Cyclic Peptoids

Foldamers are an intriguing family of biomimetic oligomers that exhibit a propensity to adopt
stable secondary structures. N-Substituted glycine oligomers, or “peptoids”, are a prototypical example of
these foldamer systems and are known to form a helix resembling that of polyproline type I. Ongoing studies
seek to improve the stability of peptoid folding and to discover new secondary structure motifs. Here, we
report that peptoids undergo highly efficient head-to-tail macrocyclization reactions. A diverse array of peptoid
sequences from pentamers to 20mers were converted to macrocyclic products within 5 min at room
temperature. The introduction of the covalent constraint enhances conformational ordering, allowing for
the crystallization of a cyclic peptoid hexamer and octamer. We present the first X-ray crystallographic
structures of peptoid hetero-oligomers, revealing that peptoid macrocycles can form a reverse-turn
conformation.