Chiral Lanthanide Research Articles

Transformations of unsaturated acyclic sugars into enantiomerically pure norbornene derivatives

The C7 acyclic unsaturated-sugar ester 1, derived from l-arabinose, and its enantiomer serve as convenient dieneophiles for chirality transfer for synthesis of optically pure carbocyclic derivatives through cycloaddition reactions. Reaction of 1 with cyclopentadiene may be controlled to give preparative access to the 5,6-disubstituted norbornene adducts 4a, 5a, and 7a, according to the conditions used. The distribution of the four possible isomeric products from this cycloaddition was quantitated, and the effect of substitutional variation on the precursor dienophile 1 was also examined. Adducts 4a and 5a were transformed into such substituted carbocycles of known absolute configuration as the methyl esters (11 and 12) of norbornene (bicyclo[2.2.1]hept-2-ene)-6-carboxylic acid and nortricyclane (tricyclo[2.2.1.02,6]heptane)-3-carboxylic acid in optically pure form, specifically through decarbonylation reactions using RhCl(PPh3)3 (Wilkinson's complex) and [Rh(dppp)2]Cl[dppp = Ph2P(CH2)3PPh2]. The optical purity of 12 was established by the use of a chiral lanthanide shift-reagent.

Stereochemical dynamics and recognition probed by lanthanide chiroptical spectroscopy

A mechanistic model for enantioselective excited-state quenching kinetics is described for systems in which quenching occurs via electronic energy transfer between chiral lanthanide (donor) and transition-metal (acceptor) complexes in solution. This model is applied to systems in which quenching rates are slow compared with translational and rotational diffusion rates of the donor and acceptor species in solution. The rate parameters derived from enantioselective quenching measurements are expressed in terms of both electronic and stereoselective contributions to intermolecular chiral discrimination, and applications are illustrated for several lanthanide (luminophore)-transition metal (quencher) systems.

Stereoselective aliphatic hydroxylation of 6-n-propylchromone-2-carboxylic acid by female Dutch rabbits.

6-n-Alkylchromone-2-carboxylic acids are metabolized solely by aliphatic oxidation. In the rabbit, the 6-n-propyl congener (PCCA) undergoes omega-1 hydroxylation exclusively. Following administration of PCCA to female Dutch rabbits (500 mumol/kg), some 77% of the dose was excreted in the urine, 41% as PCCA and 36% as 6-(2'-hydroxy-n-propyl)chromone-2-carboxylic acid. Since this metabolite is chiral, we have examined the stereochemistry of the excreted material. Diastereoisomeric (as camphanate and alpha-methoxy-alpha-(trifluoro-methyl)phenylacetate esters) and direct chiral HPLC and chiral lanthanide shift NMR have each shown the S:R ratio of the excreted metabolite to be 76:24. When rabbits were dosed with the racemic metabolite, excretion of the compound was not stereoselective. The regio- and stereo-selectivity of the aliphatic hydroxylation of PCCA are thus reflections of the selectivities of the enzyme systems responsible for its formation and suggest PCCA to be an appropriate probe compound for the study of prochiral-chiral hydroxylations.

Calibration plots to aid determination of high enantiomeric purity using chiral lanthanide shift reagents.

High enantiomeric purities are difficult to determine by NMR with chiral lanthanide shift reagents because it is difficult to identify which, if any, resonance corresponds to the minor enantiomer. We report calibration plots that use the position of the resonance of the major enantiomer to predict the position of the resonance of the minor enantiomer. Once the position of the resonance was established, integration measured enantiomeric purities as high as 99.7% ee.

NMR Studies of Drugs. Application of a Chiral Lanthanide Shift Reagent for Potential Direct Determination of Enantiomeric Excess of Methsuximide

Abstract The 200 MHz 1H NMR Spectra of methsuximide, 1,3-dimethy1-3-ogebt1-2,5-otrrikudubeduibem 1, havebeen studied in CDC13 solution with the chiral reagent, tris[3-(heptafluoropropy1-hydroxymethylene)-d-camphorato] europium (III), 2, Eu(HFC)3. Substantial lanthanide-induced shifts are seen. In addition, significant enantiomeric shift differences are observed for several of the nuclei of 1. With a 2:1 molar ratio near 1.0, the CCH3 and NCH3 signals show nearly baseline resolution between the peaks from each enantiomer, providing excellent potential for direct determinations of enantiomeric excess of samples of 1. As little as 2% of a minor enatiomer should be readily detectable.

