Abstract
The design, synthesis and structural characterization of non-natural oligomers that adopt well-defined conformations, so called foldamers, is a key objective in developing biomimetic 3D functional architectures. For the aromatic oligoamide foldamer family, use of interactions between side-chains to control conformation is underexplored. The current manuscript addresses this objective through the design, synthesis and conformational analyses of model dimers derived from 3-O-alkylated para-aminobenzoic acid monomers. The O-alkyl groups on these foldamers are capable of adopting syn- or anti-conformers through rotation around the Ar-CO/NH axes. In the syn-conformation this allows the foldamer to act as a topographical mimic of the α-helix whereby the O-alkyl groups mimic the spatial orientation of the i and i + 4 side-chains from the α-helix. Using molecular modelling and 2D NMR analyses, this work illustrates that covalent links and hydrogen-bonding interactions between side-chains can bias the conformation in favour of the α-helix mimicking syn-conformer, offering insight that may be more widely applied to control secondary structure in foldamers.
Highlights
The current manuscript addresses this objective through the design, synthesis and conformational analyses of model dimers derived from 3-O-alkylated para-aminobenzoic acid monomers
The design and synthesis of foldamers that adopt well-defined conformations represents the foundation for construction of non-natural folded structures with well-defined secondary, tertiary and quaternary structures[1,2,3,4,5,6] possessing biomimetic and emergent functions.[7,8,9,10,11]
Using established solid-supported synthesis methodologies developed by our group,[44,45] model foldamer dimers 1–3 were prepared (Fig. 1a, see Electronic supplementary information (ESI)† for syntheses of novel monomers and solid-phase assembly procedure), together with trimer 4
Summary
The design and synthesis of foldamers that adopt well-defined conformations represents the foundation for construction of non-natural folded structures with well-defined secondary, tertiary and quaternary structures[1,2,3,4,5,6] possessing biomimetic and emergent functions.[7,8,9,10,11] The aromatic oligoamide foldamer family[12,13,14,15,16,17,18,19,20,21,22,23,24,25] has received considerable attention due to their predictable and well-defined folding behaviour. Control over conformation in the aromatic oligoamide family may be achieved by harnessing judiciously positioned hydrogenbonding functionality along a planar backbone with welldefined steric constraints.[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] . We demonstrate that covalent links or hydrogen-bonding interactions between suitably functionalized side-chains bias the conformation in favour of the synconformer so as to further stabilize the helix mimicking conformer in a manner that mirrors stabilisation of helical conformation through i to i + 4 salt bridges (Fig. 1c).[31,32,43]
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