Data-Driven Strategies for the Development of Stereoconvergent Nickel-Catalyzed Cross-Couplings

Author: Chen, Emily Peijia

Year: 2026

Degree: Dissertation (Ph.D.)

Advisor: Reisman, Sarah E.

Committee Members: Nelson, Hosea M.; Hadt, Ryan G.; Fu, Gregory C.; Reisman, Sarah E.

Option: Chemistry

DOI: 10.7907/wj2k-d962

Abstract

Stereoconvergent cross-coupling reactions have emerged in recent decades as powerful methods for the construction of carbon–carbon bonds. Nickel catalysis in particular has been particularly enabling for the formation of C(sp²)–C(sp²) bonds. Stereoconvergent reductive and redox-neutral Ni-catalyzed cross-coupling reactions have been useful for the synthesis of pharmaceutically-relevant stereodefined small molecules.

Herein we describe our recent efforts in the development of new nickel-catalyzed stereoconvergent cross-coupling reactions. First, the redox-neutral nickel/photoredox dual catalytic coupling of N-heterocyclic trifluoroborates and aryl bromides is described. In collaboration with researchers at Merck, the enantioselective synthesis of N-benzylic heterocycles provides rapid access to pharmaceutically relevant motifs. We next discuss the development of a diastereoselective reductive cross coupling of meso-1,3-cyclobutyl NHP esters with aryl iodides. When chiral bis(oxazoline) ligands are employed, this reaction biases the formation of the cis isomer, prompting the exploration of the scope of the transformation using data science tools. The desire to further increase the yield and diastereoselectivity of this transformation motivated the application of a Bayesian optimizer to efficiently explore the reaction condition space. This optimization campaign led to the identification of new reductive conditions. Finally, the asymmetric coupling of 2-piperidine NHP esters and aryl iodides is described.

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