CLICK CHEMISTRY: A "CLICK" AWAY FROM DISCOVERY

The traditional process of drug discovery based on natural secondary metabolites has often been slow, costly, and labor-intensive. Even with the advent of combinatorial chemistry and high-throughput screening in the past two decades, the generation of leads is dependent on the reliability of the individual reactions to construct the new molecular framework.

Click chemistry is a newer approach to the synthesis of drug-like molecules that can accelerate the drug discovery process by utilizing a few practical and reliable reactions. Sharpless and coworkers defined what makes a click reaction as one that is wide in scope and easy to perform, uses only readily available reagents, and is insensitive to oxygen and water. In fact, in several instances water is the ideal reaction solvent, providing the best yields and highest rates. Reaction work-up and purification uses benign solvents and avoids chromatography.¹

Of the reactions comprising the click universe, the “perfect” example is the Huisgen 1,3-dipolar cycloaddition of alkynes to azides to form 1,4-disubsituted-1,2,3-triazoles (Scheme 1). The copper(I)-catalyzed reaction is mild and very efficient, requiring no protecting groups, and requiring no purification in many cases.²The azide and alkyne functional groups are largely inert towards biological molecules and aqueous environments, which allows the use of the Huisgen 1,3-dipolar cycloaddition in target guided synthesis³ and activity-based protein profiling.⁴ The triazole has similarities to the ubiquitous amide moiety found in nature, but unlike amides, is not susceptible to cleavage. Additionally, they are nearly impossible to oxidize or reduce.

Using Cu(II) salts with ascorbate has been the method of choice for preparative synthesis of 1,2,3-triazoles, but is problematic in biocojugation applications. However, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine, TBTA (Figure 1), has been shown to effectively enhance the copper-catalyzed cycloaddition without damaging biological scaffolds.⁵

Recently, Sharpless and coworkers reported the ruthenium-catalyzed cycloaddition of azides to alkynes to form the complementary 1,5-disubstituted triazoles.⁶ Several ruthenium complexes were employed, but the pentamethylcyclopentadienyl (Cp*) analogues gave the best results, with Cp*RuCl(PPh₃)₂ being employed in most cases. Whereas the Cu(I)-catalyzed reaction is limited to terminal alkynes, the Ru(II)-catalyzed reaction is active with internal alkynes as well (Scheme 2).

Of course many aliphatic azides are not commercially available. Carreira and coworkers recently reported the hydroazidation of unactivated olefins to yield alkyl azides in the presence of a cobalt catalyst prepared in situ from a Schiff base ligand and Co(BF₄)₂·6H₂O (Scheme 3).⁷ Additionally, the reaction can be coupled to the Sharpless cycloaddition to yield the 1,4-triazole in a one-pot process.

Sigma-Aldrich is pleased to offer these reagents and substrates for your research requirements in the exciting field of click chemistry.

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References:

1. For recent reviews, see: (a) Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128. (b)Kolb, H. C. et al. Angew. Chem. Int. Ed. 2001, 40, 2004.
2. (a) Rostovtsev, V. V. et al. Angew. Chem. Int. Ed.2002, 41, 2596.  (b) Tornøe, C. W. et al. J. Org. Chem. 2002, 67, 3057.
3. (a) Manetsch, R. et al. J. Am. Chem. Soc.2004, 126, 12809. (b) Lewis, W. G. et al.Angew. Chem. Int. Ed. 2002, 41, 1053.
4. Speers, A. E. J. Am. Chem. Soc. 2003, 125, 4686.
5. Chan, T.R. et al. Org. Lett 2004,6, 2853.
6. Zhang, L. et al. J. Am. Chem. Soc. 2005,127, 15998.
7. Waser, J. et al. J. Am. Chem. Soc. 2005,127, 8294.