Design and Synthesis of Iminosydnones for Fast Click and Release Reactions with Cycloalkynes.

Emerging applications in the field of chemical biology are currently limited by the lack of bioorthogonal reactions allowing both removal and linkage of chemical entities on complex biomolecules. We recently discovered a novel reaction between iminosydnones and strained alkynes leading to two products resulting from ligation and fragmentation of iminosydnones under physiological conditions. We now report the synthesis of a panel of substituted iminosydnones and the structure reactivity relationship between these compounds and strained alkyne partners. This study identified the most relevant substituents, which allow to increase the rate of the transformation and to develop a bifunctional cleavable linker with improved kinetics.

Bioorthogonal Click and Release Reaction of Iminosydnones with Cycloalkynes.

We report the discovery of a new bioorthogonal click-and-release reaction involving iminosydnones and strained alkynes. This transformation leads to two products resulting from the ligation and fragmentation of iminosydnones under physiological conditions. Optimized iminosydnones were successfully used to design innovative cleavable linkers for protein modification, thus opening up new areas in the fields of drug release and target-fishing applications. This click-and-release technology offers the possibility of exchanging tags on proteins for functionalized cyclooctynes under mild and bioorthogonal conditions.

Ultrafast Click Chemistry with Fluorosydnones.

We report the synthesis and reactivity of 4-fluorosydnones, a unique class of mesoionic dipoles displaying exquisite reactivity towards both copper-catalyzed and strain-promoted cycloaddition reactions with alkynes. Synthetic access to these new mesoionic compounds was granted by electrophilic fluorination of σ-sydnone Pd(II) precursors in the presence of Selectfluor. Their reactions with terminal and cyclic alkynes were found to proceed very rapidly and selectively, affording 5-fluoro-1,4-pyrazoles with bimolecular rate constants up to 10(4) m(-1) s(-1) , surpassing those documented in the literature with cycloalkynes. Kinetic studies were carried out to unravel the mechanism of the reaction, and the value of 4-fluorosydnones was further highlighted by successful radiolabeling with [(18) F]Selectfluor.

One-pot synthesis of 1,4-disubstituted pyrazoles from arylglycines via copper-catalyzed sydnone-alkyne cycloaddition reaction.

A robust method for constructing 1,4-pyrazoles from arylglycines was developed using the copper-catalyzed sydnone-alkyne cycloaddition reaction. The procedure offers a straightforward and general route to the pyrazole heterocycle through a three-step one-pot procedure.

Accelerated Discovery in Photocatalysis by a Combined Screening Approach Involving MS Tags.

Herein we report on the development of an MS tag screening strategy that accelerates the discovery of photocatalytic reactions. By efficiently combining mechanism- and reaction-based screening dimensions, the respective advantages of each strategy were retained, whereas the drawbacks inherent to each screening approach could be eliminated. Applying this approach led to the discovery of a mild photosensitized decarboxylative hydrazide synthesis from mesoionic sydnones and carboxylic acids as starting materials.

Sydnone-coumarins as clickable turn-on fluorescent sensors for molecular imaging.

Copper-catalyzed and copper-free sydnone-alkyne cycloaddition reactions have emerged as complementary click tools for chemical biology but their use in bioorthogonal labeling is still in its infancy. Herein, combinations of alkynes and coumarin-sydnones were screened for their ability to generate pyrazole products displaying strong fluoroscence enhancement compared to reactants. One sydnone was identified as a particularly suitable new turn-on probe for protein labeling.

Sydnone-alkyne cycloaddition: applications in synthesis and bioconjugation.

Sydnones are among the most popular mesoionic compounds studied so far for cycloaddition reactions. However, despite their good chemical stability and versatility, only a limited number of research groups have worked on their chemistry and use in organic synthesis. This feature article aims at providing an overview of the most recent developments in sydnone-alkyne cycloadditions, with particular attention on the strategies that allow us to achieving high regiocontrol and milder reaction conditions. The recent discovery that this dipole is able to undergo click and biorthogonal reactions with cycloalkynes may stimulate renewed interest from the scientific community. Given the high potential and flexibility of this family of mesoionics, we believe that major developments are to be expected both in terms of organic synthetic methodologies and biorthogonal chemistry applications in the field of chemical biology.

Copper(I)-catalyzed cycloaddition of 4-bromosydnones and alkynes for the regioselective synthesis of 1,4,5-trisubstituted pyrazoles.

Copper-catalyzed cycloaddition of alkynes with 4-bromosydnones provides a convenient, mild, and regioselective method for the synthesis of a wide range of bromopyrazoles. The broad functional group tolerance of the cycloaddition reaction and further palladium-catalyzed cross-coupling reactions allowed the preparation of polyfunctionalized 1,4,5-pyrazoles that are otherwise difficult to obtain by conventional methods.

4-Halogeno-sydnones for fast strain promoted cycloaddition with bicyclo-[6.1.0]-nonyne.

New sydnone derivatives have been synthesized and screened for their capacity to undergo fast copper-free cycloaddition reaction with bicyclo-[6.1.0]-nonyne. The influences of substitution in positions N-3 and C-4 of sydnones have been particularly studied leading to the identification of highly reactive partners for bio-orthogonal ligation reactions.