Enantiomers Of Esters Research Articles

Enantioseparation of 2-phenylcarboxylic acid esters by capillary gas chromatography

Chiral 2-arylcarboxylic acid derivatives are important intermediates for preparing 2-arylcarboxylic acids, which are non-steroidal anti-inflammatory drugs (NSAIDs). In order to separate 2-phenylcarboxylic acid ester enantiomers by capillary gas chromatography (CGC), 2, 6-di-O-pentyl-3-O-butyryl-β-cyclodextrin and 2,6-di-O-benzyl-3-O-heptanoyl-β-cyclodextrin were used as CGC chiral stationary phases, separately, and their enantioseparation abilities to enantiomers of methyl 2-phenylbutanoate, ethyl 2-phenylbutanoate, isopropyl 2-phenylbutanoate, methyl 2-phenylpropionate and cyclopentyl 2-phenylpropionate were examined. It was found that methyl 2-phenylbutanoate, methyl 2-phenylpropionate and cyclopentyl 2-phenylpropionate were successfully separated by using 2,6-di-O-pentyl-3-O-butyryl-β-cyclodextrin and 2,6-di-O-benzyl-3-O-heptanoyl-β-cyclodextrin as CGC chiral stationary phases, respectively. The enantiomer separation abilities of 2, 6-di-O-pentyl-3-O-butyryl-β-cyclodextrin to the three pairs of 2-phenylcarboxylic acid esters tested are superior to those of 2, 6-di-O-benzyl-3-O-heptanoyl-β-cyclodextrin.

Acylation of Chiral Alcohols: A Simple Procedure for Chiral GC Analysis

The use of iodine as a catalyst and either acetic or trifluoroacetic acid as a derivatizing reagent for determining the enantiomeric composition of acyclic and cyclic aliphatic chiral alcohols was investigated. Optimal conditions were selected according to the molar ratio of alcohol to acid, the reaction time, and the reaction temperature. Afterwards, chiral stability of chiral carbons was studied. Although no isomerization was observed when acetic acid was used, partial isomerization was detected with the trifluoroacetic acid. A series of chiral alcohols of a widely varying structural type were then derivatized with acetic acid using the optimal conditions. The resolution of the enantiomeric esters and the free chiral alcohols was measured using a capillary gas chromatograph equipped with a CP Chirasil-DEX CB column. The best resolutions were obtained with 2-pentyl acetates (α = 3.00) and 2-hexyl acetates (α = 1.95). This method provides a very simple and efficient experimental workup procedure for analyzing chiral alcohols by chiral-phase GC.

Chromatographic Separation of Enantiomers of Chiral Amines or Amino Alcohols as 9-Anthraldimine Derivatives Using Polysaccharide-Derived Chiral Columns

E-mail: kangjss@cnu.ac.krReceived April 21, 2011, Accepted June 9, 2011Key Words : Enantiomer separation, Chiral stationary phase, 9-Anthraldimine derivativeIn a previous study, a convenient chromatographic separa-tion for the enantiomers of amino acid methyl esters as 9-anthraldimine Schiff base derivatives on polysaccharide-derived chiral stationary phases (CSPs) was reported.

Total synthesis of crispine A enantiomers through a Burkholderia cepacia lipase-catalysed kinetic resolution

Both enantiomers of the antitumour-active alkaloid crispine A (ee = 95%) were synthesised through the Burkholderia cepacia lipase-catalysed acylation of the primary hydroxy group of N-Boc-protected 1-(3-hydroxypropyl)-6,7-bis(methyloxy)-1,2,3,4-tetrahydroisoquinoline (±)- 3 and the enantioselective hydrolysis of the corresponding O-decanoate (±)- 4 [R = (CH 2) 8Me] with a remote, four-atom distant stereogenic centre. High enantioselectivities were observed for the ( S)-selective O-acylation with vinyl decanoate in the presence of Et 3N and Na 2SO 4 in t-BuOMe at 45 °C ( E = 68), and for the ( S)-selective hydrolysis with H 2O in t-BuOMe at 45 °C ( E = 52). The enzymatic resolutions, performed in two steps, afforded the key alcohol and ester enantiomers with high enantiomeric excesses (ee ⩾ 94%). Ring-closure reactions of alcohol enantiomers (+)- 3 and (−)- 3 with thionyl chloride afforded the desired crispine A enantiomers (+)- 1 and (−)- 1 (ee ⩾ 95%).

