N,N'-linked oligoureas with proteinogenic side chains are peptide backbone mimetics belonging to the gamma-peptide lineage. In pyridine, heptamer 4 adopts a stable helical fold reminiscent of the 2.6(14) helical structure proposed for gamma-peptide foldamers. In the present study, we have used a combination of CD and NMR spectroscopies to correlate far-UV chiroptical properties and conformational preferences of oligoureas as a function of chain length from tetramer to nonamer. Both the intensity of the CD spectra and NMR chemical shift differences between alphaCH2 diastereotopic protons experienced a marked increase for oligomers between four and seven residues. No major change in CD spectra occurred between seven and nine residues, thus suggesting that seven residues could be the minimum length required for stabilizing a dominant conformation. Unexpectedly, in-depth NMR conformational investigation of heptamer 4 in CD3OH revealed that the 2.5 helix probably coexists with partially (un)folded conformations and that Z-E urea isomerization occurs, to some degree, along the backbone. Removing unfavorable electrostatic interactions at the amino terminal end of 4 and adding one H-bond acceptor by acylation with alkyl isocyanate (4 --> 7) was found to reinforce the 2.5 helical population. The stability of the 2.5 helical fold in MeOH is further discussed in light of unrestrained molecular dynamics (MD) simulation. Taken together, these new data provide additional insight into the folding propensity of oligoureas in protic solvent and should be of practical value for the design of helical bioactive oligoureas.

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.

In contrast to the situation observed in the crystal state, the urea moiety in N-Boc-N'-carbamoyl-gem-diaminoalkyl derivatives (single-residue ureidopeptides) 1-4 exclusively assumes a cis-trans conformation in solution. When R(3) = H, the resulting structure can be further stabilized by an intramolecular hydrogen bond that closes an eight-membered pseudocycle. The root-mean-square deviation calculated for heavy atoms between a peptide gamma-turn and the folded conformation that we propose to call urea turn is 0.60 A. [structure: see text]