Chiral Crown Ethers Research Articles

Synthesis of a novel crown ether derived from chiro-inositol and its catalytic activity on the asymmetric Michael addition.

A novel 18-membered chiral crown ether was prepared in four steps starting from L-quebrachitol, a chiro-inositol, and its catalytic activity in the Michael addition reaction of glycine imine with several Michael acceptors was studied.

Synthesis and Enantiomeric Selectivity of Chiral Crown Ethers.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Chromatographic Enantiomer Separation of Diphenylalanine on Chiral Stationary Phases Derived from Chiral Crown Ethers

Drug Discovery, LG Life Science Ltd., Daejon 305-380, KoreaReceived September 12, 2002Key Words : Chiral stationary phases, Enantiomer separation, DiphenylalanineThe methods that allow a simple and accurate assessmentof the enantiomeric purity of chiral compounds have beendeveloped, because they are frequently required for those inthe fields of pharmaceutical chemistry and biochemistry.

Liquid chromatographic separation of the enantiomers of fluoroquinolone antibacterials on a chiral stationary phase based on a chiral crown ether

A chiral stationary phase (CSP) recently developed by bonding (diphenyl-substituted 1,1′-binaphthyl) crown ether to silica gel for the liquid chromatographic separation of enantiomers was applied to the resolution of investigational fluoroquinolone antibacterial agents including gemifloxacin (formerly LB20304a). All fluoroquinolone compounds used in this study were resolved quite well on the CSP. Especially, the resolution of gemifloxacin and its analogs on the CSP was excellent and even greater than that on the commercial Crownpak CR(+). The resolution was found to be dependent on the type and the content of organic, acidic, and inorganic modifiers added to the mobile phase and on the column temperature.

Chiral crown ether pillared lamellar lanthanide phosphonates.

A new chiral bridging ligand, 2,2'-pentaethylene glycol-1,1'-binaphthyl-6,6'-bis(phosphonic acid), was synthesized in 40.7% overall yield in five steps and used to generate single crystals of the first porous lanthanide phosphonates with chiral crown ether pillars. Single-crystal and powder X-ray crystallography established that these chiral crown ether decorated lamellar solids retain their framework structures after the removal of their included guest molecules and serve as structural models for porous solids that are exploitable for bulk chiral separations.

Chiral recognition of secondary amines by using chiral crown ether and podand

Chiral crown ether (S,S)-3 having a pseudo-24-crown-8 ring and chiral podand (R,R)-4 were prepared and both exhibited good chiral recognition ability toward secondary amines, N-α-dimethylbenzylamine (15) and propranolol (16).

Catalytic, enatioselective Michael addition reactions

This review summarizes the tremendous achievements in the field of catalytic enantioselective Michael addition reaction involving the attack of soft nucleophiles on α,β- unsaturated systems. The reaction has evolved during past two decades, from stoichiometric to catalytic. A large number of efficient catalytic systems have been used to generate chiral Michael adducts in high optical purity. Several chiral alkaloids were used for the enantioselective addition of thiols and dialkylmalonates to cyclic and linear enones to give product in moderate to high enantioselectivity. Chiral crown ethers in conjugation with metal alkoxides were found to be the catalyst of choice for the addition of substituted α-phenylesters to linear enones. Proline derived catalysts gave product in moderate in moderate to high enantioselectivity where NO2 group was present as an activator in either Michael donor or acceptor. BINAP based catalysts were found to be superior in Michael addition of α-nitrile substituted esters to linear enones. A new class of heterobimetallic catalysts based on BINOL ligand was found to be highly versatile for an array of Michael donors and acceptors to provide products in very high optical purity. Metal complexes based on chiral N,N-dioxides were found to be superior for the addition of arylthiols to both linear and cyclic enones to have product in high enantiomeric excess.

