Chiral Crown Ethers Research Articles

Construction of chiral crown ethers in robust covalent organic frameworks for electrochromatographic enantioseparation

ABSTRACT Capillary electrochromatography (CEC) is a rapidly emerging separation technique that merges the high separation efficiency of capillary electrophoresis with the exceptional selectivity of liquid chromatography. However, it remains a synthetic challenge to design functional chiral stationary phases (CSPs) with high chemical stability against acid and base in CEC enantioseparation. Here we demonstrate that incorporating chiral crown ethers into stable covalent organic frameworks (COFs) enables efficient and stable separations of racemates by CEC. This facilitates the crafting of two three-dimensional (3D) chiral COFs by polycondensation of a chiral 1,1'-binaphyl-20-crown-6-derived dialdehyde and tetraamines with diisopropyl substituents. Both feature an 11-fold interpenetrated diamond framework, characterized by tubular open channels decorated with chiral crown ethers serving as enantioselective recognition and binding sites. These frameworks demonstrate excellent stability in water, acid and base, thanks to the presence of bulky isopropyl groups that shield the dynamic imine linkages. Moreover, the precisely defined COF channels enhanced the accessibility of the enclosed crown ethers to the analytes while providing strong protection against harsh environments, rendering them suitable for CSPs in CEC separations. They can effectively separate some important enantiomers, including ketones, epoxides and alkaline substances, when utilized as coatings on chiral columns, particularly facilitating the chiral separation of drugs. This study advances the application of COFs in electrochromatographic separations, expanding the scope of porous materials design and engineering to create COFs with targeted enantioselective properties.

Ion-pair chromatographic attribute in the retention of ammonium ion on a crown ether-based and a polysaccharide-based chiral stationary phases. Some mobile phase additives compatible with liquid chromatography-electrospray ionization-mass spectrometry

The design of the mobile phase additive useful in HPLC analysis on two types of chiral stationary phases, one based on chiral crown ether, and another based on polysaccharide derivative, was developed. CROWNPAK® CR-I, the chiral stationary phase bearing (R)- or (S)-(3,30-diphenyl-1,10-binaphtyl)-20-crown-6 (1) moiety is a useful CSP to separate primary amine enantiomers. While perchloric acid had been recommended as the mobile phase additive to attain a better separation, we have reexamined the effect of mobile phase additives and revealed that the retention of an ammonium ion is enhanced by a chaotropic or a hydrophobic anion in a water-based mobile phase like well-known ion pair chromatography in an RPLC. However, the retention was enhanced in reverse by a rather cosmotropic or a hydrophilic anion in an acetonitrile (ACN)-based mobile phase. These results looking contradictory to each other may be rationalized both in the basis of ion pair chromatography. A similar but smaller effect of pairing anion species was also observed on a polysaccharide-based CSP. Based on these findings, some types of mobile phase have been proposed and some of them were demonstrated to be compatible with liquid chromatography-electrospray ionization-mass spectrometry (ESI LC/MS).

Rhodium-Catalyzed Asymmetric Macrocyclization towards Crown Ethers Using Hydroamination of Bis(allenes).

Enantiomerically enriched crown ethers (CE) exhibit strong asymmetric induction in phase transfer catalysis, supramolecular catalysis and molecular recognition processes. Traditional methods have often been used to access these valuable compounds, which limit their diversity and consequently their applicability. Herein, a practical catalytic method is described for the gram scale synthesis of a class of chiral CEs (aza-crown ethers; ACEs) using Rh-catalyzed hydroamination of bis(allenes) with diamines. Using this approach, a wide range of chiral vinyl functionalized CEs with ring sizes ranging from 12 to 36 have been successfully prepared in high yields of up to 92 %, dr of up to >20 : 1 and er of up to >99 : 1. These vinyl substituted CEs allow for further diversification giving facile access to various CE derivatives as well as to their three-dimensional analogues using ring-closing metathesis. Some of these chiral CEs themselves display high potential for use in asymmetric catalysis.

