Toward a Click-to-Click Strategy Enabled by Sequential Reverse Cope Cyclization and Strain-Promoted Alkyne-Nitrone Cycloaddition of In Situ Generated Nitrones.

Primary hydroxylamines rapidly react with strained cyclooctynes under mild conditions to produce nitrones. A diverse set of RNHOH derivatives, including amino-acid- and carbohydrate-based substrates, undergo efficient coupling with BCN to furnish the corresponding nitrones in good yields. Comparison of several cyclooctynes highlights substantial differences in reactivity, with DBCO-acid displaying the fastest reaction (k2 > 23 M-1 s-1). The resulting nitrones can subsequently participate in strain-promoted alkyne-nitrone cycloaddition (SPANC) reactions, enabling a sequential "click-to-click" ligation of up to three components.