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

The synthesis and conformational analysis of aliphatic oligoureas containing multiple adjacent <i>N</i>-alkylated units derived from proline (i.e., Pro<sup>u</sup>) are reported. The insertion of trisubstituted ureas in the main chain of <i>N</i>,<i>N</i>′-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<sup>u</sup> repeat is flanked on both sides by canonical urea residues (e.g., oligomers <b>2</b>–<b>6</b>), one series with canonical residues on either side of the Pro<sup>u</sup> repeat (oligomers <b>12</b> and <b>23</b>), and one series consisting exclusively of Pro<sup>u</sup> residues (oligomers <b>25</b> and <b>26</b>). Spectroscopic (NMR and electronic circular dichroism) and X-ray diffraction studies reveal that the 2.5-helix formed by oligomers of <i>N</i>,<i>N</i>′-disubstituted ureas is robust enough to accommodate short oligopyrrolidine segments (Pro<sup>u</sup>)<sub><i>n</i></sub> (<i>n</i> < 7) that alone display no intrinsic folding propensity.