Oxalyl retro-peptide gelators. Synthesis, gelation properties and stereochemical effects

Abstract

In this work we report on gelation properties, self-assembly motifs, chirality effects and morphological characteristics of gels formed by chiral retro-dipeptidic gelators in the form of terminal diacids (1a-5a) and their dimethyl ester (1b-5b) and dicarboxamide (1c-5c) derivatives. Terminal free acid retro-dipeptides (S,S)-bis(LeuLeu) 1a, (S,S)-bis(PhgPhg) 3a and (S,S)-bis(PhePhe) 5a showed moderate to excellent gelation of highly polar water/DMSO and water/DMF solvent mixtures. Retro-peptides incorporating different amino acids (S,S)-(LeuPhg) 2a and (S,S)-(PhgLeu) 4a showed no or very weak gelation. Different gelation effectiveness was found for racemic and single enantiomer gelators. The heterochiral (S,R)-1c diastereoisomer is capable of immobilizing up to 10 and 4 times larger volumes of dichloromethane/DMSO and toluene/DMSO solvent mixtures compared to homochiral (S,S)-1c. Based on the results of (1)H NMR, FTIR, CD investigations, molecular modeling and XRPD studies of diasteroisomeric diesters (S,S)-1b/(S,R)-1b and diacids (S,S)-1b/(S,R)-1a, a basic packing model in their gel aggregates is proposed. The intermolecular hydrogen bonding between extended gelator molecules utilizing both, the oxalamide and peptidic units and layered organization were identified as the most likely motifs appearing in the gel aggregates. Molecular modeling studies of (S,S)-1a/(S,R)-1a and (S,S)-1b/(S,R)-1b diasteroisomeric pairs revealed a decisive stereochemical influence yielding distinctly different low energy conformations: those of (S,R)-diastereoisomers with lipophilic i-Bu groups and polar carboxylic acid or ester groups located on the opposite sides of the oxalamide plane resembling bola amphiphilic structures and those of (S,S)-diasteroisomers possessing the same groups located at both sides of the oxalamide plane. Such conformational characteristics were found to strongly influence both, gelator effectiveness and morphological characteristics of gel aggregates.

Keywords: chiral; organogel; oxalamide; retro-peptide; self-assembly.

Scheme 1

Oxalyl retro-dipetide gelators; each b to a, (a) LiOH/MeOH, H₂O; (b) H⁺; each b to c: (c) NH₃/MeOH.

Figure 1

Chiral bis(amino acid)-(I) and bis(amino alcohol)-(II)-oxalamide gelators.

Figure 2

TEM images (PWK staining) of: (S,S)-1a H₂O/DMSO gel.

Figure 3

TEM images (PWK staining) of: (S,R)-1a H₂O/DMSO gel.

Figure 4

TEM images (PWK staining) of: (S,R)-1b toluene gel showing the presence of short tape like aggregates.

Figure 5

The concentration dependence of NH and C*H chemical shifts in (S,R)-1b toluene-d₈ gel samples (concentration range 0.001–0.1 M): a) oxalamide-NH protons (▲); Leu-NH’s (Δ) and b) oxalamide-α-Leu-C*H (■) and oxalamide-β-Leu-C*H (□) protons.

Figure 6

The concentration dependence of NH and C*H chemical shifts in (S,S)-1b and its racemate (S,S)-1b/(R,R)-1b toluene-d₈ gels (concentration range 0.001–0.1 mol dm⁻³): a) (S,S)-1b oxalamide-NH protons (▲) and Leu-NH protons (Δ); the racemate oxalamide-NH protons (●) and Leu-NH protons (O); b) (S,S)-1b oxalamide-α-Leu-C*H (■);(S,S)-1b oxalamide-β-Leu-C*H (□); the racemate oxalamide-α-Leu-C*H (); racemate oxalamide-β-Leu-C*H ().

Figure 7

Temperature dependence of: a) oxalamide NH protons (▲), Leu-NH protons (Δ) and b) oxalamide-α-Leu-C*H (■) and oxalamide-β-Leu-C*H (□) chemical shifts in 0.5 mol dm⁻³ (S,R)-1b toluene-d₈ gel sample; c) and d) induced shifts of the respective protons in (S,S)-1b toluene-d₈ gel.

Figure 8

Temperature dependent CD spectra of: a) (S,R)-1b decalin gel (c = 3.4·10⁻² M); b) (S,S)-1b decalin gel (c =7.6·10⁻³ M); c) 5a ethanol gel (c =1·10-2 M) and d) (S,S)-bis(Leu)oxalamide I 1-butanol gel (c = 2.8·10⁻² M); e), f) UV spectra of (S,R)-1b (red curve), (R,S)-1b and (S,S)-1b taken in decalin at specified concentrations.

Figure 9

X-ray powder diffractograms of (a) (S,R)-1b and (b) (S,S)-1b xerogels prepared from their toluene gels.

Figure 10

(a) Fully minimized the lowest energy conformations of (S,S)-1b (top) and (S,R)-1b generated by systematic conformational search (SYBYL package; second graphic); (b) Partial Newman projections of two stereogenic centers of (S,R)-1b and (S,S)-1b showing conformations with cis-arrangement of i-Bu groups in the former (A) and trans- (B, D) and cis- (C)-arrangements of i-Bu groups in the latter.

Figure 11

Schematic presentation of the proposed (S,S)-1b and (S,R)-1b basic packing model based on XRPD, ¹H NMR, FTIR and molecular modeling results.

Figure 12

X-ray powder diffraction (XRPD) diagram of (S,R)-1a water/DMSO xerogel.