Conformationally Programmable Chiral Foldamers with Compact and Extended Domains Controlled by Monomer Structure

Foldamers are an important class of abiotic macromolecules, with potential therapeutic applications in the disruption of protein-protein interactions. The majority adopt a single conformational motif such as a helix. A class of foldamer is now introduced where the choice of heterocycle within each monomer, coupled with a strong conformation-determining dipole repulsion effect, allows both helical and extended conformations to be selected. Combining these monomers into hetero-oligomers enables highly controlled exploration of conformational space and projection of side-chains along multiple vectors. The foldamers were rapidly constructed via an iterative deprotection-cross-coupling sequence, and their solid- and solution-phase conformations were analysed by X-ray crystallography and NMR and CD spectroscopy. These molecules may find applications in protein surface recognition where the interface does not involve canonical peptide secondary structures.