Rhodium‐Catalyzed Asymmetric Macrocyclization towards Crown Ethers Using Hydroamination of Bis(allenes)

AbstractEnantiomerically enriched crown ethers (CE) exhibit strong asymmetric induction in phase transfer catalysis, supramolecular catalysis and molecular recognition processes. Traditional methods have often been used to access these valuable compounds, which limit their diversity and consequently their applicability. Herein, a practical catalytic method is described for the gram scale synthesis of a class of chiral CEs (aza‐crown ethers; ACEs) using Rh‐catalyzed hydroamination of bis(allenes) with diamines. Using this approach, a wide range of chiral vinyl functionalized CEs with ring sizes ranging from 12 to 36 have been successfully prepared in high yields of up to 92 %, dr of up to >20 : 1 and er of up to >99 : 1. These vinyl substituted CEs allow for further diversification giving facile access to various CE derivatives as well as to their three‐dimensional analogues using ring‐closing metathesis. Some of these chiral CEs themselves display high potential for use in asymmetric catalysis.

Nucleophilic Reactions Using Alkali Metal Fluorides Activated by Crown Ethers and Derivatives

We review crown ether-facilitated nucleophilic reactions using metal salts, presenting the studies using kinetic measurements and quantum chemical methods. We focus on the mechanistic features, specifically on the contact ion-pair (CIP) mechanism of metal salts for nucleophilic processes promoted by crown ethers and derivatives. Experimental verification of the CIP form of the metal salt CsF complexed with [18-Crown-6] by H-NMR spectroscopy is described. The use of chiral crown ethers and derivatives for enantioselective nucleophilic processes is also discussed.

Development of Ultra High-Performance Liquid Chromatography–Tandem Mass Spectrometry Method for Enantiomer Resolution of Thyroxine on a Chiral Crown Ether Derived Chiral Stationary Phase

Chiral discrimination of thyroxine (T4) enantiomers was performed using ultra high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) on a chiral crown ether-derived ChiroSil SCA (-) column. The different composition of mobile phases and the effect of column oven temperatures were investigated and the optimum chromatographic separation with respect to resolution and analysis time was achieved using a mixture of 60% methanol/water (v/v) with 0.1% formic acid at 40 °C having a flow rate of 1.4 mL min−1. The thermodynamic data from van’t Hoff plots of temperature experiments revealed that the enantioseparation was enthalpically favored process. The method was validated in the concentration range of 0.5–100 μg mL−1 for both enantiomers and proved to be rapid, precise, sensitive, and selective method for the enantiodiscrimination of T4 under the optimized conditions. The calibration curves of both D- and L-T4 showed an excellent linearity with coefficient of determination (R2) > 0.9997. The developed chiral method was successfully applied for a quantitative assay to check the enantiomeric purities of the six pharmaceutical formulations of levothyroxine sodium tablets and the enantiomeric impurities identified were in the range of 0.11–0.29%. This method could be applied for the determination of enantiomeric purity on pharmaceuticals and also for the monitoring of thyroid hormone levels.Graphical Abstract

Chiral Crown Ethers Accessed from Catalytic Enantioselective Desymmetrization Reactions.

A diversity of unprecedented chiral aza-crown ethers were synthesized straightforwardly from readily available and inexpensive aza-crown ethers. Catalyzed by a chiral phosphoric acid, desymmetrization of an array of symmetric N-arylated aza-crown ethers through tert-amino reaction proceeded efficiently under mild conditions to produce novel tetrahydroquinoline-fused aza-crown ethers in good to excellent yields with up to 96% ee. Our strategy opens a new route to functionalized chiral crown ethers.

