Chiral nuclear magnetic resonance shift reagents: Lanthanide mixtures with 1-(1-naphthyl) ethylurea derivatives of amino acids

Esters of 1-(1-naphthly)ethylurea derivatives of L-valine, L-leucine, L-tert-leucine, and L-proline are examined as organic-soluble chiral nuclear magnetic resonance (NMR) resolving agents. The reagents are useful for resolving the spectra of chiral sulfoxides, amines, alcohols, and carboxylic acids. Enantiomeric resolution is caused by a combination of diastereomeric effects and the different association constants of the substrates with the resolving agents. Organic-soluble lanthanide species are added to resolving agent-substrate mixtures and often enhance the enantiomeric resolution. The enhancement occurs because the substrate that exhibits weaker binding with the resolving agent is more available to bond to the lanthanide. Broadening in the spectra with lanthanides is reduced at 50°C. Enantiomeric resolution is still observed at elevated temperatures. Chirality 9:1–9, 1997. © 1997 Wiley-Liss, Inc.     

Chiral discrimination promoted by (1S,2S)-1-phenyl-2-amino-1,3-propanediol derivatives in the asymmetric Reformatsky reaction

Some 3-t-butyldimethylsilyloxy derivatives, synthesized from the cheap commercially available (1S,2S)-2-amino-1-phenyl-1,3-propanediol [(1S,2S)- 1 ], have been successfully employed as new chiral ligands in the asymmetric Reformatsky reaction on aldehydic substrates. The influence both of the substrate and of the ligand on the stereochemical pathway has been investigated by varying the structure of the carbonyl substrate and of the optically active aminodiols. © 1995 Wiley-Liss, Inc.     

Direct determination of the enantiomeric purity of (R)- and (S)-2-hydroxy-4-phenylbutyric acid

The determination of enantiomeric purity of (R)- and (S)-2-hydroxy-4-phenylbutyric acid by chiral HPLC is described. Good resolution has been obtained on covalently bonded L-hydroxyproline saturated with Cu(II) ions. The method makes possible the determination of enantiomeric purity in media containing growing cells. © 1994 Wiley-Liss, Inc.     

Chiral separation and CD characterisation of enantiomeric cyclotriphosphazene derivatives

The gem-disubstituted cyclotriphosphazene 1 reacted with piperazine (pip) to give the piperazine-bridged derivative 2, which is expected to exist in meso and racemic forms because the two PCl (pip) groups are stereogenic. The proton-decoupled (31)P NMR spectrum of 2 gave rise to two similar sets of ABX signals in a 1:1 ratio, consistent with formation of diastereoisomers. The meso and racemic forms of compound 2 were separated by column chromatography on silica gel and characterised by elemental analysis, mass spectrometry, (31)P NMR spectroscopy, and X-ray crystallography. Using HPLC with a chiral stationary phase, the racemic form of compound 2 was further separated into enantiomers, which were characterised by circular dichroism (CD) spectroscopy. This is the first report of the separation of enantiomers in the field of cyclophosphazene chemistry and hence the first CD spectra of derivatives in which the cyclophosphazene ring is at the chiral centre.     

(S)-2-chloro-2-fluoroethanoyl isocyanate,a chiral derivative of trichloroacetyl isocyanate

Carbamate diastereomers 3b-18b were prepared from easily accessible (S)-2-chloro-2-fluoroethanoyl isocyanate (1) and various secondary chiral alcohols. Compound 1 as a chiral analog of trichloroacetyl isocyanate undergoes the reaction with alcohols very fast, thus blocking the hydroxyl group for the purposes of NMR investigation. Moreover, the correlation of stereochemistry of 3b-18b with their (1)H NMR spectra revealed that the constitution as well as configuration influences regularly the values of chemical shift difference (deltadelta = delta(R) - delta(S)) except for those diastereomers bearing simple alkyl groups in the molecule. Spectral as well as crystallographic data manifest the predominant planar conformation of the central part of the molecule. Due to the good accessibility and high reactivity in particular, the acylisocyanate 1 might be considered, to some extent, an alternative for TAI giving additional information on a compound's spatial structure.     

