Accessing Improbable Foldamer Shapes with Strained Macrocycles

• Published in: Chemistry : a European journal Vol. 27; no. 43; pp. 11205 - 11215
• Main Authors: Urushibara, Ko, Ferrand, Yann, Liu, Zhiwei, Katagiri, Kosuke, Kawahata, Masatoshi, Morvan, Estelle, D'Elia, Ryan, Pophristic, Vojislava, Tanatani, Aya, Huc, Ivan
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 02.08.2021; Wiley Subscription Services, Inc; Wiley-VCH Verlag; John Wiley and Sons Inc
• Subjects: Alkylation; Amides; Chemical Sciences; Chemistry; Chemistry, Multidisciplinary; cis amide; Computer applications; Crystallography; Crystallography, X-Ray; Cyclization; fluxionality; foldamer; macrocycle; Models, Molecular; Molecular Conformation; Molecular dynamics; Monomers; NMR; Nuclear magnetic resonance; Oligomers; Physical Sciences; Polymers; Science & Technology; Simulated annealing; strained structures; TWISTED AMIDE; fluxionality; STACKING; strained structures; RECOGNITION; macrocycle; COMMUNICATION; cis amide; foldamer
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202101201

The alkylation of some secondary amide functions with a dimethoxybenzyl (DMB) group in oligomers of 8‐amino‐2‐quinolinecarboxylic acid destabilizes the otherwise favored helical conformations, and allows for cyclization to take place. A cyclic hexamer and a cyclic heptamer were produced in this manner. After DMB removal, X‐ray crystallography and NMR show that the macrocycles adopt strained conformations that would be improbable in noncyclic species. The high helix folding propensity of the main chain is partly expressed in these conformations, but it remains frustrated by macrocyclization. Despite being homomeric, the macrocycles possess inequivalent monomer units. Experimental and computational studies highlight specific fluxional pathways within these structures. Extensive simulated annealing molecular dynamics allow for the prediction of the conformations for larger macrocycles with up to sixteen monomers. Frustrating folding propensity by imposing a macrocyclic structure to an otherwise helical backbone produces improbable yet stable strained molecular shapes. Both experiments and computational studies show how aromatic oligoamide foldamers constrained within a macrocycle try to fulfill their strong propensity to adopt helical conformations by forming local loops and unfolded sites that connect helical segments. Defined fluxional conformational pathways can be evidenced in such molecules.