Designing Helical Molecular Capsules Based on Folded Aromatic Amide Oligomers

Conspectus The ab initio rational structure-based design of a synthetic molecular receptor for a given complex biomolecular guest remains an elusive objective, yet remarkable progress has been achieved in recent years. This Account deals with the use of folded artificial aromatic amide oligomers, also termed aromatic foldamers, inspired from biopolymer structures, for the design of helical molecular capsules that can recognize guest molecules, completely surround them, and isolate them from the solvent, thus giving rise to a sort of guest encapsulation associated with slow binding and release kinetics. The development of new amino acid, diacid, and diamine monomers, a main source of creativity in this field, progress in their assembly into ever longer oligoamide sequences, and the predictability of the folded structures due to their inherent rigidity and simple folding principles, allowed for the design and preparation of unimolecular and bimolecular capsule shapes. These capsules consist of molecular helices having a large diameter in the middle and a narrow diameter at both ends thus creating a cavity suitable for binding a guest molecule. The understanding of molecular recognition properties within these bioinspired containers has greatly progressed. Recognition of simple guests such as diols or amino-alcohols may thus be predicted, and hosts can be proposed for guests as complex as saccharides using first principle design. Taking advantage of the modular nature of oligomeric sequences, of their synthetic accessibility and of their propensity to grow into crystals suitable for X-ray crystallographic analysis, a structure-based iterative design methodology has been developed that eventually yielded exquisite guest selectivity, affinity, and diastereoselectivity. This methodology involves rational negative design steps during which changes in the foldamer capsule sequence are not intended to improve binding to the targeted guest but instead to exclude the binding of other guests while preserving key interactions with the target. Metal ions can also be introduced at the inner rim of foldamer capsules and eventually assist the binding of an organic guest. These results demonstrate the viability of an ab initio approach to abiotic receptor design based on aromatic foldamers. The dynamic of the capsules associated with their self-organized nature provides opportunities to not only tune guest binding and selectivity, but also guest capture and release kinetics