1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Mexiletine

Abstract The 60 MHz 1H NMR spectra of mexiletine, 1-(2,6-dimethylphenoxy)-2-propanamine, 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 reagents tris[3-(trifluoromethylhydroxymethylene)-d-camphorato]europium(III), 3, Eu(FACAM)3, and tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato]europium(III), 4, Eu(HFC)3. Substantial lanthanide-induced shifts were seen for the proton signals of 1 with each reagent. Appreciable enantiomeric shift differences were seen for both methyl signals and for each of the CH2CH proton signals using 3 and 4 that should permit direct determinations of enantiomeric excess for samples of 1. A predominant conformation for 1 is suggested based on observed splittings of the CH2 proton signals and their relative lanthanide-induced shifts.

Europium (S,S)-ethylenediamine-N,N'-disuccinate as a chiral lanthanide shift reagent for aqueous solutions

Europium (S,S)-ethylenediamine-N,N'-disuccinate as a chiral lanthanide shift reagent for aqueous solutions

ChemInform Abstract: A Facile NMR Method for Assigning Absolute Configuration of Underivatized α‐Methyl α‐Amino Acids Using a Chiral Lanthanoid Shift Reagent for Aqueous Solution.

Abstract The absolute configuration of α-methyl-α-amino acids can be easily assigned by use of the chiral lanthanoid NMR shift reagent, 1,2-propanediaminetetraacetatoeuropium(III) in aqueous solution.

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...

Stereoselectivity of energy transfer in chiral lanthanide systems

A theory of resonant energy transfer in lanthanide complexes with chiral ligands is developed within the independent systems model. The second- and third-order expressions for the amplitude of energy transfer are derived and their sensitivity to the ligand chirality is discussed. It is shown that within the presented model only the dynamic coupling mechanism gives different energy transfer rates for racemic and resolved systems. The general expression for the stereoselectivity of energy transfer is presented and its approximate value is estimated.

1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Paramethadione, 5-Ethyl-3,5-Dimethyl-2,4-Oxazolidinedione

Abstract The 60 MHz 1H NMR spectra of paramethadione, 5-ethyl-3,5-dimethyl-2,4-oxazolidinedione, 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, and the chiral reagents tris[3-(trifluoromethylhydroxymethylene)−(+)-camphorato]europium(III), 3, and tris[3−(heptafluoropropylhydroxymethylene)−(+)-camphorato]europium(III), 4.SubstantiaΔδ values and spectral simplification are achieved with 2 or 4. Significant enatiomeric shift differences, ΔΔδ, are observed with 4 that should provide direct optical purity determinations of − 1, using the C(5)CH3 or the NCH, signals with &:Iratios of 1.3–1.5. Valley height for the CCH, resonance as low as 4.8% was achieved, which should allow detection of as little as 3–4% of the minor enantiomer. Results are discussed in terms of the structural features of I and of the LSR. Substantial nb values and spectral simplification

ChemInform Abstract: Enzymatic Syntheses of Chiral sec‐Alcohols and Their NMR Chemical Shifts Induced by a Chiral Lanthanide Shift Reagent.

AbstractThe resolution of racemic (I) is accomplished via enzyme‐catalyzed transesterification in the absence of a solvent; the optical purity of (R)‐(‐)‐(I) can be improved to > 99% by esterification with phthalic anhydride and subsequent hydrolysis.

A facile nmr method for assigning absolute configuration of underivatized α-methyl-α-amino acids using a chiral lanthanoid shift reagent for aqueous solution

The absolute configuration of α-methyl-α-amino acids can be easily assigned by use of the chiral lanthanoid NMR shift reagent, 1,2-propanediaminetetraacetatoeuropium(III) in aqueous solution.

Improved Method for Optical Purity Determination of Ketazolam with Chiral Shift Reagent

Abstract An improved method for direct determination of optical purity of the novel benzodiazepine analog, ketazolam, 1, is reported. Adding the chiral lanthanide NMR shift reagent, tris[3-(heptafluoropropylhydroxymethylene)-d-camphorato] ytterbium (III), Yb(HFC)3, to racemic ketazolam in CDCl3 solution allows observation of enantiomeric shift differences for six of the ketazolam proton resonances. The C(2) methyl 1H signal is especially appropriate for the determination of optical purity since the C(2) methyl resonance of each enantiomer are clearly resolved (for accurate peak intensity determination) at 200 MHz. For racemic 1, using a molarratio of Yb(HFC)3:1 of 0.20, the valley height between the peaks of the two enantiomers′ CCH3 signals was only 4.8% of the average peak heights. Detection of as little as 2–3% of a minor enantiomer should be possible. Some aspects of the hindered phenyl rotation in 1 and the LSR-induced broadening of certain NMR signals are also discussed.

