Copper-catalyzed azide-alkyne cycloaddition ligation

Figure 5. Bioorthogonal reactions on sugars, A. Ketones react with hydrazides to give hydrazones. B. Thiols undergo Michael Reaction with maleimides. C, Azides undergo Staudinger ligation with phosphines or D. strain-promoted or copper catalyzed [3 2] cycloaddition with all nes. E. Alkynes undergo copper-catalyzed [3- 2] cycloaddition with azides.

To date, four bioorthogonal reactions have been used to label glycans on cells and in lysates hydrazone/oxime formation with ketones, thiol alkylation with maleimides, Staudinger ligation of azides with triaryl phosphines, and copper-catalyzed or strain-promoted [3+2] cycloadditions of alkynes and azides (Figure 5) (25, 26, 32, 34, 35). While each reaction has been used extensively, most recent applications have employed azido- or alkynyl-sugars due to their superior metabolic incorporation and efficient ligations. 

V. V. Rostovtsev, L. G. Green, V. V. Fokin, and K. B. Sharpless, A stepwise Huisgen cycloaddition process Copper(I)-catalyzed regioselective ligation of azides and terminal alkynes, Angew. Chem. Int. Ed., 41 (2002) 2596-2599. 

Following reports of efficient Cu(I)-catalyzed alkyne/azide cycloaddition on solid phase and in solution by Meldal [42] and Sharpless [43], respectively, the formerly obscure Huisgen reaction soared to prominence as a versatile tool for covalent chemical ligation. The so-called click reaction can be catalyzed by a number of copper sources in a variety of media (Equation 9.14). 

Functionalized 1,2,3-triazoles 86 and 87 were prepared by [2 + 3] cycloadditions of resin-bound a-azido esters 85 with substituted alkynes <02TL4059>. Regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of resin-bound alkynes 88 with azides afforded solid-supported 1,2,3-triazoles 89, which were ligated further to give 1,4-substituted-1,2,3-triazole peptide compounds <02JOC3057>. 

Rostovtsev, V.V., Green, L.G., Fokin, V.V., and Sharpless, K.B. (2002). A stepwise Huisgen cycloaddition process copper (l)-catalyzed regioselective "ligation" of azides and terminal alkynes. Angew Chem Int Ed 41 2596-2599. 

The copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) reaction [1] (Fig. lA) has been extensively employed for the site-specific labeling of oligonucleotides with various reporter groups [3,4, 7, 9,12-16], ligating DNA strands [17, 18], cross-linking complementary strands [19], for surface functionalization [20] and for the formation of bimetallic Ag-Au nanowires from DNA templates [21], Selected examples are described in the following section. 

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