Chiral Crown Ethers Research Articles

Unusual resolution of N-(3,5-dinitrobenzoyl)-α-amino acids on a chiral stationary phase based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid

While HPLC chiral stationary phases (CSPs) based on chiral crown ethers have been known useful for the resolution of only racemic primary amino compounds or some secondary amino compounds, in this study, we first demonstrated that the CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid is also useful for the resolution of N-benzoyl-α-amino acids, which do not contain a primary or secondary amino group. Especially, N-(3,5-dinitrobenzoyl)-α-amino acids were resolved better than corresponding N-(3-nitrobenzoyl)- or N-benzoyl-α-amino acids, the separation ( α) and the resolution factors ( R S) for the resolution of eight N-(3,5-dinitrobenzoyl)-α-amino acids being in the range of 1.06–1.81 and 0.54–2.81, respectively. The optimum mobile phase condition was the mixture of acetic acid–triethylamine–acetonitrile with the ratio of 0.05/0.25/100 (v/v/v).

Detection and Separation of Free Amino Acid Enantiomers by Capillary Electrophoresis with a Chiral Crown Ether and Indirect Photometric Detection

18-Crown-6 tetracarboxylic acid (18C6H4) has been successfully used as a chiral selector for capillary electrophoretic (CE), high-performance liquid chromatographic (HPLC), and gas chromatographic (GC) separation of the enantiomers of DL-amino compounds. We have previously used X-ray crystallographic analysis and HPLC with an immobilized 18C6H4 chiral stationary phase to study chiral recognition by 18C6H4 of several DL amino acids (DL-AA). In this study CE was used for chiral recognition of several DL-AA in electrolyte solution containing 18C6H4, in which the analyte (D or L amino acid) interacts freely. Among 14 DL-AA investigated, the enantiomers of nine (Glu, Ile, Met, PheG, Phe, Ser, Tyr, Val, and Thr) were successfully recognized in 4-15 mM 18C6H4. Indirect photometric detection with a cationic dye, chrysoidine, was used to monitor non-chromophoric DL-AA. Among nine successfully recognized DL-AA, the D forms of Ser, Thr and Met migrated faster than the corresponding L forms. The strengths of interactions predicted from the order of migration of each enantiomer in CE were different from those in HPLC analysis. The different enantiomer recognition probably can be ascribed to the difference between CE in which the selector is not immobilized and HPLC in which the selector is immobilized by means of a spacer.

High performance liquid chromatographic separation of dipeptide and tripeptide enantiomers using a chiral crown ether stationary phase

A chiral stationary phase (CSP) based on (-)-(18-crown-6)-2,3,11,12-tetracarboxylic acid was evaluated for the direct resolution of the enantiomers of dipeptides and tripeptides. The type and concentration of the acid and the methanol content were optimized with regard to retention time and resolution using Ala-Phe as model peptide. A mobile phase consisting of 10 mM sulfuric acid in 70% aqueous methanol was applied to the separation of a set of 16 structurally diverse dipeptides and tripeptides. Generally, the configuration of the amino acid at the N-terminus determined the enantiomer elution order. With a few exceptions the LL- and LD-enantiomers interacted stronger with the CSP compared to the corresponding DD- or DL-enantiomers. The experimental conditions also allowed the simultaneous separation of all four stereoisomers of Ala-Phe. Addition of ammonium sulfate generally reduced retention times and enantiomer resolution. Addition of triethylamine as modifier led to an overall increase of the retention times while the resolution did not show a general trend, increasing in the case of Ala-Ala but decreasing in the case of Ala-Phe.

Enantiomeric separation of 1-phenylethylamine and 1-cyclohexylethylamine in capillary electrophoresis with contactless conductivity detection

Contactless conductivity detection was employed for the detection of the enantiomers of 1-phenylethylamine and 1-cyclohexylethylamine which were separated in capillary electrophoresis with unprecedented high resolutions R s of 2.3 and 3.3, respectively, by using a combination of dimethyl-β-cyclodextrin and the chiral crown ether 18C6H 4 as chiral selectors in a citric acid buffer of pH 2.4. The conductivity measurement enabled the direct detection, i.e. without having to derivatize or resort to indirect methods, of all species including the non-UV-absorbing enantiomers of cyclohexylamine. Detection limits of 0.5 μM were achieved and the determination of enantiomeric ratios of up to 99:1 was found possible.

