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.
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.
Wiley: Angewandte Chemie International Edition: Table of Contents
Authors: Sebastian Dengler, Céline Douat, Ivan Huc