HPLC and NMR methods for the quantitation of the (R)-enantiomer in (−)-(S)-timolol maleate drug raw materials

HPLC and ¹H-NMR methods for the quantitation of the (R)-enantiomer in (?)-(S)-timolol maleate were developed and validated. The HPLC method requires a 25 cm × 4.6 mm 5 μm Chiracel OD-H (cellulose tris-3,5-dimethylphenylcarbamate) column, a mobile phase of 0.2% (v/v) diethylamine and 4% (v/v) isopropanol in hexane at a flow rate of 1 ml/min and UV detection at 297 nm. A system suitability test was devised to verify the separation of the (R)- and (S)-enantiomers of timolol from other drug-related impurities. The NMR method requires the use of a high-field NMR spectrometer (>360 MHz) and a chiral solvating agent, (?)-(R)-2,2,2-trifluoro-1-(9-anthrylethanol) (R-TFAE). The limits of quantitation were 0.05% and 0.2% (m/m) for HPLC and NMR, respectively. The methods were applied to the determination of the (R)-enantiomer in eight lots of raw material. The results for the two methods were in very good agreement, with results ranging from 0.1 to 4.1% (m/m) by HPLC and none detected to 4.3% (m/m) by NMR. The USP method for specific rotation was found to be unsuitable for detecting the presence of low levels of the (R)-enantiomer in (?)-(S)-timolol maleate. © 1994 Wiley-Liss, Inc.     

Synthesis of (R)- and (S)-3,3,3-trifluoro-2-phenylpropanoyl isocyanates and their use as reactive analogues of Mosher's acid

The title compounds have been prepared from the respective 3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acids (MTPA) by a three-step synthesis with MTPA chloride and MTPA amide as reaction intermediates. The requested compounds were obtained in high chemical yields without any change in optical purity during the preparation. To ascertain the usefulness of this auxiliary agent in the chiral analysis, isomeric 3,3,3-trifluoro-2-phenylpropanoyl isocyanates were subjected in NMR tubes to noncatalyzed reactions with 16 different commercially available chiral alcohols. The steric arrangement of all diastereomers prepared correlated well with their NMR spectral nonequivalence data (Deltadelta), thus demonstrating the regular sign distribution of Deltadelta of particular groups according to the devised molecular model. The usefulness of the novel derivatization is discussed.     

Preparation of Single-Enantiomer Biofunctional Molecules with (S)-2-Methoxy-2-(1-naphthyl)propanoic Acid

(RS)-β-Ionol and (RS)-2-methyl-4-octanol were resolved by using (S)-2-methoxy-2-(1-naphthyl)propanoic acid [(S)-MαNP acid]. The specific stereochemistry of each MαNP ester was elucidated by 2D NMR analyses, and shielding by the 1-naphthyl group was observed in both the ¹H- and ¹³C-NMR spectra. Solvolysis of the individual (S)-MαNP esters gave four single-enantiomer alcohols. The normal-phase HPLC elution order of each MαNP ester is also discussed.     

Atropisomeric property of 1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil

1-(2,6-Difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil (6), a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor, exists as a pair of atropisomers in solution, which was detected by NMR spectroscopy, and separable by HPLC. In addition to a (R)-configured benzylamine, there is a second stereogenic element due to the presence of a chiral axis between the substituted 5-phenyl group and the uracil core. The rate constant of the interconversion (k = 5.07 x 10(-5) s(-1)) of these two atropisomers was determined by proton NMR analysis of a diastereoisomer-enriched sample in aqueous solution at 25 degrees C, and the corresponding Gibbs free energy DeltaG(#) of rotation barrier (97.4 kJ mol(-1)) was calculated using the Eyring equation. The diastereoisomer half-life at physiological temperature (37 degrees C) in aqueous media was estimated to be about 46 min.     

