A tendril perversion in a helical oligomer: trapping and characterizing a mobile screw-sense reversal

Abstract

Helical oligomers of achiral monomers adopt domains of uniform screw sense, which are occasionally interrupted by screw-sense reversals. These rare, elusive, and fast-moving features have eluded detailed characterization. We now describe the structure and habits of a screw-sense reversal trapped within a fragment of a helical oligoamide foldamer of the achiral quaternary amino acid 2-aminoisobutyric acid (Aib). The reversal was enforced by compelling the amide oligomer to adopt a right-handed screw sense at one end and a left-handed screw sense at the other. The trapped reversal was characterized by X-ray crystallography, and its dynamic properties were monitored by NMR and circular dichroism, and modelled computationally. Raman spectroscopy indicated that a predominantly helical architecture was maintained despite the reversal. NMR and computational results indicated a stepwise shift from one screw sense to another on moving along the helical chain, indicating that in solution the reversal is not localised at a specific location, but is free to migrate across a number of residues. Analogous unconstrained screw-sense reversals that are free to move within a helical structure are likely to provide the mechanism by which comparable helical polymers and foldamers undergo screw-sense inversion.

Fig. 1. Helical perversions in (a) a tendril of the garden cucumber, Cucumis sativa, and (b) the cord of a telephone handset; (c) Aib and a portion of its 3₁₀ helical homo-oligomer, shown in its right-handed screw-sense conformation.

Fig. 2. The diastereoisomeric pairs of compounds 1a and 1b and 2a and 2b. Cbz = BnOCO.

Fig. 3. X-ray crystal structure viewed along, and perpendicular to, the helical axis, along with a schematic diagram of the hydrogen bonding in (a) 1a and (b) 1b. Non-hydrogen bonded CO and N–H are highlighted in yellow.

Fig. 4. CD spectra of 1a and b and 2a and b recorded at 2.4 × 10^–4 M in MeOH at 20 °C.

Fig. 5. Variation of helical excess with position in the chain for the achiral Aib5 domain of 1a and 1b (a) calculated from the chemical shift difference Δδ in the ¹³C NMR spectrum; (b) calculated from the Boltzmann distributions resulting from PMF profiles in implicit solvent (see below).

Fig. 6. Superposition of the X-ray structures (green) and a representative structure of the most populated cluster (magenta) of (a) oligomer 1a and (b) oligomer 1b. (c) Representative structure of the most populated cluster of the REMD trajectory of 1b in explicit solvent at 303.60 K. (d) Superposition of the crystallographic structure of oligomer 1b (green) and the representative structure of cluster c2 (magenta) of the REMD trajectory in explicit solvent at 303.60 K. Representative structures of clusters (e) c6 and (f) c12 from the REMD trajectory of 1b in explicit methanol at 303.60 K. The γ-turns associated with i + 2 → i hydrogen bonds are highlighted in green.

Fig. 7. PMF as a function of φ (A) and ψ (B) dihedrals for oligomer 1a and of φ (C) and ψ (D) dihedrals for oligomer 1b from REMD simulations in implicit solvent. PMF as a function of φ (E) and ψ (F) dihedrals for oligomer 1b from REMD simulation in explicit MeOH.

Fig. 8. Bip 3 and Bip-containing oligomers 4a–c, with opposing terminal screw-sense preferences and the CD-responsive Bip residue at positions 3, 5 and 7.

Fig. 9. (a) CD spectra of compounds 4a–c indicating that the Bip residue is in a P environment in 4a and 4b and in an M environment in 4c; (b) presumed principal conformation of the three isomers, with the screw-sense reversal located at Aib6. Blue indicates right-handed screw sense; red indicates left-handed screw sense.

Fig. 10. (a) Gly-containing compounds 5; (b) CD spectra of 5a, 5b and 6a recorded in MeOH at 20 °C.

Fig. 11. Oligomers containing ¹³C-labelled Aib residues enantioselectively isotopically enriched in their pro-R : pro-S methyl groups in a 3 : 1 ratio. The isotopic enrichment of residue 7 of 6b is half that of residue 5, to aid identification.

Fig. 12. Portions of the ¹³C NMR spectra recorded at 23 °C in MeOH (blue, left) and MeCN (red, right), with Δδ values in ppb, of (a) 6a, (b) 6b and (c) 6c. (d) Plot of h.e., calculated from chemical shift difference Δδ in the ¹³C NMR spectrum recorded in methanol (blue) and acetonitrile (red), against the position in the chain, showing a change from an M to a P screw-sense at around Aib4. (Negative h.e. indicates an M screw-sense.)