Chiral Crown Ethers Based on Galactopyranosides

The 1,4- and 1,6-bridged 20- and 23-membered galactocrown ethers 7, 8 and 11 were synthesized by intramolecular transglycosidation of the phenyl 1-thio-D-galactopyranosides 5, 6, and 10, respectively. The relevant precursors 5, 6, and 10 were obtained from phenyl 2,3,6-tri-O-benzyl-1-thio-β-D-galactopyranoside (2) and phenyl 2,3,4-tri-O-henzyl-1-thio-β-D-galactopyranoside (3), respectively, via two etherification steps. Compounds 2 and 3 are accessible from the same precursor, phenyl 2,3-di-O-benzyl-4,6-O-benzylidene-1-thio-β-D-galactopyranoside (1), by regioselective opening of benzylidene acetal. O-Alkylation of 2 and 3 with bis(2-chloroethyl)ether gave phenyl 2,3,6-tri-O-benzyl-4-[2-(2-chloroethoxy)ethyl]-1-thin-β-D-galactopyranoside (4) and phenyl 2,3,4-tri-O-benzyl-6-[2-(2-chloro-ethoxy)ethyl[-1-thio-β-D-galactopyranoside (9), respectively. The ensuing chain elongation of 4 was carried out with triethylene glycol and tetraethylene glycol, respectively, yielding 5 and 6. Compound 9 was alkoxylated with tetraethylene glycol under the same reaction conditions yielding phenyl 2,3,4-tri-O-benzyl-6-O-{2-[ω-hydroxy-penta-(oxyethylene)ethyl]}-1-thio-β-D-galactopyranoside (10). The yields of the chiral crowns 7, 8 and 11, obtained in the final cyclization step from the thioglycosides 5, 6, and 10, are 32-61 %, i.e., they could be more than doubled compared to previous experiments with O-glycosidic precursors. High β-stereoselectivity was found for the cyclizations to the 1,4-bridged crowns 7 and 8. In contrast the more flexible 6-O-polyethylene derivative 10 cyclized exclusively to the 1,6-bridged α-glycosidic crown ether 11.

Liquid chromatographic direct resolution of β-amino acids on a chiral crown ether stationary phase

A chiral stationary phase (CSP) prepared by bonding (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid to silica gel was used for the direct resolution of β-amino acids. To determine the optimum mobile phase composition, two β-amino acids were selected and their resolutions on the CSP were performed with variation of the types and contents of organic and acidic modifiers in the aqueous mobile phase. The chromatographic resolution behaviors were found to be dependent on the types and contents of organic and acidic modifiers in the aqueous mobile phase. From the results of these experiments, a possible optimum mobile phase composition was proposed to be a mixed solvent of 50% methanol in water containing acetic acid (10 mM). The chromatographic resolution behaviors were also found to be dependent on the column temperature, the retention (k1) and the separation factors (α) being greater at lower temperatures. At the optimum mobile phase composition, all β-amino acids tested in this study were resolved quite well on the CSP with baseline separation.

Liquid chromatographic resolution of racemic amines, amino alcohols and related compounds on a chiral crown ether stationary phase

A chiral stationary phase (CSP) based on diphenyl-substituted 1,1′-binaphthyl crown ether was applied in resolving various racemic amines, amino alcohols and α-aminocarbonyl compounds including pharmaceutically important compounds such as amphetamine analogues, mexiletine, norepinephrine and norephedrine. The resolution was quite successful. In order to find out the effects of mobile phase additives on the chromatographic resolution behaviors, four selected racemic compounds were resolved on the CSP with the variation of the type and content of organic, acidic and cationic modifiers in aqueous mobile phase and with the variation of column temperature. The resolution behaviors were quite dependent on the type and the content of organic, acidic and cationic modifiers in aqueous mobile phase and on column temperature.

Chiral Molecular Recognition in Fast Atom Bombardment Mass Spectrometry (FAB-MS) Enantiomerlabeled (EL) Guest Method Using New Chiral Bis-pyridino-18-crown-6

Korea Basic Science Institute, Yusungku Yeoeundong 52, Taejeon 305-333, KoreaReceived January 18, 2002Keywords : Chiral recognition, Chiral crown ether, FAB-MS, Enantiomer-labeled guest method.Recently, in the more highly structured host-guest complexsystems, chiral recognition has been detected by Sawada andhis co-workers using fast atom bombardment mass spectro-metry (FAB-MS) and electrospray ionization mass spectro-metry (ESI-MS).

