Nucleophilic aromatic substitutions enable diversity-oriented synthesis of heterocyclic atropisomers via non-atropisomeric intermediates
Michal Šimek,
Paritosh Dey,
Vilém Blahout,
Krishanu Mondal,
Jeanne Ernenwein,
Martin Dračínský,
Daniel Bím () and
Paulo H. S. Paioti ()
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Michal Šimek: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Paritosh Dey: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Vilém Blahout: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Krishanu Mondal: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Jeanne Ernenwein: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Martin Dračínský: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Daniel Bím: University of Chemistry and Technology
Paulo H. S. Paioti: Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences
Nature Communications, 2025, vol. 16, issue 1, 1-13
Abstract:
Abstract 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.
Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60101-z
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DOI: 10.1038/s41467-025-60101-z
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