Synthesis and Folding Propensity of Aliphatic Oligoureas Containing Repeats of Proline-Type Units

The synthesis and conformational analysis of aliphatic oligoureas containing multiple adjacent N-alkylated units derived from proline (i.e., Prou) are reported. The insertion of trisubstituted ureas in the main chain of N,N′-linked oligourea foldamers locally impairs the characteristic three centered-hydrogen bonding pattern associated with the formation of 2.5-helical structures. Three series of oligomers have been studied: one series in which the Prou repeat is flanked on both sides by canonical urea residues (e.g., oligomers 26), one series with canonical residues on either side of the Prou repeat (oligomers 12 and 23), and one series consisting exclusively of Prou residues (oligomers 25 and 26). Spectroscopic (NMR and electronic circular dichroism) and X-ray diffraction studies reveal that the 2.5-helix formed by oligomers of N,N′-disubstituted ureas is robust enough to accommodate short oligopyrrolidine segments (Prou)n (n < 7) that alone display no intrinsic folding propensity.