Enantioselective Cyclopropanation of 2‐Cyano‐3‐arylacrylates Using Carbohydrate‐Based Crown Ethers

AbstractEnantioenriched, highly functionalized cyclopropane derivatives were prepared by a simple and green approach using monosaccharide‐based chiral crown ethers as phase transfer catalysts. The Michael‐initiated ring closure (MIRC) reactions of diethyl bromomalonate with 2‐cyano‐3‐phenylacrylate took place with complete diastereoselectivity in the presence of chiral lariat ethers derived from carbohydrates and enantioselectivity up to 87 % ee was achieved. Among the catalysts tested, the monoaza‐15‐crown‐5 lariat ether having a methyl β‐d‐glucopyranoside unit and a 2‐(3,4‐dimethoxyphenyl)ethyl group on the nitrogen generated the highest asymmetric induction (87 % ee). In the reactions of analogous 2‐cyano‐3‐arylacrylates, enantioselectivity was in the range of 8–91 % ee.

Are Highly Stable Covalent Organic Frameworks the Key to Universal Chiral Stationary Phases for Liquid and Gas Chromatographic Separations?

High-performance liquid chromatography (HPLC) and gas chromatography (GC) over chiral stationary phases (CSPs) represent the most popular and highly applicable technology in the field of chiral separation, but there are currently no CSPs that can be used for both liquid and gas chromatography simultaneously. We demonstrate here that two olefin-linked covalent organic frameworks (COFs) featuring chiral crown ether groups can be general CSPs for extensive separation not only in GC but also in normal-phase and reversed-phase HPLC. Both COFs have the same 2D layered porous structure but channels of different sizes and display high stability under different chemical environments including water, organic solvents, acids, and bases. Chiral crown ethers are periodically aligned within the COF channels, allowing for enantioselective recognition of guest molecules through intermolecular interactions. The COF-packed HPLC and GC columns show excellent complementarity and each affords high resolution, selectivity, and durability for the separation of a wide range of racemic compounds, including amino acids, esters, lactones, amides, alcohols, aldehydes, ketones, and drugs. The resolution performances are comparable to and the versatility is superior to those of the most widely used commercial chiral columns, showing promises for practical applications. This work thus advances COFs with high stability as potential universal CSPs for chromatography that are otherwise hard or impossible to produce.

VCD spectroscopy reveals conformational changes of chiral crown ethers upon complexation of potassium and ammonium cations.

Two chiral derivatives of 18-crown-6, namely the host molecules 2,3-diphenyl- and 2-phenyl-18c6, serve as model systems to investigate whether VCD spectroscopy can be used to monitor conformational changes occurring upon complexation of guests. Host-guest complexes of both crown ethers were prepared by addition of KNO3. The more bulky 2,3-diphenyl-18c6 is found to undergo major conformational changes upon encapsulation of K+, which are revealed as characteristic changes of the VCD spectral signatures. In contrast, while 2-phenyl-18c6 also incorporates K+ into the macrocycle, strong conformational changes are not occurring and thus spectral changes are negligible. With an octyl ammonium cation as guest molecule, 2,3-diphenyl-18c6 shows the same conformational and spectral changes that were observed for K+-complexes. In addition, the asymmetric NH3-deformation modes are found to gain VCD intensity through an induced VCD process. An analysis of the vibrational spectra enables a differentiation of VCD active and inactive guest modes: There appears to be a correlation between the symmetry of the vibrational mode and the induced VCD intensity. While this finding makes the host-guest complexes interesting systems for future theoretical studies on the origin of induced VCD signatures, the observations described in this study demonstrate that VCD spectroscopy is indeed a suitable technique for the characterization of supramolecular host-guest complexes.

Cooperative Asymmetric Cation-Binding Catalysis.

