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.

Keywords: molecular recognition; peptides; receptors; self-assembly; supramolecular chemistry.

Figure 1

Structures of Zn(1) ⋅ 2ClO₄, Zn(2) ⋅ 2ClO₄ and Zn(3) ⋅ 2ClO₄ with bound ligand L. Structural changes from 1 are shown in red, the methylene protons in the glycinamide are shown in blue.

Scheme 1

Synthesis of Zn(II) complexes of the Aib foldamers (a) Zn(2) ⋅ 2ClO₄ and (b) Zn(3) ⋅ 2ClO₄, starting from DPA 4 and N₃Aib₄GlyNH₂ 5.

Figure 2

X‐ray crystal structure of Zn(2) ⋅ 2ClO₄. (a) Side view of M helix showing the oxygen from the GlyNH₂ of a neighboring foldamer bound to the Zn(II) ion. Selected hydrogen bonds shown to illustrate the hydrogen bonded network. (b) View showing the glycinamide C=O to Zn(II) interaction that gives head‐to‐tail polymers of M‐helical foldamers. Perchlorate counterions, water of solvation and hydrogens are not shown for clarity.

Figure 3

Partial X‐ray crystal structures showing the geometry around the metal center for (a, b) Zn(1) ⋅ 2ClO₄, (c, d) Zn(2) ⋅ 2ClO₄ (glycinamide coordinated in the place of water) and (e, f) Zn(BPTA)(Aib₈CH₂CH₂OSi(CH₃)₃) ⋅ 2ClO₄. Some hydrogens and CH₂CH₂Si(CH₃)₃ not shown for clarity.22

Figure 4

Partial ¹H NMR spectra showing the aromatic region of (a) Zn(1) ⋅ 2ClO₄ in CD₃CN and (b) Zn(3) ⋅ 2ClO₄ in CD₃OD upon the incremental addition of 0 to 2 eq. Boc−D‐Pro (with 0 to 2.4 eq. 2,6‐lutidine). Starting foldamer concentration 0.015 M. The blue boxes show changes in the resonances of (a) protons on the quinolinyl 8‐positions or (b) protons on the pyridyl 2‐positions.

Figure 5

(a) Partial structure showing the protons at the pyridyl 2‐positions of Zn(3) ⋅ 2ClO₄. (b,c) Partial ¹H NMR spectra showing the resonances from these protons in CD₃OD after addition of 2 eq. (b) Boc−D‐Pro or (c) rac‐BocPro. (d) Partial structure showing methylene protons on the GlyNH₂ of Zn(3) ⋅ 2ClO₄. (e,f) Partial ¹H VT NMR spectra from −50 to 40 °C showing these resonances in CD₃OD after addition of 2 eq. (e) Boc−D‐Pro or (f) rac‐BocPro. Each foldamer 0.014 M.