Chiral separation of gemifloxacin in sodium-containing media using chiral crown ether as a chiral selector by capillary and microchip electrophoresis.

Chiral crown ether, (+)-(18-crown-6)-tetracarboxylic acid (18C6H(4)), is an effective chiral selector for resolving enantiomeric primary amines owing to the difference in affinities between 18C6H(4) and each of the amine enantiomers. In addition to the destacking effect of sodium ion in the sample solution, the strong affinity of sodium ion to the polyether ring of crown ether is unfavorable to chiral capillary electrophoresis using 18C6H(4) as a chiral selector. In this report, the chiral separation of gemifloxacin dissolved in a saline sample matrix using 18C6H(4) was investigated. Adding a chelating agent, ethylenediaminetetraacetic acid (EDTA), to the run buffer greatly improved the separation efficiencies and peak shapes. The successful chiral separation of gemifloxacin in a urinary solution was demonstrated for both capillary and microchip electrophoresis.

A comparison of the direct and indirect LC methods for separating enantiomers of unusual glycine and alanine amino acid analogues

Reversed-phase high-performance liquid chromatographic methods were developed for the separation of the enantiomers of five glycine and twelve alanine analogues. The enantioselective separation involved two methods. The direct separations were performed on chiral stationary phases containing a macrocyclic glycopeptide antibiotic: teicoplanin (Chirobiotic T column), ristocetin A (Chirobiotic R column) or chiral crown ether (Crownpak CR(+) column). The indirect methods involved pre-column derivatization with the chiral derivatizing agents 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate andN-α-(2,4-dinitro-5-fluorophenyl)-L-alaninamide (Marfey's reagent). The different methods were compared in systematic chromatographic examinations. The effects of organic modifier content, mobile phase composition, pH and flow rate on the separation were investigated.

Synthesis and Enantiomeric Selectivity of Chiral Crown Ethers

Condensation of (4S,5S)-4,5-dihydroxymethyl-2-substituted dioxolanes with polyethylene glycols ditosylates yielded new chiral crown ethers. By potentiometry the enantioselectivity of complexing between the compounds obtained and L- and D-valine methyl ester hydrochlorides was evaluated.

定量的キラル認識マススペクトロメトリーの進歩

The developments of our quantitative chiral recognition studies in the host-guest complexations between chiral crown ethers and chiral amino acid esters by FAB, ESI, and MALDI mass spectrometry have been described. Both the enantiomer labeled (EL)-guest method and the EL-host method, which had been previously proposed by us, were successfully advanced. The relative peak intensity (IRIS) values of the diastereomeric host-guest complex ions appeared in mass spectra were especially noted, and their use to chiral recognition was illustrated. Generally, the former method was used to chiral recognition ability-determination of a given host, and the latter one was used to enantiomeric excess (e.e.)-determination of a given guest. Through the manuscript, emphasis has been put on the finding that one can detect correctly the concentration ratio of the two diastereomeric host-guest complex ions formed in a matrix solution by FAB mass spectrometry and then, that FABMS is a powerful tool for detecting chiral host-guest interactions in the host-guest complexation systems. Recent ,e.e.-determination methods by ESI mass spectrometry etc. were also summarized.

Comparison of three chiral stationary phases with respect to their enantio- and diastereoselectivity for cyclic β-substituted α-amino acids

Three chiral stationary phases were examined for the enantio- and diastereoseparation of cycloaliphatic β-substituted α-quaternary α-amino acids. Resolution of diastereomeric analytes is feasible with a chiral crown ether based column, whereas the separation of enantiomers, except for one pair of amino acids, could not be achieved. The two chiral stationary phases with the glycopeptide antibiotic teicoplanin and with the copper(II)- d-penicillamine complex, respectively, are, however, both very potent in the separation of the enantiomeric, as well as of the diastereomeric amino acids. A baseline separation of all four stereoisomeric forms in one chromatographic run was possible with the exception of one type of amino acid. The results of the method development are presented in this paper.

