Achiral Shift Reagent Research Articles

1H NMR Studies of Drugs with Achiral and Chiral Lanthanide Shift Reagents. CGP29953: Analog of the Aromatase Inhibitor, Aminoglutethimide

1-(4-Aminophenyl)-3-n-propyl-3-azabicyclo[3.1.0]hexane-2, 4-dione, compound 1 (CGP29953), is an analog of the aromatase inhibitor aminoglutethimide (AG); AG has applications in cancer treatment. We have studied the 1H NMR spectra of racemic compound 1 (in CDC13, ambient temperatures, 300-MHz) with the added achiral LSR, tris(6, 6, 7, 7, 8, 8, 8-heptafluoro-2, 2-dimethyl-3, 5-octanedionato) europium (III), compound 2, and the chiral LSR, tris[3-(heptafluoropropylhydroxymethylene)-(+) - camphorato]europium (III), compound 3. Use of compound 3 produced substantial enantiomeric shift differences for several nuclei of compound 1. 1H-1H COSY spectra were used to determine the relative sense of magnetic nonequivalence for selected nuclei of compound 1 with added compound 3. Relative lanthanide induced shift (LIS) magnitudes for compound 1. with added LSR are discussed.

NMR Studies of Hindered Rotations in Drugs. Use of Achiral and Chiral Lanthanide Shift Reagents with Mecloqualone, an Axially Chiral Drug of Abuse. Rigorous Definition of Spin Systems.

The axially chiral sedative/hypnotic drug of abuse, mecloqualone, 1, has been studied in CDC13 by 1H NMR at 60 and 300 MHz with the added achiral lanthanide shift reagent (LSR), tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5- octanedionato)europium(III), 2, and the chiral LSR, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato] europium-(III), 3. Rigorous distinctions between the two (CH)4 spin systems of 1 with added 2 or 3 were achieved by two-dimensional homonuclear chemical shift correlation spectroscopy, COSY. Substantial up field (“anomalous”) shifts were observed for several nuclei of 1 with each LSR. Use of the chiral 3 elicited enantiomeric shift differences with baseline separations for several nuclei that should permit direct determinations of enantiomeric excess. COSY spectra allow determination of the relative sense of magnetic nonequivalence of selected nuclei of 1 with 3.

NMR Studies of Drugs: Antipyrine and Analogs. I. Use of Achiral and Chiral Lanthanide Shift Reagents to Examine Hindered Rotation.

The 200 MHz 1H NMR spectra of the analgesic, antipyrine, 1, have been studied in CDC13 solution at ambient temperatures with the achiral lanthanide shift reagent (LSR) tris (6, 6, 7, 7, 8, 8, 8-heptafluoro-2, 2-dimethyl-3, 5-octanedionato) europium (III), Eu(FOD)3, 2, and with the chiral LSR, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium(III), Eu(HFC)3, 3., Lanthanide-induced shift (LIS) magnitudes and broadening of selected signals are consistent with predominant LSR binding at the carbonyl oxygen with either 2 or 3. Of the different possible conformational regimes for the N-phenyl group of 1, our results appear to rule out a slow exchange limit (SEL) system with the N-phenyl coplanar with the heterocyclic ring. Perpendicular rings in an SEL regime can not be ruled out. A rapidly-rotating N-phenyl (fast exchange limit, FEL system) would also be consistent with observed results. Accurate chemical shifts for the aryl protons (overlapped in the 200 MHz spectrum of unshifted 1) are determined from spectra with added LSR by extrapolation to zero molar ratios of [LSR]:[1]. Relative slopes in the plots of chemical shift versus [LSR]:[1] molar ratios are calculated for each proton signal of 1.

NMR Studies of Drugs. Applications of Achiral and Chiral Lanthanide Shift Reagents to Citiolone.

