Click and Copper-free Click Chemistry

The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between azides and alkynes to form 1,2,3-triazoles, as reported1 by Sharpless, was found to be so exquisitely regioselective and efficient at even the most mild conditions that Sharpless coined the term ‘Click Chemistry’ to describe it.  The use of this method for DNA modification has been somewhat delayed by the fact that copper ions damage DNA, typically yielding strand breaks.2 As these problems have now been overcome by the use of copper(I)-stabilizing ligands (e.g., tris(benzyltriazolylmethyl)amine, TBTA3), Carell et al. and Seela et al. discovered that the CuAAC reaction can be used to functionalize alkyne-modified DNA nucleobases with extremely high efficiency.4 

At Glen Research, our goal was to offer a copper-free click phosphoramidite reagent with the following properties:

  • Simple to use
  • Stable in solution on the synthesizer
  • Stable to ammonium hydroxide and AMA<
  • Excellent click performance in 17 hours or less at room temperature

From the variety of cyclooctyne-based copper-free click reagents so far described, we have chosen to offer compounds based on a dibenzo-cyclooctyne (DBCO) structure. 


References

[1] C.W. Tornoe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057-3064; V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. 2002, 114, 2708-2711; Angew. Chem. Int. Ed. 2002, 41, 2596-2599. [2] C. J. Burrows, J. G. Muller, Chem. Rev. 1998, 98, 1109 – 1151. [3] T. R. Chan, R. Hilgraf, K. B. Sharpless, V. V. Fokin, Org. Lett. 2004, 6, 2853 – 2855. [4] J. Gierlich, G. A. Burley, P. M. E. Gramlich, D. M. Hammond, T. Carell, Org. Lett. 2006, 8, 3639-3642. F. Seela, V. R. Sirivolu, Chem. Biodiversity 2006, 3, 509-514.


Explore Click and Copper-free Click Chemistry Monomers, Supports, and Kits

Our products for click and copper-free click chemistry are produced and packaged to ensure the highest performance on commercial synthesizers.

From the variety of cyclooctyne-based copper-free click reagents we have chosen to offer compounds based on a dibenzo-cyclooctyne (DBCO) structure.

Oligo-Click Kits contain an air-stable, insoluble Cu(I) source in pellet form in a pre-loaded and ready-to-use vial. Within the kit, the TBTA ligand is replaced by an activator which is compatible with both aqueous and organic solvents.

We have found THPTA to be a highly efficient ligand for click chemistry with working ranges from 10nmol up to 1000nmol, in partially organic and completely aqueous reactions. Labeling is complete in as little as 15 minutes at room temperature. The ligand CuSO4 complex exhibits no loss of activity when frozen for at least a month.

Glen Research offers our most popular labels for general interest as azides and have subsequently added azide products that are not compatible with phosphoramidite chemistry.