Tuning Peptoid Secondary Structure with Pentafluoroaromatic Functionality: A New Design Paradigm for the Construction of Discretely Folded Peptoid Structures

Peptoids, or oligomers of N-substituted glycine, are an important class of non-native polymers
whose close structural similarity to natural α-peptides and ease of synthesis offer significant advantages
for the study of biomolecular interactions and the development of biomimetics. Peptoids that are N-substituted
with α-chiral aromatic side chains have been shown to adopt either helical or “threaded loop” conformations,
depending upon solvent and oligomer length. Elucidation of the factors that impact peptoid conformation
is essential for the development of general rules for the design of peptoids with discrete and novel structures.
Here, we report the first study of the effects of pentafluoroaromatic functionality on the conformational
profiles of peptoids. This work was enabled by the synthesis of a new, α-chiral amine building block, (S)-1-(pentafluorophenyl)ethylamine (S-2), which was found to be highly compatible with peptoid synthesis
(delivering (S)-N-(1-(pentafluorophenyl)ethyl)glycine oligomers). The incorporation of this fluorinated
monomer unit allowed us to probe both the potential for π-stacking interactions along the faces of peptoid
helices and the role of side chain electrostatics in peptoid folding. A series of homo- and heteropeptoids
derived from S-2 and non-fluorinated, α-chiral aromatic amide side chains were synthesized and
characterized by circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy. Enhancement of π-stacking by quadrupolar interactions did not appear to play a significant role in stabilizing the
conformations of heteropeptoids with alternating fluorinated and non-fluorinated side chains. However,
incorporation of (S)-N-(1-(pentafluorophenyl)ethyl)glycine monomers enforced helicity in peptoids that
typically exhibit threaded loop conformations. Moreover, we found that the incorporation of a single (S)-N-(1-(pentafluorophenyl)ethyl)glycine monomer could be used to selectively promote looped or helical
structure in this important peptoid class by tuning the electronics of nearby heteroatoms. The strategic
installation of this monomer unit represents a new approach for the manipulation of canonical peptoid
structure and the construction of novel peptoid architectures.