Amphipathic Helices from Aromatic Amino Acid Oligomers

Synthetic helical foldamers are of significant interest for mimicking the conformations of naturally
occurring molecules while at the same time introducing new structures and properties. In particular,
oligoamides of aromatic amino acids are attractive targets, as their folding is highly predictable and
stable. Here the design and synthesis of new amphipathic helical oligoamides based on quinoline-derived
amino acids having either hydrophobic or cationic side chains are described. Their structures were
characterized in the solid state by single-crystal X-ray diffraction and in solution by NMR. Results of
these studies suggest that an oligomer as short as a pentamer folds into a stable helical conformation in
protic solvents, including MeOH and H2O. The introduction of polar proteinogenic side chains to these
foldamers, as described here for the first time, promises to provide possibilities for the biological
applications of these molecules. In particular, amphipathic helices are versatile targets to explore due to
their importance in a variety of biological processes, and the unique structure and properties of the
quinoline-derived oligoamides may allow new structure−activity relationships to be developed.