Chiral separation of tryptophan enantiomers by liquid chromatography with BSA-silica stationary phase

The separation of tryptophan enantiomers was carried out with medium-pressure liquid chromatography using BSA (bovine serum albumin)-bonded silica as a chiral stationary phase. The influence of various experimental factors such as pH and ionic strength of mobile phase, separation temperature, and the presence of organic additives on the resolution was studied. In order to expand this system to preparative scale, the loadability of sample and the stability of stationary phase for repeated use were also examined. The separation of tryptophan enantiomers was successful with this system. The data indicated that a higher separation factor (α) was obtained at a higher pH and lower temperature and ionic strength in mobile phase. Addition of organic additives (acetonitrile and 2-propanol) in mobile phase contributed to reduce the retention time of L-tryptophan. About 30% of the separation factor was reduced after 80 days of repeated use.     

Separation of Tryptophan Enantiomers by Ligand‐Exchange Chromatography With Novel Chiral Ionic Liquids Ligand

Chiral ionic liquids (CILs) with amino acids as cations have been applied as novel chiral ligands coordinated with Cu²⁺ to separate tryptophan enantiomers in ligand exchange chromatography. Four kinds of amino acid ionic liquids, including [L‐Pro][CF₃COO], [L‐Pro][NO₃], [L‐Pro]₂[SO₄], and [L‐Phe][CF₃COO] were successfully synthesized and used for separation of tryptophan enantiomers. To optimize the separation conditions, [L‐Pro][CF₃COO] was selected as the model ligand. Some factors influencing the efficiency of chiral separation, such as copper ion concentration, CILs concentration, methanol ratio (methanol/H₂O, v/v), and pH, were investigated. The obtained optimal separation conditions were as follows: 8.0 mmol/L Cu(OAc)₂, 4.0 mmol/L [L‐Pro][CF₃COO] ,and 20% (v/v) methanol at pH 3.6. Under the optimum conditions, acceptable enantioseparation of tryptophan enantiomers could be observed with a resolution of 1.89. The results demonstrate the good applicability of CILs with amino acids as cations for chiral separation. Furthermore, a comparative study was also conducted for exploring the mechanism of the CILs as new ligands in ligand exchange chromatography. Chirality 26:160–165, 2014. © 2014 Wiley Periodicals, Inc.     

Resolution and adrenergic activities of the optical isomers of 4-[1-(1-naphthyl)ethyl]-1H-imidazole.

Recently we synthesized a naphthalene analog of medetomidine, 4-[1-(1-naphthyl)ethyl]-1H-imidazole hydrochloride (1), and found it to be highly potent in adrenergic systems. The separation of optical isomers of this naphthalene analog was achieved by using the isomers of tartaric acid. The optical purities of the isomers were determined by HPLC using a chiral column. Using X-ray analysis the (+)-isomer was determined to have the S absolute configuration. It has been reported that the (+)-isomer of medetomidine (2) is the most potent enantiomer on alpha 2-adrenergic receptors. There were both qualitative and quantitative differences in biological activities of the optical isomers of 1 in alpha 1- and alpha 2-adrenergic receptor systems of guinea pig ileum and human platelets. (+)-(S)-1, but not (-)-(R)-1 was a selective agonist of alpha 2-mediated responses in ileum whereas (-)-(R)-1 was more potent than (+)-(S)-1 as an inhibitor of alpha 2-mediated platelet aggregation.     

Cyclodextrin‐Functionalized Monolithic Capillary Columns: Preparation and Chiral Applications

In this review, the recently reported approaches for the preparation of cyclodextrin‐functionalized capillary monolithic columns are highlighted, with few applications in chiral separations using capillary liquid chromatography (CLC) and capillary electrochromatography (CEC). Chirality 28:97–109, 2016. © 2015 Wiley Periodicals, Inc.     