The effect of analyte lipophilicity on the resolution of α-amino acids on a HPLC chiral stationary phase based on crown ether

The effect of analyte lipophilicity on the resolution of α-amino acids on a chiral stationary phase based on chiral crown ether has been examined by the chromatographic resolution trends for the resolution of a homologous series of five α-amino acids with an alkyl group of different length at the chiral center. The retention factors ( k 1 and k 2) for the two enantiomers and the separation factors (α) were found to depend on the lipophilicity of the α-amino acid. In general, the retention factors increased as the organic modifier content in the mobile phase increased, the degree of the enhancement of retention factors being dependent on the analyte lipophilicity. The separation factors also increased as the analyte lipophilicity and the organic modifier content in the mobile phase increased. Possible rationales for these behaviors have been proposed.

OPTICAL LIMITING PROPERTIES OF OPTICALLY ACTIVE METAL-FREE AND METAL PHTHALOCYANINES SUBSTITUTED WITH CHIRAL BINAPHTHYL CROWN ETHER UNITS

The optical limiting properties of five optically active phthalocynines substituted with chiral binaphthyl crown ether units, (R)- and (S)- BNCE - H 2 Pc , (R)- and (S)-BNCE-CuPc, (S)-BNCE-PbPc, were investigated in solution at 532 nm with 10 ns pulses. The experimental results indicated that the (S)- and (R)-optical isomer exhibit similar optical limiting behavior and the central metal ions, Cu or Pb in the optically active metal phthalocyanine have not significantly enhanced the optical limiting behavior compared with that of the optically active metal-free phthalocyanine. In addition, the nonlinear absorption of the optically active metal-free and metal phthalocyanines was determined by the standard open aperture Z-scan technique.

Chiral Recognizable Host-Guest Interactions Detected by Fast-Atom Bombardment Mass Spectrometry: Application to the Enantiomeric Excess Determination of Primary Amines

The enantiomeric excess ( ee) of organic amine compounds has been determined using fast-atom bombardment (FAB) mass spectrometry based on the chiral host–guest complexation systems. The method uses a 1:1 mixture of the given chiral crown ether hosts (HRRRR and HSSSS-dn), one of whose enantiomers is isotopically labeled, for the ee-determination of a given amine salt guest (G+). The peak intensity ratio { I[(HRRRR + G)+] / I[(HSSSS-dn + G)+] = IRIS} of the two diastereomeric host–guest complex ions clearly changes with the change in the ee of the guest. The intensity excess ( Ie) of the two complex ion peaks is newly defined as Ie = ( IRIS −1) / ( IRIS + 1). The two sets of mass spectrometrically obtained Ie values vs a set of ee values of phenylalanine methyl ester and leucine methyl ester hydrochlorides show excellent linear relationships through the zero point ( R2 = 0.9989 and R2 = 0.9970, respectively). This indicates the potential utility of the present ee-determination method to within ± 3% ee. Furthermore, based on the solution equilibrium distributions of the complex ions, the linearity is mathematically justified. Therefore, the ee-determination can be simplified as ee (%) = (| Ie| / | Ie(100)|) × 100: here, Ie(100) is the corresponding Ie value obtained using an enantiomerically pure (100% ee) guest as a reference. The present chiral dimethoxyphenyl crown ether host pairs employed are effective ( IRIS ≥ 1.5) for the ee-determination of most α-amino acid esters, but not effective ( IRIS ≈ 1.0) for most simple alkylamines.

CROWN ETHER ANALOGS FROM SUCROSE

A convenient synthesis of 1′,2,3,3′4,4′-hexa-O-benzylsucrose (4) from the free disaccharide is presented. Diol 4 and previously obtained 1′-O-benzyloxymethyl-2,3,3′,4,4′-penta-O-benzylsucrose (3) served as precursors for chiral crown ether analogs containing a sucrose backbone. Deprotection of macrocyclic compounds (removal of the benzyl blocks) was possible under hydrogenolysis conditions.