Reversal of Elution Order between Enantiomers of Binaphthol on an Immobilized Polysaccharide-Based Chiral Stationary Phase

Enantioseparation of 1,1??-bi-2-naphthol (BINOL) was performed on an immobilized polysaccharide-based chiral stationary phase (CSP), Chiralpak IA, in the normal-phase mode. The effects of polar modifier in the mobile phase and column temperature on retention, enantioseparation, and elution order were investigated. An interesting reversal of elution order for BINOL was observed. When ethanol was used as a polar modifier, R-BINOL was eluted first with marginal enantioseparation. Excellent enantioseparation was obtained when ethanol was replaced by 1-propanol, and S-BINOL was eluted first, this effect being retained with 2-butanol, 1-butanol, 1-pentanol or 1-hexanol as the modifier. When isoamyl alcohol was used, reversal of elution order was again observed, i.e., R-BINOL eluted first with marginal enantioseparation, similar to the case of ethanol. When cyclohexanol and cyclopentanol were used, R-BINOL was still eluted first, but enantioseparation was as good as with 1-propanol as the modifier. This is the first report of large enantioseparation obtained in both elution orders for a given selector/selectant system. A retention model based on stoichiometric displacement theory for retention (SDT-R) was investigated to fit the chromatographic data. The reason for solvent-induced reversal of elution order was elucidated based on a derivation of the retention model. Reversal of elution order for BINOL induced by the content of isoamyl alcohol was also predicted based on the model and confirmed by experiment.     

Unusual chromatographic enantioseparation behavior of naproxen on an immobilized polysaccharide-based chiral stationary phase

Enantioseparation of naproxen was performed on an immobilized polysaccharide-based chiral stationary phase (CSP), Chiralpak IA, in the normal-phase mode. The effects of polar alcohol modifier in mobile phase and column temperature on retention, enantioseparation, and elution order were investigated. Two unusual phenomena were observed. One was solvent-induced reversal of elution order for the two enantiomers. Not only the type but also the content of polar alcohol modifier could induce the reversal. Another uncommon phenomenon was peak deformation under some chromatographic conditions.     

Temperature-induced inversion of elution order in the chromatographic enantioseparation of 1,1′-bi-2-naphthol on an immobilized polysaccharide-based chiral stationary phase

In this work, the enantioseparations of 1,1′-bi-2-naphthol (BINOL) and its three derivatives were performed on an immobilized polysaccharide-based chiral stationary phase, Chiralpak IA, under normal-phase mode. The effects of the content of polar modifier in the mobile phase and the column temperature on the retention and enantioseparation were investigated in detail. Temperature-induced inversion of elution order for BINOL was observed directly when n-hexane/2-propanol (92/8, v/v) was used as mobile phase. The isoenantioselective temperature (T_iso) was calculated to be 31.4 °C. When n-hexane/2-propanol/THF (93/2/5, v/v/v) was used as mobile phase, the T_iso value decreased to −8.2 °C. Entropically driven enantioseparation which had practical application was obtained successfully (separation factor being 1.189 and 1.332 at 25 °C and 50 °C, respectively). The corresponding thermodynamic parameters for other three binaphthyl compounds were compared with that for BINOL. Some inferences about chiral recognition mechanism were stressed.     

HPLC Enantioseparation of Novel Spirobrassinin Analogs on the Cyclofructan Chiral Stationary Phases

A novel series of nine chiral analogs of spirobrassinin, which have potential biological activity, was separated for the first time on three different derivatized cyclofructan chiral stationary phases in the normal phase mode. The effects of mobile phase composition, the type and concentration of polar modifier, additives, and the analyte structure on the retention and enantioseparation were studied. The results proved that for cyclofructan-based chiral stationary phases, the R-naphthylethyl carbamate cyclofructan 6 provides the best separation efficiency for the analyzed compounds. The effect of temperature on the separation was also investigated and the corresponding thermodynamic parameters were evaluated from linear Van’t Hoff plots (lnk or lnα versus 1/T). It was found that the enantioseparation was enthalpy controlled. In addition, the elution order of the enantiomers was determined in all the cases.     

