Separation Of Diastereoisomers Research Articles

Novel Potential Anticancer Naphthyl Phosphoramidates of BVdU: Separation of Diastereoisomers and Assignment of the Absolute Configuration of the Phosphorus Center

We have previously reported our SAR optimization of the anticancer agent thymectacin. Tuning of the parent ProTide structure initially involved the amino acid and, subsequently, the aromatic masking group on the phosphate moiety. Herein, derivatives bearing the combined modifications are reported and biological evaluation is described. Moreover, separation of the diastereoisomeric final product mixture shows a different cytostatic activity for the two diastereoisomers. Through computational and NMR studies, the absolute stereochemistry of the phosphorus center of the two diastereoisomers has been suggested.

Synthesis of Isoaminile Mediated by Enzymes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Multicomponent synthesis of epoxy-tetrahydronaphthyridine and structural diversification by subsequent fragmentation

Three-component reaction of an α-isocyanoacetamide 7 , an homoallylamine 8 and an aldehyde 9 in methanol at room temperature provides oxa-bridged tricycle 4 in good to excellent yield as a mixture of two separable diastereoisomers. In this one-pot multicomponent process, one C–N, one C–O and three C–C bonds are formed with concomitant creation of five asymmetric centers and three rings. Fragmentation of epoxy-tetrahydronaphthyridine 4 affords differentially substituted 5,6,7,8-tetrahydro-1,7-naphthyridine ( 5 , 6 ) depending on the reaction conditions, providing thus additional structural diversity. A one-pot three-component synthesis of 5,6,7,8-tetrahydro-1,7-naphthyridine ( 6 ) from 7 , 8 and 9 is also documented.

Separation of 3′-azido-2′,3′-dideoxythymidine pronucleotide diastereoisomers in biological samples by CZE with cyclodextrin addition

The possibility of using capillary electrophoresis as an alternative technique to HPLC for the separation of pronucleotide diastereoisomers of AZT was investigated. In the pH range 6.2–7.2 where the analytes are stable, a chiral additive, carboxymethyl-β-CD, was found appropriate to enable the separation of the uncharged diastereoisomers. An experimental design strategy was used to study the influence of several parameters (CD and phosphate buffer concentration, methanol content of the electrolyte, injected volume, capillary length, electric field and separation temperature) on the separation and find suitable analytical conditions for monitoring the prodrugs in cell extracts. The diastereoisomers of the three tBuSATE phenylphosphotriester derivatives of AZT studied could be fully resolved within short analysis time (less than 10 min). Method validation results showed satisfactory results for linearity, accuracy and repeatability.

Synthesis and spectroscopic characterization of enantiopure protected trans-4-amino-1-oxyl-2,2,6,6-tetramethyl piperidine-3-carboxylic acid ( trans β-TOAC)

Enantiomerically pure (3 R,4 S) and (3 S,4 R) protected 4-amino-1-oxyl-2,2,6,6-tetramethylpiperidine-3-carboxylic acids were synthesized by reduction of the enamines resulting from the condensation of 3-carboxymethyl-1-oxyl-2,2,6,6-tetramethyl-4-piperidone with ( R) or ( S)-α-methylbenzylamine. While NaBH 3CN/CH 3COOH reduction gave predominantly a mixture of the two possible cis-diastereomers, the use of NaBH 4/(CH 3) 2CHCOOH resulted in a mixture of only one trans- and one cis-diastereomer. Removal of the chiral auxiliary from the separated diastereoisomers by hydrogenolysis and regeneration of the nitroxide radical gave the desired β-amino esters. The ESR spectrum of the (3 R,4 S)-enantiomer is also reported.

Development of a capillary electrophoretic method for the separation of diastereoisomers of a new human immunodeficiency virus protease inhibitor

A capillary electrophoretic (CE) method was developed for the separation of diastereoisomers of a new human immunodeficiency virus (HIV) protease inhibitor TMC114. In total 16 isomers of this drug have been synthesized (eight pairs of enantiomers). We succeeded in the separation of the eight diastereoisomers, but no enantiomers could be separated. Because of the high similarity and water-insolubility of these isomers, the separation is a real challenge. Different CE modes were tried out: capillary zone electrophoresis (CZE), nonaqueous capillary electrophoresis (NACE), micellar electrokinetic capillary chromatography (MEKC), and microemulsion electrokinetic capillary chromatography (MEEKC). Only MEEKC offered resolution of these compounds.