Enantiomer separation of α-amino acid methyl esters and some aliphatic amines as 9-anthraldimine derivatives by high performance liquid chromatography

The liquid chromatographic enantiomer separation of several alpha-amino acid methyl esters as 9-anthraldehyde Schiff base derivatives on five polysaccharide-derived chiral stationary phases (CSPs) was described. The 9-anthraldehyde imine derivatives of a-amino acid esters were prepared by stirring 9-anthraldehyde with the alpha-amino acid ester hydrochloride salts. The chromatographic conditions were 3%-10% (v/v) 2-propanol-n-hexane as the mobile phases at the flow rate of 1.0 mL/min and detected at UV 254 nm. The performance of Chiralcel OD (or Chiralcel OD-H) among the five CSPs was superior to those of the other CSPs for the resolution of 9-anthraldimine derivatives of alpha-amino acid methyl esters. The enantiomers of all a-amino acid methyl esters as the 9-anthraldimine derivatives were base-line resolved on Chiralcel OD or Chiralcel OD-H (alpha = 1.24-5.47, Rs = 2.56-13.90). The L-enantiomers of all analytes were strongerly restrained than the respective D-enantiomers on the Chiralcel OD (or Chiralcel OD-H) CSPs. The method was also used for the enantiomer separation of aliphatic amines and good separation was obtained. It is expected that the analytical method will be useful for the enantiomer resolution of other alpha-amino acid esters and amine compounds as 9-anthraldimine derivatives.

ChemInform Abstract: Catalytic Enantioselective Protonation of α‐Oxygenated Ester Enolates Prepared Through Phospha‐Brook Rearrangement.

AbstractOptimized conditions are elaborated for the direct synthesis of both enantiomers of phosphoric esters using commercially available cinchona alkaloids.

Enantioselectivity of Candida rugosa lipases (Lip1, Lip3, and Lip4) towards 2‐bromo phenylacetic acid octyl esters controlled by a single amino acid

Enantiomer discrimination by enzymes is a very accurate mechanism, which often involves few amino acids located at the active site. Lipase isoforms from Candida rugosa are very good enzymatic models to study this phenomenon as they display high sequence homology (>80%) and their enantioselectivity is often pointed out. In the present work, we investigated three lipases from C. rugosa (Lip1, Lip3, and Lip4, respectively) towards the resolution of 2-bromo-arylacetic acid esters, an important class of chemical intermediates in the pharmaceutical industry. All exhibited a high enantioselectivity, with Lip4 preferring the R-enantiomer (E-value = 15), while Lip1 and Lip3 showed an S-enantioselectivity >200. A combination of sequence and structure analysis of the three C. rugosa lipases suggested that position 296 could play a role in S- or R-enantiomer preference of C. rugosa lipases. This led to the construction by site-directed mutagenesis of Lip1 and Lip4 variants in which position 296 was, respectively, exchanged by a Gly, Ala, Leu, or Phe amino acid. Screening of these variants for their enantioselectivity toward 2-bromo phenyl acetic acid octyl esters revealed that steric hindrance of the amino acid residue introduced at position 296 controls both the enantiopreference and the enantioselectivity value of the lipase: bulkier is the amino acid at position 296, larger is the selectivity towards the S-enantiomer. To investigate further these observations at an atomic level, we carried out a preliminary modeling study of the tetrahedral intermediates formed by Lip1 and Lip4 with the (R, S)-2-bromo-phenylacetic acid octyl ester enantiomers that provides some insight regarding the determinants responsible for lipase enantiodiscrimination.