Development and Application of Crown Ether-based HPLC Chiral Stationary Phases

Crown ether-based HPLC chiral stationary phases (CSPs) have been successfully utilized in the resolution of various racemic compounds containing a primary amino group. Especially, CSPs based on chiral crown ethers incorporating chiral binaphthyl unit or tartaric acid unit and based on phenolic pseudo chiral crown ethers have shown high chiral recognition efficiency. In this account paper, a review on the development of crown etherbased HPLC CSPs, their structural characteristics and applications to the resolution of racemic compounds including chiral drugs containing a primary or secondary amino group with the variation of the type and the content of mobile phase components and with the variation of the column temperature is presented.

Synthesis of new chiral crown ethers containing a ( p-methoxyphenoxy)methyl moiety and their chiral recognition ability towards amino acid esters

Novel crown ethers 9– 13 containing a chiral subunit derived from 3-( p-methoxyphenoxy)propane-1,2-diol 7 were prepared in enantiomerically pure forms. Chiral recognition properties of these receptors towards l- and d-amino acid derivatives were examined by the UV–vis titration method. These receptors exhibit good chiral recognition towards the isomers (up to K L / K D = 5.81, ΔΔ G 0 = 4.30 kJ mol −1) in CHCl 3 at 25 °C.

Novel C2-symmetric chiral 18-crown-6 derivatives with two aromatic sidearms as chiral NMR discriminating agents

Novel C 2-symmetric chiral 18-crown-6 derivatives with two aromatic sidearms 2– 4 were prepared, and their enantiomeric recognition abilities as chiral NMR discriminating agents towards primary ammonium salts were examined. Among these chiral crown ethers, the most effective enantiomeric discrimination of racemic ammonium salts in the 1H NMR spectra was attained by the derivative with two pyrenylmethyl sidearms.

A Convenient Route to Dendritic Binaphthyl‐Containing Chiral Crown Ethers.

A Convenient Route to Dendritic Binaphthyl‐Containing Chiral Crown Ethers.

Spiro Crown Ethers Bearing (S)-1,1’-Spirobiindanes as Chiral Backbones

The synthesis of spiro chiral crown ethers ((S)-1a) and ((S)-1b) has been achieved. The combination of (S)-1a and KOH promoted the asymmetric alkylation of glycine derivative (2) with moderate enantioselectivity.

Synthesis of chiral crown ethers and complexation with chiral protonated amine compounds: X-ray crystal and nuclear magnetic resonance studies of perchlorate salt of chiral benzo-monoaza-15-crown-5 and chiral monoaza-15-crown-5

The X-ray crystal structure of IX, perchlorate salt of R-(−-2-ethyl-N-benzyl-4,7,19,13-tetraoxa-8,9-benzo-1-azacyclopentadec-8-ene has been determined. In the molecule, the protonated nitrogen atom participates in two N-H⋯O hydrogen bonds. The unusually high proton affinity of aza crown ether leads to the formation of diastreomer instead of complex formation with chiral R-(+)-1-phenyl ethyl ammonium perchlorate and S-(−)-1-phenyl ethyl ammonium perchlorate. The complex ability of host ethers was evaluated in terms of structural modification.

On-line sample cleanup and chiral separation of gemifloxacin in a urinary solution using chiral crown ether as a chiral selector in microchip electrophoresis

In chiral capillary electrophoresis of primary amine enantiomers using (+)-18-crown-6-tetracarboxylic acid (18C6H 4) as a chiral selector, the presence of alkaline metal ions in the sample solution as well as in the run buffer is undesirable due to their strong competitive binding with 18C6H 4. A channel-coupled microchip electrophoresis device was designed to clean up alkaline metal ions from a sample matrix for the chiral analysis of amine. In the first channel, the metal ions in the sample were monitored by indirect detection using quinine as a chromophore and drained to the waste. In the second separation channel, gemifloxacin enantiomers, free of the alkaline metal ions, were successfully separated using only a small amount of the chiral selector (50 μM 18C6H 4).

A Convenient Route to Dendritic Binaphthyl-Containing Chiral Crown Ethers

Novel dendritic binaphthyl-containing chiral crown ethers have been synthesised in four steps from ( R) 2,2′-dihydroxy-1,1′-binaphthyl-3,3′-dicarboxylic acid with satisfactory yield.

