A Data-Driven Approach Towards Exploring the Selectivity Space of Ni/Photoredox-Catalyzed Cross-Electrophile Couplings of Epoxides

Abstract

Cross-electrophile coupling (XEC), wherein two electrophiles are reductively coupled via a transition metal catalyst, is an important synthetic strategy that engages broad substrate pools and tolerates a wide range of sensitive functional groups. However, little is known about how selectivity, either enantioselectivity or cross-selectivity, is engendered. Herein, I investigate the origins of enantioselectivity and cross-selectivity in two Ni/photoredox-catalyzed XECs of epoxides with aryl iodides by modeling experimental output (enantioselectivity and cross- coupled yield) using molecular descriptors derived from density functional theory (DFT) calculations. Using dimensionality reduction techniques and a repeated, stratified nested cross- validation linear regression scheme, I report that enantioselectivity is highly correlated with ligand electronic features, with electron-donating ligands facilitating greater stereoinduction. Further mechanistic investigations revealed that electron-donating ligands promote enantioselectivity by engendering later, more product-like transition states via enthalpic factors. This strategy of electronic tuning can be leveraged in future asymmetric XECs. In the second Ni/photoredox-catalyzed XEC, wherein different epoxide substrates were optimized with different ligands, I report the first instance of developing a unified descriptor set for a ligand collection featuring diversity in structure, symmetry, and denticity. Modeling these descriptors against experimental cross-coupled yields revealed subtle structure–activity relationships that may be employed to engender cross-selectivity in future studies. Overall, this work demonstrates the integration of computational and data science techniques with experimental efforts to elucidate nonintuitive mechanistic underpinnings and to develop a robust machine learning workflow for future modeling efforts within XECs and transition metal catalysis.