New Applications of Chiral Bisoxazoline Ligands in Nickel-Catalyzed Asymmetric Reactions – Research by University of Cincinnati Liu Wei / Purdue University Tian Shiliang Team in Nat. Catal.
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Abstract
Nickel-catalyzed enantioconvergent cross-coupling is a crucial strategy for constructing stereodefined C(sp³) centers. However, such reactions have long relied on Ni⁰/Niᴵᴵ catalytic cycles, are only compatible with electron-rich nucleophiles, and are largely limited to activated alkyl electrophiles. The asymmetric coupling of electron-deficient fluoroalkyl nucleophiles with unactivated alkyl halides thus remains a significant challenge awaiting breakthroughs. Concurrently, while high-valent organonickel(IV) complexes have been demonstrated to possess catalytic reactivity distinct from Ni(III) species, their application in asymmetric bond-forming reactions remains underexplored. Furthermore, organic molecules containing chiral difluoromethyl (CF₂H) centers, which combine lipophilicity with hydrogen-bond-donor capabilities, serve as important bioisosteres for groups like hydroxyl and amino moieties, holding significant application value in the pharmaceutical field. Yet, the development of methods for their highly enantioselective synthesis has been slow due to limitations in catalytic systems. Recently, the collaborative team of Prof. Wei Liu (University of Cincinnati) and Prof. Shiliang Tian (Purdue University) developed a novel Ni(II)/Ni(IV) catalytic cycle based on an aryl radical-mediated oxidative addition mechanism. Employing a chiral bisoxazoline ligand, they achieved the highly enantioselective difluoromethylation of unactivated alkyl iodides. The study confirmed the key intermediates of the Ni(II)/Ni(III)/Ni(IV) cycle through X-ray crystallography, electron paramagnetic resonance spectroscopy, nuclear magnetic resonance spectroscopy, and density functional theory calculations. The catalytic system exhibits a broad substrate scope. DFT calculations clarified that the enantioselectivity-determining step is the reductive elimination from the Ni(IV) intermediate, with the steric effects between the ligand and substrate being the core reason for achieving high enantioselectivity.
Condition Screening
Substrate Scope
Mechanistic Experiments
Highlights of the Chiral Bisoxazoline Ligand Used in This Reaction:
- High Enantioselectivity Control The chiral bisoxazoline ligand is the core to achieving high enantioselectivity in this reaction. The chiral catalytic center formed upon its coordination with Ni(II) can precisely differentiate the stereochemistry of the substrates through steric effects during the critical reductive elimination step of the Ni(IV) intermediate, maintaining the enantiomeric excess (ee) values of the difluoromethylated products predominantly above 90%.
- Stabilization of High-Valent Nickel Intermediates This ligand can effectively coordinate with nickel in various oxidation states, including Ni(II), Ni(III), and Ni(IV). It is particularly capable of stabilizing the highly reactive Ni(III) and Ni(IV) key intermediates in the reaction, preventing their non-selective decomposition. This ensures the efficient operation of the Ni(II)/Ni(IV) catalytic cycle and provides a stable coordination environment for the aryl radical-mediated oxidative addition and alkyl radical capture steps.
- Compatibility with Unactivated Alkyl Substrates The catalytic system formed by the chiral bisoxazoline ligand and nickel overcomes the traditional nickel catalysis's reliance on activated alkyl electrophiles. It can efficiently accommodate various unactivated alkyl iodides while tolerating weakly coordinating groups (e.g., amides, phosphonates) and sensitive functional groups (e.g., alkenes, alkynes, aryl halides) within the substrates, showing no significant functional group tolerance issues, thereby substantially expanding the reaction's substrate scope.
- Facilitating Stereospecific Synthetic Applications This catalytic system has been successfully applied to the chiral difluoromethylation modification of bioactive molecules. Examples include the synthesis of CF₂H derivatives of the antiviral molecule fosamprenavir, the pesticide valeryl chloride, and capsaicin analogues, all maintaining high enantioselectivity and tolerating sensitive structures like epoxides and phosphonates within the substrates. This provides a practical methodological support for synthesizing chiral fluorinated pharmaceuticals and agrochemicals.
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Publication Details
Authors: Xian Zhao,# Lingfeng Yin,# Chia-Jung Yang, Andrew T. Poore, Xinyu Zhang, Stephen C. Yachuw, Chao Wang, Xiao Wang, Hairong Guan, Jeanette A. Krause, Mu-Jeng Cheng, Shiliang Tian* & Wei Liu*
Title: Enantioselective difluoromethylation of unactivated alkyl halides via a formal nickel(II/IV) cycle
DOI: 10.1038/s41929-026-01505-y