Šimek Michal, Dey Paritosh, Blahout Vilém, Mondal Krishanu, Ernenwein Jeanne, Dračínský Martin, Bím Daniel, Paioti Paulo H S
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.
Department of Organic Chemistry, Faculty of Science, Charles University, Prague, Czech Republic.
Nat Commun. 2025 May 25;16(1):4856. doi: 10.1038/s41467-025-60101-z.
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 (SAr) reactions can progress via non-atropisomeric intermediates and transition states. We put forth fast, mild, practical, regio- and chemoselective SAr 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─SiR and N─H heterocycles for synthesis of title atropisomers in seconds. Products of SAr 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 SAr processes.
阻转异构体是空间位阻较大的分子，其形成通常通过阻转异构中间体和受阻过渡态进行。因此，人们普遍认为，合成阻转异构体的活化能高于合成类似的、空间位阻较小的非阻转异构化合物。在此，我们表明，通过亲核芳香取代（SAr）反应形成阻转异构体可以通过非阻转异构中间体和过渡态进行。我们提出了快速、温和、实用、区域和化学选择性的SAr反应，这些反应从容易获得的N-H杂环和芳基氟化物开始，生成各种难以获得的杂联芳基C-N阻转异构体，以及两种使用N-SiR和N-H杂环的催化方法，可在数秒内合成标题阻转异构体。SAr反应的产物易于多样化，简化了获得无数类药物C-N阻转异构体的途径，包括大环化合物、肽以及非手性杂联芳基药物的类似物。在实验和计算数据的支持下，我们讨论了在形成立体轴的SAr过程中如何将空间排斥最小化。
