Strained cyclooctyne

Due to molecular strain, cyclooctyne is a very reactive species. Its reactions with azides proceed rapidly even at room temperature making it a convenient tool for probing structures of unstable azides. Thus, the reaction of cyclooctyne with diazide 1061 carried out in GH2CI2 at room temperature is accomplished within 2h and provides ditriazolyl derivative 1060 in 76% yield. A similar reaction of cyclooctyne with diazide 1062 leads to ditriazolyl derivative 1063 in 90% yield (Scheme 175) <2005T8904>. 

Coordination to alkynes distorts the triple bond character nearer to that of a double bond, decreasing the linearity. Utilization of the coordination effect makes it feasible to prepare cyclic alkynes whose synthesis is difficult to achieve. Highly strained cyclooctyne can be prepared by coordination. As an example, starting from (R)-pulegone, three of the four rings of the epoxydictymene skeleton 152 were constructed by the consecutive Lewis acid-promoted Nicholas reaction of allylic silane 149 to form 150, and the intramolecular Pauson-Khand reaction of 151. The total synthesis of (+)-epoxydictymene 153 from 152 has been achieved [38]. 

Like trans cycloalkenes, cycloalkynes with small rings are unstable. The carbon chain must be long enough to connect the two ends of the triple bond without introducing too much strain. Cyclooctyne is the smallest isolated cycloalkyne, though it decomposes upon standing at room temperature after a short time. 

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. 

Cycloalkynes are seldom encountered, and are not stable in small rings due to angle strain. Cyclooctyne has been isolated, but is very reactive, and will polymerize with itself quickly. Cyclononyne is the smallest stable cycloalkyne. 

The Diels-Alder reaction of pyridinones (Scheme 4) with substituted butadienes is quite effective for the synthesis of the reduced isoquinolinones 23. Ozonolysis of the olefin provides a method for the synthesis of cA-3,4-disubstituted piperidines <97TL2295>. The high pressure Diels-Alder reaction of the pyridinone 24 with the strained cyclooctyne provides the corresponding stable, bridged tricyclic cycloadduct 25 <97H(45)15>. 

FIGURE 3.29 Commercial strained cyclooctynes (dibenzylcyclooctyne (DBCO)-NHS, difluorinated cyclooctyne (DIFO) acid, bicyclenonyne (BCN) carbonate) for introduction into (bio)macromolecules. 

Figure 12.28 Conversion of strained cyclooctyne to the acyclic alkyne product can be conveniently monitored by NMR. ...

Fig. 6 Depiction showing the differences in bond angles between linear alkyne and strained cyclooctyne used in SPAAC...

Chadwick RC, Van Gyzen S, Liogier S, Adronov A (2014) Scalable synthesis of strained cyclooctyne derivatives. Synthesis 46 669-677... 

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. ... 

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. ... 

Figure 9.2 First and second generation of ring-strained cyclooctynes 28-32 ...

Fig. 14 Multistep conjugation strategy Salmonella O-antigen was first reacted with adipic acid dihydrazide and successively functionalized with a strained cyclooctyne the final conjugation step was achieved by SPAAC with different azido-CRMigy. ...

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