NMR Spectroscopic and Molecular Modelling Studies on Cyclodextrin–Dipeptide Inclusion Complexes

Abstract

Cyclodextrins (CDs) are often used to separate the enantiomers of chiral drugs by HPLC, GC, and capillary electrophoresis (CE). For dipeptides containing one aromatic amino acid, a reversal of the migration order is observed in CE upon increasing the pH value of the background electrolyte from 2.5 to 3.5. In order to understand the mechanism of chiral recognition of this phenomenon, NMR experiments, namely complexation‐induced chemical shifts (CICS) and ROESY, were performed. Comparing the CICSs obtained for the pairs Diac‐β‐CD/Ala‐Phe and HDAS‐β‐CD/Ala‐Phe and Diac‐β‐CD/Ala‐Tyr and HDAS‐β‐CD/Ala‐Tyr revealed very small changes, thereby indicating a rather weak interaction of the respective guest molecules with their host. The CICS for β‐CD and HS‐β‐CD confirmed an inclusion of the aromatic moiety into the CD cavity. It is shown that, at pH 2.5, the D,D‐enantiomer of Ala‐Tyr immerses deeper into the cavity of β‐cyclodextrin than the L,L‐enantiomer, and this was subsequently confirmed by molecular dynamics simulations. Furthermore, at pH 3.5 the immersion is shallower, as shown by the 1H and ROESY NMR findings and confirmed by the molecular dynamics simulations. The immersion depths of the dipeptides were calculated by defining a plane in the cavity to gain information about the different behaviour of the studied chemical species. The employed procedure is easily generalised to other host‐guest complexes and is expected to improve data evaluation in other cases, too. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Review of aqueous chiral electrokinetic chromatography (EKC) with an emphasis on chiral microemulsion EKC

“…Their goal was to provide guidelines for selection of a chiral agent to reduce the screening process. NMR is a popular approach for defining specific interactions leading to chiral recognition, typically for CD-analyte complexes [35,36] but also for micellar studies [37].…”

NMR Enantiodiscrimination of Polar and Apolar Substrates by Multifunctional Cyclodextrins

“…It should, however, be stressed that, above all in the cases of cyclodextrins, for which understanding of enantiorecognition phenomena often constitutes a considerable challenge, the contributions from complementary analytical methods, such as molecular model-ling, X-ray crystallography, mass spectrometry, IR spectroscopy or microcalorimetric measurements, should not be underestimated. [33,34] Experimental Section General Methods: NMR measurements were performed on a spectrometer operating at 299.94 MHz for 1 H and the temperature was controlled to ±0.1°C. All 1 H NMR chemical shifts are referenced to TMS as external standard.…”

Recent advances in peptide and peptidomimetic stereoisomer separations by capillary electromigration techniques

“…As a result, the separation of the enantiomers was observed. Moreover, the earlier described reversal of the enantiomer migration order depending on the buffer pH observed for Ala-Phe [40] and Ala-Tyr [41] when using b-CD as chiral selector triggered an NMR investigation by Kahle et al [42] in an attempt to determine the structural properties of the diastereomeric peptide-CD complexes. In this paper the complexes between Ala-Phe and Ala-Tyr with b-CD, HS-b-CD, heptakis-(2,3-diacetyl)-b-CD (Diac-b-CD), and HDAS-b-CD were investigated by determination of the complexation-induced chemical shifts (CICS) and rotational nuclear Overhauser effect spectroscopy (ROESY).…”

“…Thus, the DD-enantiomers of the peptides appeared to immerse deeper into the cavity of b-CD compared to the LL-stereoisomers at pH 2.5 while no significant difference was found for the complexes at pH 3.5. Subsequent molecular dynamics calculations also revealed differences in the immersion depths of the peptide enantiomers depending on the fact whether the compounds are included into the CD cavity as cations or zwitterions [42].…”