Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The energy-transfer-enabled biocompatible disulfide–ene reaction

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Trost, B. M. Selectivity: a key to synthetic efficiency. Science 219, 245–250 (1983).

    Article  CAS  Google Scholar 

  2. Wender, P. A. & Miller, B. L. Synthesis at the molecular frontier. Nature 460, 197–201 (2009).

    Article  CAS  Google Scholar 

  3. Takahashi, N. et al. Reactive sulfur species regulate tRNA methythiolation and contribute to insulin secretion. Nucleic Acids Res. 45, 435–445 (2017).

    Article  CAS  Google Scholar 

  4. Kowalak, J. A. & Walsh, K. A. β-methylthio-aspartic acid: identification of a novel posttranslational modification in ribosomal protein S12 from Escherichia coli. Protein Sci. 5, 1625–1632 (1996).

    Article  CAS  Google Scholar 

  5. Forouhar, F. et al. Two Fe–S cluster catalyse sulfur insertion by radical-SAM methylthiotransferases. Nat. Chem. Biol. 9, 333–338 (2013).

    Article  CAS  Google Scholar 

  6. Stubbe, J. & van der Donk, W. A. Protein radicals in enzyme catalysis. Chem. Rev. 98, 705–762 (1998).

    Article  CAS  Google Scholar 

  7. Dunbar, K. L., Scharf, D. H., Litomska, A. & Hertweck, C. Enzymatic carbon–sulfur bond formation in natural product biosynthesis. Chem. Rev. 117, 5521–5577 (2017).

    Article  CAS  Google Scholar 

  8. Kolberg, M., Strand, K. R., Graff, P. & Andersson, K. K. Structure, function, and mechanism of ribonucleotide reductases. Biochim. Biophys. Acta 1699, 1–34 (2004).

    Article  CAS  Google Scholar 

  9. Fraústo da Silva, J. J. R. & Williams, R. J. P. The Biological Chemistry of the Elements (Oxford Univ. Press: New York, NY, 2011).

  10. Damani, L. A. Sulphur-Containing Drugs and Related Organic Compounds (Wiley: Chichester, 1989).

  11. Dénès, F., Pichowicz, M., Povie, G. & Renaud, P. Thiyl radicals in organic synthesis. Chem. Rev. 114, 2587–2693 (2014).

    Article  Google Scholar 

  12. Posner, T. Beiträge zur Kenntniss der ungesättigten Verbindungen. II. Ueber die Addition von Mercaptanen an ungesättigte Kohlenwasserstoffe. Ber. Dtsch. Chem. Ges. 38, 646–657 (1905).

    Article  Google Scholar 

  13. Hoyle, C. E. & Bowman, C. N. Thiol–ene click chemistry. Angew. Chem. Int. Ed. 49, 1540–1573 (2010).

    Article  CAS  Google Scholar 

  14. Stenzel, M. H. Bioconjugation using thiols: old chemistry rediscovered to connect polymers with nature’s building blocks. ACS Macro Lett. 2, 14–18 (2013).

    Article  CAS  Google Scholar 

  15. van Dijk, M., Rijkers, D. T. S., Liskamp, R. M. J., van Nostrum, C. F. & Hennink, W. E. Synthesis and applications of biomedical and pharmaceutical polymers via click chemistry methodologies. Bioconjug. Chem. 20, 2001–2016 (2009).

    Article  Google Scholar 

  16. Huynh, V. T., Chen, G., de Souza, P. & Stenzel, M. H. Thiol–yne and thiol–ene ‘click’ chemistry as a tool for a variety of platinum drug delivery carriers, from statistical copolymers to crosslinked micelles. Biomacromolecules 12, 1738–1751 (2011).

    Article  CAS  Google Scholar 

  17. Lowe, A. B. Thiol–ene ‘click’ reactions and recent applications in polymer and materials synthesis. Polym. Chem. 1, 17–36 (2010).

    Article  CAS  Google Scholar 

  18. Tyson, E. L., Ament, M. S. & Yoon, T. P. Transition metal photoredox catalysis of radical thiol–ene reactions. J. Org. Chem. 78, 2046–2050 (2013).

    Article  CAS  Google Scholar 

  19. Tyson, E. L., Niemeyer, Z. L. & Yoon, T. P. Redox mediators in visible light photocatalysis: photocatalytic radical thiol–ene additions. J. Org. Chem. 79, 1427–1436 (2014).

    Article  CAS  Google Scholar 

  20. Keylor, M. H., Park, J. E., Wallentin, C.-J. & Stephenson, C. R. J. Photocatalytic initiation of thiol–ene reactions: synthesis of thiomorpholin-3-ones. Tetrahedron 70, 4264–4269 (2014).

    Article  CAS  Google Scholar 

  21. Chen, Y., Kamlet, A. S., Steinman, J. B. & Liu, D. R. A biomolecule-compatible visible-light-induced azide reduction from a DNA-encoded reaction-discovery system. Nat. Chem. 3, 146–153 (2011).

    Article  Google Scholar 

  22. Huang, H., Zhang, G., Gong, L., Zhang, S. & Chen, Y. Visible-light-induced chemoselective deboronative alkynylation under biomolecule-compatible conditions. J. Am. Chem. Soc. 136, 2280–2283 (2014).

    Article  CAS  Google Scholar 

  23. Nair, D. P. et al. The thiol–Michael addition click reaction: a powerful and widely used tool in materials chemistry. Chem. Mater. 26, 724–744 (2014).

    Article  CAS  Google Scholar 

  24. Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic Compounds (CRC Press: Boca Raton, FL, 2003).

  25. Zhao, J., Wu, W., Sun, J. & Guo, S. Triplet photosensitizers: from molecular design to applications. Chem. Soc. Rev. 42, 5323–5351 (2013).

