Cyclooctynes, strained, cycloaddition with

Mckay CS, Moran J, Pezacki JP (2010) Nitrones as dipoles for rapid strain-promoted 1,3-dipolar cycloadditions with cyclooctynes. Chem Commun 46(6) 931-933. doi 10.1039/b921630h... 

Figure 16 Cyclooctynes for strain-promoted cycloadditions with azides in living systems. Fluorination accelerates the cycloaddition because the electron-withdrawing fluoro substituents increase the reactivity of the ring-strained cyclooctyne.

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 Huisgen [3+2] cycloaddition between azides and alkynes is another bioorthognal ligation reaction for incorporation of probes into protein and peptide scaffolds. Two variants of this reaction have been developed using either copper(I) [218] or strained cyclooctyne molecules [219] to promote the reaction. As with the Staudinger ligation this method has found extensive use in protein and peptide labeling studies. 

McKay CS, Blake JA, Cheng J, Danielson DC, Pezacki JP (2011) Strain-promoted cycloadditions of cyclic nitrones with cyclooctynes for labeling human cancer cells. Chem Commun 47(36) 10040-10042. doi 10.1039/clccl3808a... 

The successful preparation of cycloalkynes also opened up the possibility to explore their unique chemical reactivity. In fact, the transient existence of the cycloalkyne species could initially only be indirectly corroborated by fast in situ trapping of the smaller-sized rings (seven carbons and below) before decomposition [31]. While not strictly applicable to cyclooctyne, which is the smallest cyclic alkyne that can be isolated and stored in pure form, Blomquist already noted that nevertheless careful exclusion of air was requisite to avoid rapid decomposition. More importantly, he was also the first to observe that cyclooctyne reacts explosively when treated with phenyl azide, forming a viscous liquid product [8]. This remark is in fact the first historic administration of a process that has now become known as strain-promoted azide-alkyne cycloaddition (SPAAC). 

Fig. 1 Cycloaddition reactions employed in nucleic acid labeling with reporter groups (green star). A Cu -mediated azide-alkyne cycloaddition (CuAAC) of a terminal alkyne with an azide. B Strain-promoted azide-alkyne cycloaddition (SPAAC) of an azide with a cyclooctyne derivative. C Staudinger ligation of an azide with a phosphine derivative (not a cycloaddition reaction, see below). D Norbornene cycloaddition of a nitrile oxide as 1,3-dipole and a norbornene as dipolarophile. E Inverse electron-demand Diels- Alder cycloaddition reaction between a strained double bond (norbornene) and a tetrazine derivative. F Photo-cUck reaction of a push-pull-substituted diaiyltetrazole with an activated double bond (maleimide)...

An azide-modified nucleoside has also been used for copper-free DNA detection with fluorescent cyclooctynes via strain-promoted azide-alkyne cycloaddition. 5-(Azidomethyl)-2 -deoxyuridine (AmdU) is, in contrast to various other azide containing nucleosides, stable in solution and metabolically stable and could be incorporated in cellular DNA [35]. Recently, this method has been extended for the detection of cellular RNA by 5-azidopropyl-modified UTP analogs [168]. 

Figure 14.5 Reaction scheme of copper-free strain-promoted azide-alkyne cycloaddition. The reaction occurs because of the interaction between functionahzed polymer with azide (blue) and the triple bond (red) of the reactive cyclooctyne, in absence of any catalysts.

Iridium dimer complexes catalyse the 3 + 2-cycloaddition reactions of organic azides with bromoalkynes to furnish 1,5-disubstituted 4-bromo-1,2,3-triazoles in excellent yields under mild conditions. Ruthenium(II)-azido complexes undergo 3 + 2-cycloaddition reactions with strained cyclooctynes under ambient temperatures. No reaction was observed with non-activated terminal or internal alkynes under the same conditions. Dithioic acid copper catalysts (60) catalyse the 3 + 2-cycloaddition reaction of azides with alkynes to form 1,4-disubstituted-1,2,3-triazoles in various solvents and under various temperatures. Thermal Huisgen 3 + 2-cycloaddition reactions of azides and bis(trimethylsilyl)acetylene formed 4,5-bis(trimethylsilyl)-l/f-l,2,3-triazoles in low to high yields (15-95%). The Cu(I)-catalysed 3 + 2-cycloaddition... 

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. ... 

The strain-promoted [3-1-2] cycloaddition reaction of substituted cyclooctyne with aryl azides furnishes 1,4,5-trisubstituted 1,2,3-triazoles, which have become good bioorthogonal probes. 

Triazole-substituted titanocenes may be synthesized by a strain-driven 1,3-dipolar cycloadditions between azide-functionalized titanocenes and cyclooctyne. Titanocene derivative are interesting complexes since they are a promising class of cytotoxic compounds, efficient reagents and catalysts, and organometallic gelators. Azide-substituted cationic titanocenes reacted with cyclooctyne in CH2CI2 at room temperature to give the expected product with yields between 75% and 92% [84]. 

---