Direct Chiral Liquid Chromatographic Separation of Tocainide Enantiomers on a Crownpak (Cr) Column and its Application to Pharmaceutical Formulations and Biological Fluids

Abstract

Direct chiral liquid chromatographic resolution of racemic tocainide was accomplished without any derivatization using a crownpak CR(+) column as a chiral stationary phase. The stereochemical resolution (R) with symmetrical peaks was 0.97 and a separation factor (α) of 1.44 were obtained. Optimization of separation was achieved using different concentrations of perchloric acid.     

Molecular and crystal structure of cellulose propanoate diacetate (CPDA, 2,3-di-O-acetyl-6-O-propanoyl cellulose)

The molecular and crystal structure of cellulose propanoate diacetate (CPDA, 2,3-di-O-acetyl-6-O-propanoyl cellulose) has been determined through combined X-ray fibre diagrams and electron diffraction patterns of single crystal analysis, aided by stereochemical restraints by using a constrained linked-atom least-squares refinement. The unit cell of CPDA is orthorhombic with space group P2 ₁2₁2₁ and parameters:a =1.239 nm,b =2.498 nm and c (fibre axis)=1.044 nm. Based on these data, coupled with the observed density of the crystals, there are four chains per unit cell, distributed in two antiparallel pairs of parallel chains, and the independent repeat is the disaccharide unit in each chain. A preliminary CPDA disaccharide unit was derived based on the centre residue of cellotriose undeca-acetate, and this model was refined through a conformational analysis. The best model obtained by combining the stereochemical refinement with the diffraction intensities gave R=0.272 (R=0.259) for the three-dimensional information from the X-ray fibre diagram and R=0.248 (R=0.246) for the base plane data resulting from electron diffraction analysis.     

Molecular and crystal structure of cellulose acetate dipropanoate (CADP, 6-O-acetyl-2,3-di-O-propanoyl cellulose)

The molecular and crystal structure of cellulose acetate dipropanoate (CADP, 6-O-acetyl-2,3-di O-propanoyl cellulose) has been determined by using a constrained linked-atom least-squares refinement method, combined with X-ray and electron diffractograms and stereochemical refinement. The diffraction analysis indicated that CADP crystallized in a P2 ₁ monoclinic space group with unit cell parameters:a =1.088 nm,b (unique axis)=1.593 nm,c (fibre axis)=1.509 nm and =94.1°. The best model derived from combining the stereochemical refinement with the diffraction intensities gave R=0.217 (R=0.195) for the three-dimensional information from the X-ray fibre diagram and R=0.198 for the base plane data resulting from electron diffraction analysis. In the model, the crystal structure of CADP consisted of a system of right-handed threefold helices packed in an antiparallel fashion, with two molecules passing through the unit cell.     

HPLC Separation of the Diastereomeric Glutathione Adducts of Styrene Oxide

Abstract

The four diastereomeric thioether adducts resulting from the addition of glutathione to racemic styrene oxide were separated on a Radial Pak C₁₈ column using pH 7 Tris-phosphate buffer solution containing methanol as eluent. The benzylic thioether (1) eluted earlier than the benzylic alcohol (2) regioisomers. A complete stereochemical profile was established with the first eluting stereoisomer assigned as (S,R)-1, followed by (R,R)-1, (S,R)-2, and (R,R)-2,. The diastereomers with S configuration at the benzylic carbon emerged first for each set of regioisomers. The use of glutathione as a chiral probe for the analysis of enantiomerically enriched epoxides was illustrated with β-methylstyrene oxide formed from (1R, 2S)-N,N-dimethylephedrium bromide during the course of a chiral phase-transfer synthesis of oxiranes.     

