Chiral Crown Ethers Research Articles

Synthesis of camphor based chiral crown ethers and their interactions with amino acid derivatives

Three camphor based crown ethers have been prepared, starting from (–)-(1R)-camphorquinone, in which 2- and 3-endo-substituents are used to regulate the availability of the endo-l8-crown-6 face for binding organic guests and the bridge head methyl group is available to impart enantioselectivity at the exo-face. The stereochemistry of the key intermediate 2-endo-3-endo-dimethyl bornane-2,3-diol (6) has been confirmed by a single crystal X-ray structure determination. Interactions between these crowns and antipodal phenylglycine salts have been probed using NMR and modelling techniques.

Chiral crown ethers incorporating D-glucose

A novel class of crown ether derivatives incorporating D-glucose and poly(ethylene glycol) units has been synthesized from allyl α-D-glucopyranoside by a simple and efficient strategy. The complexing properties of these compounds with alkali metal cations and ammonium ion have been evaluated by Cram's picrate method. Catalytic activity of macrocycle 2 in asymmetric Michael addition reaction was also studied. The average cavity size of these macrocycles was determined by the application of the MMX programme.

Chiral separations of amino acids by capillary electrophoresis and high-performance liquid chromatography employing chiral crown ethers

High-performance liquid chromatography with a chiral crown ether stationary phase and capillary electrophoresis (CE) with a chiral crown ether dissolved in the operating buffer were used for the separation of enantiomers of analogues of DOPA and tyrosine and some analogues of γ-aminobutyric acid (GABA). CE and HPLC yielded similar results for the DOPA and tyrosine analogues. However, for the analogues of GABA, three of the four compounds tested were well resolved by HPLC but only one was well resolved by CE. It was necessary to use an indirect detection scheme for the CE of GABA analogues. The influence of substituents on the different compounds on the resolution factors observed by the two methods is discussed, in addition to the advantages and disadvantages of the two methods in practical applications.

Enantiomeric resolution of primary amines by capillary electrophoresis and high-performance liquid chromatography using chiral crown ethers

High-performance liquid chromatography with a chiral crown ether stationary phase and capillary electrophoresis (CE) with a chiral crown ether dissolved in the operating buffer have been used for the separations of enantiomers of a variety of primary amines of pharmaceutical interest, including aminotetralin analogues, aminomethylbenzodioxane, amino derivatives of naphthalene and phenanthrene, and aminodecalin analogues. Interestingly, the enantiomers of many of these compounds were adequately resolved by only one or the other of the two methods, indicating that the techniques are complementary. The influence of the degree of complexation of analyte molecules with the crown ether on chromatographic retention, electrophoretic migration, and chiral recognition is discussed, as well as the relative advantages and disadvantages of the two methods in practical applications.

Effect of acetysal, dexamethasone and their combination on drug metabolism

The suitability of capillary electrophoresis for determining the enantiomeric purity of levodopa in a pharmaceutical formulation also containing benserazide was assessed. To this end, the pharmaceutical components were separated in a non-chiral medium that allowed the total amount of Dopa and that of benserazide to be quantified. The addition of a chiral crown ether to the background electrolyte allows to separate the enantiomers of this compounds. Optimizing the variables influencing the enantioresolution of Dopa affords a resolution high enough resolution to determine the amount of dextrodopa (the distomer) contained in levodopa (the eutomer) in a pharmaceutical. A relative limit of detection (RLD) is proposed as a measure of the lowest detectable enantiomeric impurity. The RLD for the determination of dextrodopa contained in levodopa was 0.1% and found to depend on the enantiomer migration order. The enantiomeric purity of levodopa in the pharmaceutical preparation and dextrodopa from Sigma was 99.5 and 99.95%, respectively.

Direct stereochemical resolution of 3,4-dihydroxyphenylserine using a chiral crown ether stationary phase

The direct stereochemical resolution of the four stereoisomers of 3,4-dihydroxyphenylserine was achieved on a high-performance liquid chromatographic chiral stationary phase based on a chiral crown ether. The effects of pH and temperature were investigated. The role of the crown ether ring in separating the analyte is also described.

