Zirconium Oxo Cluster‐Catalyzed Dipeptide Cyclization Evaluated by Experiments and Theory

Although peptides are essential for many areas of chemistry, key limitations still remain in their synthesis, such as high costs and poor atom economy. An ideal alternative is the catalytic peptide bond formation directly from nonactivated amino acids; however, the high‐energy barrier associated with this reaction hampers the development of suitable alternatives. In this work, we evaluated the catalytic activity of discrete zirconium oxo clusters for direct peptide bond formation, using dipeptide cyclization as model reaction. The clusters afforded several 2,5‐diketopiperazine derivatives in good‐to‐excellent yields under straightforward open‐flask conditions, without requiring the water byproduct to be scavenged from the reaction. Further mechanistic study through density functional theory calculations revealed that the mechanism involves a second substrate molecule near the reactive site of the catalysts, to streamline proton transfers that push the reaction forward. These results underline the promising potential of discrete ZrOCs as an emerging class of catalysts for the formation of peptide bonds under green, straightforward reaction conditions.