STEREOSELECTIVE REACTIONS OF CHIRAL AMINES WITH RACEMIC CHLOROPHOSPHINES

Racemic chlorophosphines react stereoselectively with chiral l-phenylethylamines or amino acid esters to give diastereomerically enriched aminophosphines 3, which were isolated as diastereomerically pure crystalline borane complexes. Oxidation, thionation, the reaction with methyl iodide provide optically active derivatives of aminophosphines. (R,S)- and (S,S)-stereomers of phosphinic acid amides were separated by crystallization and a flash-chromatography. The stereochemical properties of phosphorus acid amides were investigated. The mechanism of asymmetric induction at the trivalent phosphorus atom was rationalized.     

Resolving Agents. I. (R)-(-)-2-Amino-1-benzyloxybutane,a New Base for the Resolution of Racemic Acids

Treatment of the readily available (R)-(-)enantiomer of 2-aminobutan-1-ol 1 with sodium hydride followed by benzyl chloride afforded the O-benzyl base (R)-(-)-2. The latter was successfully used for the resolution of racemic α-methylsuccinic and α-bromosuccinic acids, as well as of the racemic α-benzylhemisuccinic esters 8 and 9 resectively.     

Determination of the Absolute Configuration of the (−)-Me(EtO)(HO)P-Mo(CO)5 Coordination Complex by Decomplexation of the Organophosphorus Ligand

Abstract

The resolution of a chiral coordination complex (1) was recently carried out in our laboratory, and some stereochemical transformations of the resolved specie have been reported (L. P. Reiff, L. J. Szafraniec, D. I. Rossman and H. S. Aaron, Inorg. Chem. 1986, 25, 0000). Decomplexation studies of its organophosphorus ligand have now been carried out. Thus, treatment of the (?)-1 complex with two molar equivalents of triphenylphosphine yields (+)-ethyl methylphosphinate (2), considerably racemized, however, due to the 120°C temperature required to achieve decomplexation. To determine its optical purity and its absolute configuration, the latter was converted into the known S-(?)-3 thioic acid and S-(?)-4 methyl ester, respectively. While the method does not appear to be of synthetic utility for the preparation of optically active (decomplexed) organophosphorus species, the absolute configuration of the S-(?)-1 coordination complex is established on the basis of these stereochemical relationships.     

A chemo-enzymatic approach to optically active 3-(4-methoxycarbonyl)phenyl-2-methyl-1-propanols

With a view to obtaining both enantiomers of 3-(4-methoxycarbonyl)phenyl-2-methyl-1-propanols, (R)-1 and (S)-1, from the respective racemate, (±)-1, the hydrolysis of its acetate, (±)-2, in the presence of porcine pancreatic lipase (PPL) has been studied. The optical puriry of (R)-1 and (S)-1 thus obtained was unsatisfactory (ee 22–27%), and could not be increased beyondee 33% by repeated enzymatic hydrolysis of the unconverted fraction of the acetate. In contrast with this, the biohydrogenation of 3-(4-methoxycarbonyl)phenyl-2-methyl-2-propen-1-ol (4) with fermentingSaccharomyces cerevisiae afforded (S)-1 of considerably higher optical purity (ee 41–90 %, depending on the strain). The stereochemical correlation of the products obtained in the two biochemical processes under study shows that the PPL-catalyzed hydrolysis of (±)-2 produces preferably (R)-1.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 761–766, April, 1995.The authors express their gratitude to the Russian Foundation for Basic Research for financial support (Grant No. 93-03-5893).     

Liquid Chromatographic Resolution of Enantiomeric Dipeptides on the Chiral Stationary Phase Derived from (S)-1-(6,7-Dimethyl-1-naphthyl)isobutylamine

Abstract

Liquid chromatographic resolution of fifteen enantiomeric dipeptide methyl esters as their N-3,5-dinitrobenzoyl derivatives was investigated on the chiral stationary phase (CSP) derived from (S)-1-(6,7-dimethyl-1-naphthyl)isobutylamine. The four stereoisomers present in each dipeptide derivative were observed to be separated quite well with the (R,R) isomer being eluted first. The separation factors for two enantiomeric pairs such as (R,R)/(S,S) and (R,S)/(S,R) and the elution orders are explained by two competing “opposite-sense” chiral recognition mechanisms.     