The 200 MHz 1H NMR spectra of citiolone, 1, have been studied in CDC13 solution at ambient temperatures with the achiral lanthanide shift reagent (LSR) tris (6, 6, 7, 7, 8, 8, 8-heptafluoro-2, 2-dimethyl-3, 5-octanedionato) europium (III), Eu (FOD)3, 2, for spectral simplification, and with the chiral LSR, tris [3-heptafluoropropylhydroxymethylene)-(+)-camphorato] europium (III), Eu (HFC)3, 3. With 3, substantial enantiomeric shift differences were obtained for the H-3, NH and CH3CO resonances, with the H-3 signals essentially baseline resolved and free from overlaps with [3]/[1] molar ratios ca. 0.8–1.0. For the acetyl signal, valley heights as low as 4–5% were achieved between the signals of the antipodes when [3]/[1] ratios ca. 0.7–0.8 were used. These conditions should permit direct determinations of enantiomeric excess of 1.

Direct determination of diastereomeric 13C-labeled ketoprofen glucuronides in human urine by nuclear magnetic resonance spectroscopy

Abstract A new method based on the 13 C-labeling and nuclear magnetic resonance (NMR) spectroscopy was developed to study the human urinary excretion of diastereomeric acylglucuronides after the oral administration of 100 mg racemic [3- 13 C]ketoprofen (KP). The urinary excretion of diastereomeric [3- 13 C]KP glucuronides formed from [3- 13 C]KP was followed by proton-decoupled 13 C NMR spectroscopy (9.4 T, 10min accumulation time) without any separation procedures such as extraction and chromatography. The C3 resonances due to the diastereomers were satisfactorily separated from each other by the addition of methyl-β-cyclodextrin as an achiral shift reagent through the formation of inclusion complexes. The C3 resonances were detected with an acceptable signal-to-noise ratio over 8 h at a therapeutic dosage. The concentrations of [ 13 C]KP glucuronides were calculated from the inverse gated decoupling and proton-decoupling experiments using [2- 13 C]glycine as an internal standard. The urinary excretion of diastereomeric [3- 13 C]KP glucuronides over 8 h amounted to 29% (downfield position) and 25% (upfield position) of the administered dose, respectively, and the former was presumed to have S -configuration. The elimination rate constants of both glucuronides were virtually the same ( K = 0.19 h −1 ). In addition, the susceptibility of the glucuronides to acyl migration as well as hydrolysis was suggested under the physiological conditions (37 °C, pH 7.3). The present direct approach is simple and convenient, and has the potential for wide application to the analysis of the labile acylglucuronides of 2-arylpropionic acids in biofluids.

Mixtures of Chiral and Achiral Chemical Shift Reagents of Europium and Their Benefits for the Determination of Enantiomeric Purity

Mixtures of Chiral and Achiral Chemical Shift Reagents of Europium and Their Benefits for the Determination of Enantiomeric Purity

Mixtures of Chiral and Achiral Chemical Shift Reagents of Europium and Their Benefits for the Determination of Enantiomeric Purity

Mixtures of Chiral and Achiral Chemical Shift Reagents of Europium and Their Benefits for the Determination of Enantiomeric Purity

NMR Studies of Drugs. Applications of Achiral and Chiral Lanthanide Shift Reagents to the Analgesic, Famprofazone: “Anomalous Shifts”

Abstract The 200 MHz 1H NMR spectra of the analgesic, famprofazone, 1, have been studied in CDCl3 solution at ambient temperatures with the achiral lanthanide shift reagent (LSR) tris (6, 6, 7, 7, 8, 8, 8-heptaf luoro-2, 2-dimethyl-3, 5-octanedionato) europium (III), Eu(FOD)3, 2, for spectral simplification, and with the chiral LSR, tris [3-(heptafluoropropylhydroxymethylene) - (+) camphorato] europium (III), Eu (HFC)3, 3. Lanthanide induced shift (LIS) magnitudes suggested predominant LSR binding at the carbonyl oxygen. Substantial enantiomeric shift differences were observed for several nuclei of 1 with added 3 which could permit direct determinations of enantiomeric excess.

