformed medicinal chemistry, and thus become one of the most frequently encountered types of reactions in synthesis planning. In this work, we for the first time introduce a chemical knowledge informed message passing neural network (MPNN) framework that directly identifies the intrinsic major products for metal-catalyzed cross-coupling reactions with regioselective ambiguity. Integrating both first principles methods and data-driven methods, our model achieves an overall accuracy of 96.51% on the test set of eight typical metal-catalyzed cross-coupling reaction types, including Suzuki–Miyaura, Stille, Sonogashira, Buchwald–Hartwig, Hiyama, Kumada, Negishi, and Heck reactions, outperforming other commonly used model types. To integrate electronic effects with steric effects in regioselectivity prediction, we propose a quantitative method to measure the steric hindrance effect. Our steric hindrance checker can successfully identify regioselectivity induced solely by steric hindrance. Notably under practical scenarios, our model outperforms 6 experimental organic chemists with an average working experience of over 10 years in the organic synthesis industry in terms of predicting major products in regioselective cases. We have also exemplified the practical usage of our model by fixing routes designed by open-access synthesis planning software and improving reactions by identifying low-cost starting materials. To assist general chemists in making prompt decisions about regioselectivity, we have developed a free web-based AI-empowered tool. Our code and web tool have been made available at https://github.com/Chemlex-AI/regioselectivity and https://ai.tools.chemlex.com/region-choose, respectively.