Determination of enantiomeric composition of (-)-(R)-2-tert-butyltetrahydroimidazolidin-4-one by polarimetry, 1H NMR, and chiral SFC

Partial resolution of rac-2-tert-butyltetrahydroimidazolidin-4-one was carried out by recrystallization of diastereomeric salts. The enantiomeric composition of enriched samples was estimated by polarimetry, (1)H NMR, and chiral SFC. Enantiomeric composition estimated by polarimetry or by (1)H NMR was directly proportional to that estimated by chiral SFC. The occurrence of solute self-association in chloroform was detected through measurements of optical and specific rotation at variable concentration of (-)-(R)-2-tert-butyltetrahydroimidazolidin-4-one. Our data suggest that solute self-association in chloroform might be independent of enantiomeric composition.     

Determination of the absolute configuration of secondary alcohols with Horeau's method including enantioselective gas chromatography

The reaction of optically active secondary alcohols with excess of racemic 2-phenylbutyric acid anhydride in pyridine proceeds at different rates to the diastereoisomeric esters (kinetic partial resolution). According to Horeau the (unknown) absolute configuration of the alcohol can be derived from the optical rotation of the remaining excess of 2-phenylbutyric acid in the reaction mixture. Measuring the optical rotation may be very difficult in cases of small absolute rotation values and may be inaccurate due to the necessity to completely remove all chiral impurities. The application of Horeau's method is greatly facilitated by gas chromatographic determination of the enantiomeric ratio of the remaining 2-phenylbutyric acid after methylation using a short capillary column with heptakis(2,6-di-O-methyl-3-O-pentyl)-β-cyclodextrin as a chiral stationary phase. Baseline resolution of the enantiomers is achieved after approximately 10 min of retention time. Due to the high selectivity of capillary gas chromatography the probability of impurities in the mixture to interfere with the measurement of the enantiomeric ratio is extremely low. © 1994 Wiley-Liss, Inc.     

Total synthesis of both enantiomers of dictyochromenol and their (Z)-isomers

Total syntheses of both enantiomers of dictyochromenol (1) and its (Z)-stereoisomer (2) were achieved with high enantiomeric purity. The results of this study reveal the relationship between the optical rotation of the resolved 1 enantiomers.     

Optical rotation detection for reversed phase HPLC: Investigation of solvent effects

Investigations into the parameters affecting the sensitivity of polarimetric detectors for the determination of enantiomeric excess by achiral HPLC are presented. The results obtained showed that the specific optical rotation of an analyte was highly sensitive to the methanol content of the mobile phase. The purpose of this short communication is to demonstrate that “off-line” optical rotation measurements are a necessary part of the method development process for successful use of polarimetric detectors. Chirality 9:122–125, 1997, © 1997 Wiley-Liss, Inc.     

Stereochemistry and enantiomeric purity of a novel anxiolytic agent, deramciclane fumarate.

The synthesis, stereostructure, and enantiomeric separation by chromatography of a new, chiral anxiolytic agent, deramciclane fumarate (2, (-)-[1R,2S,4R]-2-(2-dimethylaminoethoxy)-2-phenyl-1,7, 7-trimethylbicyclo[2.2.1]heptane fumarate, EGIS-3886), is described. The optical antipode and the racemate of compound 2 were also prepared. The structure was determined by single crystal X-ray diffraction analysis. The enantiomeric separation was accomplished by HPLC on Chiralcel OD (250 x 4.6 mm; 10 microm) and hexane-ethanol (99.5:0.5) as mobile phase at room temperature. The enantiomeric purity of the synthesized drug substance proved to be very high (>99. 9%). Some statements published earlier on the stereostructure of deramciclane fumarate are critically discussed.     

