Development of Nickel-Catalyzed Asymmetric Reductive Cross-Coupling Reactions

Author: Poremba, Kelsey Elizabeth

Year: 2019

Degree: Dissertation (Ph.D.)

Advisor: Reisman, Sarah E.

Committee Members: Stoltz, Brian M.; Reisman, Sarah E.; Fu, Gregory C.; Peters, Jonas C.

Option: Chemistry

DOI: 10.7907/ZW64-GJ97

Abstract

Asymmetric reductive cross-electrophile coupling is a powerful method to forge C–C bonds and access enantioenriched small molecules, which can be further functionalized to access scaffolds present in natural products and bioactive pharmaceutical agents. However, an innate challenge of this methodology is identifying a chiral catalyst that achieves optimal cross-selectivity and stereocontrol. Herein, we report studies on the asymmetric cross-coupling of C(sp3) electrophiles, such as benzyl chlorides, α-chloroesters, and N-hydroxyphthalimide esters, with several classes of C(sp2) electrophiles.

We describe the asymmetric Ni-catalyzed reductive cross-coupling of (hetero)aryl iodides and benzyl chlorides to prepare enantioenriched 1,1-diarylalkanes. As part of these studies, a new chiral bi(oxazoline) ligand, 4-HeptylBiOX, was developed to obtain products in synthetically useful yield and enantioselectivity. This novel ligand is demonstrated to expand the substrate scope of these stereoconvergent reductive cross- couplings to include the asymmetric cross-coupling of α-chloroesters with aryl iodides, and sterically hindered N-hydroxyphthalimide esters with alkenyl bromides. Model studies have been initiated to study the application of these reactions toward the total synthesis of cylindrocyclophane natural products.

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