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Enantioselective radical α-enolation of esters via electrochemical chiral isothiourea catalysis

Nature Catalysis volume 8, pages 957–967 (2025)Cite this article

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Abstract

Carboxylic ester motifs are prevalent in biological, chemical and materials sciences, and the asymmetric α-functionalization of simple esters plays a crucial role in the field of organic synthesis. Here we present a versatile electricity-driven asymmetric Lewis base catalysis strategy for the oxidative radical cross-coupling of simple esters with silyl enol ethers. This approach integrates the electrochemical anodic oxidation process with chiral isothiourea catalysis, enabling a polarity inversion at the nucleophilic carbon of the enolate to trigger the formation of a chiral isothiourea-bound α-carbonyl radical species from a C1-ammonium enolate. The combination of asymmetric Lewis base catalysis and electrochemistry unlocks mild oxidative radical coupling reactions, achieving up to 98% enantiomeric excess and demonstrating broad substrate compatibility. This work underscores the synthetic potential of the approach and provides a platform for advancing asymmetric electrosynthesis.

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Fig. 1: Enhancing the asymmetric radical modes of Lewis base catalysis with electricity.
Fig. 2: Optimization of the reaction conditions.
Fig. 3: Mechanistic investigations.
Fig. 4: Substrate scope for silyl enol ethers.
Fig. 5: Substrate scope of acetic acid pentafluorophenyl esters.
Fig. 6: Gram-scale synthesis and post-functionalizations.
Fig. 7: DFT calculations and proposed mechanism.

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Data availability

Crystallographic data for the structure reported in this Article have been deposited at the Cambridge Crystallographic Data Centre (CCDC) under deposition number CCDC 2378242 (3ad). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. The atomic coordinates from DFT calculations are provided in the Supplementary Data. All other data supporting the findings of this study, including experimental procedures, compound characterization, NMR and HPLC, are available within the Article and its Supplementary Information or from the authors.

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Acknowledgements

We acknowledge financial support from the National Natural Science Foundation of China (22071229 and 22471002) and the Anhui Provincial Natural Science Foundation (2308085Y12).

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  1. Institutes of Physical Science and Information Technology, Anhui University, Hefei, China

    Ning Li, Xuzhen Ye, Yong Liu & Jin Song

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  1. Ning Li
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Contributions

J.S. conceived the project. N.L. performed the experiments and analysed the data. X.Y. and Y.L. synthesized some of the substrates and catalysts. All authors discussed the results and prepared the paper.

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Correspondence to Jin Song.

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Supplementary Information

Supplementary Figs. 1–15 and Tables 1–8.

Supplementary Data 1

The atomic coordinates of the optimized computational models studied in this paper.

Supplementary Data 2

CIF of compound 3ad.

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Li, N., Ye, X., Liu, Y. et al. Enantioselective radical α-enolation of esters via electrochemical chiral isothiourea catalysis. Nat Catal 8, 957–967 (2025). https://doi.org/10.1038/s41929-025-01408-4

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