Fluorinated Aromatic Monomers as Building Blocks To Control α-Peptoid Conformation and Structure

Abstract

Peptoids are peptidomimetics of interest in the fields of drug development and biomaterials. However, obtaining stable secondary structures is challenging, and designing these requires effective control of the peptoid tertiary amide cis/trans equilibrium. Herein, we report new fluorine-containing aromatic monomers that can control peptoid conformation. Specifically, we demonstrate that a fluoro-pyridine group can be used to circumvent the need for monomer chirality to control the cis/trans equilibrium. We also show that incorporation of a trifluoro-methyl group ( N^CF₃Rpe) rather than a methyl group ( NRpe) at the α-carbon of a monomer gives rise to a 5-fold increase in cis-isomer preference.

Figure 1.

a) α-peptides and α-peptoids; b) cis-amide preference due to steric and n→ π* electronic effects (2–4); c) cis-amide preference due to inductive effects (5–8); d) K_cis/trans (CD₃OD) for monomers 1–8; e) Application of fluorine to enhance cis-isomer preference.

Figure 2.

a) Synthesis of model peptoids; b) Non-chiral di-peptoids 1, 9–10; c) Chiral di-peptoids 11, 12. d) Average K_cis/trans values for 1, 9-12. From each replica, ΔG= −RTLn(K_cis/trans) at 25 °C. Averages and SD values given for n=6; ^[a] n=5 and ^[b]n=3. ^[c] Major isomer assigned as cis, in agreement with MD data.

Figure 3.

a) Amide bond geometry in systems 1, 9 and 10. b) Experimental ¹H-¹H NOESY correlations within cis/trans conformers of 10. All Kcis/trans values as determined in CDCl3.

Figure 4.

a) The lowest-energy conformation of 12, annotated with dihedral angle definitions (see SI for details). b) Lowest-energy minima found in φ, ψ backbone dihedral scans started from cis- and trans-amide conformations with side-chain orientations χ1 = −9° and +90°. c) REMD simulations of oligomeric analogues of 12, Ac-[N^CF3Rpe]_n-Pip (n=1,2,3,4,5) showing an increasing preference to form right-handed cis-amide helices. d) Space-filling model of the predicted pentamer structure (n=5). e-f) Longitudinal views of a representative frame of the oligomer from the lowest temperature replica (300 K).

Figure 5.

a) Structure of peptoid oligomers 13–15. b) Main ¹H-NMR parameters of NSpe and N^CF3Rpe residues as analyzed in 15. c) Structure and average CD spectra (n=3) of peptoid hetero-oligomers 13 (shown in red) and 14 (shown in blue). All measurements in MeCN.