Enantiomeric purity of organophosphonates

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  • Górecki, Ł.; Berlicki, Ł.; Mucha, A.; Kafarski, P.; Ślepokura, K.; Rudzińska-Szostak, E., Phosphorylation as a Method of Tuning the Enantiodiscrimination Potency of Quinine – an NMR Study. Chirality 2012, 24, 318. View at Publisher
    Abstract

    Quinines phosphorylated at the C-9 hydroxyl group (diphenyl and diethyl phosphates) were synthesized and validated as novel effective chiral solvating agents in two alternative methods based on 1H and 31P NMR spectroscopy. Tested with a representative set of racemic analytes, the title compounds induced shift non-equivalence effects in 1H NMR signals with values up to 0.1-0.2 ppm for DNB-substituted amino acids. In terms of enantiodifferentiation extent and application range, introduction of a phosphate group was proven to be superior compared to the action of non-modified quinine. Interestingly, a temperature decrease to reach the slow exchange conditions also produced non-equivalences in the 31P NMR spectra of the selectors. Comprehensive NMR analysis showed the existence of two conformations (closed 1 and 2) for both quinines in their free forms and the open 3 arrangement for the protonated ones. The crystal structure of diethylphosphorylquinine hydrochloride dichloromethane hemisolvate revealed a similar conformation to that observed in solution. Structures of complexes of phosphorylated quinines with selected ligands were determined with the use of NMR-based molecular modeling studies..
  • Rudzińska, E.; Dziędzioła, G.; Berlicki, Ł.; Kafarski, P., Enantiodifferentiation of alpha–Hydroxyalkanephosphonic Acids in 31P NMR with Application of alpha–Cyclodextrin as Chiral Discriminating Agent. Chirality 2010, 22, 63. View at Publisher
    Abstract

    Alpha-Cyclodextrin was shown to be convenient chemical shift reagent for determination of the enantiomeric composition of alpha-hydroxyphosphonic acids by means of 31P NMR. The developed methodology appeared to be reliable, repetitive, easy to perform and simple for interpretation. Enantiomeric discrimination in the 31P NMR spectra for twelve of thirteen studied hydroxyphosphonates was achieved, with baseline separation of resonances obtained for eight compounds. In those cases, the chemical non-equivalence values ranged from 0.069 to 0.313 ppm. The studies showed that enantioselectivity is strongly influenced by the solution pD and the optimal condition was found at pD 2 or 10 depending on the guest structure. On the basis of the ROESY spectra the complexation modes of selected hydroxyphosphonates with a-cyclodextrin was postulated..
  • Rudzińska, E.; Berlicki, Ł.; Kafarski, P.; Lammerhofer, M.; Mucha, A., Cinchona alkaloids as privileged chiral solvating agents for enantiodiscrimination of N-protected aminoalkanephosphonates - a comparative NMR study. Tetrahedron Asymmetry 2009, 20, 2709. View at Publisher
    Abstract

    A series of chiral amines of increasing structural complexity, such as 1-(1-naphthyl)ethylamine, ephedrine, quinine, quinidine, 9-O-tert-butylcarbamoylquinine and 9-O-tert-butylcarbamoylquinidine was studied as chiral solvating agents for enantiodifferentiation of N-benzyloxycarbonyl derivatives of 1-aminoalkanephosphonic and phosphinic acids by means of 31P NMR spectroscopy. Among cinchona alkaloids, that induced the most significant chemical shift nonequivalences, nonsubstituted quinidine exhibited supreme effectiveness, excellent for analytical purposes (for example  = 0.348 up to 1.008 ppm for phosphinic acid analogs). The signal separation of diionic phosphonic acids’ enantiomers could be further optimized by addition of an excess of the solvating agents. The newly obtained results appeared superior when compared to the data set reported previously for the same analytes with application of cyclodextrins..
  • Rudzińska, E.; Poliwoda, A.; Berlicki, Ł.; Mucha, A.; Dżygiel, P.; Wieczorek, P.P.; Kafarski, P., Enantiodifferentiation of N-benzyloxycarbonylaminophosphonic and phosphinic acids and their esters using cyclodextrins by means of capillary electrophoresis. J. Chromat. A 2007, 1138, 284. View at Publisher
    Abstract
    Capillary electrophoresis was successfully applied for separation of the enantiomers of N-benzyloxycarbonyl-alpha-aminophosphonic and alpha-aminophosphinic acids as well as their ethyl and phenyl monoesters with the use of a range of commercially available cyclodextrins (alpha, beta and hydroxypropyl-gamma-cyclodextrins) as chiral selectors. The dependence of type and concentration of these chiral selectors as well as of pH of background electrolyte on effectiveness of separation was examined in some detail. Additionally, enantiodifferentiation of ethyl and phenyl N-protected alpha-aminophosphonic monoesters with the same set of the host molecules was studied by means of nuclear magnetic resonance. As a result, two versatile methodologies (capillary electrophoresis and 31P NMR) for simple and rapid assessment of the enantiomeric composition of various N-benzyloxycarbonyl-alpha-aminophosphonates were elaborated. 2D-ROESY experiments were applied for the investigation of the molecular recognition mechanism and structure of the guest-host assemblies..
  • Rudzińska, E.; Berlicki, Ł.; Mucha, A.; Kafarski, P., Analysis of pD Dependent Complexation of N-Benzyloxycarbonylaminophosphonic Acids by a-Cyclodextrin. Enantiodifferentation of Phosphonic Acid pKa V alues Chirality 2007, 19, 764. View at Publisher
    Abstract
    The influence of aqueous solution pD on enantioselective complexation of Nbenzyloxycarbonylaminophosphonic acids with a-cyclodextrin was investigated by means of nuclear magnetic resonance spectroscopy. The highest enentiodiscrimination was achieved at pD close the pKa of less acidic hydroxyl group of phosphonic moiety of analytes (6.5-7.5). This results from the enantioselective differentiation of pKa (up to 0.2 pD unit) upon complexation with this chemical shift reagent. Moreover, analysis of 2D-ROESY spectra proved that host-guest inclusion mode is strongly influenced by pD..
  • Rudzińska, E.; Berlicki, Ł.; Mucha, A.; Kafarski, P., Chiral discrimination of ethyl and phenyl N-benzyloxycarbonylaminophosphonates by cyclodextrins. Tetrahedron Asymmetry 2007, 18, 1579. View at Publisher
    Abstract

