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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doaj-5f010e2825364fe999afab0ba9153b322021-03-16T00:03:35ZengMDPI AGMolecules1420-30492021-03-01261629162910.3390/molecules26061629Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained CyclooctynesDiego M. Monzón0Juan Manuel Betancort1Tomás Martín2Miguel Ángel Ramírez3Víctor S. Martín4David Díaz Díaz5Departamento de Química Orgánica, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife, SpainInstituto de Bio-Orgánica Antonio González, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife, SpainInstituto de Bio-Orgánica Antonio González, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife, SpainDepartamento de Química Orgánica, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife, SpainDepartamento de Química Orgánica, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife, SpainDepartamento de Química Orgánica, Universidad de La Laguna, Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna, Tenerife, SpainCyclic 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.https://www.mdpi.com/1420-3049/26/6/1629Nicholas reactioncyclooctynepropargylic carbocationcyclizationoxacyclering strain |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Diego M. Monzón Juan Manuel Betancort Tomás Martín Miguel Ángel Ramírez Víctor S. Martín David Díaz Díaz |
spellingShingle |
Diego M. Monzón Juan Manuel Betancort Tomás Martín Miguel Ángel Ramírez Víctor S. Martín David Díaz Díaz Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes Molecules Nicholas reaction cyclooctyne propargylic carbocation cyclization oxacycle ring strain |
author_facet |
Diego M. Monzón Juan Manuel Betancort Tomás Martín Miguel Ángel Ramírez Víctor S. Martín David Díaz Díaz |
author_sort |
Diego M. Monzón |
title |
Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes |
title_short |
Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes |
title_full |
Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes |
title_fullStr |
Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes |
title_full_unstemmed |
Intramolecular Nicholas Reaction Enables the Stereoselective Synthesis of Strained Cyclooctynes |
title_sort |
intramolecular nicholas reaction enables the stereoselective synthesis of strained cyclooctynes |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2021-03-01 |
description |
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. |
topic |
Nicholas reaction cyclooctyne propargylic carbocation cyclization oxacycle ring strain |
url |
https://www.mdpi.com/1420-3049/26/6/1629 |
work_keys_str_mv |
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