1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. 2-Methyl-3-(2′-Hydroxymethylphenyl)-4(3H)-Quinazolinone, A Major Metabolite of Methaqualone

Abstract The 60 MHz 1H NMR spectra of 2-methyl-3-(2′-hydroxymethylphenyl)-4(3H)-quinazolinone, 1, a major metabolite of methaqualone, 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, and the chiral reagent tris [3-(heptafluoropropylhydroxy-methylene)-d-camphorato]europium (III), 3, Lanthanide induced shifts, Δλ, are consistent with major LSR binding at the hydroxyl, and the diastereotopic hydrogens of the CH2 are clearly anisochronous. Substantial Δλ values and spectral simplification are achieved with 2 or 3. Significant enantiomeric shift differences, ΔΔλ, are observed with 3 that should provide direct optical purity determinations of 1. Results are discused in terms of LSR binding sites and hindered rotations about selected bonds in 1.

Chiral lanthanide NMR shift reagents and equilibria with substrate enantiomers: Rationale for the observed signals

An analogy illustrating the two chemical equations that describe the simple view of the dynamic equilibria in which two enantiomers of substrate rapidly and reversibly bind to an optically pure lanthanide shift reagent to form two different bound complexes.

1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Lofexidine

Abstract The 1H NMR spectra of the potent anti-hypertensive drug, lofexidine, 1, have been studied in CDCl3 at 60 and 300 MHz. Both the achiral shift reagentr tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionatol-europium(III), 2 and the chiral reagents1 tris[3-(heptafluoropropylhydroxymethylenel-d-camphoratoleuropium(III), 3 and tris[3-(trifluoromethylhydroxymethylenel-d-camphoratoleuropium(III), 4, were employed. Substantial lanthanide induced shifts were observed with 2, 3 or 4, with the largest shifts seen for the methine at the chiral centerr followed by the signal of the NH. Enantiomeric shift differences for the CH3 signal of 1 were seen with 3 OK 4, with 4 inducing larger values of potential analytical utility. Using a non-racemic sample of 1, the (-) enantiomer was shown to have a downfield sense of magnetic nonequivalence for the methyl resonance in the presence of added 4.

Determination of Enantiomeric Purity of Tranylcypromine Sulfate by Proton Magnetic Resonance Spectroscopy with Chiral Lanthanide Shift Reagent

Optimum experimental conditions were developed for determination of the optical purity of samples of tranylcypromine sulfate by proton magnetic resonance spectroscopy after complexation with the chiral lanthanide chelate Eu(hfc)3. At a substrate concentration of 0.25M (0.125M as sulfate) in CDCl3 and an Eu(hfc)3 to substrate molar ratio of 1, the methine proton geminal to the amino group in the cyclopropane ring showed the largest induced shift and largest enantiomeric induced shift difference. From the relative intensities of the resolved (+)-CH-NH2 protons (15.77 ppm) and (-)-CH-NH2 proton (16.04 ppm), the enantiomeric purity and percentage compositions were readily calculated. The mean +/- SD recovery of (+)-tranylcypromine sulfate from synthetic enantiomeric mixtures was 101.02 +/- 2.59 (n = 6).

1H NMR Spectral Simplification with Achiral and Chiral Lanthanide Shift Reagents. Tocainide. Method for Direct Optical Purity Determination and Observation of an “Anomalous” Shift

Abstract The 60 MHz 1H NMR spectra of racemic tocainide, 1, have been studied in CDCL3 solution at 28° with the achiral shift reagent, tris(6,6,7,7,8,8,8-heptafluor-2,2-dimethyl-3,5-octanedionato)europiumIII), 2, and the chiral reagent, tris[3- (heptafluoropropylhydroxymethylene)-d-canphorato]- europium(III), 3. Substantial lanthanide induced shifts, Δδ, were served with both 2 and 3, A significant “anomalous” upfield shift for the CH signal of 1 was seen with added 2. The chiral reagent 3 led to appreciable emtiomeric shift differences for the CH3CH and amide NH signals. The potential for direct optical purity determinations of 1 using 3 was demonstrated for a non-racemic (“spiked”) sample of 1, based on the CH3 resonance. The sense of magnetic non-equivalence for these resonances was also determined.