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Enantioselective organocatalytic construction of axially chiral sulfoxides

Nature Synthesis volume 4, pages 1587–1597 (2025)Cite this article

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Abstract

The unique properties of stereogenic sulfur centres make sulfoxides highly valuable in medicinal chemistry, organic synthesis and other fields. Axially chiral sulfoxides are a class of complex organosulfur compounds with promising applications, but their synthesis remains challenging. Here we report a streamlined synthetic strategy for axially chiral sulfoxides. By leveraging the combination of rationally designed reagents and tailored catalytic systems, the method simultaneously establishes chiral sulfoxide and axial chirality in a single reaction step. This method was applied to a wide variety of substrates and resulted in products with broad functionality. The sulfinylation reaction was studied through a series of mechanistic experiments. This study provides a route to chiral sulfoxides with underexplored functionalities for potential future applications.

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Fig. 1: Chiral sulfoxide bioactive molecules and ligands, synthetic strategies and our design blueprint.
Fig. 2: Substrate scope.
Fig. 3: Thermal stability research.
Fig. 4: Gram-scale synthesis and synthetic transformations of 3a.
Fig. 5: Mechanistic investigations.

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Data availability

Data relating to the characterization of materials and products, general methods, optimization studies, mechanistic studies, HPLC chromatograms and NMR spectra 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 2335616 (3a), CCDC 2362413 (3b), CCDC 2362414 (3p) and CCDC 2442967 (10). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. The data that support the findings of this study are available in the article and its Supplementary Information.

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Acknowledgements

This study was supported by the Science and Technology Innovation Key R&D Program of Chongqing (grant number CSTB2022TIAD-STX0015 (H.Y.)), the Natural Science Foundation of Chongqing (grant numbers CSTB2023NSCQ-MSX0057 (W.Q.), CSTC2021JCYJ-JQX0019 (H.Y.)), the Graduate Research and Innovation Foundation of Chongqing, China (grant number CYB23075 (H.Y.)), the Fundamental Research Funds for the Central Universities (grant number 2023CDJKYJH009 (H.Y.)) and the National Natural Science Foundation of China (grant numbers 22271032 (H.Y.), 22471026 (W.Q.)). We thank X. Gong for X-ray crystallographic analysis.

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Authors and Affiliations

  1. Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing, People’s Republic of China

    Yu Chang, Guojie Zhou, Da Xu, Pengfei Wang, Wenling Qin & Hailong Yan

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  1. Yu Chang
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  2. Guojie Zhou
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  3. Da Xu
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Contributions

H.Y., W.Q. and P.W. conceived and directed the project. Y.C., G.Z. and D.X. designed and performed experiments. Y.C. and P.W. analysed and interpreted the experimental data. Y.C. prepared the Supplementary Information. H.Y., W.Q., P.W. and Y.C. wrote the paper. All authors discussed the results and commented on the paper.

Corresponding author

Correspondence to Hailong Yan.

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The authors declare no competing interests.

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Peer review information

Nature Synthesis thanks Hai-Ming Guo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information (download PDF )

Experimental details, Supplementary Figs. 1–12 and Tables 1–14.

Supplementary Data 1

X-ray crystallographic data for 3a, CCDC 2335616.

Supplementary Data 2

Structure factors for 3a, CCDC 2335616.

Supplementary Data 3

X-ray crystallographic data for 3b, CCDC 2362413.

Supplementary Data 4

Structure factors for 3b, CCDC 2362413.

Supplementary Data 5

X-ray crystallographic data for 3p, CCDC 2362414.

Supplementary Data 6

Structure factors for 3p, CCDC 2362414.

Supplementary Data 7

X-ray crystallographic data for 10, CCDC 2442967.

Supplementary Data 8

Structure factors for 10, CCDC 2442967.

Source data

Source Data Fig. 3 (download XLSX )

Source data for Fig. 3, the data of the racemization experiment of 3a.

Source Data Fig. 5 (download XLSX )

Source data files for Fig. 5.

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Chang, Y., Zhou, G., Xu, D. et al. Enantioselective organocatalytic construction of axially chiral sulfoxides. Nat. Synth 4, 1587–1597 (2025). https://doi.org/10.1038/s44160-025-00877-6

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