New chiral crown ethers derived from camphor and their application to asymmetric Michael addition. First attempts to rationalize enantioselection by AM1 and AMBER calculations

The synthesis of novel optically active crown ethers derived from (1 R)-(+)-camphor is described. The mechanism of their catalytic effect upon the Michael addition of phenylacetate to acrylate is discussed in terms of kinetic vs. thermodynamic control in the formation of the catalytic ion-pair complexes. The relative basicity of the complexes formed between the alkaline metals and the unprotonated chiral crown ethers plays an important role in the sterochemical outcome. AMBER and AM1 calculations support that the reaction in which the best e.e. (83%) is obtained proceeds under kinetic control.

Chiral recognition in molecular complexation for the crown ether–amino ester system. A facile FAB mass spectrometric approach

Various degrees of chiral recognition properties of chiral crown ether hosts toward amino acid ester guests are directly, easily and reliably evaluated by the enantiomer deuterium-labelled racemic guest method using conventional FAB mass spectrometry.

Cross‐chiral examinations of molecular enantioselective recognition by fast atom bombardment mass spectrometry: Host–guest complexations between chiral crown ethers and chiral organic ammonium ions

AbstractUsing fast atom bombardment (FAB) mass spectrometry (MS), cross‐chiral relationships were confirmed for the first time for the diasteromeric host‐guest complexations between the chiral crown ether host (1) and the chiral organic ammonium ion guest (2) on the basis of the relative peak intensities (RPI). Both host–guest combinations (R, R, R, R) – 1, (R) – 2 and (S, S, S, S) – 1, (S) – 2 obviously provided larger RPI values than the combination of both (R, R, R, R) – 1, (S) – 2 and (S, S, S, S) – 1, (R) – 2 by a factor of 1.6 as an averaged value: 1.87 (n = 4)/1.16 (n = 4) = 1.6. These results are consistent with the expected stabilities of the host‐guest complexations by CPK model examinations. Successfully observed cross‐chiral examinations strongly suggest a potentially useful FABMS/RPI methodology for rapidly searching newly designed and synthesized crown ether‐like host compounds with a higher degree of enantioselectivity.

Supported liquid membranes for enantioselective transport of amino acid mediated by chiral crown ether - effect of membrane solvent on transport rate and membrane stability

The effect of membrane solvent on transport efficiency and membrane stability was investigated in a crown ether-mediated enantioselective amino acid transport system. Relatively non-volatile organic liquids were evaluated as membrane solvents in a supported liquid membrane (SLM) using a microporous polymer film as solid support. For the organic liquids giving high fluxes and a high enantioselectivity, the membrane stability was assessed by operating the membranes for periods of up to 90 days. During these experiments, test-runs were repeated daily and thus the experiments were termed ‘repeated-run’ experiments. The best organic liquids were found to be o-nitrophenyl octyl ether (ONPOE) and p-nitrophenyl heptyl ether (PNPHE). SLMs with these organics were stable for more than 50 repeated-runs. The factors controlling the membrane efficiency are discussed on the basis of the physico-chemical properties of the organic liquids, and it is found that the membrane solvent must have both a high dielectric constant and low solubility in water for the SLMs to be highly stable and permeable.

Organofluorverbindungen und Fluorierungsagenzien, 9. Von Glycosylfluoriden zu chiralen Kronenethern

Organofluorine Compounds and Fluorinating Agents, 9[1a]. — From Glycosyl Fluorides to Chiral Crown EthersMethyl D‐galactofuranoside (1), methyl D‐glucofuranoside (3), 3‐O‐substituted 1,2:5,6‐di‐O‐isopropylidene‐α‐D‐glucofuranoses (5a—g), 1,2‐O‐isopropylidene‐3,5,6‐tri‐O‐methyl‐α‐D‐glucofuranose (7) as well as the trans‐decalin analog 1,2‐O‐ethanediyl‐3,4,6‐tri‐O‐methyl‐β‐D‐glucopyranose (13) are selectively transformed with deacetalisation into the corresponding acylated glycosyl fluorides 2, 4, 6a—g, 8, and 14 by HF/nitro‐methane/carboxylic acid anhydride. The reaction is realized without change of the ring size if the three‐component agent system is mixed some time before the carbohydrate is added. 3,5,6‐Tri‐O‐methyl‐2‐O‐pivaloyl‐D‐glucofuranosyl fluoride (8) and 2‐O‐(2‐acetoxyethyl)‐3,4,6‐tri‐O‐methyl‐α‐D‐glucosyl fluoride (14) are used as starting materials to synthesize three isomeric, chiral crown ethers, the bis‐β‐D‐glucofuranosido‐12‐crown‐4 derivative 12 and both stereoisomeric bis‐D‐glucopyranosido‐12‐crown‐4 derivatives 20 and 21.

