1st Generation Click Chemistry

1. The Click Reaction

Azido and alkyne functions can cyclise by an intramolecular CuI or Cu0 catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). This so-called Click Reaction, developed by K. Barry Sharpless and Morton Meldal, has meanwhile grown to a widely used type of reaction orthogonal to many other types of reactions in different kinds of applications. Both residues R1 and R2 can be used either as conjugation partners or as substrates. Due to its high thermodynamic driving force, usually greater than 20 kcal/mol, the click reaction normally proceeds rapidly to completion and also tends to be highly selective for a single product. A variety of azido and alkyne building blocks is available, where some can be incorporated into biomolecules by recombinant syntheses, in particular by non natural protein translation using the amber-suppression-based orthogonal system or by chemical reactions, for example by solid phase synthesis. Then the conjugation with a second molecule carrying the appropriate other function can be done. Tris(benzyltriazolylmethyl)amine (TBTA; RL-2010; see p. 72) is stabilizing copper(I) towards oxidation in solution by forming a complex and catalyzes effectively quantitative, regioselective Huisgen 1,3-dipolar cycloadditions between alkynes and azides (the so called ‚click‘ cycloaddition reaction), in a variety of aqueous and organic solvents. In the literature, it has been gaining widespread use as a biochemical tool for the tagging of proteins and enzymes.

References:

• A stepwise Huisegen cycloaddition process: copper (I)-catalyzed regioselective ligation of azides and terminal alkynes; Vsevolod V. Rostovtsev, Luke G. Green and K. Barry Sharpless; Angew. Chem. Int. Ed. 2002; 41: 2596-2599.
• Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(I)-catalyzed 1,3-dipolar cycloaddition of terminal alkynes to azides; Christian W. Tornøe, Caspar Christensen; Morten Meldal; J.Org.Chem. 2002; 67: 3057-3064.
• Click Chemistry: Diverse Chemical Function from a Few Good Reactions; Hartmuth C. Kolb, M. G. Finn, and K. Barry Sharpless, Angew. Chem., Int. Eng. Ed. 2001; 40: 2004-2021.
• The growing impact of click chemistry on drug discovery; Hartmuth C. Kolb and K. Barry Sharpless; Drug Discovery Today 2003; 8(24): 1128-1131.
• Cu-I-Catalyzed Alkyne-Azide „Click“ Cycloadditions from a Mechanistic and Synthetic Perspective; Victoria C. Bock, Henk Hiemstra and Jan H. van Maarseveen; Eur. J. Org. Chem. 2006; 1: 51-68.
• A3-Type Star Polymer via Click Chemistry; O. Altintas, B. Yankul, G. Hizal and U. Tunca; J. Poly. Sci.: Part A, Polymer Chem. 2006; 44: 6458-6465.
• Preparation of alumina supported copper nanoparticles and their application in the synthesis of 1,2,3- triazoles; M. Lakshmi Kantam et al.; J. Mol. Catal. A: Chem. 2006; 256: 273-277.
• A Rapid and Versatile Method to Label Receptor Ligand Using „Click“ Chemistry: Validation with the Muscarinic M1 Antagonist Pirenzepine; Dominique Bonnet et al.; Bioconjugate Chemistry 2006; 17: 1618-1623.
• Alkyne-azide click reaction catalyzed by metallic copper under ultrasound; Pedro Cintas et al.; Nature Protocols 2010; 5(3): 607-616.
• Synthesis of a DOTA-Biotin Conjugate for Radionuclide Chelation via Cu-Free Click Chemistry; Michael K. Schultz, Sharavathi G. Parameswarappa, and F. Christopher Pigge; Org. Lett. 2010; 12(10): 2398-2401.
• Polytriazoles as Copper(I)-Stabilizing Ligands in Catalysis; Timothy R. Chan, Robert Hilgraf, K. Barry Sharpless, and Valery V. Fokin; Org. Lett. 2004; 6(17): 2853–2855. doi:10.1021/ol0493094.
• “Click” Cycloaddition Catalysts: Copper(I) and Copper(II) Tris(triazolylmethyl)amine Complexes; Paul S. Donnely et al.; Chem. Commun. 2008; (21): 2459–2461. doi:10.1039/b719724a