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Leveraging electron donor–acceptor complexes for kinetic resolution in catalytic asymmetric photochemical synthesis

Nature Chemistry volume 17, pages 1722–1731 (2025)Cite this article

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Abstract

The formation of electron donor–acceptor (EDA) complexes has emerged as a powerful strategy for accessing valuable molecules. However, protocols for constructing enantio-enriched molecules are limited, typically relying on EDA complex formation between a substrate and an intermediate generated from a chiral catalyst along with another substrate. This approach facilitates the coupling of the resulting radical species, thereby enabling the controlled enantioselective formation of stereocentres. Here we introduce a kinetic resolution strategy that harnesses the formation of EDA complexes between a chiral catalyst and racemic feedstock. The key lies in the thermodynamic disparity of the chiral catalyst’s interaction with the two enantiomers of the substrate, which is critical for enabling subsequent transformations under a kinetic control. We demonstrate that photochemical reactions involving racemic azaarene-functionalized tertiary alcohols and amines, together with a chiral phosphoric acid, yield enantio-enriched derivatives containing tertiary carbon stereocentres. The utility of this approach is further exemplified by synthesizing important azaarene variants featuring tertiary or secondary C–F bonds, as well as ethylene oxides.

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Fig. 1: The development of a strategic blueprint for KR through enantio-differential formation of EDA complexes.
Fig. 2: Reaction design and optimization.
Fig. 3: Substrate scope with respect to tertiary and secondary alcohols.
Fig. 4: Substrate scope encompassed azaarene-diarene-substituted alcohols as well as a variety of tertiary and secondary amines, fluorides and ethylene oxides.
Fig. 5: Synthetic utilities.
Fig. 6: Mechanistic study.

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Data availability

The authors declare that all data supporting the findings of this study are available in the paper and its Supplementary Information. Crystallographic data for the structure of 1l have been deposited at the Cambridge Crystallographic Data Centre, under deposition no. CCDC 2416697. A copy of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures.

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Acknowledgements

This work was financially supported by the National Science Foundation of China (nos. 21925103, 22301066, 22171072, 22201068 and 22301061) and Henan Normal University.

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Authors and Affiliations

  1. Pingyuan Laboratory, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, P. R. China

    Tianju Shao, Zongxun Li, Feiyun Nie, Qiang Li & Zhiyong Jiang

  2. College of Pharmacy, Henan University, Kaifeng, P. R. China

    Xiaowei Zhao & Zhiyong Jiang

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  1. Tianju Shao
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Contributions

Z.J. conceived of and designed the experiments. T.S., Z.L., F.N. and Q.L. performed the experiments. T.S., Z.L., F.N. and X.Z. analysed and interpreted the results. T.S. prepared the Supplementary Information. Z.J. wrote the paper. All authors discussed the results and commented on the paper.

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Correspondence to Zhiyong Jiang.

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Nature Chemistry thanks Jia-Rong Chen, Charnsak Thongsornkleeb and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

(1) General information; (2) general experimental procedures; (3) selected results of screening reaction conditions; (4) control experiments; (5) mechanism studies; (6) Stern–Volmer quenching studies; (7) deuterium experiments and plausible mechanism; (8) determination of absolute configurations; (9) characterization of adducts; (10) spectral data; (11) references.

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Shao, T., Li, Z., Nie, F. et al. Leveraging electron donor–acceptor complexes for kinetic resolution in catalytic asymmetric photochemical synthesis. Nat. Chem. 17, 1722–1731 (2025). https://doi.org/10.1038/s41557-025-01973-y

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