Click Chemistry
Click chemistry is a new approach to synthesizing drug-like molecules that can accelerate the drug discovery process by utilizing a number of practical and reliable reactions. Chemist K B Sharpless and colleagues define a click reaction as one that is wide-ranging, easy to perform, uses only readily available reagents and is insensitive to oxygen and water. In fact, in some cases, water is the ideal reaction solvent, providing the best yields and highest rates. Post-reaction treatment and purification can be performed using benign solvents, and by-products can be removed without chromatography.1
Click Chemistry Reaction Processes
1,Fast synthesis speed
2,Modular
4,High yield
5,Strong stereoselectivity
6,Adhere to the 12 principles of Green Chemistry and only produce byproducts that can be removed without chromatography
Click Chemistry Reaction Characteristics 1
1,Simple reaction conditions
2,Easy availability of raw materials and reaction reagents
3,Do not use solvents or perform in benign solvents, preferably water
4,The product is easy to separate
5,The product remains stable under physiological conditions
The use of modular combinations in click chemistry has important applications in drug discovery, combinatorial chemistry, target-templated in situ chemistry, and DNA research. 1
In the reaction of clicking on the chemical universe, the "perfect" example is the 1,3-dipolar cycloaddition of alkynes and azides, or the Huisgen reaction, which generates 1,4-disubstituted 1,2,3-triazoles(Scheme 1). The reaction catalyzed by copper (I) is mild and very effective, does not require protective groups, and in many cases does not require purification. 2 The functional groups of azides and alkynes are essentially inert to biomolecules and aqueous environments, which enables Huisgen 1,3-dipolar cycloaddition to be used for target guided synthesis 3 and activity based protein analysis.4 Triazole is similar to the amide moiety commonly found in nature, but unlike amide, it is not easily cleaved. Besides, they are almost impossible to be oxidized or reduced.
Scheme 1
The use of Cu(II) salts with ascorbate is the preferred method for the preparation of synthetic 1,2,3-triazoles, but is problematic for biocondensation applications. However, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, TBTA (Fig. 1), has been shown to be effective in enhancing Cu-catalyzed cycloadditions without destroying the biological scaffold. 5
Fig 1. Tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine (TBTA)
Sharpless and colleagues reported on the ruthenium catalyzed cycloaddition reaction of azides with alkynes, forming complementary 1,5-disubstituted triazoles. Several ruthenium complexes were used, but pentamethylcyclopentadienyl (Cp *) analogues gave the best results, with Cp*RuCl(PPh3)2 being used in most cases. Although Cu (I) catalyzed reactions are limited to terminal alkynes, Ru (II) catalyzed reactions with internal alkynes are also active (Scheme 2).
Scheme 2
Of course, many aliphatic azides are not easily available on the market. Carreira and her colleagues recently reported that in the presence of a cobalt catalyst prepared in situ from Schiff base ligands and Co(BF4)2·6H2O, inactive olefins were hydrogenated and azided to form alkyl azides (Scheme 3). 7 In addition, this reaction can be coupled with the addition of Sharpless ring to generate 1,4-triazole in a one pot method.
Scheme 3
Reference
1. Kolb HC, Sharpless K. 2003. The growing impact of click chemistry on drug discovery. Drug Discovery Today. 8(24):1128-1137. https://doi.org/10.1016/s1359-6446(03)02933-7
2. Kolb H. 2001. Angew. Chem. Int. 402004.
3. Rostovtsev V. 2002. Angew. Chem. 412596.
4. Tornøe CW, Christensen C, Meldal M. 2002. Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides. J. Org. Chem.. 67(9):3057-3064. https://doi.org/10.1021/jo011148j
5. Manetsch R, Krasi?ski A, Radi? Z, Raushel J, Taylor P, Sharpless KB, Kolb HC. 2004. In Situ Click Chemistry: Enzyme Inhibitors Made to Their Own Specifications. J. Am. Chem. Soc.. 126(40):12809-12818. https://doi.org/10.1021/ja046382g
6. Lewis W. 2002. Angew. Chem. Int. . 411053.
Speers AE, Adam GC, Cravatt BF. 2003. Activity-Based Protein Profiling in Vivo Using a Copper(I)-Catalyzed Azide-Alkyne [3+2] Cycloaddition. J. Am. Chem. Soc.. 125(16):4686-4687. https://doi.org/10.1021/ja034490h