High-performance liquid chromatographic enantioseparation of monoterpene-based 2-amino carboxylic acids on macrocyclic glycopeptide-based phases

The enantiomers of five monoterpene-based 2-amino carboxylic acids were directly separated on chiral stationary phases containing macrocyclic glycopeptide antibiotics such as teicoplanin (Astec Chirobiotic T and T2) and teicoplanin aglycone (Chirobiotic TAG) as chiral selectors. The effects of pH, the mobile phase composition, the structure of the analyte and temperature on the separations were investigated. Experiments were performed at constant mobile phase compositions in the temperature range 10–40 °C to study the effects of temperature and thermodynamic parameters on separations. Apparent thermodynamic parameters and T_iso values were calculated from plots of ln k or ln α versus 1/T. Some mechanistic aspects of the chiral recognition process are discussed with respect to the structures of the analytes. It was found that the enantioseparations were in most cases enthalpy driven. The sequence of elution of the enantiomers was determined in all cases.     

BINOL derived C2-symmetric bis-sulfinates as efficient sulfinyl transfer agents in the synthesis of tert-butyl sulfoxides

The reaction of novel C₂-symmetric bis-sulfinate esters derived from (R)-BINOL with Grignard reagents affords tert-butyl sulfoxides in ee up to 97%. The desired enantiomer can be generated at will by the proper selection of BINOL.     

Enantioseparation of vesamicol and novel vesamicol analogs by high-performance liquid chromatography on different chiral stationary phases

High-performance liquid chromatography enantioseparation of vesamicol and six novel azaspirovesamicols (amino alcohols) was accomplished on different chiral stationary phases (CSPs) by using an optical rotation based chiral detector for identification of the resolved enantiomers. The Pirkle-type column Reprosil Chiral-NR was found to be most suitable for chiral resolution in normal phase (NP) mode; all compounds could be enantioseparated successfully. Also the cellulose-based column Reprosil Chiral-OM showed appropriate separation properties by using NP conditions. The amylose-type column Reprosil Chiral-AM-RP was most suitable for enantioseparation in reversed phase (RP) mode; five out of seven compounds were resolved. This CSP showed a considerably higher capability for chiral recognition of vesamicol derivatives in RP mode than the corresponding cellulose-based column Reprosil Chiral-OM-RP. Enantioseparation with the teicoplanin aglycone-based column Reprosil Chiral-AA was successful under polar ionic mobile phase conditions.     

The Study of Separation and Thermodynamics of Adsorption of the Enantiomers of Ethofumasate on a Modified Cellulose

Abstract

Cellulose and cellulose derivatives are biopolymers that are often used as stationary phases for the separation of enantiomers. Describing the mechanism of such separations is a difficult task due to the complexity of these phases. In the present study, direct enantiomeric resolution of ethofumesate has been achieved, using hexane as the mobile phase with various alcoholic modifiers on cellulose tri(3,5‐dimethylphenylcarbamate) chiral stationary phase (CDMPC CSP). The influence of the mobile phase composition and the column temperature on the chiral separation was studied. It was found that at a constant temperature and within a certain range of alcohol modifier concentration, the conformation of the polymeric phase, and the selective adsorption sites were not affected by alcohol modifier concentration. The type and the concentration of the alcoholic modifiers influenced the retention factor and the separation factor. Ethofumesate gained the best enantioseparation using sec‐butanol as alcoholic modifier at 25°C with α‐value 1.70. And the separation factor decreased with the increase of the column temperature. The van't Hoff plots were linear (R ²>0.96) for ethofumesate from 25°C to 50°C. That showed the enantioselective interactions do not change over the temperature range studied. Furthermore the values of ΔH° and ΔS° were both negative, which indicated an enthalpy‐driven separation. And the possible chiral recognition mechanism of the analyte and CDMPC was discussed. It was found that hydrogen bonding plays an important role on enantioseparation of CDMPC CSP. The inclusion and fitness of solute shape in the chiral cavity significantly contributed to the enantioseparation of solute.     

苯磺酸氨氯地平对映体在Chiralcel OJ柱上的色谱保留及拆分特性

在Chiralcel OJ手性柱上对苯磺酸氨氯地平对映体进行分离研究.考察了在正己烷流动相体系中,不同碳数、不同立体结构的醇类添加剂以及不同醇含量对分离结果的影响,同时还考察了流速及柱温对分离的影响.并通过色谱保留及热力学行为研究对药物手性识别机理进行了探讨.结果表明,在正己烷-异丙醇(90:10,体积比)为流动相,流...     

