Differential Peptide Multi‐Macrocyclizations at the Surface of a Helical Foldamer Template. Issue 44 (29th September 2022)

• Record Type: Journal Article
• Authors: Dengler, Sebastian; Douat, Céline; Huc, Ivan
• Is Part Of: Angewandte Chemie international edition. Volume 61:Issue 44(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-09-29
• Subjects: Aromatic Foldamer -- Helical Conformation -- Macrocycle -- Peptide -- Reaction Trail; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202211138
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Hybrid sequences comprising a peptide with several Cys residues and an aromatic foldamer helix with several chloroacetamide functions at its surface were synthesized. Such products may in principle form numerous macromulticyclic thioether products by intramolecularly combining all Cys residues and all chloroacetamide functions. However, we show that the reactive sites on the structurally defined helix can be placed at such locations that the peptide selectively stitches itself to form a series of different macrocycles within mostly one preferred product. Reactions were monitored by HPLC and products with two, three or four macrocycles were identified using LC–MS and NMR. The series of selective macrocyclizations define a sort of reaction trail where reaction sites otherwise identical are involved successively because of their precise positioning in space. The trails can be predicted to a large extent based on structural considerations and the assumption that smaller macrocycles form faster. Abstract : The selective formation of different macrocycles can be implemented using Cys residues within a peptide and chloroacetamides at the surface of a foldamer helix by placing the latter at precise locations. Helix rigidity and faster formation of smaller macrocycles make the favored product largely predictable.