Locking Interconversion of Aromatic Oligoamide Foldamers by Intramolecular Side‐chain Crosslinking: toward Absolute Control of Helicity in Synthetic Aromatic Foldamers

Abstract

A series of foldamers of 8-amino-2-quinoline carboxylic acid were stapled by intramolecular ring-closing olefin metathesis to generate the constrained aromatic foldamers with varying lengths of hydrocarbon side-chains. Investigations clearly revealed that the side-chain crosslinkers are capable of completely locking the interconversions of the stapled aromatic foldamers over a wide range of temperatures in CDCl , even in C D Cl . Hence, the stapled foldamers with the short hydrocarbon crosslinker can be easily separated by silica-gel chromatography to generate foldamers with stable, absolute one-handed helicity. But the stapled foldamer with the longer crosslinker is inseparable even by chiral HPLC presumably due to the fortuitous identical polarity of the diastereomer.

Control of conformation in α-helix mimicking aromatic oligoamide foldamers through interactions between adjacent side-chains

“…1a, see ESI † for syntheses of novel monomers and solid-phase assembly procedure), together with trimer 4. Dimer 1 was synthesized bearing acid and amine terminated side-chains with the hypothesis that these would promote a syn-conformer through hydrogen-bonding; evidence that such interactions between adjacent side-chains might control conformation in helix mimetics was obtained from studies in which a constraint or "staple" 30,46,47 between adjacent monomers was introduced by olefin metathesis (discussed below for trimer 4). Dimer 2 was synthesized bearing two acid sidechains as a control predicted to disfavour the syn-conformation due to repulsion of the carboxylic acids whilst dimer 3 was synthesised bearing two aliphatic side-chains and predicted to adopt a mixture of syn-and anti-conformers.…”

“…[12][13][14] Elegant studies have established the role of interactions between peripheral side chains in regulating the conformation of β-peptides, [26][27][28] however such interactions in the aromatic oligoamide family and other abiotic oligomers are less explored. 29,30 This is surprising given the role of interactions between adjacent side-chains in controlling natural peptide conformation [31][32][33][34] and in controlling conformation in self-assembled conjugated materials. 35 Our group previously reported a series of aromatic oligoamide scaffolds designed to mimic the α-helix and inhibit α-helix mediated protein-protein interactions.…”

Chiral Self‐Sorting of Diformylated N‐Hetero‐ortho‐phenylene Hexamers by Macrocyclization with Aromatic Diamines

“…[39] As the macrocycles become smaller, the number of possible conformations of the components usually decreases, which has been applied to controlling helical folding of foldamers. [40,41] For instance, homochiral self-sorting of a dynamic helical oligoamide foldamer was observed in the macrocyclic dimer formed by dynamic disulfide bridges. [35] Sorting the dynamic helices by optically active manner is, however, still difficult due to helix inversion of the helix-sense.…”

“…Especially, the exchange of dynamic covalent bonds often afford macrocycles rather than linear polymers to increase entropy [39] . As the macrocycles become smaller, the number of possible conformations of the components usually decreases, which has been applied to controlling helical folding of foldamers [40,41] . For instance, homochiral self‐sorting of a dynamic helical oligoamide foldamer was observed in the macrocyclic dimer formed by dynamic disulfide bridges [35] .…”

Fluorescent Short‐Stranded Helical Foldamers Based on L‐shaped Dibenzopyrrolo[1,2‐a][1,8]naphthyridine

“…1 H NMR, ROESY, and X‐ray structural analysis of these dimers revealed that dimers 1 and 2 have two terminal quinoline rings that overlap to a greater extent than those of dimer 3 and adopt helical conformations in both polar and nonpolar solvents as well as in the solid state. A fixed‐helical dimer 4 cross‐linked between the quinoline rings was also prepared and the fluorescence properties were evaluated. All of the dimers emitted yellow fluorescence with high quantum yields regardless of whether the dimer adopted a helical form.…”