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A series of 21 sulfoester and sulfonamide derivatives comprising two aromatic rings was synthesized to investigate the effect of the presence of either electron-donating (ED) or electron-withdrawing (EW) groups on the intramolecular π-stacking assembly. The positioning of ED or EW moieties was carried out directly on one of the aromatic rings linked to the sulfonyl or sulfonamide moieties. In contrast, the other aromatic ring (phenyl or pyridine) was connected by a –CH2–CH2– spacer with the sulfonyl or sulfonamide moiety. The purpose of having an ethyl spacer between the two aromatic rings was to achieve conformational flexibility, facilitating the intramolecular π-stacking assembly between the two aromatic rings. The use of sulfoester/sulfonamide groups allowed more conformational flexibility to attain desired orientations in solids with the interplay of the hydrogen-bonding interactions. Between the two functional groups, sulfonamides offered a more hydrogen-rich environment due to the amine moiety and may exhibit higher H-bonding propensity than the sulfoester moiety. The central idea here was to study the interplay between the hydrogen-bonding and π⋯π interactions. The substituent groups chosen were categorized as strong electron-withdrawing (–CF3 and –CN), weak electron-withdrawing (–Cl and –Br), neutral (–H), and good electron-donating (–CH3 and –OCH3) groups. Crystal structure analysis revealed the syn conformation for all the derivatives, enabling intramolecular π⋯π interactions between the two aromatic rings, whereas in the sulfonamide derivatives, the molecule takes either midway or anti conformations, except for one pyridine sulfonamide derivative, which showed the syn orientation but lacked intramolecular π-stacking interactions. The absence of any conventional H-bond forming functional groups in the sulfoester derivatives may have resulted in the syn geometry facilitated by intramolecular π-stacking interactions. Conversely, H-bond-forming functional groups in the sulfonamide derivatives could have prevented the syn conformation. The conformational analysis carried out employing density functional theory (DFT) calculations confirmed the higher stability of the syn conformation over the midway and anti orientations. [ABSTRACT FROM AUTHOR]

This paper describes the consequences of incorporating a constrained heterocyclic aromatic β-amino acid 3-aminothiophenecarboxylic acid (3-Atc) into peptides containing β-turn forming elements such as Pro-Gly motif and the effect on the secondary structural architecture of the entire peptide backbone. Conformational investigations of oligomers comprising an α,β,α peptide sequence were carried out by single-crystal X-ray diffraction, solution-state NMR, nOe-restrained MD simulation and circular dichroism studies. The results suggested that these peptide sequences assume helical architecture. The helical folding in the oligomers was found to be devoid of inter-residual H-bonding, instead found to be stabilized by a co-operative effect of 6-membered H-bonding within the 3-Atc unit and conformational restrictions of individual amino acids in the peptide backbone. [ABSTRACT FROM AUTHOR]

This communication describes the influence of β-aminobenzenesulfonic acid (SAnt) on the conformational preferences of hetero foldamers. The designed (Aib-SAnt-Aib)n and (Aib-SAnt-Pro)n oligomers display a well-defined folded conformation featuring intramolecular mixed hydrogen bonding (7/11) and intra-residual (6/5) H-bonding interactions, respectively. [ABSTRACT FROM AUTHOR]

Orthanilic acid (2-aminobenzenesulfonic acid, SAnt), an aromatic β-amino acid, has been shown to be highly useful in inducing a folded conformation in peptides. When incorporated into peptide sequences (Xaa-SAnt-Yaa), this rigid aromatic β-amino acid strongly imparts a reverse-turn conformation to the peptide backbone, featuring robust 11-membered-ring hydrogen-bonding. [ABSTRACT FROM AUTHOR]

Although known for their inferiority as hydrogen-bonding acceptors when compared to amides, esters are often found at the C-terminus of peptides and synthetic oligomers (foldamers), presumably due to the synthetic readiness with which they are obtained using protected peptide coupling, deploying amino acid esters at the C-terminus. When the H-bonding interactions deviate from regularity at the termini, peptide chains tend to "fray apart". However, the individual contributions of C-terminal esters in causing peptide chain end-fraying goes often unnoticed, particularly due to diverse competing effects emanating from large peptide chains. Herein, we describe a striking case of a comparison of the individual contributions of C-terminal ester vs. amide carbonyl as a H-bonding acceptor in the folding of a peptide. A simple two-residue peptide fold has been used as a testing case to demonstrate that amide carbonyl is far superior to ester carbonyl in promoting peptide folding, alienating end-fraying. This finding would have a bearing on the fundamental understanding of the individual contributions of stabilizing/destabilizing non-covalent interactions in peptide folding.

Two folded peptides featuring carboxamide and sulfonamide at the core of the peptide fold have been shown to possess almost similar conformational features, despite the well-known fact that carboxamides and sulfonamides have strikingly different hydrogen-bonding and geometrical preferences.

This communication describes a set of hybrid foldamers that do not feature inter-residual, but intra-residual backbone hydrogen-bonding, yet adopt a preferentially folded conformation displaying right-handed helical architecture. Conformational ordering is apparently due to the combined conformational restrictions imposed by the conformationally restricted individual amino acid residues with which the oligomers are made of.