A post-modification approach to peptide foldamers

Hydrophilic/hydrophobic patterning is a powerful strategy to control folding in non-natural polymers/oligomers. In this contribution, we present a novel strategy for the preparation of alternating hydrophilic/hydrophobic patterned non-natural peptide foldamers. This strategy relies on the post-modification of a reactive peptide precursor that can be prepared via standard solid phase peptide synthesis without the need for side chain protective groups. The peptide scaffolds consisted of an alternating sequence of L-leucine and L-allylglycine residues. Using thiol-ene chemistry, the double bonds in the side chains of the L-allylglycine units could be post-modified with cysteamine hydrochloride, thioglycolic acid, 1-thioglycerol or 2,3,4,6-tetra-O-acetyl-thio-beta-D-glucopyranose to afford alternating hydrophilic/hydrophobic patterned peptides. In agreement with the alternating hydrophilic/hydrophobic patterned primary structure, cysteamine and thioglycolic acid post-modified octapeptides were found to adopt a beta-sheet secondary structure in basic or acidic aqueous media, respectively. The proposed synthetic approach is not only of interest to generate diverse libraries of peptide foldamers from a limited number of reactive precursor scaffolds, but may also represent an attractive, general strategy for the synthesis of peptides with complex side chain functionalities that are not easily accessible via standard solid phase techniques.