NMR Studies of Agricultural Compounds. Applications of Achiral and Chiral Lanthanide Shift Reagents to the Herbicide, Fenoxaprop-Ethyl

Abstract The 200 MHz H NMR spectra of the herbicide, fenoxaprop-ethyl, 1, have been studied in CDCl3 solution at ambient temperatures as the racemic ester free base with the added chiral lanthanide shift reagent (LSR), tris [3 - (heptafluoropropylhydroxymethylene) - (+) - camphorato]europium(III), Eu(HFC)3, 2, with some additional runs using the achiral LSR, tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium(III), Eu(FOD)3, 3, for supplemental spectral simplification. With 2, definite enantiomeric shift differences (ΔΔδ) were observed only for the CH3CH2O resonance. Although increased spectral complexity for the CH2O signal was seen with added 2, this could have resulted from anisochrony of the diastereotopic protons, Ha and Hb, of this methylene group rather than true ΔΔδ, since the achiral 3 led to near-baseline separation between the CHaHbO signals. Lanthanide-induced shift (LIS) magnitudes were interpreted as consistent with predominant LSR binding at the ester carbonyl.

NMR Studies of Drugs. Applications of Achiral and Chiral Lanthanide Shift Reagents to Medetomidine. Observations of “Anomalous Shifts.”

Abstract The 60 MHz H NMR spectra of the potent, selective and specific α2-adrenoceptor agonist, medetomidine, have been studied in CDCl3 at 28±1° for the recemic free base, 1, with the added achiral lanthanide shift reagent (LSR), tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium(III), 2, for spectral simplification, and with the chiral LSRs, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium(III), 3, and tris[3-(trifluoromethylhydroxymethylene)-(+)-camphorato] europium (III), 4, for potential enantiomeric shift differences. Substantial lanthanide-induced shifts (LIS) were observed with each added LSR, consistent with LSR binding at the basic imidazole nitrogen. The three LSRs gave distinctly different LIS results for the NH signal, with substantial “anomalous” (upfield) shifts observed with 2 and smaller anomalous shifts produced with 3, at low [LSR]:[1] ratios; normal downfield shifts resulted at higher LSR levels of 2 or 3. With LSR 4, only consistent “normal” dow...

NMR Studies of Agricultural Compounds. Applications of Achiral and Chiral Lanthanide Shift Reagents to the Multifunctional Compound, Imazapyr Methyl Ester.

Abstract The 60 MHz 1H NMR spectra of the methyl ester derivative, 1, of the imidazolinone herbicide, imazapyr, have been studied in CDC13 at 28±1° (as the racemic free base) with the added achiral lanthanide shift reagent (LSR), tris(6, 6, 7, 7, 8, 8, 8-heptafluoro-2, 2-dimethyl-3, 5-octanedionato) europium (III), 2, for spectral simplification, and with the chiral LSR, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium(III), 3, to induce enantiomeric shift differences (ΔΔδ). An additional series of runs employed the chiral LSR, tris[3-(trifluoromethylhydroxymethylene)-(+)-camphorato]europium(III), 4. Substantial lanthanide-induced shifts (LIS) were observed with each added LSR. Added 3. appeared to elicit large ΔΔδ magnitudes for H-6 on the pyridine ring (alpha to nitrogen), whereas 4. caused smaller ΔΔδ values for the quaternary and isopropyl methyls on the imidazolinone ring.

NMR Studies of Drugs. Applications of Achiral and Chiral Lanthanide Shift Reagents to Acifran Methyl Ester. LSR Binding to a Multifunctional Substrate.

Abstract The antihyperlipoproteinemic agent, acifran, has been studied as its racemic methyl ester, 1, by 60 MHz 1H NMR in CDC13 solution at 28±1° with the added achiral lanthanide shift reagent (LSR), tris(6, 6, 7, 7, 8, 8, 8-heptaf luoro-2, 2-dimethyl-3, 5-octanedionato-europium(III), Eu (FOD)3, 2, for spectral simplification, and with the chiral LSRs, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium(III), Eu(HFC)3, 3, and tris[3-(trifluoromethylhydroxymethylene)-(+)-camphorato]europium(III), Eu (FACAM)3, 4, for potential determinations of enantiomeric excess. Relative lanthanide-induced shift (LIS) magnitudes with the three LSRs were interpreted as consistent with major lanthanide binding at the 4-oxo carbonyl, but contrasting behavior in observed enantiomeric shift differences (ΔΔδ) with 3 versus 4 may suggest different bound complex geometries for 3 or 4 with 1.

NMR Studies of Agricultural Products. Applications of Achiral and Chiral Lanthanide Shift Reagents to the Fungicide, Triadimefon.