Chiral separation of flurbiprofen enantiomers by preparative and simulated moving bed chromatography

This study presents the chiral resolution of flurbiprofen enantiomers by preparative liquid chromatography using the simulated moving bed (SMB) technology. Flurbiprofen enantiomers are widely used as nonsteroidal anti‐inflammatory drugs, and although demonstrate different therapeutic actions, they are still marketed as a racemic mixture. The results presented here clearly show the importance of the selection of the proper solvent composition for the preparative separation of flurbiprofen enantiomers. Chiral SMB separation is carried out using a laboratory‐scale unit (the FlexSMB‐LSRE®) with six columns, packed with the Chiralpak AD® stationary phase (20 μm). Results presented include the experimental measurement of equilibrium and kinetic data for two very different solvent compositions, a traditional high hydrocarbon content [10%ethanol/90%n‐hexane/0.01% trifluoroacetic acid (TFA)] and a strong polar organic composition (100%ethanol/0.01%TFA). Experimental data, obtained using the two mobile phase compositions, are used to predict and optimize the SMB operation. After selecting 10%ethanol/90%n‐hexane/0.01%TFA as the most appropriate solvent composition, three feed concentrations of racemic flurbiprofen were considered. Using 40 g/l of racemic flurbiprofen feed solution, the purities for both outlet streams were above 99.4%, the productivity was 13.1 g_feed/(L_bed h), and a solvent consumption of 0.41 L_solvent/g_feed was achieved. Chirality, 2011. © 2011 Wiley‐Liss, Inc.     

Preparation and application of a new doubly tethered chiral stationary phase containing N-CH3 amide linkage based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid

A new doubly tethered chiral stationary phase (CSP 5) based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid was developed by attaching the second tethering group to silica gel through a carbon atom of the first tethering group of the corresponding singly tethered CSP (CSP 2) containing an N-CH3 tertiary amide linkage, which was previously developed in our laboratory, in order to enhance the CSP stability without the loss of chiral recognition efficiency. The new CSP was quite effective in the resolution of various racemic alpha-amino acids, amines, and amino alcohols, and the chiral recognition efficiency of the new CSP was even greater than that of the corresponding singly tethered CSP especially in terms of the resolution factors (RS). The stability of the new CSP was greater than that of the corresponding singly tethered CSP. The chromatographic resolution behaviors of the new CSP were generally consistent with those of the corresponding singly tethered CSP.     

Preparation of single-enantiomer biofunctional molecules with (S)-2-methoxy-2-(1-naphthyl)propanoic acid

(RS)-beta-Ionol and (RS)-2-methyl-4-octanol were resolved by using (S)-2-methoxy-2-(1-naphthyl)propanoic acid [(S)-MalphaNP acid]. The specific stereochemistry of each MalphaNP ester was elucidated by 2D NMR analyses, and shielding by the 1-naphthyl group was observed in both the 1H- and 13C-NMR spectra. Solvolysis of the individual (S)-MalphaNP esters gave four single-enantiomer alcohols. The normal-phase HPLC elution order of each MalphaNP ester is also discussed.     

Investigations of molecular recognition aspects related to the enantiomer separation of 2-methoxy-2-(1-naphthyl)propionic acid using quinine carbamate as chiral selector: An NMR and FT-IR spectroscopic as well as X-ray crystallographic study

The chiral recognition mechanism of a cinchona alkaloid-based chiral stationary phase (CSP) showing high enantiomer discrimination potential for 2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid) was investigated. Conformational and structural analyses of the 1:1 complexes of 9-O-(tert-butylcarbamoyl) quinine selector (SO) and MalphaNP acid (selectand, SA) were carried out employing NMR spectroscopy in solution, Fourier-transform infrared (FT-IR) spectroscopy, and solid-state X-ray diffraction analysis. Intramolecular NOEs of a soluble analogue of the CSP afforded the conformational states of the free and complexed form of the selector. The (1)H-NMR spectra revealed that the free form of the SO constitutes anti-open as well as anti-closed and/or syn-closed conformers. Upon complexation with the (S)-MalphaNP acid enantiomer to form the more stable diastereomeric associate, a conformational transition of the selector takes place, resulting in the synthesis of the anti-open conformer nearly exclusively. FT-IR spectra reveal that, besides the primary ion-pairing interaction, stereoselective hydrogen bonding stabilizes the more stable complex via the amide hydrogen of the SO. X-ray diffraction analysis of 9-O-(tert-butylcarbamoyl)quinine and (S)-MalphaNP acid complex further revealed the occurrence of a bidentate H-bond-mediated ionic interaction between SO and SA as well as the lack of pi-pi interaction in the 1:1 complex, and corroborated the conclusions derived from spectroscopic and chromatographic studies.     

