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

Controlling amide bond geometries and the secondary structures of β-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 "β-azapeptoids" with confined dihedrals. We discuss how the acylhydrazide sidechains in these molecules enforce trans amide geometries (ω ~180°) via steric and stereoelectronic effects. We also show that the Θ(C_α -C_β ) and Ψ(OC-C_α ) backbone torsions of β-azapeptoids occupy a narrow range (170-180°) that can be rationalized by the staggered conformational preference of the backbone methylene carbons and a novel backbone n_O →σ*_Cβ-N interaction discovered in this study. However, the ϕ (C_β -N) torsion remains freely rotatable and, depending on ϕ, 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 β-azapeptoid dimers. We show that ϕ of β-azapeptoids can be controlled by incorporating a bulky substituent at the backbone β-carbon, which could provide complete control over all the backbone dihedrals. Finally, we show that the ϕ and Ψ dihedrals of β-azapeptoids resemble that of a PPII helix and they retain PPII structure when incorporated in Host-guest proline peptides.