Asymmetric cation-binding catalysis in principle enables the use of (alkali) metal salts, otherwise insoluble in organic solvents, as reagents and effectors in enantioselective reactions. However, this concept has been a formidable challenge due to the difficulties associated with creating a highly organized chiral environment for cations and anions simultaneously. Over the last four decades, various chiral crown ethers have been developed as cation-binding phase-transfer catalysts and examined in asymmetric catalysis. However, the limited ability of chiral crown ethers to generate soluble reactive anions in a confined chiral cage offers a restricted reaction scope and unsatisfactory chirality induction. To address the constraints of monofunctional chiral crown ethers as cation-binding catalysts, it is therefore desirable to develop a cooperative cation-binding catalyst possessing secondary binding sites for anions, which enables the generation of a reactive anion within a chiral cage of a catalyst. This account summarizes our design, development, and applications of chiral BINOL-based oligoethylene glycols (oligoEGs) as a new type of bifunctional cation-binding catalyst. We initially found that achiral oligoEGs were efficient promoters in nucleophilic fluorination with potassium fluoride. Thereby, we hypothesized that, by breaking the closed cyclic ether unit of chiral crown ethers, the free terminal -OH groups could activate the electrophiles by hydrogen bonding whereas the ether oxygens could act as the Lewis base to coordinate metal ions, thus generating soluble anions in a confined chiral cage. This hypothesis was realized by synthesizing a series of chiral variants of oligoEGs by connecting two 3,3'-disubstituted-BINOL units with glycol linkers. Readily available BINOL-based chiral oligoEGs enabled numerous asymmetric transformations out of the reach of chiral monofunctional crown ether catalysts. We have demonstrated that this new type of bifunctional cation-binding catalysts can generate a soluble fluoride anion from alkali metal fluorides, which can be a versatile chiral promoter for diverse asymmetric catalytic reactions, kinetic resolution (selectivity factor of up to ∼2300), asymmetric protonation, Mannich reactions, tandem cyclization reactions, and the isomerization of allylic alcohols and hemithioacetals. We have also successfully utilized our chiral oligoEG catalysts along with alkali metal salts of carbon- and heteroatom-based nucleophiles, respectively, for asymmetric Strecker reactions and the asymmetric synthesis of chiral aminals. The power of our cooperative cation-binding catalysis was exemplified by kinetic resolution reactions of secondary alcohols, achieving highly enantioselective catalysis with only <1 ppm loading of an organocatalyst with high TOFs (up to ∼1300 h-1 at 1 ppm catalyst loading). The broadness and generality of our cooperative asymmetric cation-binding catalysis can be ascribed, in a similar fashion, to active-site architectures of enzymes using allosteric interactions, highly confined chiral cages formed by the incorporation of alkali metal salts in the catalyst polyether chain backbone, and the cooperative activation of reacting partners by hydrogen-bonding and ion-ion interactions. Confining reactive components in such a chiral binding pocket leads to enhanced reactivity and efficient transfer of the stereochemical information.

Enantioselective metabolomics by liquid chromatography-mass spectrometry

Metabolomics strives to capture the entirety of the metabolites in a biological system by comprehensive analysis, often by liquid chromatography hyphenated to mass spectrometry. A particular challenge thereby is the differentiation of structural isomers. Common achiral targeted and untargeted assays do not distinguish between enantiomers. This may lead to information loss. An increasing number of publications demonstrate that the enantiomeric ratio of certain metabolites can be meaningful biomarkers of certain diseases emphasizing the importance of introducing enantioselective analytical procedures in metabolomics. In this work, the state-of-the-art in the field of LC-MS based metabolomics is summarized with focus on developments in the recent decade. Methodologies, tagging strategies, workflows and general concepts are outlined. Selected biological applications in which enantioselective metabolomics has documented its usefulness are briefly discussed. In general, targeted enantioselective metabolomics assays are often based on a direct approach using chiral stationary phases (CSP) with polysaccharide derivatives, macrocyclic antibiotics, chiral crown ethers, chiral ion exchangers, donor-acceptor phases as chiral selectors. Rarely, these targeted assays focus on more than 20 analytes and usually are restricted to a certain metabolite class. In a variety of cases, pre-column derivatization of metabolites has been performed, especially for amino acids, to improve separation and detection sensitivity. Triple quadrupole instruments are the detection methods of first choice in targeted assays. Here, issues like matrix effect, absence of blank matrix impair accuracy of results. In selected applications, multiple heart cutting 2D-LC (RP followed by chiral separation) has been pursued to overcome this problem and alleviate bias due to interferences. Non-targeted assays, on the other hand, are based on indirect approach involving tagging with a chiral derivatizing agent (CDA). Besides classical CDAs numerous innovative reagents and workflows have been proposed and are discussed. Thereby, a critical issue for the accuracy is often neglected, viz. the validation of the enantiomeric impurity in the CDA. The majority of applications focus on amino acids, hydroxy acids, oxidized fatty acids and oxylipins. Some potential clinical applications are highlighted.

