Novel urea-linked cinchona-calixarene hybrid-type receptors for efficient chromatographic enantiomer separation of carbamate-protected cyclic amino acids

Abstract

Two novel diastereomeric cinchona-calixarene hybrid-type receptors (SOs) were synthesized by inter-linking 9-amino(9-deoxy)-quinine (AQN)/9-amino(9-deoxy)-epiquinine (eAQN) and a calix[4]arene scaffold via an urea functional unit. Silica-supported chiral stationary phases (CSPs) derived from these SOs revealed, for N-protected amino acids, complementary chiral recognition profiles in terms of elution order and substrate specificity. The AQN-derived CSP showed narrow-scoped enantioselectivity for open-chained amino acids bearing pi-acidic aromatic protecting groups, preferentially binding the (S)-enantiomers. In contrast, the eAQN congener exhibited broad chiral recognition capacity for open-chained as well as cyclic amino acids, and preferential binding of the (R)-enantiomers. Exceedingly strong retention due to nonenantioselective hydrophobic analyte-calixarene interactions observed with hydro-organic mobile phases could be largely suppressed with organic mobile phases containing small amounts of acetic acid as acidic modifier. With the eAQN-calixarene hybrid-type CSP particularly high levels of enantioselectivity could be achieved for tert-butoxycarbonyl (Boc)-, benzyloxycarbonyl (Z)- and fluorenylmethoxycarbonyl (Fmoc)-protected cyclic amino acids using chloroform as mobile phase, e.g. an enantioselectivty factor alpha >5.0 for Boc-proline. Increasing amounts of acetic acid compromised enantioselectivity, indicating the crucial contributions of hydrogen bonding to chiral recognition. Comparison of the performance characteristics of the urea-linked eAQN-calixarene hybrid-type CSP with those of structurally closely related mutants provided evidence for the active involvement of the urea and calixarene units in the chiral recognition process. The urea linker motif was shown to contribute to analyte binding via multiple hydrogen bonding interactions, while the calixarene module is believed to support stereodiscrimination by enhancing the shape complementarity of the SO binding site.

Preparation and evaluation of a deoxycholic‐calix[4]arene hybrid‐type receptor as a chiral stationary phase for HPLC

“…Four novel carbamate and urea‐linked cinchona‐calixarene hybrid chiral stationary phases were prepared and evaluated for the enantioseparation of amino acids. These CSPs exhibited broad chiral recognition capacity for the separation of carbamate‐protected cyclic amino acids . Most recently, we have introduced a chiral HPLC stationary phase based on cone calix[4]arene functionalized at the upper rim with l ‐alanine units for chiral separation .…”

Preparation and evaluation of a chiral HPLC stationary phase based on cone calix[4]arene functionalized at the upper rim with l‐alanine units

“…These types of stationary phases showed excellent selectivity for the separation of aromatic positional isomers and enantiomers of chiral compounds (Chelvi et al, ; Chelvi, Yong, & Gong, ). In another work, the novel carbamate and urea‐linked cinchona–calixarene chiral stationary phases exhibited broad chiral recognition capacity for amino acids (Krawinkler, Maier, Sajovic, & Lindner, ). The silica‐bonded derivatives of alanine have previously been studied by Pirkle et al, but the combination of alanine and calixarenes has not been studied yet (Fernandes et al, ).…”

Improvement of chiral stationary phases based on cinchona alkaloids bonded to crown ethers by chiral modification

“…A lot of anion‐exchange‐type CSPs based on quinine (QN)/quinidine (QD) derivatives have been developed and their enantiorecognition capabilities and enantiorecognition mechanisms toward some chiral compounds have been investigated in detail . These QN/QD‐based CSPs possess excellent chiral recognition capabilities for chiral acidic compounds.…”