Programmable Helicity and Macrocycle Symmetry in β-Peptides via Site-Selective Thioamide Substitution

Area of Science:

• Chemical Synthesis
• Supramolecular Chemistry
• Materials Science

Background:

• Thioamides are minimalist amide isosteres that precisely modulate peptide conformation via altered hydrogen-bond geometry and polarity.
• Previous studies examined thioamides individually, but lacked positional control within β-peptides to direct secondary structure.
• Controlling β-peptide helicity, curvature, and topology is crucial for designing novel foldamers and biomaterials.

Purpose of the Study:

• To present a general and experimentally validated strategy for programming β-peptide secondary structure with atomic precision.
• To demonstrate the use of site-selective thioamide substitution as a minimalist backbone modification.
• To expand the accessible structural and functional space for foldamer chemistry.

Main Methods:

• Utilized trans-2-aminocyclopentanecarboxylic acid (ACPC) foldamers as a model system.
• Employed site-selective thioamide substitution for backbone modification.
• Developed gram-scale, solution-phase synthesis for β-peptides up to 32-mers.
• Investigated orthogonal editing via mild Ag(I)-mediated backbone conversion.

Main Results:

• Achieved precise control over β-peptide secondary structure through strategic thioamide placement.
• Enabled the formation of hybrid 12/8-helices, backbone-encoded curvature, and conical 16/12-helices.
• Synthesized symmetry-defined macrocycles inaccessible by conventional methods.
• Demonstrated gram-scale synthesis of the longest reported β-peptides (>4 kDa) and efficient orthogonal editing.

Conclusions:

• Established a unified framework for controlling β-peptide helicity and topology via minimal backbone editing.
• Significantly expanded the structural and functional repertoire of foldamer chemistry.
• Highlighted broad applicability to organic synthesis, supramolecular chemistry, biomolecular engineering, and peptide-inspired materials.