Synthesis of new bis-BINOL-2,2′-ethers and bis-H8BINOL-2,2′-ethers evaluation of their Titanium complexes in the asymmetric ethylation of benzaldehyde

The preparation by means of different synthetic paths of a series of bis-BINOL and bis-H₈BINOL ligands is described. The ligands consist of two BINOL or H₈BINOL fragments, joined by diverse linkages through the oxygen at the 2′-position of the arylic fragments. These ligands were applied to the Ti(OⁱPr)₄ catalyzed asymmetric alkylation of benzaldehyde with Et₂Zn. The performance of these catalysts is very sensitive to the nature of the ether linkage. The ligand with a propylene link shows better enantioselectivity (ca. 70%) than those with two or four carbon atoms joining the BINOL fragments. Furthermore, using the propylene link, but replacing (R)-BINOL by (R)-H₈BINOL, a significant improvement in the stereoselectivity of the catalysts was achieved (ca. 80% ee in (R)-1-phenylpropan-1-ol). A cooperative effect was observed between the chirality at the BINOL fragment and that of a (S,S)-4,5-bis(methylene)-2,2-dimethyl-1,3-dioxolane link, derived from tartaric acid. When this chiral link combines with two (S)-BINOL fragments, the alkylation of benzaldehyde in toluene produces 70% ee of (S)-1-phenylpropan-1-ol, while the (R)-BINOL derivative ligand with the same link, in identical conditions, yields only 40% ee of the (R)-alcohol.     

LC Separation of γ-Amino Acid Enantiomers

Three underivatized γ-amino acids were successfully enantioseparated by high-performance liquid chromatography on macrocyclic glycopeptide based chiral stationary phases. The effects of the alcohol modifier in the mobile phase and the column temperature on the enantioseparation were investigated. Apparent thermodynamic parameters were calculated from the plots of ln k or ln α versus 1/T. Some mechanistic aspects of chiral recognition are discussed with respect to the structures of the analytes. It was found that the enantioseparations were enthalpy-driven, the double bond in the analyte exerting a significant influence on the chiral recognition.     

Direct high-performance liquid chromatographic enantioseparation of free α-, β- and γ-aminophosphonic acids employing cinchona-based chiral zwitterionic ion exchangers

We report a chiral high-performance liquid chromatographic enantioseparation method for free α-aminophosphonic, β-aminophosphonic, and γ-aminophosphonic acids, aminohydroxyphosphonic acids, and aromatic aminophosphinic acids with different substitution patterns. Enantioseparation of these synthons was achieved by means of high-performance liquid chromatography on CHIRALPAK ZWIX(+) and ZWIX(-) (cinchona-based chiral zwitterionic ion exchangers) under polar organic chromatographic elution conditions. Mobile phase characteristics such as acid-to-base ratio, type of counterion, and solvent composition were systematically varied in order to investigate their effect on the separation performance and to achieve optimal separation conditions for the set of analytes. Under the optimized conditions, 32 of 37 racemic aminophosphonic acids studied reached baseline separation when we employed a single generic mass-spectrometry-compatible mobile phase, with reversal of the elution order when we used (+) and (-) versions of the chiral stationary phase.

Chromatographic Enantioseparation of Ten Amino Acid Amide Derivatives on Three Polysaccharide-Based Chiral Stationary Phases

Enantioseparation of ten kinds of amino acid amide derivatives bearing aniline moieties on three polysaccharide-based chiral stationary phases (CSPs) was first systematically investigated. The chromatographic experiments were performed in the normal phase mode, namely, with n-hexane and 2-propanol as mobile phase. The effects of chiral columns, concentration of 2-propanol and column temperature on the enantioseparation were studied in detail. These compounds can be well resolved on Chiralcel OD-H column with the resolution above 1.5. Enantioseparation mechanism of chiral analytes and the CSPs are proposed based on the thermodynamic analysis of the experimental data. Our study establishes a simple, fast and efficient analytical method for amino acid amide derivatives by chiral HPLC, and provides a reference for enantioseparation of chiral amino acid amide derivatives and similar chiral compounds.     

