Backbone thioamide directed macrocyclisation: lactam stapling of peptides

A novel method for lactam stapling of Asp/Lys-containing peptides has been developed that does not require coupling agents. A backbone thioamide is incorporated at the N-terminal side of the aspartate residue. Ag(i)-promoted activation of the thioamide in the vicinity of the Asp carboxylate generates a cyclic isoimide intermediate that is trapped by the Lys amine to generate the macrolactam. This method is suitable for generation of i,i+2, i,i+3, and i,i+4-spaced lactam-bridged peptides.

Automated summary

A novel method for lactam stapling of Asp/Lys-containing peptides has been developed. This method does not require coupling agents and involves the incorporation of a backbone thioamide to generate cyclic isoimide intermediates that are then trapped by Lys amine, resulting in the formation of lactam-bridged peptides with i,i+2, i,i+3, and i,i+4 spacings.