Diels-Alder Cycloadditions for Peptide Macrocycle Formation.

Macrocyclization can confer enhanced stability, target affinity, and membrane permeability to peptide scaffolds, all of which are desirable properties for chemical probes and therapeutics. A wide array of macrocyclization chemistries have been reported over the last few decades; however, these often have limited compatibility with each other and across chemical environments, thus restricting access to specific molecular properties. In an effort to address some of these limitations, we recently described the use of Diels-Alder [4 + 2] cycloadditions for peptide macrocyclization. Among the attributes of this chemistry, we demonstrated that Diels-Alder cyclization can template diverse peptide secondary structures, proceed in organic or aqueous environments, and endow improved pharmacologic properties on cyclized peptides. Here, we present synthetic processes and characterization methods for the synthesis of Diels-Alder cyclized peptides.