Bioorthogonal Azide-Thioalkyne Cycloaddition Catalyzed by Photoactivatable Ruthenium(II) Complexes.

Alejandro Gutiérrez‐González,Paolo Destito,José L Mascareñas,Fernando López,Cibran Pérez‐González,José R Couceiro

doi:10.1002/anie.202103645

Abstract

Tailored ruthenium sandwich complexes bearing photoresponsive arene ligands can efficiently promote azide–thioalkyne cycloaddition (RuAtAC) when irradiated with UV light. The reactions can be performed in a bioorthogonal manner in aqueous mixtures containing biological components. The strategy can also be applied for the selective modification of biopolymers, such as DNA or peptides. Importantly, this ruthenium‐based technology and the standard copper‐catalyzed azide–alkyne cycloaddition (CuAAC) proved to be compatible and mutually orthogonal.

Highlights

Bioorthogonal reactions, by enabling the covalent modification of specific reactants or biomolecular targets in complex biological environments, have brought a paradigm shift on the potential of chemistry for interrogating or/and altering biology.[1,2] Within the “toolbox” of bioorthogonal reactions, those that are catalyzed by transition metals are especially attractive, owing to their intrinsic metal-dependent characteristics, and the possibility of tuning the reactivity by adjusting the characteristics of the catalyst.[3]
Several control experiments and careful analysis by NMR and ESI-MS allowed to discover that the poorer performance of Ru2 was likely due to the formation of secondary ruthenium-containing products
We could identify Ru2’, which results from an unprecedented ruthenium-promoted trimerization of thioalkynes, a process that generates a chelating dithiofulvene ligand (Figure 2).[18]

Summary

Introduction

Bioorthogonal reactions, by enabling the covalent modification of specific reactants or biomolecular targets in complex biological environments, have brought a paradigm shift on the potential of chemistry for interrogating or/and altering biology.[1,2] Within the “toolbox” of bioorthogonal reactions, those that are catalyzed by transition metals are especially attractive, owing to their intrinsic metal-dependent characteristics, and the possibility of tuning the reactivity by adjusting the characteristics of the catalyst.[3]. Chemie related cycloadditions in water, using nickel,[12] rhodium[13] or iridium catalysts,[14] albeit only the latter has been shown to operate in biological mixtures All these new metal-catalyzed azide–alkyne cycloaddition reactions, including our ruthenium-catalyzed process, have demonstrated effectivity only when the concentration of reagents is in the mid to high millimolar range. We demonstrate that this technology is fully orthogonal with the CuAAC and, it can be used for the chemoselective modifications of small peptides and ssDNAs, for instance, for the introduction of fluorogenic tags

Results and Discussion

Conclusion

Conflict of interest