Phospholipids Chiral at Phosphorus. 13. Stereochemical Comparison of Phospholipase A2, Lecithin-Cholesterol Acyl Transferase,and Platelet-Activating Factor

Abstract

Thiophospholipids and thiophosphate analogs of platelet activating factor were synthesized and used to compare the stereochemical properties in three different biological systems. Phospholipase A₂ shows high stereo-specificity, and this has been substantiated by computer graphics. Lecithin-cholesterol acyl transferase shows no stereospecificity. Platelet aggregation shows, preliminarily, a small degree of stereospecificity.     

An Expeditious Total Synthesis of (±)-Sempervirol, (±)-Sugiol and (±)-Xanthopherol Methyl Ether by Acid-Catalyzed Cyclialkylation Route

An expeditious total synthesis of (±)-sempervirol (7) (±)-sugiol (8), and (±)-xanthopherol methyl ether (9) by extension of a simple general route is described. The stereochemical results of the cyclialkylation of 2-(2-p) and (2-m-isopropylphenylethyl)-1,3,3-trimethylcyclohexanols (1e) and (1f) follow the general pattern observed earlier.     

Stereochemistry of the aldol condensation of benzaldehydes with alpha-chloro esters : An example of the gauche effect of adjacent polar bonds

Under irreversible conditions, the stereochemical course of the aldol condensation of benzaldehydes with esters R¹CHClCO₂R (R¹ = H or Me) in the presence of NaH, NaOR or KOR depends only on the nature of R. Solvent and temperature have negligible effects. The reaction has been performed with eight ortho- or para-substituted benzaldehydes; only in the case of o-methoxybenzaldehyde has a different stereochemical result been obtained. Possible transition states for the Darzens reaction are discussed and it is shown that all of the data are consistent with a mechanism involving addition of a pyramidal carbanion to the aldehyde CO group via the rotameric forms predicted on the basis of the gauche effect     

Kinetic Resolution of Piperazine-2-Carboxamide by Leucine Aminopeptidase. An Application in the Synthesis of the Nucleoside Transport Blocker (-) Draflazine

The resolution of N-t-Boc-piperazine carboxamide 5 proceeded smoothly in the presence of leucine aminopeptidase to produce acid (S)-1 and amide (R)-5 with good optical purity. Sequential alkylation and functional group manipulation of carboxamide (S)-5 provided the known nucleoside transport blocker draflazine (-) 2.     

Enantiomeric Resolution of Amino Acids by Reversed Phase High Performance Liquid Chromatography Using a New Chiral Mobile Phase

Abstract

The synthesis of a new chiral agent, (R,R) (-)N, N'-trans-1, 2-dihexylcyclohexanediamine, for the chromatographic resolution of racemates is reported. Highly selective separations of D- and L-isomers of free and Dns-amino acids were accomplished on a reversed-phase column using in the mobile phase a Cu(II) complex of the above chiral selector. The procedure was extended to resolve diastereomeric derivatives, which were obtained by reaction of an optically active amine with o-phthaldeyde in the presence of N-acetyl-L-cysteine.     

A Simple and Rapid Method for the Separation of the (R)- and (S)-Enantiomers of the Tetrahydroisoquinoline Alkaloid Salsolinol by High-Performance Liquid Chromatography

Abstract

A high-performance liquid chromatographic technique for the separation of the optical isomers of salsolinol is described. The simple and rapid method allows the direct resolution of the enantiomers without derivatization. A complete separation (baseline resolution) of (R)-(+)-salsolinol and (S)-(-)-salsolinol could be achieved on a Chiral=Si 100 ß-cyclodextrin column using water mixed with 10% methanol (v/v) and 0.05% trifluoroacetic acid (v/v) as mobile phase. Analyses carried out at a flow rate of 1.0 ml/min were accomplished in less than 12 minutes.     

