Helix-Forming Propensity of Aliphatic Urea Oligomers Incorporating Noncanonical Residue Substitution Patterns

Aliphatic N,N′-linked
oligoureas are peptidomimetic foldamers
that adopt a well-defined helical secondary structure stabilized by
a collection of remote three-center H-bonds closing 12- and 14-membered
pseudorings. Delineating the rules that govern helix formation depending
on the nature of constituent units is of practical utility if one
aims to utilize this helical fold to place side chains in a given
arrangement and elaborate functional helices. In this work, we tested
whether the helix geometry is compatible with alternative substitution
patterns. The central −NH–CH­(R)–CH2–NH–CO– residue in a model oligourea pentamer
sequence was replaced by guest units bearing various substitution
patterns [e.g., −NH–CH2–CH2–NH–CO–, −NH–CH2–CH­(R)–NH–CO–,
and −NH–CH­(R1)–CH­(R2)–NH–CO−],
levels of preorganization (cyclic vs acyclic residues), and stereochemistries,
and the helix formation was systematically assessed. The extent of
helix perturbation or stabilization was primarily monitored in solution
by Fourier transform IR, NMR, and electronic circular dichroism spectroscopies.
Our results indicate that although three new substitution patterns
were accommodated in the 2.5-helix, the helical urea backbone in short
oligomers is particularly sensitive to variations in the residue substitution
pattern (position and stereochemistry). For example, the trans-1,2-diaminocyclohexane unit was experimentally found to break the
helix nucleation, but the corresponding cis unit did not. Theoretical
calculations helped to rationalize these results. The conformational
preferences in this series of oligoureas were also studied at high
resolution by X-ray structure analyses of a representative set of
modified oligomers.