Abstract
The Kinugasa reaction has become an efficient method for the direct synthesis of β-lactams from substituted nitrones and copper(I) acetylides. In recent years, the reaction scope has been expanded to include the use of water as the solvent, and with micelle-promoted [3+2] cycloadditions followed by rearrangement furnishing high yields of β-lactams. The high yields of stable products under aqueous conditions render the modified Kinugasa reaction amenable to metabolic labelling and bioorthogonal applications. Herein, the development of methods for use of the Kinugasa reaction in aqueous media is reviewed, with emphasis on its potential use as a bioorthogonal coupling strategy.
Highlights
Nitrones are emerging as biocompatible 1,3-dipoles that are tunable, hydrolytically stable, and highly reactive in cycloadditions with strained alkynes forming stable isoxazoline ring structures [1,2,3,4,5,6]
Recent progress in expanding the scope of the reaction has afforded the transition from requiring polar aprotic reaction media to an ‘on water’ approach, as well as employing detergents to allow for a micelle-promoted reaction to occur in aqueous medium [12]
Bioorthogonal labelling strategies, which are employed to chemically link reporter molecules to biomolecular targets in live environments, require the use of rapid and selective coupling reactions that proceed in a non-toxic manner under physiological conditions [14,15,16,17,18,19]
Summary
Nitrones are emerging as biocompatible 1,3-dipoles that are tunable, hydrolytically stable, and highly reactive in cycloadditions with strained alkynes forming stable isoxazoline ring structures [1,2,3,4,5,6]. A wide variety of ligation strategies has been developed over the past decade for this purpose which makes use of exogenous functional groups that cause minimal disruption of the native biochemical processes occurring in the delicate reaction medium These coupling reactions are propelled by a selection of driving forces, such as the release of ring strain [1,20,21], the expulsion of environmentally benign gasses [22,23], or the formation of strong amide bonds at the expense of weaker linkages executed through condensation [24] or rearrangement [13]. Despite the variety of reaction modes, each bioorthogonal labelling strategy is rooted by a common goal: to covalently link two modular components as efficiently as possible [25] With this perspective in mind, existing chemistries can be rejuvenated and optimized for application in a variety of new environments. Rearrangement (CuANCR) [13]—as a bioorthogonal strategy for metabolic labelling
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