Comparative Study of the Enantioseparation of Uniconazole and Imazalil by HPLC on Various Cellulose Chiral Columns

Abstract

This paper reported the enantioseparation of uniconazole and imazalil using four different self‐prepared cellulose derivative columns, namely, CTB, CTMB, CTPC, and CDMPC. The mobile phase composition including the type of the alcohol modifier and the ethanol concentration in hexane changed, and the influence on the retention factor (k′); for each enantiomer, the separation factor (α) and the resolution (R_S) was studied. The influence of the structures of the analytes on the chiral separation was investigated. The results showed that uniconazole obtained the best resolution of 2.16 on CTPC, while imazalil obtained the best separation on CTMB, with the maximal resolution of 4.83. It was concluded that the structure of solutes and CSP play a key role in the chiral recognition. And the chiral attraction between them is the predominant factor.     

Phospholipids chiral at phosphorus. synthesis,absolute configurations and applications

Abstract

The synthesis of P-chiral phospholipids is described and their application in stereochemical studies is discussed.     

脲衍生物型手性固定相拆分噻利洛尔对映体

用脲衍生物型手性固定相直接拆分了药物对映体噻利洛尔。优化的正相色谱流动相的组成为正己烷／１,２－二氯乙烷／乙醇（７７∶２１∶２,Ｖ／Ｖ／Ｖ）。实验表明,流动相中乙醇含量的改变对分离度产生了较大的影响;不同极性调节剂的使用表现出了不同的拆分效果。最后讨论了异构体的出峰次序,认为异构体与固定相的手性中心之一的氢键作用力是造成异构体分离的主要因素。     

Stereoselective synthesis of trans-3-functionalized-4-pyrazolo[5,1-b]thiazole-3-carboxylate substituted β-lactams: Potential synthons for diverse biologically active agents

Abstract

An efficient protocol for the stereoselective synthesis of pyrazolo[5,1-b]thiazole-3-carboxylate tethered β-lactam conjugates 8a–j from novel pyrazolo [5,1-b]thiazole-3-carboxylate substituted Schiff’s bases 6a–f is reported here. The reaction between various ketene precursors and novel Schiff’s bases 6a–f afforded exclusive formation of trans-β-lactams 8a–j. The substrate scope of this approach was investigated extensively by varying different groups (R, Z). All the novel compounds were characterized using various spectroscopic techniques, such as FT-IR, ¹H NMR, ¹³C NMR, elemental analysis, ¹³C NMR (DEPT-135), and mass spectrometry in representative cases. Single crystal X-ray crystallographic study of trans-ethyl 7-(1-(4-methoxyphenyl)-4-oxo-3-phenoxyazetidin-2-yl)-6-methyl-2-(methylthio)pyrazolo[5,1-b]thiazole-3-carboxylate 8a has confirmed the molecular structure and the stereochemical outcome. To the best of our knowledge, the synthesis of such types of Schiff’s bases and β-lactam conjugates has not been reported so far.     

(1S,2R)-N-(3,5-Dinitrobenzoyl) Norephedrine Bonded to Silica Gel as a Chiral Stationary Phase for the Liquid Chromatographic Separation of Enantiomers

Abstract

A Chiral Stationary Phase (CSP 3) was prepared by connecting (1S,2R)-N-(3,5-dinitrobenzoyl) norephedrine to a silica support through an ester linkage. CSP 3 was found to show some differences from CSP 1, derived from N-(3,5-dinitrobenzoyl) phenylglycine, in the resolution of N-acyl-1-aryl-1-aminoalkanes. For example, CSP 3 was found to show greater chiral recognition for conformationally rigid analytes than does CSP 1. On the other hand, CSP 1 was found to resolve flexible analytes better than CSP 3. To explain the chiral recognition behavior on CSP 3, the role of the conformational flexibility of CSP 3 in chiral recognition is proposed.