Asymmetric Nickel-Catalyzed Cross-Coupling of Acetals and Epoxides

Abstract

Transition metal-catalyzed C–C bond formation is among the most impactful synthetic transformations for chemists across disciplines. Recently, leveraging radicals as reactive intermediates for Ni catalysis has drastically broadened the range of chemical structures accessible and enables the coupling of many distinct coupling partners. In particular, the ability to harness prochiral radicals or engage in stereoablative Csp3–X bond activation has enabled a range of novel asymmetric reactions of acetals and epoxides to deliver highly enantioenriched ether- and alcohol-containing products. This dissertation describes the development of three novel methodologies leveraging distinct activation strategies for acetals and epoxides.

The modular reductive coupling of acetals is described, demonstrating the complementarity of acetals as reactive partners to their more traditional aldehyde counterparts. The coupling of acetals with symmetric anhydrides and vinyl electrophiles delivers the corresponding ether product to classical reactions of aldehydes such as the benzoin condensation and the Nozaki–Hiyama–Kishi reaction. These reactions proceed under a single set of conditions via the proposed intermediacy of an α-oxy radical.

Previous efforts in asymmetric catalysis with acetals using an ion-pairing strategy have been limited in scope due to restrictions in compatible nucleophiles. A stereoselective arylation based on the reductive generation of α-oxy radicals from acetals is described. Using this new reactive intermediate, the scope of C–C bonds able to be formed selectively from acetals is greatly expanded due to the modularity of cross- coupling. Computational efforts have been applied to help explain the impact of substrate structure on selectivity and the mechanism of stereoinduction.

A stereoselective arylation of epoxides is described, enabled by a bis-imidazole ligated nickel catalyst. This chemistry is a photo-assisted reductive coupling transformation that uses a photocatalyst and stoichiometric amine as a terminal reductant in place of typical heterogeneous metal reductants for cross-electrophile reactions. Multivariate linear regression studies were performed in order to understand the underlying ligand features that engender selectivity across both bis-oxazoline and bis- imidazole ligands, as well as the reactions of both epoxides and aziridines.