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Atroposelective organocatalytic nucleophilic aromatic substitution for C–O bond construction

Nature Catalysis volume 9, pages 448–459 (2026) Cite this article

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Abstract

The development of catalytic asymmetric strategies for directly constructing axially chiral diaryl ethers presents a substantial challenge owing to the inherent flexibility of the C–O bond and sterically congested substitution patterns that typically suppress both reactivity and enantioselectivity. Here we report an organocatalytic C–O bond-forming reaction that enables the facile synthesis of these chiral scaffolds. Employing a peptide-mimic phosphonium salt catalyst, this method exhibits broad substrate scope and achieves exceptional performance (up to 99% yield, 99% e.e.) under mild conditions. The efficacy of this methodology is further demonstrated through the late-stage diversification of complex molecular architectures, including derivatives of commercially available drugs. Mechanistic investigations delineate a peptide-mimic phosphonium salt-promoted stepwise nucleophilic aromatic substitution (SNAr) pathway, where the initial nucleophilic attack plays a pivotal role, serving as the determinant step for both rate and stereochemistry. Collectively, this work provides an efficient and enantioselective route to axially chiral diaryl ethers, opening practical avenues for integrating simple motifs into value-added, complex molecular architectures.

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Fig. 1: Motivation and design of PPS-catalysed atroposelective synthesis of C–O axially chiral scaffolds.
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Fig. 2: Optimization of reaction conditions.
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Fig. 3: Substrate scope.
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Fig. 4: Late-stage diversification.
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Fig. 5: Product elaborations and stereochemical stability of C–O atropisomers.
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Fig. 6: Mechanistic studies.
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Fig. 7: Theoretical calculations.
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Data availability

All information relating to optimization studies, experimental procedures, mechanistic studies, DFT calculations, HPLC spectra, NMR spectra, high-resolution mass spectrometry and optical rotation data are available in the Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2263766 (8) and CCDC 2307018 (rac-53). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

Financial support was provided by the National Natural Science Foundation of China (grant nos. 22222109 to T.W., 21921002 to T.W., 22101189 to T.W., 22371190 to T.W. and 22193012 to X.-S.X.), National Key R&D Program of China (grant no. 2018YFA0903500 to T.W.), Beijing National Laboratory for Molecular Sciences (grant no. BNLMS202101 to T.W.), Sichuan Science Foundation for Distinguished Young Scholars (grant no. 2023NSFSC1921 to T.W.), Sichuan Provincial Natural Science Foundation (grant nos. 2022NSFSC1181 to T.W. and 2024NSFSC1122 to T.W.), Fundamental Research Funds from Sichuan University (grant no. 2020SCUNL108 to T.W.), the CAS Project for Young Scientists in Basic Research (grant no. YSBR-095 to X.-S.X.) and Fundamental Research Funds for the Central Universities. We thank the College of Chemistry and the Analytical and Testing Center of Sichuan University, and X. Ren, J. Li and D. Deng from the College of Chemistry Sichuan University for HRMS and NMR testing, respectively.

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Author notes

  1. These authors contributed equally: Yan Guo, Lu Yu, Siqiang Fang.

Authors and Affiliations

  1. Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, People’s Republic of China

    Yan Guo, Siqiang Fang, Shanshan Ding, Zhaowei Bao, Jixing Che & Tianli Wang

  2. State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, People’s Republic of China

    Lu Yu

  3. State Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials and Shanghai–Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, People’s Republic of China

    Lu Yu & Xiao-Song Xue

  4. School of Chemistry and Materials Science Hangzhou Institute of Advanced Study, University of Chinese Academy of Science, Hangzhou, People’s Republic of China

    Xiao-Song Xue

  5. Beijing National Laboratory for Molecular Sciences, Beijing, People’s Republic of China

    Tianli Wang

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  1. Yan Guo
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  2. Lu Yu
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  3. Siqiang Fang
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Contributions

T.W. conceived and designed this project, and wrote the paper. Y.G., S.F., S.D. and J.C. jointly conducted the experiments described in this paper and analysed the data. S.F. and Z.B. conducted the crystallographic studies. L.Y. and X.-S.X. carried out the DFT calculations. All the authors contributed to the analysis and interpretation of the data.

Corresponding authors

Correspondence to Xiao-Song Xue or Tianli Wang.

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Supplementary Information (download PDF )

Supplementary Figs. 1–34, Tables 1–19, methods and references.

Supplementary Data

Crystallographic data for compound 8.

Supplementary Data

Crystallographic data for compound rac-53.

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Cartesian coordinates of optimized structures.

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Guo, Y., Yu, L., Fang, S. et al. Atroposelective organocatalytic nucleophilic aromatic substitution for C–O bond construction. Nat Catal 9, 448–459 (2026). https://doi.org/10.1038/s41929-026-01522-x

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