Abstract The 60 MHz 1H NMR spectra of the systemic agricultural fungicide, triadimefon, 1, have been studied in CDCl3 at 28±1° (as the racemic free base) with the added achiral lanthanide shift reagent (LSR), tris(6, 6, 7, 7, 8, 8, 8-heptafluoro-2, 2-dimethyl-3, 5-octanedionato) europium(III), Eu(FOD)3, 2, for spectral simplification, and with the chiral LSR, tris [3-(heptafluoropropylhydroxymethylene)-(+) -camphorato)europium(III), Eu(HFC)3, 3, to induce enantiomeric shift differences (ΔΔδ) for several nuclei. Significant ΔΔδ values were seen for the two protons of the heterocyclic ring, the OCH methine, and aryl H-2′, 6′ of the chlorophenoxy ring. For each of these nuclei exhibiting ΔΔδ with added 3, the ΔΔδ magnitudes reached maximum values with 3: 1 molar ratios ca. 0. 18–0. 29, and decreased with higher levels of 3. To confirm analytical utility of 3 for % e. e. determinations of 1, a nonracemic (“spiked”) sample of racemic 1, with added R-(−) triadimefon, was examined with 3. At low 3: 1 ratios, bot...

NMR Studies of Drugs. Applications of Achiral and Chiral Lanthanide Shift Reagents to a 5-Substituted-4-thiazolidinone

Abstract The 60 MHz 1H NMR spectra of racemic 5-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methyl]-4-thiazolidinone, 1, have been studied in CDCl3 solution at 28° with the achiral lanthanide shift reagent (LSR), tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium (III), 2, and the chiral LSRs, tris[3-(heptafluoropropylhydroxymethylene)- (+)-camphoratojeuropium(III), 3, and tris[3-(trifluoromethylhydroxymethylene-(+) -camphorato]europium (III), 4, Significant enantiomeric shift differences were observed in the presence of added 3, for the aryl protons of 1 that should permit direct determination of enantiomeric excess. Relative magnitudes of lanthanide-induced shift for the different nuclei of 1 with the three LSRs are compared and discussed in terms of preferred LSR binding sites. A favored conformation of 1 with respect to rotation about the C(5)-CH2 bond is suggested.

NMR Studies of Drugs. Sulindac Methyl Ester. Applications of Achiral and Chiral Lanthanide Shift Reagents

Abstract The potent nonsteroidal anti-inflammatory agent, sulindac, (Z) -5-fluoro-2-methyl-1-{[4-(methylsulfinyl) - phenyl]methylene} -1H-indene-3-acetic acid, has been examined by 1H NMR as its methyl ester in CDCl3 solution with the added achiral lanthanide shift reagent (LSR) tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium (III), Eu (FOD)3, 2, for spectral simplification, and with the chiral LSRs, tris[3-(heptafluoropropylhydroxymethylene) - (+) - camphorato] europium (III), 3, and tris[3-(trifluoromethyl-hydroxymethylene) - (+) -camphorato] europium (III), 4, to induce enantiomeric shift differences (ΔΔδ) for several nuclei. Studies employed 60 and 300 MHz spectrometers. At the higher frequency, analytically useful ΔΔδ values were observed with added 3 for the aryl protons ortho to the methylsulfinyl group that should permit direct determinations of enantiomeric excess (% ee). By conversion of sulindac samples to the methyl ester, use of 3 would then formally constitute an ee ...

NMR Studies of Drugs. Use of Lanthanide Shift Reagents in Polar Solvent with Thalidomide

Abstract The 200.1 MHz 1H NMR spectra of thalidomide, 1, have been studied in CD3CN solution at ambient temperatures with the achiral shift reagent, tris (6, 6, 7, 7, 8, 8, 8-heptafluoro-2, 2-dimethyl-3, 5-octanedionato) europium (III), 2, and the chiral reagent, tris [3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]europium (III), 3. The use of sufficiently high LSR:1 molar ratios served to compensate for competitive binding of LSR by the polar solvent, and permitted substantial lanthanide-induced shifts to be observed with 2 or 3. With 3, significant enantiomeric shift differences were produced for the methine NCH multiplets of each enantiomer to be fully separated from one another, offering the potential for direct determination of enantiomeric excess of 1.

