Summary: | Cyclic products can be obtained through the intramolecular version of the Nicholas reaction, which requires having the nucleophile connected to the alkyne unit. Here, we report the synthesis of 1-oxa-3-cyclooctynes starting from commercially available (1<i>R</i>,3<i>S</i>)-camphoric acid. The strategy is based on the initial preparation of propargylic alcohols, complexation of the triple bond with Co<sub>2</sub>(CO)<sub>8</sub>, and treatment with BF<sub>3</sub>·Et<sub>2</sub>O to induce an intramolecular Nicholas reaction with the free hydroxyl group as nucleophile. Finally, oxidative deprotection of the alkyne afforded the cyclooctynes in good yields. Notably, large-sized R substituents at the chiral center connected to the O atom were oriented in such a way that steric interactions were minimized in the cyclization, allowing the formation of cyclooctynes exclusively with <i>(R) </i>configuration, in good agreement with theoretical predictions. Moreover, preliminary studies demonstrated that these cyclooctynes were reactive in the presence of azides yielding substituted triazoles.
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