Siu-Choon Ng

Recent development of cyclodextrin chiral stationary phases and their applications in chromatography.

The current article reviews the development and applications of novel cyclodextrin chiral stationary phases (CD-CSPs) in liquid chromatography (LC), capillary electrochromatography (CEC), gas chromatography (GC) and supercritical fluid chromatography (SFC) over the period of January 2007 to March 2012. The synthetic routes of CD-CSPs, as well as the presence of selective functional groups in effecting inclusion complexation and molecular interactions have been found to exert profound influence in the enantioseparation process. In this article, various synthetic and functional groups immobilization strategies of novel CD-CSPs, and their applications in chiral resolution using different chromatography techniques are discussed. After introducing the topic in Section 1, Section 2 describes novel CD-CSPs in LC applications, where the CSPs are classified according to its coating approaches (physical and chemical manners) for ease of readership. Section 3 discusses recent development of CD-CSPs in open tubular CEC (OT-CEC), packed-bed CEC (P-CEC), pseudostationary phase CEC (PSP-CEC) and monolithic CEC. The last part illustrates novel CD-CSPs in gas chromatography (GC) and supercritical fluid chromatography (SFC).

Facile synthesis of mono-6-amino-6-deoxy-α-, β-, γ-cyclodextrin hydrochlorides for molecular recognition, chiral separation and drug delivery

We describe a protocol for the synthesis of mono-6-amino-6-deoxy-cyclodextrin hydrochloride (CD-NH3Cl), applicable to α-, β- and γ-cyclodextrin. These structurally simplest, highly water-soluble cationic cyclodextrins can be widely used in molecular recognition, chiral separation and drug delivery studies. Starting from commercially available chemicals, CD-NH3Cl is synthesized in four steps: (i) selective tosylation of cyclodextrin by the use of p-toluenesulfonyl chloride to afford mono-6-(p-toluenesulfonyl)-6-deoxy-cyclodextrin (Ts-CD); (ii) azide substitution of Ts-CD with sodium azide to afford mono-6-azido-6-deoxy-cyclodextrin (CD-N3); (iii) reduction of CD-N3 with triphenylphospine followed by hydrolysis to prepare mono-6-amino-6-deoxy-cyclodextrin (CD-NH2); and (iv) treatment of CD-NH2 with hydrochloric acid to afford the titled CD-NH3Cl with good yield. The overall protocol requires ∼2 weeks.

Enantioseparation of a novel “click” chemistry derived native β-cyclodextrin chiral stationary phase for high-performance liquid chromatography

A novel native beta-cyclodextrin chiral stationary phase was prepared via click chemistry with cuprous iodide-triphenylphosphine complex as the catalyst and applied for enantioseparation of Dns-amino acids, substituted phenyl and phenoxy group modified propionic acids, flavonoids, and some pharmaceutical compounds such as nimodipine, propranolol, brompheniramine and bendroflumethiazide in reversed-phase high-performance liquid chromatography. The studied analytes could be resolved under different separation conditions. The resolution of Dns-DL-Leu could reach 5.08 using a mobile phase consisting of 1% (w/w) triethylammonium acetate buffer (pH 4.11) and methanol (50:50 v/v). The effects of buffer pH and the content of organic modifier on enantioseparation of Dns-amino acids by this novel chiral phase were being investigated. The separation results demonstrate that click chemistry, a versatile reaction, affords a facile approach towards the preparation of stable chiral stationary phases.

Synthesis of cationic single-isomer cyclodextrins for the chiral separation of amino acids and anionic pharmaceuticals

We describe a protocol for the synthesis of mono-6A-(1-butyl-3-imidazolium)-6A-deoxy-β-cyclodextrin chloride (BIMCD), a cationic, water-soluble cyclodextrin used in the chiral separation of amino acids and anionic pharmaceuticals by capillary electrophoresis. Starting from commercially available chemicals, BIMCD is synthesized in five steps. The first step involves a nucleophilic substitution between p-toluenesulfonyl chloride and imidazole to afford 1-(p-toluenesulfonyl)imidazole (A). In the second step, a nucleophilic substitution between β-cyclodextrin and A affords mono-6A-(p-toluenesulfonyl)-6A-deoxy-β-cyclodextrin (B). In the third step, a nucleophilic substitution between 1-bromobutane and imidazole affords 1-butylimidazole (C). In the fourth step, a nucleophilic addition between A and C affords BIMCD tosylate. In the final step, anion exchange using an ion-exchange resin yields BIMCD as a highly water-soluble solid. Each step takes up to 2 d, including the time required for product purification. The overall protocol requires approximately 6 d.

