Metal‐ and Strain‐Free Bioorthogonal Cycloaddition of o‐Diones with Furan‐2(3H)‐one as Anionic Cycloaddend

Abstract

The development of new bioorthogonal reactions with mutual orthogonality to classic bioorthogonal reactions such as the strain-promoted azide-alkyne click reaction and the inverse-electron-demand Diels-Alder reaction is of great importance in providing chemical tools for multiplex labelling of live cells. Here we report the first anionic cycloaddend-promoted bioorthogonal cycloaddition reaction between phenanthrene-9,10-dione and furan-2(3H)-one derivatives, where the high polarity of water is exploited to stabilize the highly electron-rich anionic cycloaddend. The reaction is metaland strain-free, which proceeds rapidly in aqueous solution and on live cells with a second-order rate constant up to 119 M À 1 s À 1 . The combined utilization of this reaction together with the two other widely used bioorthogonal reactions allows for mutually orthogonal labelling of three types of proteins or three groups of living cells in one batch without cross-talking. Such results highlight the great potential for multiplex labelling of different biomolecules in live cells.

Synthesis of Methylene Tetrahydrofurane‐Fused Carbohydrates

“…In 2018, the photoclick reaction between 9,10‐phenanthraquinone and electron rich alkenes, such as vinyl ethers to produce fluorogenic cycloadducts was reported [34] . Besides the synthetic significance of this type of photochemical reactions, the resulting fluorescent properties of the products have also been exploited in bioorthogonal labeling experiments to visualize polymers, proteins and even cells [34,47,48] . Their use has been also reported in 18 F‐PET tracers [49] .…”

Fluorescence turn-on by photoligation – bright opportunities for soft matter materials

“…112 However, it should be noted that the PQ can spontaneously and rapidly react with furan-2(3H)-one derivatives, via thermal cycloaddition, in water. 113 Since its report in 2018, the PQ-VE photoligation has gained considerable traction in so matter materials applications. Specically, Adronov and co-workers prepared a conjugated polymer that contains the PQ moiety in the backbone, and effectively functionalised the polymer with several electron-rich alkenes under visible light irradiation, forming uorescent pendent groups.…”

“… 112 However, it should be noted that the PQ can spontaneously and rapidly react with furan-2(3H)-one derivatives, via thermal cycloaddition, in water. 113 …”

Hydrazonyl Sultones as Stable Tautomers of Highly Reactive Nitrile Imines for Fast Bioorthogonal Ligation Reaction

“…In particular, the ring–chain tautomerism, in which one of the tautomers is in the cyclic form, is crucial in biological chemistry. More recently, less stable minor tautomers but with high reactivity have been exploited in the concerted cycloaddition reactions. , In harnessing reactive intermediates for bioorthogonal reactions, here we report the design and synthesis of hydrazonyl sultones (Figure c) as stable tautomers of the highly reactive nitrile imines, the characterization of their stability in aqueous media and their selective reactivity toward bicyclo[6.1.0]­non-4-yn-9-ylmethanol (BCN) in the 1,3-dipolar cycloaddition reaction, and the demonstration of their utility in bioorthogonal modification of proteins in solution and on live cells.…”