NMR Studies of Drugs. 5-Methyl-5-phenylhydantoin. Applications of Lanthanide Shift Reagents in Polar Solvents to a Non-Chelating Substrate

Abstract The 200.1 MHz 1H NMR spectra of 5-methyl-5-phenylhydantoin, 1, have been studied in CD3CN solution at ambient temperatures with the achiral shift reagent, tris (6, 6, 7, 7, 8, 8, 8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium (III), 2, and the chiral reagent, tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato] europium (III), 3. Although 1 cannot chelate the LSRs, use of sufficiently high LSR:1 molar ratios served to compensate for competitive binding of LSR by the polar solvent, and permitted substantial lanthanide-induced shifts to be observed with 2 or 3. With 3, significant enantiomeric shift differences were produced for the ortho aryl protons and for the CH3 signals. The ortho proton signal appears to offer excellent potential for direct determination of enantiomeric excess of 1. These results demonstrate the utility of LSRs 2 or 3 even in a polar solvent with a nonchelating substrate.

NMR Studies of Drugs. Application of Achiral and Chiral Lanthanide Shift Reagents to α-Ethyl-α-Phenylsuccinimide

Abstract The 60 MHz 1H NMR spectra of 3-ethyl-3-phenylpyrrolidine-2,5-dione, 1, were studied in CDCl3 at 28° using the achiral lanthanide shift reagent (LSR) tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium(III), Eu(FOD)3 2, for spectral simplification, and the chiral LSR, tris[3-heptafluoropropylhydroxymethylene)-(+)-camphorato]-europium(III), Eu(HFC)3 3, to induce enantiomeric shift differences (δδδ) for several nuclei. A non-racemic sample of 1 was treated with 3 to determine the sense of magnetic nonequivalence of selected nuclei. Significant δδδ is seen for the signals of the methyl and aryl ortho protons. Modest δδδ can also be seen for the NH signal and for one of the H-4 protons, although LSR-induced broadening for the two latter signals is severe. The (-) enantiomer appeared to exhibit an upfield sense of magnetic nonequivalence (3:1 molar ratio ca. 0.15—0.35) for the methyl signal but a downfield sense for Hortho (3:1 ratio ca. 0.6).

1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Methastyridone, 2,2-Dimethyl-5-(2-Phenylethenyl)-4-Oxazolidinone

Abstract The 60 MHz 1H NMR spectra of methastyridone, 2,2-dimethyl-5-(2-phenylethenyl)-4-oxazolidinone, 1, have been studied at 28° in CDCl3 solution with the achiral reagent tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium(III), 2, Eu(FOD)3, and the chiral reagent tris[3-(heptafluoropropylhydroxy-methylene)-d−camphorato]europium(III), 3, Eu(HFC)3.

1H NMR Spectral Simplification with Chiral Solvating Agents and with Achiral and Chiral Lanthanide Shift Reagents.Cis-4,5-Dihydro-4-Methyl-5-Phenyl-2-Oxazolamine, “Cis-4-Methylaminorex,” a Potent Stimulant and Anorectic

Abstract The 60 MHz 1H NMR spectra of racemic (+)-cis-4,5-dihydro-4-methyl-5-phenyl-2-oxazolamine, 1, have been studied at 28° in CDC13, solution with the achiral lanthanide shift reagent (LSR), tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato) europium(III), 2, and the chiral reagent tris[3−(heptafluoropropylhydroxymethy1ene)-d-camphor-ato]europium(III), 3. Additional NMR studies were performed at 400 MHz in CDC1, solution at 24° using the chiral solvating agents (CSA), (E)-(-)-2,2,2-trifluoro-1- (9-anthryl) ethanol, 4, and (R) - (+) -α-methoxy- α-(trifluoromethy1)phenylacetic acid, 5. Substantial enantiomeric shift differences, for the CH3, signal of 1 using 3 or 5, and for the ortho aryl protons using4, which should make possible direct optical purity determinations of 1. Accurate 400 MHz data f o r chemical shifts and vicinal coupling constants of, of racemic cis-1 are presented, and compared with values for (optically active) (-)-trans-1; some dfferences are seen compared to previously r...