The Challenge of Conformational Isomerism in Cyclic Peptoids

Peptoids (N-substituted glycine oligomers) are an increasingly important class of peptidomimetic foldamers with conspicuous bioactivities, high degree of resistance to enzymatic degradation, and ability to form stable secondary structures. The intrinsic rigidity of their oligoamide framework (due to n→π*, side chains NCα–H···O=C n→σ*, and backbone Cα–H···O=C interactions), can be magnified by cyclization to afford macrocyclic species with unexpected stereochemical, topological and biochemical attributes. In this minireview the implications of conformational chirality, a largely overlooked source of chirality in medium and large size cyclic peptoids, are addressed. The exploration of the unique structural and recognition properties of macrocyclic peptoid biomimetics unravels potential strategies for design and development of sequence-defined (cyclo)oligomers where conformational isomerism is an issue