Synthesis of heptakis(2,3,6-tri-<I>O</I>-methoxymethyl)-β-cyclodextrin and its application in gas chromatography

A new chiral stationary phase for gas chromatography, heptakis (2, 3, 6-tri-O-methoxymethyl)-beta-cyclodextrin, was synthesized by substituting the 2,3,6-OH groups of beta-cyclodextrin with methoxymethyl groups, and a coated capillary column for gas chromatography was made by coating this new stationary phase with static method. The chromatographic properties and separation abilities of the prepared stationary phase were studied. The test results showed that it possessed good separation abilities to Grob test mixture, disubstituted benzene isomers (e. g. nitrotoluenes, bromotoluenes, dichlorobenzenes, dimethylbenzenes) and some chiral compounds such as methyl 2-hydroxypropionates, ethyl 2-hydroxypropionates, methyl 2-methylsulfonylpropionates. The comparison of chiral separation results between 2,3,6-tri-O-methoxymethyl-beta-cyclodextrin and 2,3,6-tri-O-methyl-beta-cyclodextrin showed that the separation abilities of the two stationary phases were different and complementary to each other for some chiral ester enantiomers.

Regio- and diastereoselective fluorination of alicyclic β-amino acids

A regio- and stereoselective approach to fluorinated β-aminocyclohexene or cyclohexane esters has been developed, starting from a bicyclic β-lactam (1). The procedure involves six or seven steps, based on regio- and stereoselective iodolactonization, lactone opening and hydroxy-fluorine exchange. The method has been extended to the synthesis of fluorinated amino ester enantiomers.

The influence of water on the memory effect of the amylose tris(3,5-dimethylphenyl carbamate) stationary phase

Acid/base modifiers are sometimes used as additives in normal phase elution on columns packed with CHIRALPAK ® AD ®. These modifiers affect enantioseparations in ways that are not yet fully understood for the lack of systematic studies. Shifts of the selectivity of certain pairs of enantiomers upon exposure of the column to these modifiers is amply documented. Furthermore, once the modifier has been removed from the mobile phase, the modified selectivity remains, which has been named the Memory Effect. After a column has been exposed to an eluent stream containing acidic/basic modifiers, this particular column no longer separates certain enantiomeric pairs with the same selectivity as a modifier naive column. This makes the transfer of developed methods from one to other CHIRALPAK AD columns difficult to predict, if the selectivity needs to be similar between the two columns. We selected four enantiomeric pairs for a systematic study of this Memory Effect. The selectivity of 4-chlorophenylalanine ethyl ester improves after a solution of ethanesulfonic acid (ESA) is percolated through the column. The selectivity of Propranolol and Tröger's base increases after a solution of Diiospropylamine is percolated through the column. The selectivity of Propranolol and Tröger's base enantiomers is inversely affected by percolation of the acid solution. The 4-chlorophenylalanine ethyl ester enantiomers is inversely affected by percolation of the base solution. In contrast, the selectivity of trans-stilbene oxide (TSO) is not affected by either modifier. Analytical studies of the stationary phase suggest that slow protonation/deprotonation of water molecules attached to the carbamate moiety may be responsible for the acid/base Memory Effect. To further the understanding of the effect of water on the Memory Effect, mobile phases – spiked with water (0.01–0.43%) – were used to measure changes in the Memory Effect. Finally, we showed that the influence of water on the Memory Effect can be minimized by percolating through the column a sufficiently concentrated solution of the appropriate base while using dried mobile phases.

ChemInform Abstract: Kinetics and Molecular Modelling Studies on the Stereoselective Hydrolysis of Enantiomeric Esters by Dipeptide Catalysts.

The rate constants of the catalytic hydrolysis of short and long chain N-acylphenylalanine p-nitrophenyl esters by a series of optically active dipeptide catalysts in the presence of surfactant aggregates are presented in order to evaluate their catalytic efficiency and stereoselectivity. Circular dichroism spectra of dipeptide catalysts have also been measured in order to estimate the most probable and stable conformation in micellar solution. On the basis of the kinetic stereoselectivities and CD spectra, molecular modelling studies have been performed in order to determine the preferred conformations and energies of dipeptide catalysts and chiral substrates in the presence of surfactants. An analysis of minimum–energy conformations obtained from the calculation reproduces the sense of the kinetic stereoselectivities.

