Nucleophilic aromatic substitutions enable diversity-oriented synthesis of heterocyclic atropisomers via non-atropisomeric intermediates

Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00635519" target="_blank" >RIV/61388963:_____/25:00635519 - isvavai.cz</a>
Alternative codes found
RIV/00216208:11310/25:10501170 RIV/60461373:22340/25:43932873
Result on the web
<a href="https://doi.org/10.1038/s41467-025-60101-z" target="_blank" >https://doi.org/10.1038/s41467-025-60101-z</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1038/s41467-025-60101-z" target="_blank" >10.1038/s41467-025-60101-z</a>

Result language
angličtina
Original language name
Nucleophilic aromatic substitutions enable diversity-oriented synthesis of heterocyclic atropisomers via non-atropisomeric intermediates
Original language description
Atropisomers are sterically hindered molecules whose formation typically proceeds via atropisomeric intermediates and encumbered transition states. It is therefore largely accepted that the activation energy is higher for synthesis of atropisomers than for synthesis of similar, less sterically congested non-atropisomeric compounds. Here we show that atropisomer formation by nucleophilic aromatic substitution (SNAr) reactions can progress via non-atropisomeric intermediates and transition states. We put forth fast, mild, practical, regio- and chemoselective SNAr reactions that generate a diverse array of difficult-to-access heterobiaryl C─N atropisomers starting with readily available N─H heterocycles and aryl fluorides, as well as two catalytic methods employing N─SiR3 and N─H heterocycles for synthesis of title atropisomers in seconds. Products of SNAr are readily diversifiable, streamlining access to countless drug-like C─N atropisomers, including macrocycles, peptides, and analogs of achiral heterobiaryl pharmaceuticals. Supported by experimental and computational data, we discuss how steric repulsion is minimized in stereogenic axis-forming SNAr processes.
Czech name
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Czech description
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Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
—
OECD FORD branch
10401 - Organic chemistry

Project
<a href="/en/project/GM24-11562M" target="_blank" >GM24-11562M: Catalytic Stereoselective Synthesis of Elusive Atropisomers for Accelerating Drug Discovery</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

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