Conformational Studies of -Azapeptoid Foldamers: A New Class of Peptidomimetics with Confined Dihedrals

Controlling amide bond geometries and the secondary structures of beta-peptoids is a challenging task as they contain several rotatable single bonds in their backbone. Herein, we describe the synthesis and conformational properties of novel "beta-azapeptoids" with confined dihedrals. We discuss how the acylhydrazide sidechains in these molecules enforce trans amide geometries (omega similar to 180 degrees) via steric and stereoelectronic effects. We also show that the Theta(C-alpha-C-beta) and Psi(OC-C-alpha) backbone torsions of beta-azapeptoids occupy a narrow range (170-180 degrees) that can be rationalized by the staggered conformational preference of the backbone methylene carbons and a novel backbone n(O)->sigma*(C beta-N) interaction discovered in this study. However, the phi (C-beta-N) torsion remains freely rotatable and, depending on phi, the sidechains can be parallel, perpendicular, and anti-parallel relative to each other. In fact, we observed parallel and perpendicular relative orientations of sidechains in the crystal geometries of beta-azapeptoid dimers. We show that phi of beta-azapeptoids can be controlled by incorporating a bulky substituent at the backbone beta-carbon, which could provide complete control over all the backbone dihedrals. Finally, we show that the phi and Psi dihedrals of beta-azapeptoids resemble that of a PPII helix and they retain PPII structure when incorporated in Host-guest proline peptides.