A Cu(I)-catalysed click reaction generates ROS-triggered cleavable linkages in aqueous media

Click reactions that form functional linkages are rare. Among the few catalytic options, none directly delivers a cleavable connector. Here we introduce copper(I)-catalysed allene-ketone addition (CuAKA), an operationally simple reaction that is mutually orthogonal to CuAAC (copper(I)-catalysed azide-alkyne cycloaddition) and CuPDF (copper(I)-catalysed phenoxydiazaborinine formation). These three catalytic click strategies can be merged for efficient assembly of multifunctional entities. We show that CuAKA can be used to link an allene-bound drug molecule in aqueous media to a ketone-containing derivative of unprotected penetratin, a solubilizing and cell penetrating peptide. The viability of an allyl-metal complex runs counter to the long-held notion that C-C σ-bond formation and carbonyl addition are not suitable for click chemistry. We also show that CuAKA-generated linkages can be controllably cleaved (by rupturing a C-C bond) at 37 °C in a 68-86 μM solution of aqueous hydrogen peroxide. The advance underscores the versatility of functional click-generated connectors in biologically relevant environments.