Catalytic atroposelective macrocyclization for constructing dominant rotors in peptides

Three-dimensional conformations determine the physicochemical and biological properties of macrocycles. Axially chiral biaryl fragments, which are widely found in macrocyclic natural products and drugs, have been evaluated as dominant rotors in synthetic cyclic peptides. While the corresponding constructs are powerful tools for influencing backbone conformations of macrocycles, their stereoselective installation remains challenging and underexplored. Here, we report a catalytic atroposelective macrocyclization strategy for constructing dominant rotors from azido peptides incorporating aryl alkyne building blocks via intramolecular rhodium-catalyzed azide-alkyne cycloaddition (RhAAC). This macrocyclization delivers structurally diverse, ring-size-tunable macrocyclic peptides bearing triazole-based biaryl rotors with high atroposelectivity. Comprehensive NMR analyses, X-ray crystallography, and computational studies reveal key conformational features of macrocyclic products and elucidate the role of dominant rotors in dictating overall molecular conformation. This AAC-mediated atroposelective macrocyclization provides a versatile platform for accessing axially chiral macrocyclic peptides and expands the dominant rotor strategy toward stereochemically programmed conformational control.