Cyclo‐Polyproline: Chameleonic All‐Peptide Macrocycles With Induced‐Fit Host‐Guest Recognition

Abstract

ABSTRACT We report the design, synthesis, and characterization of a novel class of all‐peptide macrocycles, Cyclo‐Polyprolines ( CP ). Exploiting the precision of Fmoc‐based solid‐phase peptide synthesis (SPPS) and head‐to‐tail macrocyclization, this platform grants unparalleled control over the macrocycle's primary sequence and secondary structure, offering a viable route toward exo ‐/ endo ‐functionalization and addressing a bottleneck of traditional synthetic host macrocycles. The resulting CP scaffold is highly amphiphilic, exhibiting excellent solubility in both organic and aqueous media. Structural analysis via NMR spectroscopy and single‐crystal x‐ray diffraction reveals a distinct chameleonic character: the macrocycle shifts from an all‐junctions‐ cis conformation in organic solvents to a predominantly all‐junctions‐ trans isomer in water. We demonstrate that this transition is driven by a cooperative hydration effect, wherein water molecules stabilize the expanded framework through precise two‐point hydrogen bonding. Demonstrating responsive host‐guest capabilities, CP undergoes induced‐fit isomerization to bind ligands, successfully forming, among other species, an all‐peptide pseudo‐rotaxane. This methodology establishes a robust platform for creating functionalized, proline‐based hosts with significant potential in medicinal chemistry, drug delivery, and organocatalysis, thereby bridging the gap between supramolecular systems and enzyme mimetics.