Helix-Forming Oligoureas: Temperature-Dependent NMR, Structure Determination, and Circular Dichroism of a Nonamer with Functionalized Side Chains

Abstract

Dedicated to Professor Dieter Seebach on the occasion of his 65th birthdayTo further investigate the degree of structural homology between g-peptides A and N,N'-linked oligoureas B, we prepared oligourea nonamer 2 containing Ala, Val, Leu, Phe, Tyr and Lys side chains. Oligomer 2 was synthesized on solid support from activated monomers, i.e., from enantiomerically pure succinimidyl {2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethyl}carbamates 3a ± f that are further substituted at C(2) of the ethyl moiety. These precursors were conveniently prepared from N-Fmoc-protected b 3 -amino acids with corresponding side chains. Detailed NMR studies (DQF-COSY, TOCSY, and ROESY) in (D 5 )pyridine revealed that 2 adopts a regular (P)-2.5 helical secondary structure very similar to that previously determined for oligourea heptamer 1 and closely related to the (P)-2.6 14 helix of g-peptides. Temperature-dependent NMR further demonstrated the conformational homogeneity and remarkable stability of the structure of 2 in pyridine. The CD spectrum of 2 (0.2 mm) was recorded in MeOH with the aim to gain more information about the conformation of oligoureas. In contrast to 2.6-helical g-peptides, which display only a weak or no Cotton effect, oligourea 2 exhibits an intense positive Cotton effect at ca. 203 nm ([V] 373000 deg cm 2 dmol À1 ) that decreases only slowly upon increasing the temperature.

The Canonical Helix of Urea Oligomers at Atomic Resolution: Insights Into Folding‐Induced Axial Organization

“…All four oligoureas, including short tetramer 1 , are fully helical in the solid state (Figure 1 and 2; Supporting Information, Figure S1) 33. They adopt a right‐handed 2.5‐helical fold that matches the conformation initially proposed from NMR spectroscopy studies of oligoureas in solution 23–25. Octamer 3 , which has one single conformation in the crystal, has a nearly perfect repeat of 2.5 residues per turn (Figure 1 a) and a rise per turn of 5.1 Å.…”

Consequences of Isostructural Main‐Chain Modifications for the Design of Antimicrobial Foldamers: Helical Mimics of Host‐Defense Peptides Based on a Heterogeneous Amide/Urea Backbone

“…However, further development of 1 was limited by synthetic hurdles. Stepwise elongation of 1 on a Rink resin using monomers protected with N ‐fluorenylmethoxycarbonyl (Fmoc) groups3e, 7, 8 resulted in poor overall yields. The purity of crude product based on C 18 reverse‐phase HPLC was only 17 % 9.…”

Peptidomimicry with C2‐Symmetric Oligourea Derivatives of 1,2‐Diaminocyclohexane and 1,2‐Diphenyl‐1,2‐diaminoethane: Chirality and Chain Length‐Dependent Conformation

“…To unveil the synergy between residues necessary for secondary‐like structures, we studied chain length dependence in CD spectra of ( 1 R ) n , and 1 R −(1 S 1 R ) x . The observed λ max 195–205 nm was reminiscent of similar oligomers to which helical conformation was assigned . Chromophoric aromatic residues complicate interpretation of the CD curves ,.…”