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Visible light activation enables desulfonylative cross-coupling of glycosyl sulfones

Nature Synthesis volume 1, pages 967–974 (2022)Cite this article

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Abstract

Identifying a general bench-stable precursor of multifunctional sugar residues that is also amenable to further activation under mild conditions remains a great challenge in carbohydrate chemistry. Here, we show that heteroaryl glycosyl sulfones undergo desulfonylative cross-coupling with electrophiles in the presence of a Hantzsch ester and a weak base under visible light illumination at ambient temperature. Illumination was found to initiate the reactivity of an in situ-generated Hantzsch ester–base complex, triggering single-electron transfer steps that activate sulfones and afford glycosyl radicals, which are readily utilized for a range of stereocontrolled carbon–carbon and carbon–sulfur bond formations. Importantly, the heteroaryl glycosyl sulfones can be synthesized on a multi-gram scale. Furthermore, this catalyst- and transition metal-free approach enables sulfone donors of various monosaccharides and glycans to be transformed to synthetically valuable glycosides with high stereochemical purity and broad functional group tolerance. This method overcomes previous limitations in scope, scalability and donor instability.

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Fig. 1: The importance of C-glycosides and synthetic approaches to access them via glycosyl radicals.
Fig. 2: Reaction development and mechanistic investigations.

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Data availability

All of the data are available within the text and Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre under deposition numbers 2130777 (compound 18), 2126413 (compound SI-8), 2126409 (compound S-d12), 2126410 (compound S-d9) and 2126412 (compound S-d6).

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Acknowledgements

This research was supported by the Research Scholarship Block from the Ministry of Education, Singapore (C-143-000-207-532, C-141-000-777-532 and C-141-000-333-532 to M.J.K.). We thank G. K. Tan (National University of Singapore) for the X-ray crystallographic analysis.

Author information

Authors and Affiliations

  1. Department of Chemistry, National University of Singapore, Singapore, Singapore

    Quanquan Wang, Boon Chong Lee, Ting Jun Tan, Yi Jiang, Wei Han Ser & Ming Joo Koh

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Contributions

Q.W., B.C.L., T.J.T., Y.J. and W.H.S. developed the cross-coupling method and conducted the mechanistic studies. M.J.K. directed the investigations. M.J.K. wrote the manuscript with revisions made by the other authors.

Corresponding author

Correspondence to Ming Joo Koh.

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Peer review

Peer review information

Nature Synthesis thanks Christian Pedersen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peter Seavill, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Supplementary Tables 1–8, Figs. 1–61, experimental details and X-ray crystallographic data.

Supplementary Data 1

Crystallographic data for compound S-d12 (CCDC-2126409).

Supplementary Data 2

Crystallographic data for compound S-d9 (CCDC-2126410).

Supplementary Data 3

Crystallographic data for compound S-d6 (CCDC-2126412).

Supplementary Data 4

Crystallographic data for compound SI-8 (CCDC-2126413).

Supplementary Data 5

Crystallographic data for compound 18 (CCDC-2130777).

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Wang, Q., Lee, B.C., Tan, T.J. et al. Visible light activation enables desulfonylative cross-coupling of glycosyl sulfones. Nat. Synth 1, 967–974 (2022). https://doi.org/10.1038/s44160-022-00162-w

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