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., Pro^u) 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 Pro^u repeat is flanked on both sides by canonical urea residues (e.g., oligomers 2–6), one series with canonical residues on either side of the Pro^u repeat (oligomers 12 and 23), and one series consisting exclusively of Pro^u 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 (Pro^u)_n (n < 7) that alone display no intrinsic folding propensity.