Fragment-Based Design and Synthesis of Symmetrical bis-Peptidotriazoles Using Alkylidene bis-Amide Formations and Subsequent Triazole Ligation with β-Acetamido Carbonyl Scaffolds

Abstract

A novel and efficient fragment-based assembly of symmetrical bis-peptidotraizoles has been developed based on double Sharpless azide–alkyne click chemistry. A new Cu(II) catalyzed protocol with a wide substrate scope was developed for accessing the symmetrical alkylidene bis-azidoamide fragment that yields the products in very good yields at room temperature without employing column purifications. The propargylated β-acetamido ketone fragment was accessed using another Cu(II) catalyzed room temperature MCR protocol. A fast double-click reaction (2 h) of symmetrical alkylidene bis-azidoamides with propargylated β-acetamido ketone fragments leads to the formation of unusual symmetrical bis-peptidotriazoles.