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Stepwise-controllable catalytic asymmetric Atherton–Todd reaction to access diverse P(V)-stereogenic compounds

Nature Chemistry volume 18, pages 23–32 (2026) Cite this article

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Abstract

The Atherton–Todd (A–T) reaction has long been regarded as a cornerstone method for synthesizing a wide array of phosphorus(V) compounds. However, despite its vast synthetic potential, achieving precise stereocontrol in this transformation remains a challenge. Here we present the highly efficient and direct asymmetric A–T reaction, using biomimetic peptide–phosphonium salt catalysts to enable the stepwise and precise synthesis of a diverse array of phosphorus(V)-based scaffolds. We demonstrate the efficient generation of three distinct stereogenic phosphorus(V) species—phosphoryl chlorides, phosphinates and phosphonates—while maintaining exceptional functional group compatibility and delivering outstanding enantioselectivity. Our mechanistic studies, complemented by density functional theory calculations, uncover the ability of the peptide–phosphonium salt catalysts to modulate the chiral environment, selectively recognizing and pre-assembling phosphorus substrates and/or nucleophilic species. This finely tuned chiral cavity facilitates a stepwise-controllable, enantioselective A–T reaction, providing an elegant strategy for the synthesis of stereochemically defined phosphorus ligands, bioactive molecules and oligonucleotides.

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Fig. 1: Methods for accessing stereogenic-at P(V) platform molecules and A–T reaction.
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Fig. 2: Diverse derivatization of P(Ⅴ) platform molecules.
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Fig. 3: Mechanistic studies.
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Fig. 4: DFT investigations.
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Data availability

The data supporting the findings of this study are available within the paper and Supplementary Information (experimental procedures and characterization data). Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2159172 (A1), 2179499 (D16), 2219305 (E13) and 2338033 (H10). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures.

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Acknowledgements

We dedicate this paper to Q.-H. Fan on the occasion of his 60th birthday. We sincerely thank Q.-H. Fan (Institute of Chemistry, Chinese Academy of Sciences) for his valuable discussions and suggestions, and X. Feng (Sichuan University) for his tremendous support of this study. Financial support was provided by the National Natural Science Foundation of China (grant nos. 22222109, 21921002, 22371190, T.W.; 22122109, 22271253, W2512004 X.H.) National Key R&D Program of China (2018YFA0903500, T.W.; 2022YFA1504301, X.H.) Beijing National Laboratory for Molecular Sciences (grant no. BNLMS202101, T.W.) Sichuan Science Foundation for Distinguished Young Scholars (grant nos. 2023NSFSC1921, T.W.) Sichuan Provincial Natural Science Foundation (grant nos. 2022NSFSC1181, 24NSFSC6590, T.W.) Fundamental Research Funds for the Central Universities (grant nos. 2020SCUNL108, T.W.; 226-2022-00140, 226-2022-00224, 226-2023-00115 and 226-2024-00003, X.H), the Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study (grant no. SN-ZJU-SIAS-006, X.H.) CAS Youth Interdisciplinary Team (grant no. JCTD-2021-11, X.H.) the State Key Laboratory of Clean Energy Utilization (grant no. ZJUCEU2020007, X.H.) the State Key Laboratory of Physical Chemistry of Solid Surfaces (grant no. 202210, X.H.) the Leading Innovation Team grant from Department of Science and Technology of Zhejiang Province (grant no. 2022R01005, X.H.) Open Research Fund of School of Chemistry and Chemical Engineering of Henan Normal University (grant no. 2024Z01, X.H.) the Science and Technology Innovation Program of Hunan Province (grant no. 2022RC1112, J.-P.T.) the Hunan Provincial Natural Science Foundation (grant no. 2024JJ5107, J.-P.T.) We also acknowledge the College of Chemistry and the Analytical & Testing Center of Sichuan University, and we thank J. Li and D. Deng from the College of Chemistry Sichuan University for HRMS and NMR testing, respectively. Calculations were performed on the high-performance computing system at Department of Chemistry, Zhejiang University.

Author information

Author notes

  1. These authors contributed equally: Fan Wang, Jian-Ping Tan, Ganlu Qian.

Authors and Affiliations

  1. Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, P. R. China

    Fan Wang, Jian-Ping Tan, Siqiang Fang, Zanjiao Liu, Kehan Li, Jiayan Zheng, Jia-Hong Wu & Tianli Wang

  2. Key Laboratory of Environmental Catalysis and Waste Recycling, College of Materials and Chemical Engineering, Hunan Institute of Engineering, Hunan, P. R. China

    Jian-Ping Tan

  3. Center of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, P. R. China

    Ganlu Qian & Xin Hong

  4. School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, P. R. China

    Xin Hong

  5. Beijing National Laboratory for Molecular Sciences, Beijing, P. R. China

    Tianli Wang

  6. State Key Laboratory of Green Pesticide, Guizhou University, Guiyang, P. R. China

    Tianli Wang

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Contributions

T.W. conceived and supervised the project. F.W., J.-P.T., Z.L., J.Z., K.L. and J.-H.W. performed the experiments and analysed the data. F.W. and J.-P.T. carried out the synthesis of starting materials and collected the data. X.H. designed and supervised the computational mechanistic investigation. G.Q. carried out the theoretical computations. F.W., S.F. and T.W. co-wrote the paper.

Corresponding authors

Correspondence to Xin Hong or Tianli Wang.

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Nature Chemistry thanks Wenjun Tang, Donghui Wei and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Gram-scale preparation and synthetic transformation of stereogenic-at-P(V) compounds.

a, Gram-scale preparations. b, Transformation of SPOs (A) into diverse chiral phosphine ligands and catalysts. See general procedure VIII/X in Supplementary Information 7.2. *The product E13 was recrystallized once from a DCM/n-hexane mixture, affording optically pure compound in >99% ee with 86% yield.

Extended Data Fig. 2 DFT investigations containing DFT structure details.

a. Free energy profile and DFT structure details of P6-catalysed system. b. Free energy profile and DFT structure details of P3-catalysed system.

Extended Data Table 1 Additional Scope of P6-catalytic asymmetric A-T reaction
Full size table
Extended Data Table 2 Additional Scope of P3-catalytic asymmetric A-T reaction
Full size table

Supplementary information

Supplementary Information (download PDF )

Supplementary Figs. 1–38, Discussion and Tables 1–22.

Supplementary Data 1 (download PDF )

Full set of NMR spectra for reported compounds.

Supplementary Data 2 (download ZIP )

Cartesian coordinates for reported DFT structures.

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Wang, F., Tan, JP., Qian, G. et al. Stepwise-controllable catalytic asymmetric Atherton–Todd reaction to access diverse P(V)-stereogenic compounds. Nat. Chem. 18, 23–32 (2026). https://doi.org/10.1038/s41557-025-02025-1

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