Investigations into the chirality of the metabolic sulfoxidation of cimetidine

The individual enantiomers of cimetidine sulfoxide were resolved by preparative chromatography using a Chiralcel OC stationary phase and were characterized by the determination of optical rotation and circular dichroism spectra. Cimetidine sulfoxide was isolated from the urine of two healthy male volunteers following oral administration of cimetidine (400 mg). Urine was collected every 2 h for 12 h postdosing, after which time HPLC analysis indicated negligible recovery of the drug as the sulfoxide. Some 7% of the dose was recovered as cimetidine sulfoxide over this period. The enantiomeric composition of cimetidine sulfoxide was determined by sequential achiral—chiral chromatography using the OC phase. Over the collection period the enantiomeric ratio was found to be constant in all samples at (+/?) of 71 ± 2.5:29 ± 2.5. The enantiomeric composition of cimetidine sulfoxide was also determined in rat urine (24 h) following the administration of cimetidine (30 mg/kg po) to male Wistar rats (n = 7). The enantiomeric ratio in this case was found to be (+/?) 57 ± 2.3:43 ± 2.3. These preliminary data indicate that sulfoxidation of cimetidine is stereoselective with respect to the (+)-enantiomer and that species variation in enantiomeric composition occurs. © 1994 Wiley-Liss, Inc.     

Thehalose mycolates from Nocardia asteroides,Nocardia farcinica,Gordona lentifragmenta and Gordona bronchialis

Isolation of glycolipids from Nocardia asteroides, N. farcinica, Gordona lentifragmenta and G. bronchialis, by column chromatography of lipid extracts on a 50% (w/w) mixture of silicic acid and silica gel H, is described. The isolated materials were partially characterized by infrared spectroscopy, optical rotation and refractive index measurements, and by identifying the products of alkaline hydrolysis. Analytical studies showed that the glycolipids released only trehalose in the aqueous phase while mycolic acids were the constituent fatty acids identified.The isolated lipids are trehalose esters in which the trehalose molecule is esterified with mycolic acids.     

Chiral symmetry breaking: Experimental results and computer analysis of a liquid-phase autoxidation

The autoxidation of tetralin is treated as a model reaction system to define the applicability of stereospecific autocatalysis. This concept, predicting a spontaneous amplification of enantiomeric excess generated by an autocatalytic chemical reaction, is used in several theoretical models as an explanation for the origin of natural optical activity. The reaction system investigated obeys the basic criteria of these models: a chiral intermediate (tetralin hydroperoxide) is produced from an achiral substrate (tetralin) via an autocatalytic pathway where the feedback mechanism is expected to generate a state of broken chiral symmetry. In order to test the amplification capacity of this reaction a computer analysis of the kinetic scheme is performed. This simulation is derived from the known kinetic scheme of autoxidation and is validated by fitting the experimentally observed data of hydroperoxide evolution. Calculations show that this model allows powerful amplification of enantiomeric excess and a transient amplification of the optical rotation. It is also demonstrated that the model system exhibits pronounced sensitivity toward any loss of absolute configuration of the involved chiral species. Since an amplification effect results exclusively at a high degree of stereoselectivity, it is concluded that stereospecific autocatalysis is possible in systems which show template reactions, crystallization, or colloidal effects. © 1993 Wiley-Liss, Inc.     

Polarimetric detection in high-performance liquid chromatography

Chiroptical detection for HPLC is particularly useful as a selective detection method for chiral molecules, and in enantiomeric purity determination with partial chiral separation or without chiral separation. The recent development of laser-based polarimeters with microdegree sensitivity has increased the applicability of optical rotation detection in HPLC. The detection limit of these instruments is submicrogram on-column for many chiral compounds in analytical HPLC. A variety of applications of the selective detection of optically active molecules are reviewed. The use of polarimetric detection with partial chiral separation is considered, both as an aid to method development and for enantiomeric purity determination. Finally applications to enantiomeric purity determination without chiral separation are reviewed, with the dual use of nonchirally selective and chiroptical detectors to determine the total amount and optical purity of the analyte. Determinations of chiral purity for samples of high enantiomeric excess are described, which with laser-based instrumentation may give accuracies of better than +/- 1% with sample loadings of 50 micrograms on an achiral column. Applications to the study of enantioselective reactions are also considered, with determination of enantiomeric excess in near-racemates to better than +/- 0.1%.     