Chiral separations of mandelic acid by HPLC using molecularly imprinted polymers

Styrene is used in a variety of chemical industries. Environmental and occupational exposures to styrene occur predominantly through inhalation. The major metabolite of styrene is present in two enantiomeric forms, chiral R- and S- hydroxy-1-phenyl-acetic acid (R-and S-mandelic acid, MA). Thus, the concentration of MA, particularly of its enantiomers, has been used in urine tests to determine whether workers have been exposed to styrene. This study describes a method of analyzing mandelic acid using molecular imprinting techniques and HPLC detection to perform the separation of diastereoisomers of mandelic acid. The molecularly imprinted polymer (MIP) was prepared by non-covalent molecular imprinting using (+) MA, (-) MA or (+) phenylalanine, (-) phenylalanine as templates. Methacrylic acid (MAA) and ethylene glycol dimethacrylate (EGDMA) were copolymerized in the presence of the template molecules. The bulk polymerization was carried out at 4ºC under UV radiation. The resulting MIP was grounded into 25~44¼m particles, which were slurry packed into analytical columns. After the template molecules were removed, the MIP-packed columns were found to be effective for the chromatographic resolution of (±)-mandelic acid. This method is simpler and more convenient than other chromatographic methods.

A Stereodivergent Asymmetric Approach to Difluorinated Aldonic Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Selectivity and the Separation of Isomers of Low Molecular Weight Polystyrenes

The separation of diastereoisomers of polystyrene has been investigated on carbon‐clad zirconia (CCZ), C18, and diamond C18 stationary phases using eluents of widely different properties. Eluents were chosen according to their selectivity, solvent polarity index, and polymer solubility constants. Acetonitrile mobile phases in combination with CCZ produced the best diastereoisomer separations, however, when methanol was employed as the mobile phase, the separation profiles were very similar, except that retention was greatly increased. Retention and isomer separation decreased when isopropanol was employed. Surprisingly, some diastereoisomer separation was still apparent using the CCZ column and a 99% hexane/1% isopropanol mobile phase, although none was observed for the same solvent mixture on a C18 column. Indeed, significant diastereoisomer separation was only obtained on the C18 column‐using acetonitrile as the mobile phase, but the resolution was far inferior to that observed on the CCZ column. The diamond C18 surface, which is a hybrid of C18 and CCZ, gave separations that were intermediate between those of the parent surfaces, with enhanced molecular weight selectivity in comparison with CCZ, but slightly less discrimination on the basis of stereochemistry. Polystyrenes eluted unretained if either dichloromethane or tetrahydrofuran were used as the mobile phases on all stationary phases.

A stereodivergent asymmetric approach to difluorinated aldonic acids.

A (bromodifluoromethyl)alkyne has been deployed in a stereoselective route to difluorinated aldonic acid analogues, in which a Sharpless asymmetric dihydroxylation reaction and diastereoisomer separation set the stage for phenyl group oxidation.

Properties of poly-aminophenylboronate coatings in capillary electrophoresis for the selective separation of diastereoisomers and glycoproteins

The polymerisation of 3-aminophenylboronic acid (APBA) in aqueous environment has been used for the open tubular modification of capillary electrophoresis (CE) capillaries. Being poly-APBA endowed with boronic acid, aromatic rings and secondary amines groups, it posses a variety of functional groups affecting selectivity. Diastereoisomers (e.g. ascorbic and isoascorbic acid) and proteins (e.g. haemoglobins) were successfully separated onto poly-APBA column, by means of a combination of electrophoresis and open tubular electrochromatography. The mechanism of selection was investigated: results indicate an interplay between enhancing or silencing the contribution of the protonable functionalities (amino groups, boronic acid). The properties of APBA polymer coating make it attractive for CE separation and for further application in affinity separations and chip technologies.

Investigation of chromatographic conditions for the separation of cefuroxime axetil and its geometric isomer

The optimal chromatographic conditions for the separation of the syn- and anti-geometric isomers of cefuroxime axetil applying RP-HPLC and micellar liquid chromatography (MLC) methods were investigated. The possibility to separate diastereoisomers of syn- and anti-cefuroxime axetil was observed. Investigations were performed using three columns, two classical silicas and one with hybrid particle technology. Three aqueous-organic and one micellar mobile phases were used. The best results were achieved using micellar mobile phase. Optimization study was performed using different micellar mobile phases. MLC method is sensitive and applicable in purity and stability testing.

Stationary phase with specific surface properties for the separation of estradiol diastereoisomers

The aim of this study was to develop a procedure that enabled the separation of estradiol diastereoisomers. For this purpose a series of stationary phases with different surface properties has been utilized. Two of them contain various interaction sites, such as: cholesterol, n-acylamide, amine and silanols localised in the organic layer bonded to the surface of silica gel (SG-CHOL and SG-CHOL/AP). The other one contains mainly alkylamide ligands and also residual aminopropyl and silanol groups (SG-AP), as well as the last one consisting of hydrocarbonaceous material (SG-C 18). In order to select the best type of stationary phase for this analysis, after chromatographic separation of 17-α-estradiol and 17-β-estradiol, selectivity and resolution of the analytes were compared. The best separation of hormones was obtained for SG-CHOL packing, as a consequence of the structure and the properties of this stationary phase. To better understand the retention mechanism and the properties of the stationary phases, used in the separation of steroid compounds, the functional group contributions ( τ) were compared with Hansch substituent constants ( π).

