Synthesis of Large‐ and Medium‐Sized Heterobiaryl Atropisomeric Rings and Atropopeptides by Catalytic Intramolecular SNAr
- 1Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague Czech Republic
- 2Department of Organic Chemistry Faculty of Science Charles University Prague Czech Republic
- 3Department of Physical Chemistry University of Chemistry and Technology Prague Czech Republic
Abstract
We report the first examples of catalytic, intramolecular N‐heterocycle arylation by nucleophilic aromatic substitution (SNAr), a general method for synthesis of highly strained macrocycles and medium‐sized heterobiaryl atropisomeric rings. Key to the approach is the ability to generate a strong base catalytically, as the desired cyclizations can be problematic under non‐catalytic conditions. Substitution reactions catalyzed by Brønsted bases often suffer from poor turnover because leaving groups are poorly basic. We put forth a process in which base regeneration does not depend on pK a considerations, but on reaction of a fluoride catalyst (Lewis base) with an organosilane (base‐embedding electrophile). Our protocol is amenable to an unprecedented broad range of heterocycles and highly functionalized and sterically hindered fluoroarenes. Despite ring strain, direct formation of C─N stereogenic axis can be carried out with linear substrates unbiased for cyclization and with tryptophan‐containing peptides. We provide synthesis of drug‐like cyclic and atropisomeric molecules which are elusive in medicinal chemistry screenings, as well as a direct macrocyclization route toward stereochemically and structurally diverse atropopeptides, molecules inspired by bioactive and naturally occurring ribosomally synthesized post‐translationally modified peptides (RiPPs). This work establishes a unique disconnection toward cyclic heterobiaryl molecules and catalysis that is to unlock other transformations.
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BibTeX
@article{kejani2026synthesis,
title = {{Synthesis of Large‐ and Medium‐Sized Heterobiaryl Atropisomeric Rings and Atropopeptides by Catalytic Intramolecular SNAr}},
author = {Alireza Abbasi Kejani and Paritosh Dey and Nicholas H. Stillman and Daniel M. Andrade and Michal Šimek and Martin Dračínský and Daniel Bím and Paulo H. S. Paioti},
journal = {Angewandte Chemie (International Ed. in English)},
year = {2026},
month = sep,
doi = {10.1002/anie.8290035},
url = {https://doi.org/10.1002/anie.8290035},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Synthesis of Large‐ and Medium‐Sized Heterobiaryl Atropisomeric Rings and Atropopeptides by Catalytic Intramolecular SNAr
AU - Alireza Abbasi Kejani
AU - Paritosh Dey
AU - Nicholas H. Stillman
AU - Daniel M. Andrade
AU - Michal Šimek
AU - Martin Dračínský
AU - Daniel Bím
AU - Paulo H. S. Paioti
PY - 2026
DA - 2026/09/21
JO - Angewandte Chemie (International Ed. in English)
DO - 10.1002/anie.8290035
UR - https://doi.org/10.1002/anie.8290035
AB - We report the first examples of catalytic, intramolecular N‐heterocycle arylation by nucleophilic aromatic substitution (SNAr), a general method for synthesis of highly strained macrocycles and medium‐sized heterobiaryl atropisomeric rings. Key to the approach is the ability to generate a strong base catalytically, as the desired cyclizations can be problematic under non‐catalytic conditions. Substitution reactions catalyzed by Brønsted bases often suffer from poor turnover because leaving groups are poorly basic. We put forth a process in which base regeneration does not depend on pK a considerations, but on reaction of a fluoride catalyst (Lewis base) with an organosilane (base‐embedding electrophile). Our protocol is amenable to an unprecedented broad range of heterocycles and highly functionalized and sterically hindered fluoroarenes. Despite ring strain, direct formation of C─N stereogenic axis can be carried out with linear substrates unbiased for cyclization and with tryptophan‐containing peptides. We provide synthesis of drug‐like cyclic and atropisomeric molecules which are elusive in medicinal chemistry screenings, as well as a direct macrocyclization route toward stereochemically and structurally diverse atropopeptides, molecules inspired by bioactive and naturally occurring ribosomally synthesized post‐translationally modified peptides (RiPPs). This work establishes a unique disconnection toward cyclic heterobiaryl molecules and catalysis that is to unlock other transformations.
SN - 1433-7851
SN - 1521-3773
ER -