Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes

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>)-ca...

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Bibliographic Details
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
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Online Access:https://www.mdpi.com/1420-3049/26/6/1629
Description
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.
ISSN:1420-3049