4-Amino-1-oxyl-2,2,6,6-tetramethylpiperidine-3-carboxylic acid (β-TOAC), the first spin-labelled, cyclic, chiral β-amino acid resolved in an enantiomerically pure state

Amination of 3-carboxymethyl-1-oxyl-2,2,6,6-tetramethyl-4-piperidone with ( R)-α-methylbenzylamine, NaBH 3CN reduction of the resulting enamine and removal of the chiral auxiliary from the separated diastereoisomers, led to enantiomerically pure (3 S,4 S) and (3 R,4 R) methyl 4-amino-1-oxyl-2,2,6,6-tetramethylpiperidine-3-carboxylates.

Synthesis, structure elucidation, and olfactometric analysis of lilac aldehyde and lilac alcohol stereoisomers.

Structure elucidation of the lilac aldehyde and lilac alcohol stereoisomers was ascertained by (1)H nuclear magnetic resonance (NMR) spectroscopy, including intramolecular nuclear Overhauser effects of the separated diastereoisomers and anisotropic effects of the diastereomeric 2-phenylpropionyl ester, and (1)H, (1)H COSY NMR spectroscopy of synthesized (5'R)-configured stereoisomers, synthesized from (R)-linalool. Direct stereodifferentiation of the eight stereoisomers of lilac aldehyde and lilac alcohol, respectively, has been achieved, using enantioselective capillary GC. The elution order of the isomers was deduced from the chromatographic behavior of the (5'R)-configured diastereoisomers. Additionally, the odor thresholds of lilac aldehyde and lilac alcohol stereoisomers are reported.

Separation of triadimefon and triadimenol enantiomers and diastereoisomers by supercritical fluid chromatography

The enantiomeric separation of triadimenol and triadimefon on a Chiralpak AD column using supercritical fluid chromatography, was studied in this work. The effect of different modifiers (methanol, ethanol and 2-propanol) was tested, with methanol and ethanol providing the best results for the enantiomeric separation of the two compounds. The enantioseparation of a mixture of triadimenol and triadimefon (six stereoisomers) was achieved in only 15 min using a gradient of ethanol, 200 bar, 35 °C and a flow-rate of 2 ml/min. The separation of triadimenol diastereoisomers on different achiral columns (diol, silica and ODS) was also investigated. In this case, the type of organic modifier to be used depended on the stationary phase, the Spherex Diol being the column that gave the best separation. Using this column, resolutions higher than 3 were obtained in analysis times of 5 min with any of the modifiers checked.

Separation of diastereoisomers of podophyllum lignans by micellar electrokinetic chromatography

Seven pairs of diastereoisomers of podophyllum lignans at 2-position, including two pairs of spin-labeled compounds, were separated by micellar electrokinetic chromatography with 5 m M sodium tetraborate–20 m M NaH 2PO 4–120 m M sodium dodecylsulfate–30% (v/v) 2-propanol (pH 6.5–7) within 35 min. The migration behaviors of the compounds with different types and concentrations of organic modifiers were studied. The method can be used to identify the purification of the lignans, monitor the 2-H configuration transformation, and determine the 2-H configuration of the spin-labeled derivatives.

(2S)-1-(4-Methoxyphenyl)-N-[(1R)-2-(4-methoxyphenyl)-1- methylethyl]-2-propanamine in Crude p-Methoxyamphetamine (PMA) Produced by the Leuckart Method

The synthesis and separation of both diastereoisomers of 1-(4-methoxyphenyl)-N-[2- (4-methoxyphenyl)-1-methylethyl]-2-propanamine as markers of clandestine p-methoxyamphetamine have been described. The stereochemistry of the meso diastereomer was established by crystallographic method.

CARBON CLAD ZIRCONIA AND SEPARATIONS OF THE DIASTEREOISOMERS OF LOW MOLECULAR WEIGHT POLYSTYRENES

The general aim of this work was to illustrate the exceptional resolving power of carbon clad zirconia surfaces for the separation of diastereoisomers of low molecular weight polystyrenes. Separations are reported in which four diastereoisomers of n-butyl polystyrene with four configurational repeating units were separated in less than two minutes. Some variability between lot numbers of carbon clad zirconia was observed, which should be noted by chromatographers. Perhaps the most critical aspect that emerged from this study was that stationary phase materials from differing batches should never be mixed, particularly for long term studies.

Kinetic resolution of amines with enantiopure 3-N,N-diacylaminoquinazolin-4(3H)-ones

The title compounds (DAQs) are chiral when the two N-acyl groups are different because of the absence of rotation around the N–N bond (a chiral axis). Enantiopure DAQs have been obtained by incorporation of a chiral centre in enantiopure form either into the substituent at the Q2-position or into one of the N-acyl groups, or into both, followed by separation of diastereoisomers. This separation is unnecessary in one case because conversion of the N-monoacylaminoquinazolinone (MAQ) into the DAQ is completely diastereoselective. Neither is separation of diastereoisomers necessary with 3-[N,N-di-(S)-2-acetoxypropanoylamino]-2-diphenylmethylquinazolin-4(3H)-one 37a: this DAQ 37a has its N–N bond rendered a chiral axis by the bias in its imide moiety wholly in favour of one exo/endo conformation.