J. Am. Chem. Soc. 136, 13590–13593 (2014)

The very high conversions reached by 'click' reactions under mild conditions make them very popular for modular syntheses — and none more so than the copper-catalysed azide–alkyne cycloaddition (CuAAC). To avoid the use of a copper catalyst, it has also been shown that cyclooctyn substrates can be used in a strain-promoted azide–alkyne cycloaddition (SPAAC) reaction that is often exploited for bioorthogonal labelling. However, if a molecule contains both a cyclooctyne and a terminal alkyne, any azide added for a cycloaddition will be swiftly mopped up by the cyclooctyne — and protecting groups for cyclooctynes are scarce.

Now, Suguru Yoshida and Takamitsu Hosoya, leading a team from Tokyo Medical and Dental University and the Tokyo Institute of Technology, have exploited a copper salt to both protect a cyclooctyne, and then catalyse the CuAAC reaction on a terminal alkyne in the same molecule. Yoshida, Hosoya and co-workers screened a variety of coinage metal salts, and found that addition of a slight excess of (MeCN)4CuBF4 quantitatively formed an isolable octyne–Cu complex that was unreactive towards free azides. The Cu–alkyne complex could be disrupted by the addition of aqueous ammonia, regenerating the cyclooctyne and making it available for strain-promoted azide–alkyne cycloaddition.

Using copper as both a protecting group and catalyst, a CuAAC reaction followed by a SPAAC reaction were carried out on a single molecule in a one-pot, three-step process. An excess of copper salt was used — one equivalent for protection and the remaining pre-dissolved for the CuAAC step — after which a copper-binding ligand suitable for CuAAC catalysis was added with an excess of azide in order to react with a terminal alkyne on the same molecule. Addition of aqueous ammonia unmasked the cyclooctyne, which reacted immediately with the remaining azide. It was also shown that two different azides could be used in the CuAAC and SPAAC reaction steps. The combined protection–reaction strategy opens the door for modular click syntheses of cyclooctyne-containing compounds.