China Pharmaceutical University Team Led by Yao Hequan and Lin Aijun Reports Angewandte Chemie Study on Novel Application of Chiral Phosphoric Acids as Ligands
Created on 2025.12.03
Introduction
Chiral bridged bicyclic skeletons are widely found in natural products and bioactive molecules, but their efficient asymmetric synthesis remains challenging. Existing desymmetrization cyclization methods for alkenes predominantly rely on two-electron transfer processes. Catalytic enantioselective radical desymmetrization cyclization of unactivated internal alkenes had not been achieved due to difficulties in stereocontrol and the instability of alkyl radical intermediates. Recently, a team led by Professors Yao Hequan and Lin Aijun at China Pharmaceutical University developed a copper-catalyzed enantioselective radical desymmetrization cyclization of cyclopentenes using chiral phosphoric acids (CPAs) as ligands. Through peroxo-amination and alkylamination strategies, they accomplished the first catalytic asymmetric peroxidation of unactivated internal alkenes, efficiently synthesizing chiral 6-peroxy-2-azabicyclo[2.2.1]heptan-3-ones and 6-alkyl-2-azabicyclo[2.2.1]heptan-3-ones containing one quaternary and two adjacent tertiary carbon stereocenters with high yields and excellent stereoselectivity.
Condition Optimization
Mechanistic studies and density functional theory (DFT) calculations revealed that the formation of substrate-Cu(II) complexes and the addition of nucleophilic radicals to coordinated alkenes are key steps governing stereoselectivity.
Reaction conditions: 1 (0.1 mmol), 2a (0.3 mmol), [Cu] (10 mol%), chiral ligand (12 mol%) in solvent (0.1 M) at 30°C under argon atmosphere, 30 h. Isolated yields are given. Enantiomeric excess (ee) and diastereomeric ratio (dr) were determined by chiral HPLC analysis.
Substrate Scope
The methodology demonstrated broad substrate compatibility, including aryl (with methyl, methoxy, halogen, etc. substituents), alkyl (benzyl, isopropyl, cyclopropyl, etc.), and heterocyclic (thiophene, furan, etc.) substituted cyclopentenes, as well as various alkyl radical precursors. All substrates were transformed with high yields (75%–98%) and excellent stereoselectivity.
Advantages of Chiral Phosphoric Acid Ligands
- Core Stereocontrol for High Selectivity: The synergistic effect between CPA and the copper catalyst precisely controls the spatial configuration of the radical addition transition state, avoiding unfavorable steric repulsions. This enables exceptional stereoselectivity (up to 95% ee and >20:1 dr). DFT-calculated enantiomer ratio (98.5:1.5) closely matches experimental results (97.5:2.5), validating the crucial role of CPAs in stereocontrol.
- Dual Functional Attributes: In the absence of CPA, the reaction proceeds with only 40% yield, affording racemic product. The addition of CPA not only increases the yield to 92% but also enables efficient chiral induction, overcoming the key challenges of stereocontrol and radical intermediate instability in the radical cyclization of unactivated internal alkenes.
- Structural Tunability for Broad Applicability: BINOL-derived CPAs with different substituents are adaptable to a wide range of substrates.
- Stereodivergent Synthesis for Comprehensive Isomer Access: By employing CPAs of different configurations, all four stereoisomers of 6-hydroxy-2-azabicyclo[2.2.1]heptan-3-one can be prepared stereodivergently from the 6-peroxy product, significantly enhancing the synthetic utility of this methodology.
Available CPA Ligands
Anhui Catlab Technology Co., Ltd. offers a chiral phosphoric acid and phosphoramide reagent kit comprising 7 advantageous catalyst structures and supports custom synthesis services.
Reference
- Authors: Jing Zhong+, Mengxian Li+, Jiao Ma, Zimo Zhang, Hao Fang, Shang Gao, Aijun Lin,* and Hequan Yao*
- Title: Copper-Catalyzed Enantioselective Radical Desymmetrizing Cyclization of Cyclopentenes: Access to Chiral 2-Azabicyclo[2.2.1]Heptan-3-ones
- DOI: 10.1002/anie.202521476