Lipase-catalyzed enantioselective esterification of mono-aza-benzo-15-crown-5-ether derivatives in organic media

For the purpose of developing a new chiral crown ether unit as a chiral synthon, three racemic mono azabenzo-15-crown-5-ethers, i.e. (R,S)-1-(6,7,9,10,12,13,15,16-octahydro-5,8,14,17-tetraoxa-11-aza-benzocyclopentadecen-11-yl)-propan-2-ol, (R,S)-2-(6,7,9,10,12,13,15,16-octahydro-5,8,14,17-tetraoxa-11-aza-benzocyclopentadecen-11-yl)-1-phenyl-ethanol and (R , S)-1-[2-(6,7,9,10,12,13,15,16-octahydro-5,8,14,17-tetraoxa-11-aza-benzocyclopentadecen-11-ylmethyl)-phenyl]-ethanol were esterified with vinyl acetate using a lipase from Candida antarctica. The enzymatic acylation of alcohols produced monoacylated products. Two optically active azacrown ethers, (R)-propionic acid 1-methyl-2-(6,7,9,10,12,13,15,16-octahydro-5,8,14,17-tetraoxa-11-aza-benzocyclopentadecen-11-yl)-ethyl ester and (R)-acetic acid 1-[2-(6,7,9,10,12,13,15,16-octahydro-5,8,14,17-tetraoxa-11-aza-benzocyclopentadecen-11-ylmethyl)-phenyl]-ethyl ester were obtained within 48% and 36% yields, respectively and, at an enantiometric excess of over 99% in each case.

Synthesis of novel chiral monoaza-15-crown-5 ethers and their molecular recognition of amino acid esters

The chiral monoaza-15-crown-5 ethers 4 and 5 were prepared from L-phenylalaninol and L-leucinol, respectively. The molecular recognition of these chiral crown ethers for L-amino acid ethyl esters was characterised by UV-visible spectroscopy. Binding constants ( Ka), free-energy changes (–Δ Go), enthalpy changes (Δ H) and entropy change (Δ S) values were determined for hosts 4 and 5 with L-amino acid ethyl ester hydrochlorides in CHCl3.

Phase Transfer Catalyzed Asymmetric Epoxidation of Chalcones Using Chiral Crown Ethers Derived from D‐Glucose, D‐Galactose, and D‐Mannitol.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Phase Transfer Catalyzed Asymmetric Epoxidation of Chalcones Using Chiral Crown Ethers Derived from D‐Glucose and D‐Mannose.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Enantioselective transport of amino acids as their potassium and sodium salts by optically active diaza-18-crown-6 ethers having arene sidearms

The enantioselective transport of amino acids as their sodium and potassium salts has been investigated by optically active diaza crown ethers. The reversed enantioselectivity of chiral crown ether 1 was observed.

Synthesis and Characterisation of Macrocyclic Diamino Chiral Crown Ethers

A benign and efficient synthesis of chiral macrocyclic ‘aza-crown’ ethers of varying ring size is reported. The synthesis involves a Schiff base condensation of ether linked dialdehydes of varying chain length and (1R,2R)-(–)-1,2-diaminocyclohexane under mild conditions to yield the macrocycles, which are subsequently reduced to yield the diamino analogues.

Phase-transfer catalyzed asymmetric epoxidation of chalcones using chiral crown ethers derived from d-glucose, d-galactose, and d-mannitol

Chiral monoaza-15-crown-5 lariat ethers synthesized from d-glucose, d-galactose, and d-mannitol have been applied as phase-transfer catalysts in the enantioselective epoxidation of chalcones with tert-butylhydroperoxide. The type of monosaccharide on the crown ether and the substituents at the nitrogen atom of the crown-ring has a major influence on both the chemical yield and enantioselectivity. Among the catalysts, the crown ether annellated to methyl-4,6- O-benzylidene-α- d-glucopyranoside, with 3-hydroxypropyl side arm at the nitrogen atom 1f proved to be the most effective (92% ee). The enantioselectivity was also affected by the substituents on the aromatic rings of the chalcone. The absolute configurations of epoxyketones 6a, 6b, 6d, 6i, 6k, and 6m were determined by CD spectroscopy; the complete stereostucture of 6b was determined by single crystal X-ray analysis.

Lewis Acid Catalyzed Asymmetric Hydroxymethylation of Silicon Enolates in Aqueous Media.

AbstractFor Abstract see ChemInform Abstract in Full Text.