Accommodation of α-substituted residues in the β-peptide 12-helix: Expanding the range of substitution patterns available to a foldamer scaffold

β-Amino acid oligomers composed exclusively of homochiral trans-2-aminocyclopentanecarboxylic acid (ACPC) residues and/or related pyrrolidine-based residues are known to favor a specific helical secondary structure that is defined by 12-membered ring C=O(i)- -H - N(i+3) hydrogen bonds ("12-helix"). The 12-helix is structurally similar to the familiar α-helix and therefore represents a source of potential α-helix-mimics. The 12-helix will be most useful in this regard if this conformational scaffold can be employed to arrange specific sets of protein-like side chains in space. Here we examine whether the 12-helix tolerates insertion of acyclic β-amino acid residues bearing a substituent in the α-position ("β²-residues"). Seventeen homologous β-peptide heptamers have been prepared in which one to four β²-residues reside among ACPC and/or pyrrolidine residues. Circular dichroism comparisons suggest that β²-residues have a lower 12-helical propensity than do residues preorganized by a five-membered ring, as expected, but that β-peptides containing β²-residues at one or two of the seven positions retain a significant preference for 12-helix formation. These results indicate that a limited number of β²-residues can be used to introduce side chains at specific positions along the surface of a 12-helix.