A Modular Strategy for Collagen-Mimetic Peptides Using Diastereoselective Ugi Reactions

Here, we report a highly efficient and modular strategy to synthesize characteristic tripeptide units via diastereoselective Ugi multicomponent reactions and use them to construct collagen-mimetic peptides (CMPs). Biocatalytic desymmetrization of prochiral cyclic amines provides optically pure chiral imines, which are combined with readily available isocyanides and amino acid building blocks to generate stereodefined tripeptide modules for solid-phase peptide synthesis. Monoamine oxidase N (MAO-N) mediated desymmetrization afforded imines in excellent enantiomeric excess (>99% ee), while the corresponding tripeptide modules were obtained with high diastereomeric ratios (>92:8 d.r.). After assembly into medium-sized CMPs, Circular Dichroism (CD) spectroscopy confirmed triple-helix formation. The synthetic analogues exhibited melting temperatures (Tm) of up to 39.2 °C, corresponding to a decrease of only 3.2 °C relative to the parent Hyp CMP sequence. Molecular dynamics (MD) simulations revealed that the bicyclic substituents optimize local packing via enhanced inter-chain van der Waals interactions and localized desolvation, rendering the fully folded analogues thermodynamically indistinguishable. This strategy enables the modular introduction of unnatural proline analogues into CMPs and provides a platform to rapidly evaluate how proline-analogue structure and stereochemistry influence triple-helix formation and stability.