Environment-independent 14-helix formation in short β-peptides: Striking a balance between shape control and functional diversity

We report a significant and unanticipated advance in the study of β-amino acid-based foldamers: a small proportion of highly preorganized residues can impart high stability to a specific helical secondary structure in water. Most of the residues in these β-peptides (2 and 3) are intrinsically flexible. Flexible β-amino acids can be readily and enantiospecifically prepared in functionally diverse forms, but preorganized residues with side chains are rare and challenging to synthesize. Our findings demonstrate that interspersing a few copies of an unfunctionalized but rigid residue among a larger number of flexible residues with diverse side chains is a viable strategy for creating β-peptides that adopt the 14-helix conformation and therefore display side chains in a predictable spatial arrangement. These results are significant because they enhance the prospects of developing β-peptides with useful activities.