Molecular Recognition by Zn(II)‐Capped Dynamic Foldamers

Abstract Two α‐aminoisobutyric acid (Aib) foldamers bearing Zn(II)‐chelating N‐termini have been synthesized and compared with a reported Aib foldamer that has a bis(quinolinyl)/mono(pyridyl) cap (BQPA group). Replacement of the quinolinyl arms of the BQPA‐capped foldamer with pyridyl gave a BPPA‐capped foldamer, then further replacement of the linking pyridyl with a 1,2,3‐triazole gave a BPTA‐capped foldamer. Their ability to relay chiral information from carboxylate bound to Zn(II) at the N‐terminus to a glycinamide‐based NMR reporter of conformational preference at the C‐terminus was measured. The importance of the quinolinyl arms became readily apparent, as the foldamers with pyridyl arms were unable to report on the presence of chiral carboxylate in acetonitrile. Low solubility, X‐ray crystallography and 1H NMR spectroscopy suggested that interfoldamer interactions inhibited carboxylate binding. However changing solvent to methanol revealed that the end‐to‐end relay of chiral information could be observed for the Zn(II) complex of the BPTA‐capped foldamer at low temperature.


Instruments
All 1 H and 13 C nuclear magnetic resonance (NMR) spectra were obtained using Bruker AVANCE 400 or 500 spectrometers. Chemical shifts are quoted in parts per million (ppm) and coupling constants (J) are quoted in Hz to the nearest 0.

Materials
All reactions were carried out in oven-dried glassware under an atmosphere of nitrogen using standard anhydrous techniques. All reagents were obtained from commercially available sources and used without further purification, or where indicated prepared internally. All products were dried on a rotary evaporator followed by connection to a high vacuum system to remove any residual solvent. Flash chromatography was performed on silica gel (Merck 60H, 40-60 nm, 230-300 mesh) or alumina (Merck, activated, neutral, Brockmann I). Analytical thin layer chromatography (TLC) was performed on Macherey Nagel alugram SIL G/UV254 or TLC Aluminium oxide 60 F254, neutral plates and were visualised by UV (254 nm), ninhydrin or potassium permanganate dyes where appropriate.

The extent of screw-sense control of either Zn(2) . 2ClO4 or Zn(3) . 2ClO4 by a chiral 'controller', in this case
Boc-D-Pro, can be determined by NMR spectroscopy using the anisochronicity in the diastereotopic geminal protons of the glycinamide probe. This level of screw-sense control can be deduced from the anisochronicity at the glycinamide (Δδ gly ); a larger splitting signifies greater control.
In the case of Zn(2) . 2ClO4, the addition of 1-4 equivalents of Boc-D-Pro revealed no changes in anisochronicity or chemical shifts, even for the amide NH resonances, although broadening was observed.
Foldamer Zn(2) . 2ClO4 may be aggregating through a head-to-tail interaction, which prevents the carboxylate interacting with the Zn 2+ metal centre. Broadening may occur due to changes in the rate of interfoldamer association. 1 eq. 0 eq. S12
The binding of the chiral 'controller' Boc-D-Pro can be observed in the pyridyl aromatic and methylene protons. On binding, the equivalent pyridyl protons become non-equivalent and anisochronicity is observed with both pyridyls now being identified individually. This was most noticeable for proton d of the pyridyl rings that becomes diastereotopic and spits into two separate systems (d and d') displaying as doublets.
Unfortunately, there was no evidence of stereochemical information being relayed through the 310 helix. Anisochronicity at the Aib CH3 groups and the glycinamide was absent. This suggests that the triazole insulates the transmission of stereochemical information as previously seen by Boddaert et.al

VT-NMR spectra of Zn(3) . 2ClO4 (either Boc-D-Pro or rac-BocPro bound) in CD3OD
VT-NMR spectra of Zn(3) . 2ClO4 (Boc-L-Pro bound) and Zn(3) . 2ClO4 (rac-BocPro) were obtained in CD3CN over the temperature range of 40 °C to −40 °C (Figures S4 and S6). As expected, the cis and trans rotameric forms of the coordinated BocPro were observed in both Boc-D-Pro bound and rac-BocPro bound Zn(3) . 2ClO4, although partially hidden by the methylene protons. Slower interchange between the M and P helical conformations of the Aib foldamer were also observed upon a decrease in temperature. Line broadening of the ABX-system for Zn(3) . 2ClO4 (rac-BocPro bound) ascribed to the GlyNH2 protons (resonances between 3.5 and 3.7 ppm in Figure S5a) and the Aib CH3 protons (resonances between 1.1 and 1.7 ppm in Figure S5b) were observed on a decrease in temperature from 0 °C to −40 °C. Unfortunately, decoalescence of the NMR signals was not reached within the temperature range suitable for CD3OD.

Fitting of titration data
The change in the chemical shift of the protons at the pyridyl 2-positions of Zn(3) . 2ClO4 (0.014 M in CD3OD) upon titration with 0 to 2 eq. of Boc-D-Pro and 2,6-lutidine (1.2 eq. relative to Boc-D-Pro) was measured. The resulting data was fitted to 1:1 binding isotherm using the Nelder-Mead (Simplex) algorithm in the 1:1 NMR fitter at http://app.supramolecular.org/bindfit/. 5

Crystal data and structure refinement for Zn(2) . 2ClO4
Data for Zn (2) . 2ClO4 were collected on a dual source Rigaku FR-X rotating anode diffractometer using CuKα wavelength, at a temperature of 150K and reduced using CrysAlisPro 171.40.14d. 6 Absorption correction was performed using empirical methods (SCALE3 ABSPACK) based upon symmetry-equivalent reflections combined with measurements at different azimuthal angles. 6 The structure was solved using Shelxt 2014/5 and refined against all F 2 values using   Figure S14: Representation of the asymmetric plot of Compound Zn (2) . 2ClO4 in the crystal. Disorder, solvent and counter anions removed for clarity. (blue = nitrogen, white = carbon, green = fluorine, hydrogens included. Ellipsoids 50% probability). Plot produced using Olex2 and POV-ray. 8,9