Cycloaddition reactions CuAAC

Keywords Bioorthogonal reaction Transition metal Cycloaddition reaction CuAAC reaction Unnatural amino acids... 

In the mechanism of the CuAAC reaction described above, the metal catalyst activates terminal alkyne for reaction with a Cu-coordinated azide. This mode of reactivity operates with other dipolar reagents as well. In fact, the first example of a copper-catalzyed 1,3-dipolar cycloaddition reaction of alkynes was reported for nitriones by Kinugasa in 1972 [124]. An asymmetric version of the Kinugasa reaction was developed by Fu et al. in 2002 [125, 126]. 

CuAAC Copper-catalyzed azide-alkyne cycloaddition reaction... 

Fig. 9 Schematic representation for the ABPP strategy using CuAAC reaction. CuAAC copper(I)-catalyzed azide-alkyne cycloaddition, ABPP activity-based protein profiling...

In addition to the Ru- and Ag-catalyzed cycloaddition reaction, Homeff and coworkers developed an Rh-catalyzed transannulation reaction of 1,2,3-triazoles with nitriles (Fig. 12) [128]. The CuAAC product iV-sulfonyl 1,2,3-triazoles remains reactive and can react with nitriles to form the imidazole products through an Rh-... 

Fig. 1 Cycloaddition reactions employed in nucleic acid labeling with reporter groups (green star). A Cu -mediated azide-alkyne cycloaddition (CuAAC) of a terminal alkyne with an azide. B Strain-promoted azide-alkyne cycloaddition (SPAAC) of an azide with a cyclooctyne derivative. C Staudinger ligation of an azide with a phosphine derivative (not a cycloaddition reaction, see below). D Norbornene cycloaddition of a nitrile oxide as 1,3-dipole and a norbornene as dipolarophile. E Inverse electron-demand Diels- Alder cycloaddition reaction between a strained double bond (norbornene) and a tetrazine derivative. F Photo-cUck reaction of a push-pull-substituted diaiyltetrazole with an activated double bond (maleimide)...

To date, a few examples of iEDDA reactions on nucleic acids in vitro and in cells were reported. In 2010, Jaschke et al. [76] reported the first example of DNA modification by the inverse-electron-demand Diels-Alder reaction between nor-bomene dienophiles and tetrazine-derivatives. 3 - and 5 -terminal labeling, as well as internal modification of DNA with norbomenes and subsequent iEDDA reaction, was demonstrated [76]. Yields of 96 % are observed using a 1 1 stoichiometry of DNA and tetrazine derivative [76]. Lower reactant concentrations and considerably lower excess of labeling reagent (usually 1 3 stoichiometry) compared to CuAAC, as well as the absence of any toxic catalysts, shows the potential of this cycloaddition reaction for in cell and in vivo applications. 

Thongh the high ef ciency, orthogonahty, and simplicity of CuAAC reactions have prompted rapid and extensive adoption of the method in the eld of macromolecular engineering, the use of copper is undesirable and a cause of concern in the context of biomaterials synthesis. This has generated interest in new metal-free azide-alkyne cycloaddition reactions (discussed below) which do not suffer from toxicity issues. 

Though tremendous success has been achieved with the development of Cu(I)-mediated Huisgen 1,3-dipolar cycloaddition reaction of azides and acetylenes as a robust and ef cient synthetic tool, it has several limitations which inclnde the need for a metal catalyst, an inability to photochemi-cally control the reaction or to conduct the reaction in the absence of solvent. In comparison, the century-old addition of thiols to alkene (the hydrothiolation of a C=C bond), which is currently called thiol-ene coupling (TEC), has many of the attributes of chck chemistry without, however, some of the aforesaid disadvantages of the CuAAC reaction. 

Describe the main criteria that should be satis ed for a reaction to be called a click reaction How would you justify the inclusion of the following reactions into the pantheon of click reactions (a) Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions (b) strain-promoted azide-alkyne coupling (SPAAC) reactions (c) Diels-Alder (DA) cycloaddition reactions (d) thiol-ene (TE) reactions and (e) thiol-yne (TY) reactions ... 

Dendritic nanoreactor 1 was also employed as a recyclable micellar nanoreactor, stabilizer, and activator of Cu -catalyzed alkyne—azide cycloaddition click reaction, CuAAC reaction, in the presence of a very low amount (only 0.1%) of Cu (hexabenzyltren) Br (tren = triaminoethylantine) catalyst, 4, in aqueous media (Fig. 6.24) [60]. 

Currently, copper-catalyzed and copper-free alkyne-azide cycloadditions are the most widely applied cycloaddition reactions for the modification of biomolecules. We developed an approach based on the combination of CuAAC or strain-promoted copper-free variants with enzymatic tailing (and optional enzymatic hgation), which allows the convenient postsynthetic introduction of an azide into existing unmodified RNA strands (chemically or enzymatically synthesized or even isolated from biological sources) at a desired position, and the subsequent functionalization with a wide variety of commercially available or self-synthesized functional alkynes [16c]. 

Even though the CuAAC is a rather new reaction, more than 800 publications on Cu AAC chck chemistry has been pubhshed (May 2008), and it has been extensively reviewed. The focus of this chapter will be on azides in 1,3-dipolar cycloaddition reactions, mainly catalyzed by transition metals, in peptide chemistry. Protein ligation and protein modification by dipolar cycloaddition reactions has been reviewed and will not be included. Angell and Burgess published an excellent review on peptidomimetics generated by CuAAC in early 2007 with a thorough overview of the field and since then more than twenty new pubhcations describing dipolar cycloaddition reactions in peptide chemistry have appeared. 

Copper-catalyzed azide-alkyne cycloadditions have become increasingly popular due to their almost quantitative formation of 1,4-substituted triazoles, regioselectively, and the remarkable functional group tolerance, which is important when dealing with peptides or peptidomimetics. The majority of publications on dipolar cycloaddition reactions in peptide chemistry has focused on the CuAAC and reported peptide bond isosteres, side-chain functionalization, glycoconjugation, macrocyclization and isotopic labeling of peptides. We will most likely see an inaeasing number of applications where peptides are modified by dipolar cycloadditions in the future. 

Below, first a brief summary of the state-of-the-art for more traditional design of dendrimers is given, after which we focus on the use of the CuAAC, Diels-Alder cycloaddition reactions and thiol-ene chemistry for the preparation of these dendritic structures. 

The use of AB2 monomers containing an internal triple bond as A-unit and two azides as B-units for the synthesis of hyperbranched polymers was developed by the same group (Figure 8.7) (Scheel et al., 2004). Hyperbranched polymers containing a mixture of 1,4- and 1,5-substituted triazoles were obtained, as the internal alkynes can only react via the classical thermal induced 1,3-dipolar cycloaddition reaction. However, it was possible to synthesize fully soluble products by low-temperature (45 °C) autopolymerization in bulk. The end product contains a large number of reactive azide functionalities that can be further postfunctionalized by CuAAC reaction with the desired alkyne-containing compound. 

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