Preparation of Passion Fruit-Typical 2-Alkyl Ester Enantiomers via Lipase-Catalyzed Kinetic Resolution

The preparation of ester enantiomers (acetates, butanoates, hexanoates and octanoates) of the secondary alcohols 2-pentanol, 2-heptanol and 2-nonanol via lipase-catalyzed kinetic resolutions was investigated. Conversion rates and stereochemical courses of esterification and hydrolysis reactions catalyzed by commercially available enzyme preparations were followed for the homologous series of these passion fruit-typical 2-alkyl esters by capillary gas chromatography using heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-beta-cyclodextrin as chiral stationary phase. An efficient method was developed to prepare the ester enantiomers via lipase-catalyzed esterifications: optically pure (R)-2-alkyl esters (ee > 99.9%) were obtained by esterification of the racemic alcohols with enantioselective Candida antarctica lipase B (immobilized) as catalyst. The subsequent esterification of the unreacted alcohols using lipase from Candida cylindracea yielded the optically enriched (S)-esters (ee > 81.4%). The separation of the products via liquid solid chromatography using a mixture of silica gel and aluminum oxide (basic) resulted in high chemical purities and yields (> 40 mol %).

The effect of humic acid and ash on enantiomeric fraction change of chiral pollutants

The aim of the study was to determine changes of enantiomeric fraction (EF) of chiral compounds interacting with components of soil and to describe the effect of amount of soil components on EF value. Soil components (humic acid and ash) were isolated from soil using method recommended by the International Humic Substance Society (IHSS). Dichloromethane was used as an extraction solvent for extraction of polychlorinated biphenyls (PCBs), mecoprop and its methyl ester enantiomers from humic acid (HA) and ash. The extracts were analyzed by a high performance liquid chromatography (HPLC). HPLC columns filled with silica gel modified by permethylated cyclodextrine acting as a chiral selector were used for analytical separation of enantiomers. The results confirm the stereoselective effect of soil components on extractable amount of individual enantiomers. Significant changes of EF of chiral pollutants were observed for investigated PCBs enantiomers (HA 0.49–0.45, ash 0.50–0.58) and for mecoprop-methyl ester (HA 0.55–0.59, ash 0.49–0.34), smaller changes of EF were observed for mecoprop (HA 0.52–0.50, ash 0.49–0.50). The changes of EF were dependent on an amount of humic acid and ash. Inverse trends of humic acid EF changes were obtained comparing to trends of EF changes of ash.

Chromatographic Properties of 2,3-Di-O-allyl-6-O-acyl-β-cyclodextrins as Chiral Stationary Phases of Capillary GC

Three 2,3-di-O-allyl-6-O-acyl-β-cyclodextrins, 2,3-di-O-allyl-6-O-valeryl-β-cyclodextrin, 2,3-di-O-allyl-6-O-heptanoyl-β-cyclodextrin, and 2,3-di-O-allyl-6-O-octanoyl-β-cyclodextrin, were synthesized and their chromatographic properties were investigated. 2,3-di-O-allyl-6-O-acyl-β-cyclodextrins cannot only separate the enantiomers of methyl 2-chloropropionate, methyl 2-bromopropionate, methyl 2-hydroxypropionate, allethrone acetate, propargyllone acetate, and 1-(2,4-dichlorophenyl)ethanol, but also possess enantiomer separation abilities to some enantiomers of pyrethroic acid methyl esters and epoxides. The enantiomer separation results on the three 2,3-di-O-allyl-6-O-acyl-β-CDs were used to draw some empirical rules about enantiomer separation together with the enantiomer separation results on other CDs. Acyl groups on CDs, especially 3-position acyl groups on CDs, are favorable for the enantiomer separation of pyrethroic acid methyl esters, while acyl groups on 6-position of CDs are beneficial for the enantiomer separation of epoxides, but allyl on CDs are less favorable for enantiomer separation than pentyl. The empirical rules summarized here have some practice significances in selecting CGC chiral stationary phase for solving enantiomer separation problems. Also, the three 2,3-di-O-allyl-6-O-acyl-β-CDs may be used in practical chiral analysis.

