There are numerous bioorthogonal ligation and cleavage reactions in the field of Chemical Biology. However, relatively few exchange reactions have been developed which can ligate two species while simultaneously ejecting a carbogenic moiety from one of the ligating partners. Exchange reactions of this form have important applications in Chemical Biology. For example, the Staudinger ligation has been previously modified to function as an exchange reaction. The result was a small molecule Capture-Tag-Release (CTR) probe that could covalently label native enzymes without altering their intrinsic function. However, its reliance on the Staudinger phosphine resulted in a reaction that was air sensitive and would likely exhibit poor cellular uptake, limiting its utility in living systems. Herein we report a new exchange reaction, based on an inverse-electron-demand Diels-Alder (iEDDA) cycloaddition. In our proof-of-principle experiment, a carbogenic moiety is transferred from a strained alkene to a tetrazine. This new reaction has the potential to become a second-generation CTR probe and to expand the toolbox of Chemical Biology.

Towards a bioorthogonal exchange reaction based on an inverse-electron-demand Diels-Alder (iEDDA) cycloaddition

254th National Meeting (2017)

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