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.