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

To further investigate the degree of structural homology between γ‐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 β³‐amino acids with corresponding side chains. Detailed NMR studies (DQF‐COSY, TOCSY, and ROESY) in (D₅)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)‐2.6₁₄ helix of γ‐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 γ‐peptides, which display only a weak or no Cotton effect, oligourea 2 exhibits an intense positive Cotton effect at ca. 203 nm (Θ]=+373000 deg cm² dmol⁻¹) that decreases only slowly upon increasing the temperature.