Chiral Bisoxazoline Ligands Enable Nickel-Catalyzed Enantioselective C(sp³)–O Bond Construction via Dynamic Kinetic Control
Created on 01.09
I. Research Background and Significance
Chiral ethers are key structural motifs in bioactive molecules, but enantioselective C(sp³)–O bond formation from racemic alkyl electrophiles remains a persistent challenge. Conventional methods rely on enantiopure substrates, facing limitations in substrate accessibility, harsh reaction conditions, and structural diversity. Existing metal-catalyzed enantioconvergent C–O coupling strategies are largely restricted to π-activated electrophiles.
The team of Prof. Yuli He and Hequan Yao at China Pharmaceutical University developed a nickel-catalyzed enantioconvergent reaction using chiral bisoxazoline ligands, achieving dynamic kinetic resolution (DKR) via halide-driven substrate racemization. This method enables the coupling of racemic secondary alkyl halides with hydroxamic acids under mild, air- and moisture-tolerant conditions, providing efficient access to enantiomerically enriched O-alkylhydroxamates.
II. Reaction Design and Breakthrough
Published in: Journal of the American Chemical Society (JACS)
Authors: Jinze Du, Xiaoying Fu, Siming Xie, Yue Wang, Hequan Yao, Yuli He
Key Innovations:
- Dynamic Kinetic Control: Halide-induced in situ racemization enables complete substrate conversion without external racemization catalysts.
- Mild Conditions: Reactions proceed efficiently under ambient atmosphere, eliminating the need for strict anhydrous/anaerobic operations.
- High Stereoselectivity: Enantiomeric excess (ee) consistently exceeds 93%, surpassing conventional approaches.
Standard Reaction Conditions:
- Catalyst: Ni(OTf)₂ (5–10 mol%)
- Ligand: Chiral bisoxazoline (6–12 mol%)
- Substrates: Racemic secondary alkyl bromide (1.0 equiv) + hydroxamic acid (1.2–3.0 equiv)
- Base: K₃PO₄ (2.0 equiv)
- Solvent: DMSO/THF mixture, room temperature
- Yields and ee values determined by ¹H NMR and chiral HPLC, respectively
III. Advantages of Chiral Bisoxazoline Ligands
- Precise Stereocontrol The rigid chiral pocket formed by Ni–bisoxazoline complexes governs the stereochemistry of S_N2 transition states, achieving >93% ee consistently.
- Broad Substrate Scope Hydroxamic Acids: Aromatic, aliphatic, and heterocyclic variants are well-tolerated. Alkyl Halides: Compatible with esters, thioethers, halogenated arenes, trifluoromethyl groups, and sterically hindered propargyl/cycloalkyl substrates.
- Excellent Stability and Practicality The catalytic system operates efficiently under ambient conditions, enhancing reproducibility and operational simplicity.
- Synergistic Dynamic Kinetic Resolution Ligand design synergizes with halide-driven racemization, enabling complete substrate conversion without additional reagents.
IV. Applications in Drug Synthesis
The methodology was applied to concise syntheses of pharmacologically relevant molecules:
- Rho Pathway Inhibitor (S)-CCG-1423: Synthesized in only 3 steps from commercial materials.
- γ-Secretase Inhibitor LY411575: Efficient access to its chiral ether intermediate with high enantioselectivity.
V. Technical Support and Ligand Availability
To support further research, Anhui Kaitai Laibo offers a series of chiral bisoxazoline ligands and custom synthesis services.
VI. Publication Details
Journal: Journal of the American Chemical Society
DOI: 10.1021/jacs.5c18000
Highlight: First nickel-catalyzed enantioconvergent C(sp³)–O coupling via dynamic kinetic control, providing a robust platform for chiral ether synthesis.