Stabilising Peptoid Helices Using Non‐Chiral Fluoroalkyl Monomers

Diana Gimenez,Steven L Cobb,Juan A Aguilar,Elizabeth H C Bromley

doi:10.1002/ange.201804488

Abstract

AbstractStability towards protease degradation combined with modular synthesis has made peptoids of considerable interest in the fields of chemical biology, medicine, and biomaterials. Given their tertiary amide backbone, peptoids lack the capacity to hydrogen‐bond, and as such, controlling secondary structure can be challenging. The incorporation of bulky, charged, or chiral aromatic monomers can be used to control conformation but such building blocks limit applications in many areas. Through NMR and X‐ray analysis we demonstrate that non‐chiral neutral fluoroalkyl monomers can be used to influence the Kcis/trans equilibria of peptoid amide bonds in model systems. The cis‐isomer preference displayed is highly unprecedented given that neither chirality nor charge is used to control the peptoid amide conformation. The application of our fluoroalkyl monomers in the design of a series of linear peptoid oligomers that exhibit stable helical structures is also reported.

Highlights

Stability towards protease degradation combined with modular synthesis has made peptoids of considerable interest in the fields of chemical biology, medicine, and biomaterials
That the synergistic application of steric and non-covalent n! p* interactions (NCIs) in aromatic systems could be used to design stable cis-amide peptoid monomers (e.g., Ns1npe, 2).[8]
It is not possible to use the aforementioned NCIs to stabilize the cis-amide conformation of alkyl peptoid monomers, and the design of stable peptoid helices remains dominated by the use of chiral aromatic residues (e.g., 1 and 2).[9]

Summary

Introduction

Stability towards protease degradation combined with modular synthesis has made peptoids of considerable interest in the fields of chemical biology, medicine, and biomaterials. All of the fluorinated dipeptoids (11–13) showed an enhanced preference for the cis-amide conformation (Figure 3). Incorporation of a second fluorine atom further increased the cis-amide preference.

Results

Conclusion