Abstract
Sulfur(VI) fluoride exchange click chemistry is a formidable tool to rapidly and effectively link chemical structures. Despite advances in the field in recent years, the installation of the sulfonyl fluoride handle still requires the use of purpose-designed, expensive and non-atom-economic reagents. The use of the SO2F2 for sulfonyl fluoride synthesis has been thwarted by the difficulties associated with the manipulation and dosage of this toxic gas, and by its apparent low reactivity with amino functionalities. Here we report a modular flow platform that can generate on demand, and efficiently dose, gaseous SO2F2. The use of flow technologies allows many lingering limitations of this transformation to be overcome, resulting in reduced reaction times, efficient reactivity and broad substrate scope. The effectiveness of the process was demonstrated by the successful synthesis of a diverse set of fluorosulfates and sulfamoyl fluorides, including those derived from biorelevant compounds, peptides and proteins.
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The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information.
Change history
31 January 2024
A Correction to this paper has been published: https://doi.org/10.1038/s44160-024-00489-6
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Acknowledgements
We acknowledge financial support from the European Union H2020 research and innovation program for an ERC CoG grant for T.N. (FlowHAT, number 101044355) and a Marie S. Curie Grant fellowship for D.M. (ELECTRORGANO, number 101022144), the Spanish Government-MCIN, the national agency of investigation-AEI/10.13039/501100011033, and the European Regional Development Fund-ERDF for project PID2020-120584RB-I00 to O.B. and and FPU Fellowship (FPU19/01969 and EST22/00303) to M.B.
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M.B. and D.M. conceived the project. M.B., D.M. and J. S. performed and analysed the experiments. O.B. and T.N.G. supervised the ligation of peptides and proteins. Z.Z., A.Y.V., A.F.G.G. and T.N.G. performed the analyses of the ligation of peptides and proteins. T.N. directed the project. M.B., D.M. and T.N. have written the manuscript with contributions from all the authors.
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Supplementary Figs. 1–76, Tables 1–22, Discussion, NMR spectra and Schemes 1–4.
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Bernús, M., Mazzarella, D., Stanić, J. et al. A modular flow platform for sulfur(VI) fluoride exchange ligation of small molecules, peptides and proteins. Nat. Synth 3, 185–191 (2024). https://doi.org/10.1038/s44160-023-00441-0
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DOI: https://doi.org/10.1038/s44160-023-00441-0
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