    Article  CAS  Google Scholar 

  26. Atta, M. et al. The methylthiolation reaction mediated by the radical-SAM enzymes. Biochim. Biophys. Acta 1824, 1223–1230 (2012).

    Article  CAS  Google Scholar 

  27. Stillwell, W. G. Methylthiolation: a new pathway of drug metabolism. Trends Pharmacol. Sci. 2, 250–252 (1981).

    Article  CAS  Google Scholar 

  28. Ciamician, G. The photochemistry of the future. Science 36, 385–394 (1912).

    Article  CAS  Google Scholar 

  29. Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).

    Article  CAS  Google Scholar 

  30. Twilton, J. et al. The merger of transition metal and photocatalysis. Nat. Rev. Chem. 1, 0052 (2017).

    Article  CAS  Google Scholar 

  31. Skubi, K. L., Blum, T. R. & Yoon, T. P. Dual catalysis strategies in photochemical synthesis. Chem. Rev. 116, 10035–10074 (2016).

    Article  CAS  Google Scholar 

  32. Metternich, J. B. & Gilmour, R. Photocatalytic E→Z isomerization of alkenes. Synlett 27, 2541–2552 (2016).

    Article  CAS  Google Scholar 

  33. Lu, Z. & Yoon, T. P. Visible light photocatalysis of [2+2] styrene cycloadditions by energy transfer. Angew. Chem. Int. Ed. 51, 10329–10332 (2012).

    Article  CAS  Google Scholar 

  34. Blum, T. R., Miller, Z. D., Bates, D. M., Guzei, I. A. & Yoon, T. P. Enantioselective photochemistry through Lewis acid-catalyzed triplet energy transfer. Science 354, 1391–1395 (2016).

    Article  CAS  Google Scholar 

  35. Welin, E. R., Le, C., Arias-Rotondo, D. M., McCusker, J. K. & MacMillan, D. W. C. Photosensitized, energy transfer-mediated organometallic catalysis through electronically excited nickel(II). Science 355, 380–385 (2017).

    Article  CAS  Google Scholar 

  36. Hopkinson, M. N., Gómez-Suárez, A., Teders, M., Sahoo, B. & Glorius, F. Accelerated discovery in photocatalysis using a mechanism-based screening method. Angew. Chem. Int. Ed. 55, 4361–4366 (2016).

    Article  CAS  Google Scholar 

  37. Teders, M., Gómez-Suárez, A., Pitzer, L., Hopkinson, M. N. & Glorius, F. Diverse visible-light-promoted functionalizations of benzotriazoles inspired by mechanism-based luminescence screening. Angew. Chem. Int. Ed. 56, 902–906 (2017).

    Article  CAS  Google Scholar 

  38. Benati, L., Montevecchi, P. C. & Spagnolo, P. Free-radical reactions of benzenethiol and diphenyl disulphide with alkynes. Chemical reactivity of intermediate 2-(phenylthio)vinyl radicals. J. Chem. Soc. Perkin Trans. 1, 2103–2109 (1991).

    Article  Google Scholar 

  39. Collins, K. D. & Glorius, F. A robustness screen for the rapid assessment of chemical reactions. Nat. Chem. 5, 597–601 (2013).

    Article  CAS  Google Scholar 

  40. Gensch, T., Teders, M. & Glorius, F. Approach to comparing the functional group tolerance of reactions. J. Org. Chem. 82, 9154–9159 (2017).

    Article  CAS  Google Scholar 

  41. Snyder, J. J., Tise, F. P., Davis, R. D. & Kropp, P. J. Photochemistry of alkenes. 7. EZ isomerization of alkenes sensitized with benzene and derivatives. J. Org. Chem. 46, 3609–3611 (1981).

    Article  CAS  Google Scholar 

  42. Lowry, M. S. et al. Single-layer electroluminescent devices and photoinduced hydrogen production from an ionic iridium(III) complex. Chem. Mater. 17, 5712–5719 (2005).

    Article  CAS  Google Scholar 

  43. Murov, S. L., Carmichael, I. & Hug, G. L. Handbook of Photochemistry 2nd edition (Marcel Dekker, New York, 1993).

  44. Guldi, D. M., Neta, P. & Asmus, K.-D. Electron-transfer reactions between C60 and radical ions of metaloporphyrins and arenes. J. Phys. Chem. 98, 4617–4621 (1994).

    Article  CAS  Google Scholar 

  45. Mojr, V. et al. Tailoring flavins for visible light photocatalysis: organocatalytic [2+2] cycloadditions mediated by a flavin derivative and visible light. Chem. Commun. 51, 12036–12039 (2015).

    Article  CAS  Google Scholar 

  46. Feng, M., Tang, B., Liang, S. H. & Jiang, X. Sulfur containing scaffolds in drugs: synthesis and application in medicinal chemistry. Curr. Top. Med. Chem. 16, 1200–1216 (2016).

    Article  CAS  Google Scholar 

  47. Devendar, P. & Yang, G. F. Sulfur-containing agrochemicals. Top. Curr. Chem. 375, 82 (2017).

    Article  Google Scholar 

  48. Shieh, P. & Bertozzi, C. R. Design strategies for bioorthogonal smart probes. Org. Biomol. Chem. 12, 9307–9320 (2014).

    Article  CAS  Google Scholar 

  49. Kolb, H. C., Finn, M. G. & Sharpless, K. B. Click chemistry: diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. 40, 2004–2021 (2001).

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Corresponding authors

Correspondence to Dirk Guldi or Frank Glorius.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary information

Details on chemical compound information and characterization data, experimental details, spectra and mechanistic experiments

Reporting summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41557-018-0102-z

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing