On‐Demand Ligate and Release Strategy Based on Photoclick Reaction in Tandem with Pd‐Mediated Deallylation

Abstract The development of chemoselective tools that can conjugate, modify, and decouple chemical groups from biomacromolecules has enabled the study of biological processes at increasing levels of fidelity. Until recently, these tools can either couple chemical entities to biomacromolecules or decouple them, but not both. A method that can perform these functions in distinct steps on demand would be highly useful. To that end, we devised a new‐to‐nature strategy by bringing together and modifying two biocompatible transformations. In this new strategy, ligation is accomplished via the photoclick reaction between an allenyl motif with 9,10‐phenanthrenequinone which installs an allyl group at the site of conjugation. This allyl group can then be selectively utilized as a handle for phenolic release via Pd‐mediated deallylation. As a proof of concept, we demonstrated its utility in the selective labeling and delabeling of model protein scaffolds and cellular matrix. This multifunctional method paves the way for a controllable “ligate and release” strategy that enables on‐demand visualization of biological entities but with an in built release mechanism to restore their original state.