Azides cycloaddition, applications

Click chemistry also found applications in peptides and peptidomimetics. Alkyne-azide cycloaddition between two peptide strands provided an efficient convergent synthesis of triazole ring-based P-tum mimics <07CC3069>. The synthesis of a-substituted prolines has been accomplished by microwave-assisted Huisgen 1,3-dipolar cycloaddition between azides and orthogonally protected a-propynyl proline in the presence of Cu(I) sulfate <07SL2882>. The synthesis of new trifluoromethyl peptidomimetics with a triazole moiety has been reported <07TL8360>. 

Liang L, Astruc D (2011) The copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction and its applications. An overview. Coord Chem Rev 255 2933-2945... 

Click chemistry is commonly used in organic synthesis due to its high yield and its rapid kinetic. Although Cu-catalyzed allqme-azide cycload-dition, also called CuAAC, is the most utilized one, " " the intrinsic toxicity of the copper catalyst and its associated removal difficulties limit its application in biology. For instance, to improve dendrimer s water solubility, PEG groups are often incorporated via this method but a recent study conducted by Week and coworkers has observed substantial copper contamination in them. Copper-free strain promoted allq ne-azide cycloaddition (SPAAC) has been more and more employed to avoid this drawback.Nevertheless this last method introduces rigid cyclooctatriazole units that can modify the dendrimer scaffold and thus its properties. 

Kappe and co-workers proposed an application of a microwave-assisted Huisgen 1,3-dipolar cycloaddition of terminal acetylenes and azides 70, imder Cu(I) catalysis, as an example of click chemistry to obtain a collection of... 

In another paper, the same authors investigated the 1,3-dipolar cycloaddition on 2-(lH)-pyrazine scaffolds 72 and electron-rich azides, using Cu(0) and CUSO4 as pre-catalysts. To demonstrate the versatility of this approach, they reported the generation of different templates (73 in Scheme 25) as an application of cUck chemistry . They also investigated the Diels-Alder reaction of the so obtained triazoles with dimethyl acetylenedicarboxylate (DMAD), under microwave irradiation. The latter reaction allowed obtaining various pyridinones in good yields (74 and 75 in Scheme 25) [57]. 

An in depth account of intramolecular 1,3-dipoIar cycloadditions involving dipoles such as nitrUe oxides, sUyl nitronates, H-nitrones, azides, and nitrUimines is presented with particular emphasis on the stereochemistry during the cycloaddition. Various methods employed for the generation of the dipoles and their applications to stereoselective synthesis are also discussed. 

Click chemistry has been particularly active in various fields this year. For example, ample applications of click chemistry have been seen in carbohydrate chemistry. Various /weiido-oligosacchardies and amino acid glycoconjugates were synthesized via an intermolecular 1,3-dipolar cycloaddition reaction using easily accessible carbohydrate and amino acid derived azides and alkynes as building blocks <06JOC364>. The iterative copper(I)-catalyzed... 

S. Dedola, S. A. Nepogodiev, and R. A. Field, Recent applications of the Cul-catalysed Huisgen azide-alkyne 1,3-dipolar cycloaddition reaction in carbohydrate chemistry, Org. Biomol. Chem.., 5 (2007) 1006-1017. 

If the cycloaddition and cycloreversion steps occurred under the same conditions, an equilibrium would establish and a mixture of reactant and product olefins be obtained, which is a severe limitation to its synthetic use. In many cases, however, the two steps can very well be separated, with the cycloreversion under totally different conditions often showing pronounced regioselectivity, e.g. for thermodynamic reasons (product vs. reactant stability), and this type of olefin metathesis has been successfully applied to organic synthesis. In fact, this aspect of the synthetic application of four-membered ring compounds has recently aroused considerable attention, as it leads the way to their transformation into other useful intermediates. For example aza[18]annulene (371) could be synthesized utilizing a sequence of [2 + 2] cycloaddition and cycloreversion. (369), one of the dimers obtained from cyclooctatetraene upon heating to 100 °C, was transformed by carbethoxycarbene addition to two tetracyclic carboxylates, which subsequently lead to the isomeric azides (368) and (370). Upon direct photolysis of these, (371) was obtained in 25 and 28% yield, respectively 127). Aza[14]annulene could be synthesized in a similar fashion I28). 

Since the discovery of triazole formation from phenyl azide and dimethyl acetylenedicarboxylate in 1893, synthetic applications of azides as 1,3-dipoles for the construction of heterocychc frameworks and core structures of natural products have progressed steadily. As the 1,3-dipolar cycloaddition of azides was comprehensively reviewed in the 1984 edition of this book (2), in this chapter we recount developments of 1,3-dipolar cycloaddition reactions of azides from 1984 to 2000, with an emphasis on the synthesis of not only heterocycles but also complex natural products, intermediates, and analogues. 

For intramolecular 1,3-dipolar cycloadditions, the application of nitrones and nitrile oxides is by far most common. However, in increasing frequency, cases intramolecular reactions of azomethine ylides (76,77,242-246) and azides (247-259) are being reported. The previously described intermolecular approach developed by Harwood and co-workers (76,77) has been extended to also include intramolecular reactions. The reaction of the chiral template 147 with the alkenyl aldehyde 148 led to the formation of the azomethine ylide 149, which underwent an intramolecular 1,3-dipolar cycloaddition to furnish 150 (Scheme 12.49). The reaction was found to proceed with high diastereoselectivity, as only one diaster-eomer of 150 was formed. By a reduction of 150, the proline derivative 151 was obtained. 

Acyl azides which produce the nitrenes 3 and 4 upon photolysis are the most suitable for synthetic applications of cycloaddition reactions. Therefore, this subchapter will mainly deal with alkoxycarbonyl and aroyl nitrenes. 

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