Design and synthesis of trans-3-aminopyran-2-carboxylic acid (APyC) and alpha/beta-peptides with 9/11-helix

A new beta-amino acid, trans-3-aminopyran-2-carboxylic acid (APyC), was designed and synthesized from (R)-glyceraldehyde derivative and used in the synthesis of alpha/beta-peptides in a 1 : 1 alternating pattern with D-Ala. The presence of oxygen atom at the C beta(2)-position in APyC was envisaged to provide opportunity for additional interaction. These hybrid peptides have shown the presence of 9/11-helix through extensive NMR and MD studies. The amide protons of D-Ala, in addition to participating in 9-mr H-bonding with CO of succeeding beta-residue, were also involved in additional electrostatic interaction with pyran ring oxygen of preceding beta-residue, which facilitated further stabilization to the 9/11-mixed helix. The study thus results in a new 'motif' for a 9/11-helix, and the first example from a cyclic beta-amino acid.