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Click and chemically triggered declick reactions through reversible amine and thiol coupling via a conjugate acceptor

Nature Chemistry volume 8, pages 968–973 (2016)Cite this article

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Abstract

The coupling and decoupling of molecular units is a fundamental undertaking of organic chemistry. Herein we report the use of a very simple conjugate acceptor, derived from Meldrum's acid, for the sequential ‘clicking’ together of an amine and a thiol in aqueous conditions at neutral pH. Subsequently, this linkage can be ‘declicked’ by a chemical trigger to release the original amine and thiol undisturbed. The reactivity differs from that of other crosslinking agents because the selectivity for sequential functionalization derives from an altering of the electrophilicity of the conjugate acceptor on the addition of the amine. We describe the use of the procedure to modify proteins, create multicomponent libraries and synthesize oligomers, all of which can be declicked to their starting components in a controlled fashion when desired. Owing to the mild reaction conditions and ease of use in a variety of applications, the method is predicted to have wide utility.

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Figure 1: A general schematic of amine and thiol addition to the conjugate acceptor.
Figure 2: The conjugate acceptor 1 can be used to make branched assemblies.
Figure 3: The conjugate acceptor 1 can be used to functionalize a surface reversibly with thiols.
Figure 4: The conjugate acceptor 1 can be used to functionalize peptides reversibly with small molecules and other peptides.
Figure 5: The conjugate acceptor 1 can be used to functionalize a protein reversibly with thiol-terminated PEG chains.
Figure 6: The conjugate acceptor 1 can be used to synthesize oligomers of different lengths.

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Acknowledgements

We acknowledge financial support from the Defense Advanced Research Projects Agency (N66001-14-2-4051 to E.V.A.), the National Science Foundation (CHE-1212971 to E.V.A.; CHE1402753 to J.S.B.), Welch Regents Chair (F-0046 to E.V.A.) and the Welch Foundation (F-1155 to J.S.B.).

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Authors and Affiliations

  1. Department of Chemistry, University of Texas, 1 University Station A1590, Austin, 78712, Texas, USA

    Katharine L. Diehl, Igor V. Kolesnichenko, Scott A. Robotham, J. Logan Bachman, Ye Zhong, Jennifer S. Brodbelt & Eric V. Anslyn

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  1. Katharine L. Diehl
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  2. Igor V. Kolesnichenko
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Contributions

K.L.D. helped conceive and design the experiments, performed them and analysed the data, and wrote the first draft of the paper. I.V.K. also helped conceive and design experiments, carried them out and analysed the data, and edited the paper. S.A.R. analysed synthesized compounds using mass spectrometry. J.L.B. helped synthesize starting materials for experiments performed herein. Y.Z. performed preliminary experiments that demonstrated the utility of the Meldrum's acid conjugate acceptor 1. J.S.B. contributed analysis tools and E.V.A. conceived and/or designed experiments and edited the paper.

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Correspondence to Eric V. Anslyn.

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Diehl, K., Kolesnichenko, I., Robotham, S. et al. Click and chemically triggered declick reactions through reversible amine and thiol coupling via a conjugate acceptor. Nature Chem 8, 968–973 (2016). https://doi.org/10.1038/nchem.2601

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