Year: 2026
Type: article
Abstract: A bioorthogonal click-to-release reaction employing cyclooctynes and N , N -dialkylhydroxylamines is described. The reaction is characterized by a tandem retro-Cope/Cope elimination reaction sequence in which strain-promoted hydroamination of a cyclooctyne by a N , N -dialkylhydroxylamine reagent is relayed into Cope elimination of the resulting enamine N -oxide. β-elimination of the N -hydroxyenamine product then results in bond cleavage. The reaction is regioselective, the cleavage is directional, the primary hydroamination reaction exhibits second order rate constants up to 2 M -1 s -1 , and the ensuing elimination steps are not rate limiting up to millimolar levels of hydroxylamine. The transformation enables the rapid and complete cleavage of a chemical bond in biologically relevant settings using reagents with a small molecular footprint. We demonstrate the importance of reagent size in an application involving the chemical activation of protein function using hydroxylamines that are tuned for either rapid kinetics or constrained spaces. Access limitations to enzyme active sites are a major determinant of reagent choice in bioorthogonal cleavage reaction applications.
DOI: 10.1021/jacs.6c05497
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W7165942944