Synthesis of cationic β-cyclodextrin derivatives and their applications as chiral stationary phases for high-performance liquid chromatography and supercritical fluid chromatography

Four cationic beta-cyclodextrin derivatives, namely mono-6-(3-methylimidazolium)-6-deoxy-perphenylcarbamoyl-beta-cyclodextrin chloride (MPCCD), mono-6-(3-methylimidazolium)-6-deoxyper(3,5-dimethylphenylcarbamoyl)-beta-cyclodextrin chloride (MDPCCD), mono-6-(3-octylimidazolium)-6-deoxyperphenylcarbamoyl-beta-cyclodextrin chloride (OPCCD) and mono-6-(3-octylimidazolium)-6-deoxyper(3,5-dimethylphenylcarbamoyl)-beta-cyclodextrin chloride (ODPCCD), have been synthesized and physically coated onto porous spherical silica gel to obtain novel chiral stationary phases (CSPs). The performances of these CSPs are studied on high-performance liquid chromatography (HPLC) and supercritical fluid chromatography (SFC) using 18 racemic aryl alcohols as test analytes. Among these four CSPs, OPCCD shows the best separation results for all analytes on both HPLC and SFC analyses. Chromatographic studies reveal that the CSPs consisting of an n-octyl group on the imidazolium moiety and phenylcarbamoyl groups on the cyclodextrin ring provide enhancement of analyte-chiral substrate interactions over CSPs bearing the methyl group on the imidazolium moiety and 3,5-dimethylphenylcarbamoyl groups on the cyclodextrin ring.

Sub-2 μm porous silica materials for enhanced separation performance in liquid chromatography

Fully or partially sub-2 μm porous silica materials have garnered strong interests as column packing materials in separation and analytical technologies due to the promise of rapid separation, enhanced efficiency and separation resolution. Silica support materials of different morphology and sub-2 μm size have been developed to improve separation performances in liquid chromatography (LC) and capillary electrochromatography (CEC). The current review highlights the recent development of sub-2 μm fully/partially porous silica materials and the demonstrations of their enhanced performance in achiral and chiral chromatography.

Novel β-cyclodextrin chiral stationary phases with different length spacers for normal-phase high performance liquid chromatography enantioseparation.

Cyclodextrin and its derivatives are widely used as selectors of chiral stationary phases (CSPs) for high performance liquid chromatography (HPLC) due to their unique molecular structure and resolution capability. Three mono(6(A)-N-(ω-alkenylamino)-6(A)-deoxy)perphenylcarbamoylated β-cyclodextrin (PICD) based CSPs with different length spacers have been prepared, with their enantioseparation abilities evaluated with 10 model racemates including aromatic alcohols, flavanone compounds, amine and non-protolytic compounds under normal-phase conditions. The effect of spacer length and surface loading on the enantioseparation performance of CSPs is investigated herewith. The results indicate that higher surface loading 6C-PICD displays the best enantioselectivities towards selected racemates under normal-phase conditions.

Click immobilized perphenylcarbamated and permethylated cyclodextrin stationary phases for chiral high-performance liquid chromatography application

Two cyclodextrin-based chiral stationary phases have been prepared by immobilization of functionalized mono-6-azido-beta-CD derivatives to alkynyl modified silica via click chemistry and applied to the HPLC enantioseparation of various chiral compounds. The perphenylcarbamated CD CSP (CCP-CSP) exhibited excellent chiral recognition of a wide range of analytes including racemic aryl alcohols, flavonoids, bendroflumethiazide, atropine and some beta-blockers. Methanol proved to be a better organic modifier than acetonitrile for most of the analytes with the exception of bendroflumethiazide. The click chemistry immobilized permethylated CD CSP (CCM-CSP) afforded poor chiral recognition for most analytes, but could resolve non-aromatic ionone derivatives which were not separated on CCP-CSP. These results suggest that resolution with cyclodextrin derived CSPs depend on a complex interplay of host-guest inclusion, hydrogen bonding, pi-pi and hydrophobic interactions.

Sub-1-micron mesoporous silica particles functionalized with cyclodextrin derivative for rapid enantioseparations on ultra-high pressure liquid chromatography.

Mesoporous silica particles of relatively uniform sub-1-micron size (0.6-0.9 μm) were successfully prepared by a modified synthesis strategy and applied in chiral separation in an ultra-high pressure liquid chromatography system. These particles were prepared via a ternary surfactant system (Pluronic P123, F127 and hexadecyltrimethyl-ammonium bromide) and subsequently derivatized with perphenylcarbamoylated-β-cyclodextrin moieties. The mesoporous silica particles, despite their submicron size, enabled low back-pressure operation on an ultra-high pressure liquid chromatography system at a maximum flow rate of 2 ml/min. In addition, the particles possessed high surface area (480 m(2)/g) and thus afforded high cyclodextrin derivative loading (32 μmol/g), demonstrating rapid enantioseparation and good resolution of 6 basic and neutral racemates.

“Click” preparation of hindered cyclodextrin chiral stationary phases and their efficient resolution in high performance liquid chromatography

This communication reports the preparation of two new cyclodextrin (CD) chiral stationary phases (CSPs): heptakis(6-deoxy-6-azido)-β-CD and heptakis(6-deoxy-6-azido-phenylcarbamoylated)-β-CD CSPs that perform quite differently to our previously reported click immobilized CD-CSPs. These CSPs are sterically congested at the narrow mouth of the CD and exhibit chiral discrimination between over 40 pairs of enantiomers in high performance liquid chromatography. The free hydroxyl CSP afforded better separation of indoprofen, ketoprofen, Trögers base, hydroxyl, carboxylic and dansyl amino acids than did the phenylcarbamoylated CSP, while the latter was better at resolving aryl alcohols, flavonoids, β-blockers and β-agonists. The current work shows that enantiodiscrimination achieved with different CSPs for different classes of analyte may be correlated with CD accessibility and peripheral functionality.