Controlling Helix Handedness in Water‐Soluble Quinoline Oligoamide Foldamers

Abstract

For biological applications, the control of the helix handedness of water‐soluble quinoline‐based oligoamide foldamers has been investigated by the installation of chiral end groups at either the C or N terminus. This has resulted in the development of monomer units capable of unequivocally inducing helical sense without impacting the aqueous solubility. Furthermore, we showed that very slow helix handedness inversion in water can be exploited. The incorporation of a chiral moiety with no handedness‐induction properties allows the chromatographic separation of P and M helices as diastereoisomers with kinetically locked handedness.

Computational Prediction and Rationalization, and Experimental Validation of Handedness Induction in Helical Aromatic Oligoamide Foldamers

“…Same as the camphanyl case, the metadynamics FEPs of morpholine‐functionalized 2 a (Figure a) and 2 b (Figure S2, Supporting Information) are consistent with each other. Calculations predict higher stability for ( M )‐ 2 a /( P )‐ 2 b in agreement with experimental observations . However, the computationally obtained 0.6–0.8 kcal mol −1 free‐energy difference, roughly corresponding to a 75:25 bias, is slightly lower than the experimentally determined bias of about 97:3 .…”

“…These compounds had not been synthesized at the start of the computational studies. Their design followed the same simple principle as the design of 2 a / 2 b , that is, that a stereogenic center has a higher chance to promote helix handedness bias if it is placed close to the aromatic backbone. In the case of compounds 3 a to 6 b , the stereogenic center is located at the C terminus of the helix, thus leaving the N terminus available for further functionalization at the end of solid phase oligomer synthesis .…”

“…For example, in the 1 H NMR spectrum of 21 in [D 6 ]benzene containing TFA (5 equiv), the minor species is hardly detectable (Figure e). Thus, one can envisage incubating longer oligomers in this solvent mixture in order to effectively induce handedness, and to then carry out studies in aqueous medium in which handedness will be kinetically locked …”

“…An oligomer such as 1 a (Figure ), which bears a (1 R )‐(+)‐camphanyl group, should be exclusively M helical. In search of a less bulky and less hydrophobic group, we subsequently described a quinoline unit bearing a morpholine‐based stereogenic center at the N terminus that also effectively induces handedness . Oligomer 2 a with R chirality should be exclusively left‐handed as well.…”

“…An important aspect of this work is that both computational and experimental studies were carried out in chloroform whereas the final use of these molecules is meant to be in water. This is because helix stability in water is so large that handedness inversion does not occur anymore—helicity is kinetically inert at 25 °C for octamers or longer oligomers. Thus, helix handedness bias per se may not occur in water.…”