Abstract
Sterically hindered aryl C-glycosides are biologically important, yet their stereoselective synthesis remains challenging due to severe anomeric congestion. Here we report a next-generation, ligand-enabled, stereospecific Pd-catalyzed glycosyl cross-coupling that efficiently delivers sterically hindered aryl C-glycosides with exclusive anomeric control. Two underexplored biarylmonophosphine ligands, featuring P-bound 3,5-bis(trifluoromethyl)phenyl groups and methoxy or isopropoxy substituents at the 2’- and 6’-positions of the lower aryl ring, are uniquely effective for this challenging C-glycosylation. The scope and practicality of this next-generation Stille glycosylation are demonstrated in over 65 examples, including (un)protected sugars, deoxy sugars, and oligosaccharides. Crystallography reveals that bromide-bridged dimeric Pd(II) complexes as intrinsic features of diarylbiaryl monophosphine ligands, while natural bond orbital (NBO) analysis shows that subtle ligand electronics control the selectivity between β-methoxy elimination and C–C reductive elimination. This predictable, highly chemo- and stereoselective protocol expands the glycosylation toolbox, enables glycomimetic drug discovery, and informs rational ligand design.
Data availability
The authors declare that the data supporting the findings of this study, including experimental details and compound characterization, are available within the article and its Supplementary Information file. All data are available from the corresponding author upon request. Source data are provided with this paper. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 2489072 (OA5), 2489073 (OA6), 2489150 (OA7), 2489074 (OA8). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Source data are provided with this paper.
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Acknowledgements
We acknowledge support by the National Key Research & Development Program of China (Grant No. 2023YFA1508800) to F.Z., the National Natural Science Foundation of China (Grant No. 22301178, and 22577072) to F.Z., the National Natural Science Foundation of China (Grant No. 22301180) to B.Y., the Fundamental Research Funds for the Central Universities (Grant No. 25×010202131) to F.Z., Shanghai Municipal Science and Technology Major Project to F.Z., the Open Grant from the Pingyuan Laboratory (2023PY-OP-0102) to F.Z., the Open Fund from the State Key Laboratory of Antiviral Drugs (Grant No. SKLAD-2024-0103) to B.Y., the Foundation of National Facility for Translational Medicine (Shanghai) to F.Z. We sincerely thank Prof. Feliu Maseras (Institute of Chemical Research of Catalonia, ICIQ) for the valuable guidance and advice on the computational studies. We also thank Guoqiang Cheng for assistance in contributing reversed anomeric stannanes.
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F.Z. conceived and supervised the project. B.Y., S.C., Y.H., and J.S. carried out the experiments and analyzed the data. Y.L. conducted the DFT calculations and data analysis. W.Z. and B.Z. provided valuable suggestions. F.Z., B.Y., and Y.L. discussed the results and wrote the manuscript with input from all authors. All authors have read and approved the final version of the manuscript.
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Yang, B., Chen, S., Han, Y. et al. Ligand-enabled next-generation glycosyl Stille cross-coupling for the stereospecific synthesis of sterically hindered aryl C-glycosides. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69859-2
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DOI: https://doi.org/10.1038/s41467-026-69859-2
