Angew. Chem. Int. Ed. Engl., doi:10.1002/anie.201305645

The discovery of new chemical reactions can be driven by serendipity, rational design or—increasingly—screening. Recent research reported the use of sandwich immunoassays as a method to identify coupling of fragments attached to antibody tags. Kolodych et al. now employ this method to search for new [3+2] cycloaddition reactions akin to the well-known Huisgen cycloaddition, or azide-alkyne click reaction. The authors screened 11 dipoles, 8 'dipolarophiles' and 31 transition metal catalysts in 96-well plates; of the nearly 3,000 reactions tested, 51 yielded hits, and 42 of these were new. As the initial yields were low, the authors further optimized the reactions by screening different reaction conditions; once improved, the reactions were analyzed to determine their efficiency, chemoselectivity and cross-reactivity with biological samples. Four reactions reached yields of more than 50% after optimization, and one of these—the coupling of arylsydnones with alkynes—is a known reaction but has always required harsh conditions to yield limited product. The reaction screening performed here identified copper phenanthroline complexes as catalysts able to reach up to 99% yield and capable of converting a variety of substrates, even in the presence of cell culture media. This 'Cu-catalyzed sydnone-alkyne cycloaddition' (CuSAC) is a welcome addition to the chemical biologist's toolbox.