The development of new chemical strategies for the preparation of cyclic peptide analogs 

Discovery and characterization of bioactive macrocycles have inspired chemists in the drug discovery. The ring-shaped cyclic peptides are of particular significance showing remarkable capacity of functional fine-tuning. Compared to linear peptides, peptide cycles remain variability of amino acid residues as well as ring size, but can significantly resist degradation by exo- and endoproteases, which enables the practical use of cyclic peptides in therapeutic potential. Cyclic peptides particularly cyclic tetrapeptides (CTPs) are important model ligands acting as reverse turns for protein specific recognition.  To this end, a copper(I)-mediated denitrogenative reaction has been successfully developed in the preparation of cyclic tetrapeptide amidine analogues. The highly reactive ketenimine intermediate triggers the key intramolecular cyclization by terminal amino group with the formation of a β-aimno acid amidine linkage. The chemistry developed here provides a new synthetic route in the preparation of cyclic α3β-tetrapeptide analogs which are rich of the information to the conformational study of macrocycles as well as important biological active peptides. With the success of this Cu(I)-catalyzed macrocyclization, two histone deacetylase (HDAC) inhibitor analogs whose frameworks constituted by cyclic α3β-tetrapeptides  have been successfully synthesized. Several new chemical strategies are ongoing to accelerate the collection of various cyclic peptides with specific size and functional groups!