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

Abstract

AbstractControlling 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(Cα‐Cβ) and Ψ(OC‐Cα) 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 nO→σ*Cβ‐N interaction discovered in this study. However, the ϕ (Cβ‐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.