Following the lipase catalyzed enantioselective hydrolysis of amino acid esters with capillary electrophoresis using contactless conductivity detection

AbstractThe progress of the enzymatic hydrolysis of racemic mixtures of the enantiomers of the methyl esters of serine and threonine was monitored. This was possible in a reaction vessel of 1.5 mL by direct sampling of volumes in the nanoliter‐range directly into an electrophoresis capillary. Contactless conductivity detection was used for quantification as the analytes are not accessible by UV‐detection in capillary electrophoresis. Porcine pancreatic lipase and wheat germ lipase both showed a preference for the L‐enantiomers of both amino acid esters. The selectivity of the porcine lipase between the two L‐esters of the two amino acids was also studied and it was found that the production of L‐threonine had priority over L‐serine. Chirality, 2010. © 2009 Wiley‐Liss, Inc.

Ring closure reactions of bicyclic prolinol and prolin ester enantiomers

Starting from the of bicyclic proline ester, ethyl exo-2-azabicyclo[2.2.1]heptane-3-carboxylate (+)-5 several hydantoines and thiohydantoines were prepared by acidic ring closure of the corresponding urea or thiourea derivatives. Enantiomer (-)-5 was reduced to 2-azanorbornylmethanol 12, which was transformed to 5,8-methanooxazolo- and thiazolo[3,4-a] pyridine derivatives. The structures, stereochemistry and relative configurations of the synthesized compounds were proved by NMR.

Determination, purity assessment and chiral separation of levodopa methyl ester in bulk and formulation pharmaceuticals

A sensitive, reliable and reproducible HPLC method with electrochemical detection (HPLC-ECD) has been developed for the separation and quantification of levodopa methyl ester (LDME) and its impurities such as levodopa (l-DOPA), 3-methoxytyrosine (MTS) and l-tyrosine (TS) in bulk drug and pharmaceutical dosage form. The separation was performed on an LC18 column by isocratic elution with methanol-acetonitrile-50 mm potassium dihydrogen phosphate (8:2:90, v/v/v) containing 5 mm sodium 1-hexanesulfonate, 5 mm EDTA and 5 mm sodium chloride, adjusted with phosphoric acid to a pH of 3.2 as mobile phase. The correlation coefficients of linear regression for LDME, L-DOPA, MTS and TS were more than 0.999. The detection limits for L-DOPA, MTS and TS were 3.15, 2.04 and 2.88 ng/mL, respectively. The precision was checked in terms of F-test variance ratio using potentiometric titration as reference. The separation of dopa methyl ester enantiomers by chiral chromatography is also described. This method is capable of separating the two enantiomers with a selection of 1.4 and a resolution of 8.4. Both methods were found to be stable and useful in the quality control of the bulk material and formulations.

Liquid chromatographic enantiomer resolution of N‐fluorenylmethoxycarbonyl α‐amino acids and their ester derivatives on polysaccharide‐derived chiral stationary phases

The liquid chromatographic enantiomer separation of N-fluorenylmethoxycarbonyl (FMOC) protected alpha-amino acids and their ethyl ester derivatives was performed on polysaccharide-derived chiral stationary phases, Chiralcel OD, Chiralpak AD, and Chiralpak AS. In general, Chiralcel OD and Chiralpak AD showed good performance for resolution of N-FMOC alpha-amino acids and their ethyl esters, respectively. All investigated N-FMOC alpha-amino acid enantiomers were baseline separated on Chiralcel OD or Chiralpak AD, whereas N-FMOC alpha-amino acid ethyl ester enantiomers were baseline resolved (alpha = 1.15-3.03) on Chiralpak AD, except for two analytes. The L-enantiomers of all examined FMOC alpha-amino acid ethyl ester derivatives are preferentially retained on Chiralpak AD, while the elution orders of the other enantiomer separations are not consistent.

