Copper -free cycloaddition cyclooctyne derivatives

A drawback of the copper(l)-catalyzed variant of this reaction is the presence of the transition metal, which is potentially toxic for hving cells. Therefore, ring-strained cyclooctyne derivatives have been introduced as substrates for the azide-alkyne cycloaddition whose reaction with the azide does not require a transition metal catalyst (Figure 16). The driving force of the corresponding copper-free click reaction stems for the release of ring strain associated with the conversion of the cyclooctyne s triple bond into a double bond. Fluorine substituents make the system even more reactive. ... 

The [3+2] cycloaddition reaction of azides with terminal olefins is of considerable interest in the modification of biomolecules, because the azide group is abiotic in animals. Especially, the Cu(i) catalyzed cycloaddition reaction of azides with terminal alkynes achieves regioselective formation of 1,4-disubstituted 1,2,3-triazoles and this reaction is currently referred to as click chemistry . In the thermal reaction of azides with terminal alkynes, about 1 1 mixtures of 1,4- and 1,5-disubstituted 1,2,3-triazoles are obtained. Likewise, disubstituted alkynes afford mixtures of the stereoisomers. In order to avoid the cellular toxicity caused by the copper catalyst, Cu-free click chemistry is of considerable interest. The use of strained cyclooctyne derivatives as dipolarophiles was proposed recently. In this manner a novel 6,7-dimethoxyazacyclooct-4-yne was constructed from a glucose analogue s. The disadvantage of this reaction is its significantly slower reaction rate but introduction of fluoro groups adjacent to the triple bond achieves some rate enhancement. ... 

Scheme 16.21 Cyclooctyne derivatives for use in copper-free, strain-promoted azide-alkyne [3+2] cycloadditions designed by Bertozzi (81,83," and Boons j- The second-generation difluorinated derivative 84 is easier to synthesize than 83...

---