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Development of Nickel-Catalyzed Asymmetric Cross-Coupling Reactions


DeLano, Travis Jon (2022) Development of Nickel-Catalyzed Asymmetric Cross-Coupling Reactions. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/pzfp-ad90.


Asymmetric cross-coupling reactions have emerged in recent decades as powerful tools for the formation of valuable carbon–carbon bonds in the synthesis of enantioenriched small molecules. Nickel catalysis in particular has proven to be an especially powerful tool for the formation of C(sp²)–C(sp³) bonds in part due to the propensity of nickel catalysts to access odd oxidation states and interact with radical intermediates. Application of asymmetric nickel catalysis to a variety of radical precursors has resulted in the development of a broad range of stereoconvergent reductive and redox-neutral cross coupling reactions, allowing for the highly enantioselective formation of many synthetically useful and biologically relevant molecules.

Herein we describe our recent efforts in the development of new nickel-catalyzed enantioselective cross-coupling reactions. First, an enantioselective reductive cross- coupling of alkenyl and benzyl halides was rendered electroreductive. Careful electrochemical cell design proved critical for this reaction, which represents the first report of an enantioselective nickel-catalyzed electroreductive cross coupling reaction. We next discuss our development of an enantioselective reductive cross coupling of ⍺-chloroesters with aryl iodides. This reaction proceeds with especially high ee when β-branched substrates are employed, prompting the development of a multivariate linear regression model to probe the origin of the observed enantioselectivity trends. Finally, a redox-neutral nickel/photoredox co-catalyzed coupling of ⍺-N-heterocyclic potassium alkyl trifluoroborates and aryl bromides is reported. This reaction, developed in collaboration with researchers at Merck, provides rapid enantioselective access to motifs commonly found in bioactive molecules.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:nickel; catalysis; asymmetric catalysis; electrochemistry; photoredox; reductive cross-coupling
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Reisman, Sarah E.
Thesis Committee:
  • Robb, Maxwell J. (chair)
  • See, Kimberly
  • Stoltz, Brian M.
  • Reisman, Sarah E.
Defense Date:18 April 2022
Funding AgencyGrant Number
NSF Graduate Research FellowshipDGE-1144469
NSF Center for Synthetic Organic ElectrochemistryCHE-2002158
Record Number:CaltechTHESIS:04272022-163740814
Persistent URL:
Related URLs:
URLURL TypeDescription adapted for Chapter 1 adapted for Chapter 2
DeLano, Travis Jon0000-0002-2052-611X
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:14563
Deposited By: Travis DeLano
Deposited On:17 May 2022 17:52
Last Modified:15 Jun 2022 19:42

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