Comparative Liquid Chromatographic Enantiomer Resolution on Two Chiral Stationary Phases Derived from Amylose Tris(3,5-dimethylphenylcarbamate)

Polysaccharide-derived chiral stationary phases (CSPs) are known to show high chiral recognition ability in HPLC and have been extensively used to separate a broad range of racemic compounds. These type CSPs are usually prepared coating or adsorbing the polysaccharide derivatives on silica gel. Therefore, the solvents such as chloroform, methylene chloride, and tetrahydrofuran which dissolve or swell the chiral selectors of the polysaccharide derivatives cannot be used as mobile phases. For example, in case of Chiralpak AD prepared by coating amylose tris(3,5dimethylphenylcarbamate) derivative, one of the widely used polysaccharide type CSPs, suitable mobile phases like hexane, 2-propanol and ethanol should be used for the column safety. It may be damaged in case of even the use of only a little amount of inappropriate solvents used as mobile phases and/or sample solvents. These limitations represent a disadvantage for new applications using these CSPs and, especially, preparative separation due to solubilization of analytes. To overcome these problems, therefore, the development of polysaccharide-derived covalently bonded CSPs has been of great interest and various results of different attempts have been reported. Recently, Chiralpak IA prepared by chemically bonding amylose tris(3,5-dimethylphenylcarbamate) derivative on silica gel, which is used as the same chiral selector of coated type Chiralpak AD has been introduced. In this study, we present the comparative liquid chromatographic enantiomer resolution of N-fluorenylmethoxycarbonyl (FMOC) protected αamino acids ethyl ester derivatives on two polysaccharidederived CSPs, covalently bonded type Chiralpak IA and coated type Chiralpak AD. This is the first report concerning the comparison of the chiral separations on Chiralpak IA and Chiralpak AD using normal mobile phases. For enantiomer separation of N-FMOC α-amino acids ester derivatives, very a few results on CSPs have been reported. Rizzi has separated three FMOC α-amino acids methyl esters enantiomers on cellulose triacetate type column. Miyazawa et al. have reported on the resolution of only one analyte of FMOC 2-aminobutanoic acid methyl ester enantiomers among many different N-protected amino acid derivatives. Kusters et al. have reported on the resolution of fifteen N-FMOC α-amino acids methyl and isopropyl esters enantiomers on a polysaccharide-derived CSP. To our knowledge, our results are the first reported for the enantiomer resolution of N-FMOC α-amino acids ethyl ester derivatives. Table 1 shows the effect of mobile phase on the enantiomer separation of some N-FMOC α-amino acids ethyl esters on Chiralpak IA. The enantioselectivities and retention times are greatly influenced by the nature of mobile phase. As shown in Table 1, in general, 5% 2propanol in hexane as a mobile phase afforded the greatest enantioselectivity with the highest resolution factor, whereas 20% chloroform in hexane afforded the lowest enantioselectivity. It is notable that the elution orders of three analytes using 10% tetrahydrofuran or 10% ethyl acetate or 20% chloroform in hexane are different from those using 5% 2-propanol in hexane. Table 2 shows the comparative data of enantiomer separation of N-FMOC α-amino acids ethyl esters on Chiralpak IA and Chiralpak AD using 2-propanol in hexane as a mobile phase. In general, Chiralpak IA showed slightly lower enantioseparation than Chiralpak AD for enantioresolution of N-FMOC α-amino acids ethyl esters. Several results have reported that a certain decrease in the enantio-

Asymmetric synthesis of both enantiomers of esters and γ-lactones from optically active 1-chlorovinyl p-tolyl sulfoxides and lithium ester enolates with the formation of a tertiary or a quaternary carbon stereogenic center at the β-position

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides having two different substituents at the 2-position, which were synthesized from aldehydes or unsymmetrical ketones and ( R)-(−)-chloromethyl p-tolyl sulfoxide in two or three steps, with the lithium enolate of tert-butyl acetate gave optically active adducts in 99% chiral induction from the sulfur stereogenic center. The adducts were converted to optically active esters, carboxylic acids, and γ-lactones, which have a tertiary or a quaternary carbon stereogenic center at the β-position. A synthesis of optically active spiro-lactones was realized starting from 2-cyclohexenone by this method.