Development of Ni-Catalyzed Asymmetric Reductive Cross-Coupling Reactions

Citation

Kadunce, Nathaniel Thomas (2016) Development of Ni-Catalyzed Asymmetric Reductive Cross-Coupling Reactions. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9JS9NDR. https://resolver.caltech.edu/CaltechTHESIS:06032016-162550993

Abstract

Over the last half century, the development of metal-catalyzed cross-coupling reactions has transformed the toolkit of transformations available to synthetic chemists. From the very beginning of this effort, researchers have studied the application of these reactions to afford enantioenriched products via asymmetric catalysis. A great deal of success has been achieved in this arena, giving rise to an ever-growing number of chiral catalysts for a wide range of transformations. Despite these efforts, inherent difficulties in the reactivity of C(sp³) electrophiles with the most common noble metal catalysts have limited the development of these substrates until more recently. A resurgence of interest in Ni-catalysis has enabled the stereoconvergent cross-coupling of C(sp³) electrophiles with many partners, opening doors to access these challenging chiral products.

Reductive cross-coupling, involving the union of two different electrophiles, has emerged still more recently, and had previously not been employed asymmetrically. Herein we describe our efforts to develop the first Ni-catalyzed asymmetric reductive cross-couplings of C(sp³) halides to afford highly enantioenriched products. In the first such reaction, the coupling of acyl chlorides with benzylic chlorides affords acyclic α-tertiary ketone products. Following this, we describe the coupling of new C(sp³) partners, α-chloronitriles, with challenging Lewis-basic heteroaryl iodides, enabled by the development of a novel PHOX ligand scaffold. Finally, we report the extension of a more general dioxane/TMSCl solvent condition to new asymmetric reductive couplings, including that of heteroaryl iodides with benzylic chlorides, as well as additional preliminary results with new substrate classes.

Thesis Files