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

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/00216208:11310/25:10501170 RIV/60461373:22340/25:43932873

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

<a href="/cs/project/GM24-11562M" target="_blank" >GM24-11562M: Katalytická stereoselektivní syntéza nepolapitelných atropoizomerů pro urychlení objevu léků</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Nature Communications

ISSN

2041-1723

e-ISSN

2041-1723

Svazek periodika

16

Číslo periodika v rámci svazku

May

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

13

Strana od-do

4856

Kód UT WoS článku

001494122300003

EID výsledku v databázi Scopus

2-s2.0-105006414198