Enantioselective complexation of carbohydrate or crown ether hosts with organic ammonium ion guests detected by FAB mass spectrometry

Enantioselective host-guest complexation has been demonstrated by FAB mass spectrometry. Among several carbohydrates, a modified β-mannofuranoside 6b as well as chiral crown ethers 10 and 13, differentiates a chiral ammonium ion guest such as the (1-(1-naphthyl)ethyl)ammonium ion. The relative peak intensity (RPI) method has been applied to the evaluation of such diastereomeric complex ions where the peak intensity of the target host (M)-guest (A + ) complex ion I((M+A) + ) is compared to that of the internal standard host (R)-guest (A + ) ion I((R+A) + ): the RPI value=I((M+A) + )/I((R+A) + )

Determination of the enantiomeric purity of 5,6‐ and 6,7‐dihydroxy‐2‐aminotetralins by chiral HPLC

Abstract5,6‐ and 6,7‐Dihydroxy‐2‐aminotetralin (ADTN), racemic dopamine receptor agonists, were resolved into their enantiomers by a new chiral HPLC assay. The separation was performed on a Crownpack CR column, which contains an 18‐crown‐6‐type chiral crown ether as a chiral selector. The chiral recognition is based on the compiexation of the protonated primary amino group and the oxygen atoms inside the cavity of the crown ether. The amino group is attached to the chiral centre and therefore these compounds could be resolved. Mobile phase was perchloric acid pH 2.0 and the detection was UV at 200 nm. Resolution factors were 3.1 for 5,6‐ADTN and 1.1 for 6,7‐ADTN resulting in very low limits of quantitation (<0.1%) of the enantiomer present as impurity. Data on the validation of the assay and on the stability of the column are also reported. © 1993 Wiley‐Liss, Inc.

Preparation and enantiomer recognition behaviour of crown ethers containing cis-1-phenylcyclohexane-1,2-diol and trans-1,2-diphenylcyclohexane-1,2-diol as a chiral subunit

Pig liver esterase-mediated hydrolysis of (±)-cis-2-acetoxy-1-phenylcyclohexanol 5 gave (+)-cis-1-phenylcyclohexane-1. 2-diol 4 of high optical purity, from which (–)-trans-1, 2-diphenylcyclohexane-1, 2-diol 8 has been prepared. Using these diols (+)-4 and (–)-8 as a chiral subunit, chiral crown ethers (–)-1, (–)-2 and (–)-3 have been prepared and their chiral recognition behaviour toward (±)-1, 2-diphenylethylamine hydrochloride and methyl (±)-phenylglycinate hydrochloride in enantiomer differential transport has been examined. The enantiomer selectivities of these crown ethers in complexation with racemic ammonium salts have been interpreted on the basis of CPK molecular model examination of the diastereoisomeric complexes.

アームド・クラウンエーテルの合成と機能化

Armed crown ethers and related armed macrocycles are presented as specific host molecules which are characterized by macrocyclic ligands and cation-ligating sidearms. Since they form dynamic and three dimensional complexes, they have potential as effective receptors, carriers, catalysts, and other functional molecular devices. This review describes new strategies for syntheses and functionalizations of armed crown ethers : (1) computer-aided molecular design of Li+ ion-specific receptors, (2) high pressure synthesis of Ag+ ion-specific carriers, (3) lipase-catalyzed optical resolution of chiral crown ethers and their application, and (4) armed crown ether-containing molecular assembly for effective Cu2+ ion separation. These clearly indicate that rational molecular design and refined synthetic method are required to develop a new, specific host molecule.

