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The energy-transfer-enabled biocompatible disulfide–ene reaction

Nature Chemistry volume 10, pages 981–988 (2018)Cite this article

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Abstract

Sulfur-containing molecules participate in many essential biological processes. Of utmost importance is the methylthioether moiety, present in the proteinogenic amino acid methionine and installed in tRNA by radical-S-adenosylmethionine methylthiotransferases. Although the thiol–ene reaction for carbon–sulfur bond formation has found widespread applications in materials or medicinal science, a biocompatible chemo- and regioselective hydrothiolation of unactivated alkenes and alkynes remains elusive. Here, we describe the design of a general chemoselective anti-Markovnikov hydroalkyl/aryl thiolation of alkenes and alkynes—also allowing the biologically important hydromethylthiolation—by triplet–triplet energy transfer activation of disulfides. This fast disulfide–ene reaction shows extraordinary functional group tolerance and biocompatibility. Transient absorption spectroscopy was used to study the sensitization process in detail. The hereby gained mechanistic insights were successfully employed for optimization of the catalytic system. This photosensitized transformation should stimulate bioimaging applications and carbon–sulfur bond-forming late-stage functionalization chemistry, especially in the context of metabolic labelling.

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Fig. 1: Chemoselective anti-Markovnikov hydrothiolation of alkenes—allowing the biologically important hydromethylthiolation—enabled by triplet–triplet photosensitization of disulfides.
Fig. 2: Hypothesis-driven luminescence screening and reaction profile of the chemoselective anti-Markovnikov disulfide–ene reaction.
Fig. 3: Scope of the disulfide–ene hydrothiolation of alkenes and alkynes.
Fig. 4: Proposed reaction mechanism of the photosensitized disulfide–ene reaction derived from diverse mechanistic studies.
Fig. 5: Improvement of the photocatalytic system based on mechanistic investigation, access to sulfoxides and sulfones by stepwise oxidation of thioethers and biocompatibility screening of the disulfide–ene reaction.

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Acknowledgements

The authors thank K. Gottschalk, L. Roling, S. Hüwel, W. Dörner and S. Wulff for experimental and technical assistance and R. Honeker, L. Candish and Z. Nairoukh for helpful discussions (all WWU Münster). This work was supported by the Deutsche Forschungsgemeinschaft (Leibniz Award to F.G. and RE2796/6-1 to A.R.) and by the Fonds der Chemischen Industrie (doctoral fellowship to L.A. and Dozentenpreis to A.R.). M.T. thanks SusChemSys 2.0 for general support.

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Authors and Affiliations

  1. Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Münster, Germany

    Michael Teders, Felix Strieth-Kalthoff, Adrián Gómez-Suárez, Roman Kleinmans & Frank Glorius

  2. Department für Chemie und Pharmazie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany

    Christian Henkel, Axel Kahnt & Dirk Guldi

  3. Institut für Biochemie, Westfälische Wilhelms-Universität Münster, Münster, Germany

    Lea Anhäuser & Andrea Rentmeister

  4. Cells-in-Motion Cluster of Excellence (EXC1003-CiM), Westfälische Wilhelms-Universität, Münster, Germany

    Andrea Rentmeister

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Contributions

M.T., F.S.-K., A.G.-S., R.K. and F.G. designed, performed and analysed the catalytic and mechanistic experiments. C.H., A.K. and D.G. designed, performed and analysed transient absorption data and related spectroscopic mechanism studies. L.A. and M.T. designed and performed the biocompatibility screening experiments. M.T., C.H., L.A., F.S.-K., A.R., D.G. and F.G. prepared the manuscript, with contributions from all authors.

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Correspondence to Dirk Guldi or Frank Glorius.

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Teders, M., Henkel, C., Anhäuser, L. et al. The energy-transfer-enabled biocompatible disulfide–ene reaction. Nature Chem 10, 981–988 (2018). https://doi.org/10.1038/s41557-018-0102-z

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