Characterization of warfarin unusual peak profiles on oligoproline chiral high performance liquid chromatography columns

Unusual peak profiles of warfarin were characterized on two oligoproline chiral stationary phases (CSPs). The pattern of 1st peak (S(−)) broadening and the 2nd peak (R(+)) compression was observed under mobile phase of hexane (0.1% TFA)/2-propanol (IPA) on a triproline CSP 1, and with other alcohol modifier such as ethanol, 1-propanol, 1-butanol, 2-butanol, and tert-butanol as well. Through analyzing system peak of additives, the unusual peak profile was interpreted by perturbation of TFA additive system peak. The unusual peak profile was also found in enantioseparation of coumachlor and on a covalently bonded doubly tethered diproline CSP 2. The pattern of 1st peak (S(−)) broadening and the 2nd peak (R(+)) compression can change to pattern of 1st peak compression and the 2nd peak broadening from 15 to 50 °C. Chiral separation of warfarin created nonlinear van’t Hoff plots on CSP. No peak broadening/compression were observed with methyl tertiary butyl ether or ethyl acetate as the modifier. The peak shapes of the two warfarin enantiomers can thus be tuned by varying alcohol concentration and column temperature. High separation factor and resolution may be carried out to tune the peak profiles into Langmuir/anti-Langmuir band-shape composition. Using none hydrogen donor modifier may avoid interference of the TFA system peak.     

Enantioseparation of Amino Acid Derivatives with a Cellulose-Based Chiral Stationary Phase

Five structurally related amino acid derivatives were enantioseparated by HPLC with a commercially available chiral stationary phase, Chiralcel OD-H. The chromatographic experiments were performed in the normal phase mode. n-Hexane/polar alcohol was used as mobile phase. Excellent baseline enantioseparations could be obtained for all these solutes. The effects of the concentration of polar alcohol and the column temperature on the retentions and enantioseparations were studied in detail. From the van't Hoff plots the corresponding apparent thermodynamic parameters were derived. Mechanism aspects of chiral recognition were discussed based on the relationship between the thermodynamic parameters and the structures of the solutes. It was found that the substituent of the phenyl group on the residual group of the amino acid derivatives was close relevant to thermodynamic origin of enantioseparation. Much better enthalpy–entropy compensation effect was obtained by plotting the differential, rather than the original, thermodynamic parameters.     

Supported catalysts incorporating BINOL units: towards heterogeneous asymmetric catalysis

Optically pure BINOL species were immobilized on two different types of support: organic (cross linked polystyrene) and inorganic (silica). The synthesis of the reticulated polystyrene gels was achieved via the radical crosslinking polymerization of a protected divinyl-(R)-BINOL derivative. The deprotection resulted in polystyrene networks incorporating free (R)-BINOL entities. Silica hybrid materials containing (R)-binaphthyl units were synthesized by sol–gel processing of a trialkoxysilylated (R)-BINOL-bis-carbamate precursor. Both materials were tested as chiral auxiliaries in enantioselective catalysis. The polystyrene-BINOL gels show similar catalytic properties compared to molecular (R)-BINOL and appears as a classical heterogenized catalyst system. Contrarily, the silica hybrid materials incorporating BINOL entities show significantly increased catalytic properties compared to the molecular catalyst in homogeneous solution. A supramolecular effect of the silica matrix on the stability and the selectivity of the catalyst system can be concluded. To cite this article: P. Hesemann, J.J.E. Moreau, C. R. Chimie 6 (2003).     

HPLC enantioseparation of β2‐homoamino acids using crown ether‐based chiral stationary phase

RP high‐performance liquid chromatographic methods were developed for the enantioseparation of eleven unusual β²‐homoamino acids. The underivatized analytes were separated on a chiral stationary phase containing (+)‐(18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid as chiral selector. The effects of organic (alcoholic) and acidic modifiers, the mobile phase composition and temperature on the separation were investigated. The structures of the substituents in the α‐position of the analytes substantially influenced the retention and resolution. The elution sequence was determined in some cases: the S enantiomers eluted before the R enantiomers.     

