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<p>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 <i>σ</i>-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.</p><p></p>

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

  • 期刊论文

  • 发表日期：

    2026年4月24日

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  • Meagan E. Hackey,
  • Michele Formica,
  • Valentin Bauer,
  • Nahid S. Alavijeh,
  • Yue Fu,
  • Elise A. Naudin,
  • Ali Nikbakht,
  • Dima Yassine,
  • Paulo H. S. Paioti,
  • Juan del Pozo,
  • Peng Liu,
  • Amir H. Hoveyda

摘要

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.