Among the most ubiquitous scaffolds in medicinal chemistry, biological chemistry, and glycobiology are ?-substituted amines and ethers. The goal of the proposed research program is to define a general and modular catalytic strategy that enables the enantioselective synthesis of these structural motifs, including those imbedded within heterocyclic frameworks, in much the same way that cross coupling serves as an all-purpose and powerful protocol for the assembly of Csp2-Csp2 bonds. To achieve this goal, we will exploit the ability of low-valent transition metal catalysts to undergo oxidative addition to iminium and oxocarbenium ions and show that this underutilized activation mode offers a versatile entry to alkyl cross-coupling reactions. In this contribution, we will pursue catalyst design and development for enantioselective arylation, heteroarylation, and alkylation of readily available and stable N,O-acetals and acetals using organoboronate and organozinc reagents (Specific Aim 1). The substituted dihydroquinolines, piperidines, chromenes, and pyrans that we will obtain from these studies constitute the core structural elements of small molecules that exhibit an array of pharmacological activities.
In Specific Aim 2, we will develop a new class of stable Ni precatalyst that is easily activated to Ni(0) and enables more efficient and convenient Suzuki-Miyaura cross-coupling reactions. Reaction development will also demonstrate that the iminium/oxocarbenium ion activation mode facilitates unprecedented bond constructions with simple feedstock chemicals such as electron-deficient olefins and carbon dioxide for the synthesis of allylic ethers, allylic amines, and ?-amino acids (Specific Aim 3).

Public Health Relevance

The goal of the proposed research is to establish a new cross-coupling methodology for the synthesis of single enantiomer ?-substituted amines and ethers. In so doing, the research will directly impact the biomedical mission of the NIH by providing efficient and selective access to some of the most ubiquitous chemical scaffolds in human medicines and biologically active small molecules.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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Princeton University
Schools of Arts and Sciences
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Heinz, Christoph; Lutz, J Patrick; Simmons, Eric M et al. (2018) Ni-Catalyzed Carbon-Carbon Bond-Forming Reductive Amination. J Am Chem Soc 140:2292-2300
Wu, Kevin; Doyle, Abigail G (2017) Parameterization of phosphine ligands demonstrates enhancement of nickel catalysis via remote steric effects. Nat Chem 9:779-784
Stache, Erin E; Rovis, Tomislav; Doyle, Abigail G (2017) Dual Nickel- and Photoredox-Catalyzed Enantioselective Desymmetrization of Cyclic meso-Anhydrides. Angew Chem Int Ed Engl 56:3679-3683
Nielsen, Matthew K; Shields, Benjamin J; Liu, Junyi et al. (2017) Mild, Redox-Neutral Formylation of Aryl Chlorides through the Photocatalytic Generation of Chlorine Radicals. Angew Chem Int Ed Engl 56:7191-7194
Shields, Benjamin J; Doyle, Abigail G (2016) Direct C(sp3)-H Cross Coupling Enabled by Catalytic Generation of Chlorine Radicals. J Am Chem Soc 138:12719-12722
Lutz, J Patrick; Chau, Stephen T; Doyle, Abigail G (2016) Nickel-catalyzed enantioselective arylation of pyridine. Chem Sci 7:4105-4109
Ahneman, Derek T; Doyle, Abigail G (2016) C-H functionalization of amines with aryl halides by nickel-photoredox catalysis. Chem Sci 7:7002-7006
Joe, Candice L; Doyle, Abigail G (2016) Direct Acylation of C(sp(3))-H Bonds Enabled by Nickel and Photoredox Catalysis. Angew Chem Int Ed Engl 55:4040-3
Shields, Jason D; Gray, Erin E; Doyle, Abigail G (2015) A modular, air-stable nickel precatalyst. Org Lett 17:2166-9
Arendt, Kevin M; Doyle, Abigail G (2015) Dialkyl Ether Formation by Nickel-Catalyzed Cross-Coupling of Acetals and Aryl Iodides. Angew Chem Int Ed Engl 54:9876-80

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