Copper‐Chelating Azides for Efficient Click Conjugation Reactions in Complex Media

Abstract

The concept of chelation‐assisted copper catalysis was employed for the development of new azides that display unprecedented reactivity in the copper(I)‐catalyzed azide–alkyne [3+2] cycloaddition (CuAAC) reaction. Azides that bear strong copper‐chelating moieties were synthesized; these functional groups allow the formation of azide copper complexes that react almost instantaneously with alkynes under diluted conditions. Efficient ligation occurred at low concentration and in complex media with only one equivalent of copper, which improves the biocompatibility of the CuAAC reaction. Furthermore, such a click reaction allowed the localization of a bioactive compound inside living cells by fluorescence measurements.

In Vitro and In Vivo Antiviral Studies of New Heteroannulated 1,2,3-Triazole Glycosides Targeting the Neuraminidase of Influenza A Viruses

“…The afforded azidomethyl derivatives of benzimidazole, benzoxazole, and benzothiazole, 3a-c were then allowed to react with terminal acetylenic glucopyranoside sugars 4-6, incorporating the acetylated D-glucose, D-galactose, or D-xylose moiety, under modified copper-catalyzed click 1,3-dipolar cycloaddition to produce the corresponding 1,2,3-triazole-N-linked glycosides 7-9, in 84-96% yields (Figure 3). ethanol/DMF/water in quantitative yields, as previously reported [36,37] (Figure 2). The afforded azidomethyl derivatives of benzimidazole, benzoxazole, and benzothiazole, 3ac were then allowed to react with terminal acetylenic glucopyranoside sugars 4-6, incorporating the acetylated D-glucose, D-galactose, or D-xylose moiety, under modified copper-catalyzed click 1,3-dipolar cycloaddition to produce the corresponding 1,2,3-triazole-N-linked glycosides 7-9, in 84-96% yields (Figure 3).…”

“…The 2-bromomethyl-derivatives of benzimidazole ( 2a ), benzoxazole ( 2b ), and benzothiazole ( 2c ) were prepared via an adapted procedure as shown in Figure 2 [ 33 , 34 , 35 ]. Azidation of the heteroaryl bromide 2a – c was accomplished in hot ethanol/DMF/water in quantitative yields, as previously reported [ 36 , 37 ] ( Figure 2 ). The afforded azidomethyl derivatives of benzimidazole, benzoxazole, and benzothiazole, 3a – c were then allowed to react with terminal acetylenic glucopyranoside sugars 4 – 6 , incorporating the acetylated d -glucose, d -galactose, or d -xylose moiety, under modified copper-catalyzed click 1,3-dipolar cycloaddition to produce the corresponding 1,2,3-triazole-N-linked glycosides 7 – 9 , in 84–96% yields ( Figure 3 ).…”

“…Thin-layer chromatography (TLC) was used to mentor all reactions. The benzoxazole, benzimidazole, and benzothiazole azides 3a-c were prepared by the reaction of their corresponding halide compounds 2a-c with sodium azide according to previously reported procedures [34][35][36][37][38] The terminal acetylenic sugars were prepared according to the procedure of Mereyala and Gurrala [40]. Thus, to a solution of β-D-glucopyranose pentaacetate, β-D-galactopyranose pentaacetate, or β-D-xylopyranose pentaacetate (25.6 mmol) in dichloromethane (200 mL) was added freshly distilled propargyl alcohol (1.8 mL, 30.7 mmol) and BF 3 .Et 2 O (4.8 mL, 38.4 mmol) at 0 • C, and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, anhydrous K 2 CO 3 (4.8 g) was added, and stirring was continued for a further 30 min.…”

Biomedical applications of copper-free click chemistry: in vitro, in vivo, and ex vivo

“…Bevilacqua et al and Kennedy et al also demonstrated cell labelling by CuAAC using similar bis(tert-butyltriazoly) ligand and Cu(II)-bis-L-histidine complex, respectively. 15,16 To overcome this limitation fundamentally and increase the convenience, other chemists have increased the reactivity of alkynes using ringstrain which enables an azide-alkyne reaction without the need for a cytotoxic copper catalyst. These strain-promoted azidealkyne cycloaddition reactions (SPAAC) have favourable second order reaction rate constants (approximately 0.1 M À1 s À1 ) under aqueous conditions without a catalyst.…”

Organometallic catalysis in biological media and living settings

“…Chelating azides(22) used by Taran and coworkers to form N3-Cu complexes(23) to promote the CuAAC[94].…”