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Issue 10, 2014
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Conformationally strained trans-cyclooctene with improved stability and excellent reactivity in tetrazine ligation

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Abstract

Computation has guided the design of conformationally-strained dioxolane-fused trans-cyclooctene (d-TCO) derivatives that display excellent reactivity in the tetrazine ligation. A water soluble derivative of 3,6-dipyridyl-s-tetrazine reacts with d-TCO with a second order rate k2 366 000 (±15 000) M−1 s−1 at 25 °C in pure water. Furthermore, d-TCO derivatives can be prepared easily, are accessed through diastereoselective synthesis, and are typically crystalline bench-stable solids that are stable in aqueous solution, blood serum, or in the presence of thiols in buffered solution. GFP with a genetically encoded tetrazine-containing amino acid was site-specifically labelled in vivo by a d-TCO derivative. The fastest bioorthogonal reaction reported to date [k2 3 300 000 (±40 000) M−1 s−1 in H2O at 25 °C] is described herein with a cyclopropane-fused trans-cyclooctene. d-TCO derivatives display rates within an order of magnitude of these fastest trans-cyclooctene reagents, and also display enhanced stability and aqueous solubility.

Graphical abstract: Conformationally strained trans-cyclooctene with improved stability and excellent reactivity in tetrazine ligation

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Publication details

The article was received on 08 May 2014, accepted on 07 Jul 2014 and first published on 08 Jul 2014


Article type: Edge Article
DOI: 10.1039/C4SC01348D
Author version available: Download Author version (PDF)
Citation: Chem. Sci., 2014,5, 3770-3776
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    Conformationally strained trans-cyclooctene with improved stability and excellent reactivity in tetrazine ligation

    A. Darko, S. Wallace, O. Dmitrenko, M. M. Machovina, R. A. Mehl, J. W. Chin and J. M. Fox, Chem. Sci., 2014, 5, 3770
    DOI: 10.1039/C4SC01348D

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