Phenanthridine-based nitrones as substrates for strain-promoted alkyne-nitrone cycloadditions

Over the past decade, bioorthogonal chemistry that facilitates the efficient conjugation of biomolecules has expanded from the copper-catalyzed azide-alkyne cycloadditions to a multitude of diverse reactions, varying additives and reactional partners, and most often offering better alternatives with faster rates and lower toxicity of employed reactants. Among these, the copper-free strain-promoted cycloaddition reactions have been demonstrated to be more promising, offering a reaction without toxic metal catalysts, and with faster inherent kinetic rate constants. The strain-promoted azide-nitrone cycloadditions are easily tunable from both the (strained) alkyne and nitrone perspective, both compounds giving the opportunity to modulate the rate of reaction by substituting various positions. Previously, acyclic nitrones have been evaluated in the strain-promoted alkyne-nitrone reactions, however, they were notably prone to hydrolysis. Some five-member ring endocyclic nitrones developed concomitantly offered the advantage of relatively fast kinetics and better resistance to degradation in aqueous conditions, and have been successfully used for labelling of biomolecules in living systems. Herein we have prepared and studied nitrones inspired by the phenanthridine scaffold that efficiently undergo strain-promoted alkyne-nitrone reactions. Phenanthridine nitrones react fast with strained cyclooctynes with large bimolecular rate constants while maintaining bioorthogonality and resistance to hydrolysis.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author