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

Thioamides─minimalist amide isosteres in which sulfur replaces the backbone carbonyl oxygen─offer a precise means to modulate peptide conformation through altered hydrogen-bond geometry and polarity. This work presents a general and experimentally validated strategy for programming β-peptide secondary structure with atomic precision, using site-selective thioamide substitution as a minimalist backbone modification. While thioamides have been studied individually, their positional control within β-peptides to direct helicity, curvature, and topology has not been achieved before. Using <i>trans</i>-2-aminocyclopentanecarboxylic acid (ACPC) foldamers as a model system, we show that strategic thioamide placement enables hybrid 12/8-helices, backbone-encoded curvature, and conical 16/12-helices; symmetry-defined macrocycles (pseudo-<i>C</i>₂, pseudo-<i>C</i>₃, pseudo-<i>C</i>₄) inaccessible by conventional β-peptide synthesis; gram-scale, solution-phase synthesis of β-peptides up to 32-mers (>4 kDa), the longest reported to date; and orthogonal editing via mild Ag(I)-mediated backbone conversion to all-amide analogs in 97-99% yield, allowing folding to be programmed with temporary thioamide units before conversion to the desired scaffold. These advances establish a unified framework for controlling β-peptide helicity and topology through minimal backbone editing, significantly expanding the accessible structural and functional space for foldamer chemistry. The concepts and methodologies are broadly applicable to organic synthesis, supramolecular chemistry, biomolecular engineering, and peptide-inspired materials.