Chiral recognition and enantiomeric resolution based on host-guest complexation with crown ethers in capillary zone electrophoresis

A chiral crown ether is successfully used as a pseudostationary phase in capillary zone electrophoresis to separate optically active amines. On the basis of the results obtained from the separation of more than 20 amines, two recognition mechanisms are proposed: (I) the four crown ether substituents act as chiral bariers for the guest molecules and (II) lateral electrostatic interactions occur between host and guest. These results are confirmed by thermodynamic studies on the host-guest complexes

Improved crown ether-based chiral stationary phase

An improved crown ether-based chiral stationary phase (CSP) was prepared by dynamic coating of a reversed-phase silica gel with a new chiral crown ether which was designed to have more lipophilicity than the previously used one, while preserving the basic structure responsible for chiral recognition. The CSP showed not only excellent enantioselectivity for amino acids, but also higher stability against organic solvents in the mobile phase. No desorption of the crown ether from the support was observed in a mobile phase containing up to 40% of methanol. An increase in methanol concentration in the mobile phase gave rise to a decrease in the retention of amino acids and an increase in the “apparent” enantioselectivity, i.e., the separation coefficient and the resolution factor. A possible retention mechanism is proposed to explain these behaviours.

Capillary zone electrophoresis of the enantiomers of aminoalcohols based on host‐guest complexation with a chiral crown ether

Capillary zone electrophoresis of the enantiomers of aminoalcohols based on host‐guest complexation with a chiral crown ether

Preparation and use of fluorine-containing carbohydrates as building blocks for glycosidations or for chemistry with new protective groups

As our initial results have shown ( Synthesis 1991, 885), systems from anhydrous hydrogen fluoride/nitromethane/carboxylic acid anhydride are convenient reagent mixtures for selective one-pot syntheses of pyranosyl or furanosyl fluorides. This method is especially of interest for efficient syntheses of furanosyl fluorides. We now show that the reaction time and temperature can have an important influence on the anomeric composition of the fluorides. Additional examples are introduced to yield fluorinated sugars by cleavage of acetal or ketal functions and simultaneous acylation; for example: ▪ The reagent mixtures were also designed to prepare specific building blocks for glycosidations. Thus, the acetals 3 from the ‘decaline type’ have proved to be suitable starting materials for new chiral crown ethers. The glycosidations can be catalyzed by BF 3. ▪ Finally, a new fluorine-containing protective group for carbohydrates was developed. We succeeded in producing cyclic acetals of monosaccharides with hexafluoroacetone. This is the first example of acetalization of a vicinal diol with the named ketone.

Regioselective Transformations of 2′,3′‐Seconucleosides into Anhydro Structures and Chiral Crown Ethers

AbstractIntramolecular cyclisation of properly protected and activated derivatives of 2′,3′‐secouridine ( = 1‐{2‐hydroxy‐1‐[2‐hydroxy‐1‐(hydroxymethyl)ethoxy]‐ethyl}uracil; 1) provided access to the 2,2′‐, 2,3′‐, 2,5′‐, 2′,5′‐, 3′,5′‐, and 2′,3′‐anhydro‐2′,3′‐secouridines 5, 16, 17, 26, 28, and 31, respectively (Schemes 1–3). Reaction of 2′,5′‐anhydro‐3′‐O‐(methylsulfonyl)‐ (25) and 2′,3′‐anhydro‐5′‐O‐(methylsulfonyl)‐2′,3′‐secouridine (32) with CH2CI2 in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene generated the N(3)‐methylene‐bridged bis‐uridine structure 37 and 36, respectively (Scheme 3). Novel chiral 18‐crown‐6 ethers 40 and 44, containing a hydroxymethyl and a uracil‐1‐yl or adenin‐9‐yl as the pendant groups in a 1,3‐cis relationship, were synthesized from 5′‐O‐(triphenylmethyl)‐2′,3′‐secouridine (2) and 5′‐O,N6‐bis(triphenylmethyl)‐2′,3′‐secoadenosine (41) on reaction with 3,6,9‐trioxaundecane‐1,11‐diyl bis(4‐toluenesulfonate) and detritylation of the thus obtained (triphenylmethoxy) methylcompound 39 and 43, respectively (Scheme 4).