Synthesis of chiral threefold and sixfold functionalized macrocyclic imidazole peptides

Starting from 4-oxa- or 4-azasubstituted 2-amino-3-oxoesters and (S)-valine, chiral imidazole diamino monocarboxylic acids as well as diamino dicarboxylic acids were prepared in a few synthetic steps. Macrolactamization of the side chain protected imidazole amino acids yields the corresponding 18- and 24-membered ring analogues of the naturally occurring cyclic peptide Westiellamide with various anchoring sites. The threefold functionalized scaffolds 2b-4b and the sixfold functionalized scaffold 5 are versatile central modules for artificial receptors and ligands. Structural investigations of threefold functionalized scaffolds based on oxazole and N-methylimidazole units by DFT modeling are provided.

Graphical abstractStarting from 4-oxa- or 4-azasubstituted 2-amino-3-oxoesters and (S)-valine, macrocyclic imidazole peptides with three and six anchoring sites were prepared in a few synthetic steps.Download full-size image