Enantioseparation of selected chiral sulfoxides in high‐performance liquid chromatography with polysaccharide‐based chiral selectors in polar organic mobile phases with emphasis on enantiomer elution order

The separation of the enantiomers of 17 chiral sulfoxides was studied on polysaccharide‐based chiral columns in polar organic mobile phases. Enantiomer elution order (EEO) was the primary objective in this study. Two of the six chiral columns, especially those based on amylose tris(3,5‐dimethylphenylcarbamate) and cellulose tris(4‐chloro‐3‐methylphenylcarbamate) (Lux Cellulose‐4) proved to be most successful in the separation of the enantiomers of the studied sulfoxides. Interesting examples of EEO reversal were observed depending on the chiral selector or the composition of the mobile phase. For instance, the R‐(+) enantiomer of lansoprazole eluted before the S‐(?) enantiomer on Lux Cellulose‐1 in both methanol or ethanol as the mobile phase, while the elution order was opposite in the same eluents on amylose tris(3,5‐dimethylphenylcarbamate) with the S‐(?) enantiomer eluting before the R‐(+) enantiomer. The R‐(+) enantiomer of omeprazole eluted first on Lux Amylose‐2 in methanol but it was second when acetonitrile was used as the mobile phase with the same chiral selector. Several other examples of reversal in EEO were observed in this study. An interesting example of the separation of four stereoisomers of phenaminophos sulfoxide containing chiral sulfur and phosphor atoms is also reported here.     

Enantiomeric separation in high-performance liquid chromatography using novel β-cyclodextrin derivatives modified by R-configuration groups as chiral stationary phases

Two new chiral stationary phases (CSP) were successfully prepared through bonding β-cyclodextrin (CD) derivatives modified by R-configuration groups (R-CPGCD, R-HMPGCD) to silica gel. Nineteen chiral nitro aromatic alcohol derivatives were separated under the polar organic and the reversed phase modes. Better enantioseparation was obtained in the reversed phase mode. The resolution values of the analytes ranged from 1.98 to 7.57 and from 2.19 to 8.14 on R-CPGCD and R-HMPGCD CSPs, respectively, using a mobile phase composed of methanol/water (v/v, 40/60). Better enantioseparation was obtained on R-HMPGCD CSP than on R-CPGCD CSP because of stronger hydrogen bonding and π-π interactions between the substituents on the cyclodextrin derivatives and the analytes. For different analytes, the increasing electronic density of the benzene ring was found to be favorable to the enantioseparation of the test analytes. The thermodynamic parameters showed that the enantioseparation of analytes was enthalpy-controlled and a lower temperature aided the enantiomeric separation of the solutes on the two CSPs. MD simulations were used to investigate the recognition mechanism between the chiral selectors and the analyte using R-, S-2-naphthalenemethanol and R-CPGCD and R-HMPGCD complexes as examples. S-2-naphthalenemethanol had the stronger interactions with R-CPGCD and R-HMPGCD than the R-isomer. The substituent derivatized on R-CPGCD and the cyclodextrin cavity contributed to the discrimination of the S-isomer, but only the derivatized group on R-HMPGCD was found to play a major role in separating prosess. In addition, the larger free energy deviation of the R- and S-isomers in the R-HMPGCD system brought about a higher resolution value (R_s = 8.14).     

手性流动相添加剂法拆分西那卡塞原料及中间体

以自制1-萘万古霉素(Na-VAN)为手性固定相(CSP),D-酒石酸(D-Tar)、L-酒石酸二乙酯(L-TADE)、D-酒石酸二乙酯(D-TADE)分别为手性流动相添加剂(CMPA),建立了西那卡塞原料1-(1-萘基)乙胺(化合物1)及西那卡塞中间体(化合物2)的高效液相色谱手性拆分方法。考察了流动相中醇类改性剂、CMPA对对映体分离的影响,初步探讨了手性识别机理。以Na-VAN为CSP,正相模式下,添加不同种类的CMPA,化合物1、化合物2均可获得一定程度的分离,其中以D-TADE为CMPA时,化合物1、化合物2获得最佳分离。结果表明,醇的分子体积、CMPA的立体构型均对手性分离有影响。