Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes

• Main Authors: Diego M. Monzón, Juan Manuel Betancort, Tomás Martín, Miguel Ángel Ramírez, Víctor S. Martín, David Díaz Díaz
• Format: Article
• Language: English
• Published: MDPI AG 2021-03-01
• Series: Molecules
• Subjects: Nicholas reaction; cyclooctyne; propargylic carbocation; cyclization; oxacycle; ring strain
• Online Access: https://www.mdpi.com/1420-3049/26/6/1629

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 Co₂(CO)₈, and treatment with BF₃·Et₂O 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.