    Enantiodifferentiation of N-protected ethyl and phenyl a-aminophosphonates with application of commercially available cyclodextrins as chiral solvating agent was studied by means of nuclear magnetic resonance spectroscopy. Four cyclodextrins (a-CD, b-CD, g-CD and HP-g-CD) were chosen due to the differences in the size of their inner cavities and substitution of the rim, which in turn might change the affinity of the compounds analyzed to these chiral selectors. The influence of solution pD and host concentration on the enantiodiscrimination efficiency was also studied. As a result, a methodology for the simple and rapid assessment of the enantiomeric composition of various N-benzyloxycarbonyl-a-aminophosphonates has been elaborated upon. 2D Rotating frame nuclear Overhauser and exchange spectrometry experiments and continuous variation methods were applied for establishing the molecular recognition mechanism and structure of the guest–host assemblies..
  • Berlicki, Ł.; Rudzińska, E.; Mucha, A.; Kafarski, P., Cyclodextrins as NMR probes in the study of the enantiomeric compositions of N-benzyloxycarbonylamino-phosphonic and phosphinic acids. Tetrahedron-Asymmetry 2004, 15, 1597. View at Publisher
    Abstract

    The inclusion complexes of a- and hydroxypropyl-g-cyclodextrins with N-benzyloxycarbonyl protected a-aminophosphonic and a-aminophosphinic acids were studied by means of NMR spectroscopy. Cyclodextrins appear to be a useful tool for determining the enantiomeric excess of all the examined amino acid mimetics. Stoichiometry and geometry of selected complexes were investigated. 2D ROESY experiments and continuous variation methods indicated that there are three possible types of complexation: two of guest/host ratio being 1:1 and one of 1:2 stoichiometry. Molecular modelling studies confirmed the proposed modes of complexation. .
  • Berlicki, Ł.; Rudzińska, E.; Kafarski, P., Enantiodifferentiation of aminophosphonic and aminophosphinic acids with alpha- and beta-cyclodextrins. Tetrahedron-Asymmetry 2003, 14, 1535. View at Publisher
    Abstract

    Cyclodextrins were used as chiral selectors for the 31P NMR determination of the enantiomeric excess of aminoalkanephosphonic and aminoalkanephosphinic acids. Most of these acids form inclusion complexes with a- and/or b-cyclodextrin and upon increasing the cyclodextrin to aminophosphonic acid molar ratio 31P NMR signals for (R)- and (S)-enantiomers separate. ROESY spectra allowed the determination of structures of the inclusion complexes. .
  • Rudzinska, E.; Wieczorek, P.; Kafarski, P., Separation of aminoalkanephosphonic acid enantiomers by indirect UV detection capillary electrophoresis with application of cyclodextrins. Electrophoresis 2003, 24, 2693. View at Publisher
    Abstract
    Indirect UV detection capillary electrophoresis (CE) was used for the separation of aminoalkanephosphonic acid (AP) enantionners by applying commercially available cyclodextrins as chiral discriminators. The results show that the separation of the enantiomers depends on pH of the background electrolyte, the molar ratio of cyclodextrin to aminophosphonic acid, and on the type of the applied chiral selector. Optimization of process conditions allowed enantiomeric baseline separation or partial separation of 12 out of 14 alpha-aminophosphonic acids studied. This type of CE might therefore be successfully used for routine determination of enantiomeric purity of aminophosphonic acids. .
  • Rudzinska, E.; Dzygiel, P.; Wieczorek, P.; Kafarski, P., Separation of aromatic aminophosphonic acid enantiomers by capillary electrophoresis with the application of cyclodextrins J. Chromatogr. A 2002, 979, 115
    Abstract
    The detailed studies concerning capillary electrophoresis separation of aminophosphonic acid enantiomers with various commercially available cyclodextrins are presented. The obtained results show that the separation of these stereoisomers is dependent on pH of background electrolyte, concentration of cyclodextrin as well as on the type of applied chiral selector. The separation mechanism is based on the co-operative effect of hydrogen bond type interactions enhanced by hydrophobic forces and sterical constrains between aminophosphonate and cyclodextrin. With application of elaborated method, enantiomeric baseline or partial separation of 18 alpha-aminophosphonic acids was achieved. This separation can be successfully used for routine aminophosphonic acids enantiopurity determination..
  • Dzygiel, P.; Rudzinska, E.; Wieczorek, P.; Kafarski, P., Determination of optical purity of phosphonic acid analogues of aromatic amino acids by capillary electrophoresis with alpha-cyclodextrin. J. Chromatogr. A 2000, 895, 301
    Abstract
    A simple and efficient method for the determination of enantiomeric purity of structurally diverse phosphonic and phosphinic acid analogues of phenylalanine and phenylglycine using capillary electrophoresis is presented. These preliminary studies indicated that the enantiomer separation is strongly dependent on the structure of the aminophosphonic acid..