Folding Patterns in a Family of Oligoamide Foldamers

Abstract

A series of small, unsymmetrical pyridine-2,6-dicarboxylamide oligoamide foldamers with varying lengths and substituents at the end groups were synthetized to study their conformational properties and folding patterns. The @-type folding pattern resembled the oxyanion-hole motifs of enzymes, but several alternative folding patterns could also be characterized. Computational studies revealed several alternative conformers of nearly equal stability. These folding patterns differed from each other in their intramolecular hydrogen-bonding patterns and aryl-aryl interactions. In the solid state, the foldamers adopted either the globular @-type fold or the more extended S-type conformers, which were very similar to those foldamers obtained computationally. In some cases, the same foldamer molecule could even crystallize into two different folding patterns, thus confirming that the different folding patterns are very close in energy in spite of their completely different shapes. Finally, the best match for the observed NOE interactions in the liquid state was a conformation that matched the computationally characterized helix-type fold.

Conformational properties and folding analysis of a series of seven oligoamide foldamers

“…However, some tendency to favour certain crystal forms according to solvent size and type was observed: DMF, DMA, acetonitrile and acetone solvates are isomorphous, as are also ethanol and methanol solvates and ethyl acetate and toluene solvates. A common theme in all crystal structures is still the tendency to strongly favour the @-conformation (Table 1, Figure 1a) with 20 and c) open @-like conformation (1@-Form II). Examples of foldamer 1 crystal packing d) a chain packing structure (C(7) motif, 1@-DMA), e) a pair ring structure ( !…”

“…In our previous studies, we investigated the conformational variance of a series of oligoamide foldamers by computational, single crystal X-ray diffraction and NMR spectroscopic methods. 19,20 The oligoamide foldamers were able to adopt a conformation -among other almost equally stable conformers -where three intramolecular hydrogen bonds are formed to single carbonyl oxygen, closely resembling an oxyanion hole motif found in the active sites of enzymes 21 . In enzymes, an oxyanion hole motif consists of two or more hydrogen bond donors, which can form hydrogen bonds to a negatively charged oxygen atom of a reaction intermediate thus stabilising it and lowering the energy cost of the reaction.…”

“…22,23 Our previous studies showed that relatively small alterations in chemical structure and crystallization conditions have an effect on the preferred folding patterns of oligoamides, but the calculated energy difference between the observed folding patterns is very small. 20 Herein we present a more detailed solid state structural study of a series of seven oligoamide foldamers (Scheme 1) summarizing their conformational features, polymorphism and solvate formation, as well as the variance in crystal packing caused by the conformational preferences, small changes in their chemical structure and crystallization conditions. 1) with different hydrogen bonding properties and electron donating and withdrawing end groups.…”

“…Foldamers 7 and 8 have five aromatic rings connected by four amide bonds like foldamer 1 but also an electron density withdrawing cyano group (7) or, electron density donating methoxy group (8) attached to the para position at one end of the molecule. Foldamers 1-7 fold into two distinct conformations, denoted as @-and S-conformations according to our previous article 20 (Scheme 2). Foldamers 2, 5 and 7 were found to adopt both conformations, whereas foldamers 1 and 3 crystallized exclusively in the @-conformation and foldamers 4 and 6 only in the S-conformation.…”

“…With the smallest foldamers 2 and 3 only one type of @ conformation is possible and S conformer may also form via intermolecular hydrogen bonding. The main reason behind the popularity of the proto-helical @-conformation and the sigmoidal S-conformation are the several simultaneous intramolecular hydrogen bonds, which stabilize the conformers almost equally, as evidenced by DFT calculations 20 and the prevalence of both conformers in the crystal structures. The steric effects are likely to contribute to the conformation as well, especially in the case of foldamer 6 with a bulkier aliphatic group, which lead to a slight preference of more open and less compact S-conformer to minimize the steric strain.…”