Chiral synthesis of (2S,3S)-2-(2-morpholin-2-yl-2-phenylmethoxy)phenol

Resolution of (2RS,3RS)-2-[alpha-(2-methoxymethoxyphenoxy)phenylmethyl]morpholine, 11, with (+) mandelic acid led to the formation of (+)-(2S,3S)-2-[alpha-(2-methoxymethoxyphenoxy)phenyl methyl] morpholine (11a). Compound 11 was synthesized in seven steps from (2RS,3RS)-cinnamyl alcohol-2,3-epoxide (4), with an overall yield of 17%. Cleavage of the methoxymethyl group of the Fmoc derivative 12 with catalytic amounts of p-toluenesulfonic acid in methanol afforded (+)-(2S,3S)-2-(2-morpholin-2-yl-2-phenylmethoxy)phenol 2. The synthetic utility as well as the configuration of compound 2 has been demonstrated by converting (S,S)-2-(2-morpholin-2-yl-2-phenylmethoxy)phenol 2 to (2S,3S)-2-[alpha-(2-ethoxyphenoxy)phenylmethyl]morpholine (1) and (2S,3S)-2-(2-methoxyphenoxy) benzyl)morpholine (16), two potential norepinephrine reuptake inhibitors under clinical evaluation.     

Cytotoxic and genotoxic effects of (R)- and (S)-ricinoleic acid derivatives

(R)-ricinoleic acid is the main component of castor oil from Ricinus communis L. Due to the presence of the hydroxyl group in homoallylic position and asymmetrically substituted carbon atom, it may undergo a number of chemical and biochemical transformations resulting in the products with some specific bioactivities. Conversion of (R)-ricinoleic acid into its (S)-enantiomer enables synthesis of both (R)- and (S)-ricinoleic acid derivatives and comparison of their biological activities. In the present research, (R)- and (S)-ricinoleic acid amides synthesized from methyl ricinoleates and ethanolamine or pyrrolidine as well as acetate derivatives of ethanolamine amides were studied to demonstrate their biological activities using HT29 cancer cells. Double staining of cells with fluorochromes (Hoechst 33258/propidium iodide) as well as 2,′7′-dichlorodihydrofluorescein (DCF) and comet assays were performed. Both the tested amides and acetates caused DNA damage and induced apoptotic and necrotic cell death. In the case of (R)- and (S)-enantiomers of one of the tested acetates, significant difference in the ability to induce DNA damage was observed, which showed the impact of the stereogenic center on the activities of these compounds.     

Spacer length effect of a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid

A new chiral stationary phase (CSP) containing 11 methylene-unit spacer was prepared by bonding (+)-(18-crown-6)-2,3,11,12-carboxylic acid to aminoundecylsilica gel. The new CSP was superior to the one containing three methylene-unit spacer in the resolution of alpha-amino acids, beta-amino acids, amines, and amino alcohols in terms of both the separation (alpha) and the resolution factors (R(S)). In the resolution of alpha-amino acids on the new CSP containing a long spacer, the retention factors (k(1)) were quite small compared to those on the CSP containing a short spacer. However, in the resolution of relatively more lipophilic beta-amino acids, amines, and amino alcohols, the retention factors (k(1)) were generally greater on the CSP containing a long spacer than on the CSP containing a short spacer. All of these resolution behaviors have been rationalized by the effective competition of the ammonium ions (R-NH(3)(+)) generated by the residual undecylamino groups of the new CSP under acidic condition with the ammonium ions (R-NH(3)(+)) of analytes for the complexation inside the cavity of the crown ether ring of the CSP and the effective lipophilic interaction between the CSP and the relatively more lipophilic analytes.