This review assesses the mechanistic aspects of transition metal-mediated uncaging reactions, with the goal of aiding the rational development of new caging groups/catalysts for chemical biology and drug-delivery applications.

Owing to their bioorthogonality, transition metals have become very popular in the development of biocompatible bond‐cleavage reactions. However, many approaches require design and synthesis of complex ligands or formulation of nanoparticles which often perform poorly in living cells. This work reports on a method for the generation of an active palladium species that triggers bond‐cleaving reactions inside living cells. We utilized the water‐soluble Na2PdCl4 as a simple source of PdII which can be intracellularly reduced by sodium ascorbate to the active Pd0 species. Once generated, Pd0 triggers the cleavage of allyl ether and carbamate caging groups leading to the release of biologically active molecules. These findings do not only expand the toolbox of available bioorthogonal dissociative reactions but also provide an additional strategy for controlling the reactivity of Pd species involved in Pd‐mediated bioorthogonal reactions.

Owing to their bioorthogonality, transition metals have become very popular in the development of biocompatible bond-cleavage reactions. However, many approaches require design and synthesis of complex ligands or formulation of nanoparticles which often perform poorly in living cells. This work reports on a method for the generation of an active palladium species that triggers bond-cleaving reactions inside living cells. We utilized the water-soluble Na 2 PdCl 4 as a simple source of Pd II which can be intracellularly reduced by sodium ascorbate to the active Pd 0 species. Once generated, Pd 0 triggers the cleavage of allyl ether and carbamate caging groups leading to the release of biologically active molecules. These findings do not only expand the toolbox of available bioorthogonal dissociative reactions but also provide an additional strategy for controlling the reactivity of Pd species involved in Pd-mediated bioorthogonal reactions.