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Photocatalytic coupling of unprotected sugars and N-heteroarenes

Nature Synthesis (2026)Cite this article

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Abstract

C-heteroaryl glycosides, predominantly in unprotected forms, are common entities in bioactive molecules and have extensive applications in chemistry and biology. However, the chemical synthesis of these glycosides remains challenging owing to the lack of methods that directly leverage naturally occurring (native) sugars as substrates. Here we show that fully unprotected native sugars, capped as redox-active glycosyl sulfide donors, can be merged with N-heteroarenes in the presence of triethylamine and a photocatalyst under mild visible-light irradiation. The C–C coupling transformation proceeds with control over chemo-, site- and stereoselectivities and is compatible with a diverse range of N-heteroarenes bearing acidic and basic functional groups. The utility of this method is highlighted by the glycosylation of nucleosides, as well as by the direct coupling of d-mannose with pentoxifylline to generate a compound exhibiting glycogen-metabolism-inhibitory properties. In contrast to previously established mechanisms, the photocatalytic species is found to trigger the in situ generation of a thiyl radical that promotes hydrogen atom transfer to afford the target product, with triethylamine serving as a reductant through photoinduced charge-transfer complexation with the glycosyl sulfide.

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Fig. 1: Direct photocatalytic coupling of native sugars and N-heteroarenes.
Fig. 2: Evaluation of reaction parameters for the photocatalytic coupling of glycosyl sulfide and N-heteroarene.
Fig. 3: Mechanistic investigations.
Fig. 4: Scope of the reaction with various unprotected sugars.
Fig. 5: Scope of the reaction with various N-heteroarenes.
Fig. 6: Late-stage modification of nucleosides and bioactivity investigation.

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Data availability

Crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre under deposition numbers CCDC-2449025 (46) and CCDC-2449026 (31). All other data are available in the Article or its Supplementary Information.

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Acknowledgements

This research is supported by the Ministry of Education of Singapore Academic Research Fund Tier 2: A-8002999-00-00 (M.J.K.), the National Research Foundation, Prime Minister’s Office, Singapore under its Campus for Research Excellence and Technological Enterprise (CREATE) SM3 programme and A*STAR under its Manufacturing, Trade and Connectivity (MTC) Programmatic Fund: M25O1b0015 (M.J.K.). We thank I. I. Roslan (National University of Singapore) for the X-ray crystallographic measurements.

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Author notes

  1. These authors jointly supervised this work: Eric Chun Yong Chan, Ming Joo Koh.

Authors and Affiliations

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

    Qian-Yi Zhou, Jun Wu, Songge Li & Ming Joo Koh

  2. Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Singapore, Republic of Singapore

    Daniel Zhi Wei Ng, Wei Liang Leow & Eric Chun Yong Chan

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  1. Qian-Yi Zhou
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Contributions

M.J.K. and Q.-Y.Z. conceived the work. Q.-Y.Z. conducted the optimization and reaction scope studies. Q.-Y.Z., J.W. and S.L. conducted the mechanistic studies. D.Z.W.N. and W.L.L. conducted the biological studies under the direction of E.C.Y.C. M.J.K. directed the research. All authors contributed to the writing of the manuscript.

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Correspondence to Eric Chun Yong Chan or Ming Joo Koh.

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Nature Synthesis thanks Yong-Min Liang, Feng Zhu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Joel Cejas-Sánchez, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information (download PDF )

Supplementary Sections 1–11, including Supplementary Figs. 1–13, Discussion and Tables 1–9.

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Supplementary Crystal 1

Crystallographic data for compound 31, CCDC 2449026.

Supplementary Data 2

Crystallographic data for compound 46, CCDC 2449025.

Source Data Supplementary Fig. 11 (download XLSX )

The raw data of cyclic voltammograms of Supplementary Fig. 11.

Source Data Supplementary Fig. 13 (download ZIP )

The raw data of bioactivity investigation of Supplementary Fig. 13.

Source Data Supplementary Fig. 2 (download ZIP )

The raw data of UV–vis spectroscopy studies of Supplementary Fig. 2.

Source Data Supplementary Fig. 5 (download XLSX )

The raw data of the quenching ability of NEt3 of Supplementary Fig. 5.

Source Data Supplementary Fig. 7 (download XLSX )

The raw data of the quenching ability of isoquinoline of Supplementary Fig. 7.

Source Data Supplementary Fig. 4 (download XLSX )

The raw data of the quenching ability of the glycosyl donor of Supplementary Fig. 4.

Source Data Supplementary Fig. 6 (download XLSX )

The raw data of the quenching ability of NEt3 and thiol of Supplementary Fig. 6.

Source data

Source Data Fig. 2 (download XLSX )

Statistical source data for Fig. 2b.

Source Data Fig. 3 (download XLSX )

Statistical source data for Fig. 3c.

Source Data Fig. 6 (download XLSX )

Statistical source data for Fig. 6b.

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Zhou, QY., Ng, D.Z.W., Wu, J. et al. Photocatalytic coupling of unprotected sugars and N-heteroarenes. Nat. Synth (2026). https://doi.org/10.1038/s44160-025-00980-8

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