Development of Strategies for Nickel-Catalyzed Asymmetric Reductive Cross-Couplings

Author: Hernández-Mejías, Ángel D.

Year: 2026

Degree: Dissertation (Ph.D.)

Advisor: Reisman, Sarah E.

Committee Members: Nelson, Hosea M.; Stoltz, Brian M.; Clemons, William M.; Reisman, Sarah E.

Option: Chemistry

Abstract

Ni-catalyzed asymmetric reductive cross-coupling reactions provide rapid and modular access to enantioenriched building blocks from simple electrophile precursors. Reductive coupling reactions that can diverge via a common organometallic intermediate into two distinct families of enantioenriched products are particularly versatile yet underdeveloped. Here, we describe the development of a bis(oxazoline) ligand that enables the desymmetrization of meso-anhydrides. When secondary benzylic electrophiles are employed, doubly stereoselective acyl cross-coupling proceeds to give ketone products with catalyst control over three newly formed stereogenic centers. Alternatively, the use of primary alkyl halides in the presence of an additional halogen atom transfer catalyst results in decarbonylative alkylation to give enantioenriched β-alkyl acids. Analysis of reaction rates for a range of both catalysts and substrates supports the notion that tuning the different electrophile activation steps with the two catalysts is required for enhanced reaction performance. These studies illustrate how reaction design can diverge a common Ni-acyl intermediate to either acyl or decarbonylative coupling products and highlight how dual ligand systems can be used to engage unactivated alkyl halides in Ni-catalyzed asymmetric reductive coupling.