Currently utilized bioorthogonal reactions excel at linking two molecules, but the resulting connection does not display any further reactivity. This lack of chemical flexibility among bioorthogonal reactions exists in stark contrast to the full capabilities of organic chemistry. Reversible and environmentally controlled (dependent on pH, light, etc.) reactions are particularly intriguing to bring to the biological forefront. The bioorthogonal quadricyclane ligation, in which a quadricyclane covalently binds to a nickel bis(dithiolene) complex, affords uniquely reactive products hitherto unseen among bioorthogonal reactions. Upon UV irradiation, the quadricyclane-nickel bis(dithiolene) adduct cleaves to provide a norbornadiene moiety and the original nickel bis(dithiolene). As a strained alkene, the resulting norbornadiene allows for a variety of potential further elaborations on its chemical structure such as cycloadditions or a thiol-ene reaction. Thus, the incorporation of a single quadricyclane moiety can allow for click, unclick, and re-click chemistries. Here we report using the quadricyclane ligation to successfully purify a protein using a click-unclick methodology, as well as studies in further reacting the norbornadiene product of the photocleavage.

Development of the quadricyclane ligation into a multimodal bioorthogonal reaction: Click, unclick, re-click

251st National Meeting (2016)

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