Click Chemistry in Drug Discovery
Among the click chemical reaction family, the most interesting one may be the Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction between terminal alkynes and organic azides (Huisgen reaction) to produce 1,4-disubstituted 1,2,3-triazoles (Scheme 1).1 As a "good" click reaction, this reaction is reliable, high-yield, easy to carry out, unaffected by air or moisture, and tolerant of a wide range of functional groups. In many cases, water is the ideal reaction solvent, providing the best yield and fastest reaction rate. Normally, the cycloaddition product is a solid and does not require chromatographic purification. The 1,2,3-triazole ring has stable chemical properties and is not easily hydrolyzed, oxidized, reduced, or other modes of cleavage. The above characteristics make Cu(I-catalyzed azide-alkyne acetylene cyclization an important means of developing drug molecular libraries in the process of new drug development.2
Scheme1
The use of Cu(II) salts to form catalytically active Cu(I) in the presence of ascorbic acid as a reducing agent has been the method of choice for the preparation and synthesis of 1,2,3-triazoles, but may be problematic for biocoupling applications. Cu(I) salts such as [Cu(CH3CN)4]PF6 can be used directly in the presence of the stabilizing ligand tris[(1-phenylmethyl-1H-1,2,3-triazol-4-yl) methyl]amine, TBTA (Figure 1).3 TBTA has been shown to effectively enhance copper-catalyzed cycloaddition reactions without destroying the biological scaffold.
Figure1. TBTA（T162437）
Although the click reaction catalyzed by Cu(I) provides a pathway to obtain 1,4-disubstituted triazole, transition metal variants can obtain complementary 1,5-disubstituted triazole isomers. In the presence of catalyst Cp*RuCl(PPh3)2, treating terminal or internal alkynes with azides provides a high yield cycloadduct with fully controlled region specificity (Scheme 2). 4
Scheme2
Many organic azides are not readily available on the market.Carreira and colleagues recently reported the Co(II)-catalyzed hydroazidation of unactivated olefins with tosyl azide (TsN3) to afford alkyl azides (Scheme 3).5 The catalyst was readily prepared in situ from Co(BF4)2-6H2O and Schiff base ligands. It is compatible with mono-, di-, and tri-substituted olefins in the hydrogen azide reaction and fully demonstrates theMarkovnikov selectivity. In addition, the reaction can be coupled with Sharpless triazole cycloaddition to give 1,4-triazoles in a one-pot method.
Scheme3
Aladdin can provide a wide range of reagents, catalysts and ligands for your click chemistry research needs.
Reference
1.Rostovtsev V. 2002. Angew. Chem.. Int. Ed.. 412596.
2.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
3.Kolb H. 2001. Angew. Chem.,. Int. Ed. 402004.
4.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
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