Unusual enantiomeric separation due to residual amines in chiral crown ether stationary phase linked by long alkyl chain

A new chiral stationary phase (CSP) in which (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid was linked to a silica gel surface through a long alkyl chain and which did not contain additional aminoundecyl groups was prepared. Generally, when enantiomers containing a primary amine group are optically resolved using a crown-ether-type CSP, a higher resolution is achieved if the surface of the CSP does not contain any residual amine. In this study, the chiral separation factor and resolution factor of a CSP with a long alkyl chain such as the aminoundecyl group were unusually low in the absence of the residual aminoundecyl groups.In this study, a chiral column was prepared by introducing a chiral selector having a long alkyl chain on the surface of silica gel to separate enantiomers of α-amino acids. Furthermore, it was confirmed that the residual-amine-containing CSP, which was easier to synthesize, facilitated more effective enantiomeric separation than the CSP without residual amines.

Enantiomeric resolution of quinolones on crown ether CSP: Thermodynamics, chiral discrimination mechanism and application in biological samples

The enantiomers of quinolone racemates were resolved using chiral crown ether within 8 min. Thermodynamics data and modeling results were used to determine chiral recognition mechanism. The column used was (+)-Crownpack column (250 mm × 4.6 mm, 5 µm) with three mobile phases I: ACN:Water (80:20) + 10 mM H2SO4 and 10 mM CH3COONH4, II: ACN:Water (80:20) + 20 mM perchloric acid and III: EtOH:Water (80:20) + 20 mM perchloric acid. The flow rate of the mobile phases was 1.0 mL/min with UV detection at different wavelengths. The ranges of retention (k), separation (α), and resolution (Rs) factors were 1.00–5.40, 1.37–2.00 and 1.50–3.30. The tailing factor was 1.o for all peaks with 900–2325 as the number of theoretical plates were 8.0–10.0 and 32.4–22.1 µg. The difference in enthalpy, entropy and free energy varied in the range of −0.350 to −0.024, 18.74 × 10−4 to 3.94 × 10−4 and −0.918 to −0.143, respectively. The thermodynamic and docking results showed chiral discrimination due to physical forces of amnio group cations penetration into the chiral cavity of the chiral selector following hydrogen bindings. The binding energy of S-enantiomers was higher than R-enantiomers; confirming stronger binding of S-enantiomers with CSP than R-enantiomers. The described chiral-HPLC method was used for the analysis of the quinolone enantiomers in urine samples and the results were quite satisfactory. Therefore, the reported method may be used for the enantiomeric separation of quinolone enantiomers in urine samples.

Highly Stable Zr(IV)-Based Metal-Organic Frameworks for Chiral Separation in Reversed-Phase Liquid Chromatography.

Separation of racemic mixtures is of great importance and interest in chemistry and pharmacology. Porous materials including metal-organic frameworks (MOFs) have been widely explored as chiral stationary phases (CSPs) in chiral resolution. However, it remains a challenge to develop new CSPs for reversed-phase high-performance liquid chromatography (RP-HPLC), which is the most popular chromatographic mode and accounts for over 90% of all separations. Here we demonstrated for the first time that highly stable Zr-based MOFs can be efficient CSPs for RP-HPLC. By elaborately designing and synthesizing three tetracarboxylate ligands of enantiopure 1,1'-biphenyl-20-crown-6, we prepared three chiral porous Zr(IV)-MOFs with the framework formula [Zr6O4(OH)8(H2O)4(L)2]. They share the same flu topological structure but channels of different sizes and display excellent tolerance to water, acid, and base. Chiral crown ether moieties are periodically aligned within the framework channels, allowing for stereoselective recognition of guest molecules via supramolecular interactions. Under acidic aqueous eluent conditions, the Zr-MOF-packed HPLC columns provide high resolution, selectivity, and durability for the separation of a variety of model racemates, including unprotected and protected amino acids and N-containing drugs, which are comparable to or even superior to several commercial chiral columns for HPLC separation. DFT calculations suggest that the Zr-MOF provides a confined microenvironment for chiral crown ethers that dictates the separation selectivity.

