Spontaneous Resolution of Helical Building Blocks through the Formation of Homochiral Helices in Two Dimensions

• Published in: Angewandte Chemie International Edition 2022-08, Vol.61 (34), p.e202205914-n/a
• Main Authors: Lin, Xiang, Kou, Bohan, Cao, Jinlian, Weng, Peimin, Yan, Xiaosheng, Li, Zhao, Jiang, Yun‐Bao
• Format: Article
• Language: English
• Subjects: Aromatic compounds; Bonding strength; Chiral Resolution; Crystallization; Crystals; Halogen Bonds; Helices; Hydrogen Bonds; Phenylthiourea; Supramolecular Helices; β-Turns
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202205914

Spontaneous resolution leading to conglomerate crystals remains a significant challenge. Here we propose the formation of orthogonal homochiral supramolecular helices in at least two dimensions to allow spontaneous resolution. We suggest the design rationale that the chiral species is made into helical building blocks to allow the helix formation. As a proof‐of‐concept, acetylalanine was made into a helical short azapeptide, its N‐amidothiourea derivative containing a β‐turn structure, to which a halogen atom was further introduced at the phenylthiourea aromatic ring. The resultant folded species undergoes both intermolecular hydrogen and halogen bonding across the turn structure to form orthogonal intermolecular hydrogen‐bonded and halogen‐bonded supramolecular helices in two dimensions, and undergoes chiral resolution upon crystallization. Meanwhile, counterparts containing either an F‐substituent with weak halogen bonding or no halogen atom crystallize as racemic compounds. Acetylalanine was made into a folded N‐amidothiorea derivative containing a β‐turn and further modified with a halogen substituent (I, Br, Cl). Intermolecular halogen and hydrogen bonding, both across the turn structure, independently lead to supramolecular helices of homochirality orthogonal in two dimensions and thereby spontaneous resolution. Derivatives containing no halogen atom or a fluorine atom crystallize as racemic compounds.