Fast enantiomeric separation of amino acids using liquid chromatography/mass spectrometry on a chiral crown ether stationary phase

Fast enantiomeric separation of amino acids was studied by liquid chromatography/mass spectrometry (LC/MS) on a chiral crown ether stationary phase. A chiral crown ether bonded silica column (3mm internal diameter (i.d.), 5cm long) packed with 3μm particles was employed instead of a 15cm column packed with 5μm particles used in our previous study. In addition, the extra-column variance, becoming more serious for smaller columns, was reduced by replacing 0.127mm i.d. post-column tubes with shorter, smaller-diameter (0.0635mm i.d.) tubes. The results demonstrated the benefits of using shorter columns packed with smaller particles and the reduction of the extra-column band broadening for fast enantiomeric separation. Finally, the enantiomeric separation of 18 pairs of proteinogenic amino acids was achieved within 2min with a resolution (Rs) > 1.5 for each pair using an isocratic mobile phase of acetonitrile/water/trifluoroacetic acid (ACN/W/TFA)= 96/4/0.5, and a flow rate 1.2mL/min at 30°C. This is the highest throughput method for simultaneous chiral separation of all proteinogenic amino acids except proline to date.

Synthesis of New Chiral Crown Ethers Containing Phosphine or Secondary Phosphine Oxide Units

The transition-metal complexes of phosphine and secondary phosphine oxide compounds can be used in various catalytic reactions. In this paper, the synthesis and characterization of eight new crown ethers containing trivalent phosphorus in their macroring are reported. These macrocycles are promising candidates as ligands for catalytic reactions.

Stereoselective Determination of Thyroxine Enantiomers on Chiral Crown Ether Column by UPLC‐ESI‐Tandem Mass Spectrometry

Enantioseparation of thyroxine using chiral crown ether type column.

Chiral separation of underivatized amino acids in supercritical fluid chromatography with chiral crown ether derived column.

The supercritical fluid chromatographic separation of underivatized amino acids was explored using immobilized chiral crown ether column CROWNPAK CR-I (+) and mass spectrometric detection. The type of modifier, acidic additives, and the role of water were investigated. Enantioseparation was achieved for all 18 amino acids investigated with short retention times (less than 3 minutes) and average resolution of greater than 5.0. Analysis of enantiomerically pure standards demonstrated the D enantiomer eluted first for all amino acids using a CROWNPAK CR-I (+) column.

Synthesis of chiral crown ethers derived from d-galactose and their application in enantioselective reactions

A few new α- and β-d-galactopyranoside-based chiral lariat ethers of monoaza-15-crown-5 type were synthesized. These macrocycles proved to be efficient catalysts in a few asymmetric reactions under mild phase transfer conditions. The catalytic effect of the lariat ethers with methoxy, ethoxy, isopropoxy and aryloxy substituents on the C-1 of the sugar unit in both α and β positions was compared. In the presence of β-d-galactopyranoside-based crown ethers, the asymmetric Darzens condensation of α-chloroacetophenone and benzaldehyde, the epoxidation of trans-chalcone, the cyclopropanation (MIRC reaction) of benzylidenemalononitrile and 2-benzylidene-1,3-indandione with diethyl bromomalonate were performed with enantioselectivities of 61%, 64%, 86% and 96%, respectively. In all reactions, the β-anomers were more efficient in terms of enantioselectivity than the α forms.