Online monitoring of preferential crystallization of enantiomers

Polarimetry is used for continuous online monitoring of optical resolution by preferential crystallization. In combination with refractometry the liquid phase composition is determined, allowing one to follow the resolution progress quantitatively. The measurement techniques were calibrated up to relatively high solution concentrations and combined with the crystallizer. The resolution of DL-threonine was performed by preferential crystallization experiments in aqueous solution varying several process parameters like supersaturation, seed amount, initial enantiomeric excess, and scale. The resolution progress can be conveniently described by profiles of the optical rotation (polarimetric signal) and the crystallization pathway in the corresponding ternary phase diagram. The method outlined is applicable for dynamic process optimization and control purposes in "quasi-continuous" chiral separation processes.     

Melatonin receptor agents: synthesis, resolution by HPLC on polysaccharides chiral stationary phases, absolute configuration, and pharmacology of the enantiomers of (+/-)-N-[[2[(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]acetamide

In order to obtain milligram amounts of the enantiomers of tetrahydronaphthalenic derivative 5 to be tested for binding to the melatonin sites, preparative HPLC employed a mobile phase consisting of n-hexane-alcohol and a silica-based cellulose tris-methylbenzoate (Chiralcel OJ) using isocratic conditions and multiple repetitive injections. The preparative separation was optimized by adjusting the sample size from a scale-up of the analytical method. The enantiomeric elution order was reversed by the change from the carbamate type phase (Chiralcel OD-H) to the benzoate type phase (Chiralcel OJ) in analytical mode. The optical rotation and the circular dichroism spectra of the single enantiomers were determined after separation. The absolute stereochemistry of the two enantiomers of (+/-)-N-[2-(7-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)ethyl]acetamide 5 was established by X-ray crystallographic analysis. The purity obtained was sufficient for a first screen of their biochemical properties: the (-)-(S) enantiomer shows more affinity for melatonin receptors MT1, MT2 and is responsible of the selectivity towards MT2.     

Ring-expanded analogues of natural oxetanocin: (+) and (-) hydroxymethyl isodideoxyadenosine

New enantiomeric isonucleoside analogues related to natural oxetanocin have been synthesized from D-glucosamine and D-glucose. The structures of the target compounds were confirmed by NMR, HRMS, UV, single crystal X-ray, and optical rotation data. Stability studies with respect to purine nucleoside phosphorylase and adenosine deaminase show that these compounds are not substrates. Antiviral results are discussed.     

RING-EXPANDED ANALOGUES OF NATURAL OXETANOCIN: (+) AND (−) HYDROXYMETHYL ISODIDEOXYADENOSINE

New enantiomeric isonucleoside analogues related to natural oxetanocin have been synthesized from D-glucosamine and D-glucose. The structures of the target compounds were confirmed by NMR, HRMS, UV, single crystal X-ray, and optical rotation data. Stability studies with respect to purine nucleoside phosphorylase and adenosine deaminase show that these compounds are not substrates. Antiviral results are discussed.     

Kinetics of chiral resolution in stirred crystallization of D/L‐glutamic acid

Stirred crystallization of racemic (D/L)‐glutamic acid (Glu) in the presence of small amounts of L‐ or D‐lysine (Lys) was studied for the effect of transient chiral resolution by monitoring the time evolution of optical rotation and the concentration of the solution. The presence of a small amount of L‐ or D‐Lys retards the crystallization rate of the corresponding enantiomer of Glu in a chirally selective manner, giving rise to transient optical resolution of racemic Glu during crystallization. The optical rotation of the Glu solution was found to increase from zero to a value corresponding to an enantiomeric excess (ee) of 22–35% and subsequently decreases to zero over a period of many hours. During this process, the ee of the crystallized Gu is nearly 100% during the first 35 min and then it decreases slowly to zero. Our results indicate that the time at which the ee of the solution reaches its maximum and the maximum value of the ee show a nonlinear dependence on the initial mole fraction of the chiral impurity. The effect of the impurity is highly chirally selective, indicating “molecular recognition.” Chirality 11:343–348, 1999. © 1999 Wiley‐Liss, Inc.     

Enantiomeric and mesomeric mandelate complexes of molybdenum -- on their stereospecific formations and absolute configurations

The stereospecific formation and absolute configuration of R-homocitrate coordinated FeMo-co in nitrogenase was mimicked through the structural analyses of a collection of enantiomeric and mesomeric mandelato molybdenum complexes, i.e., (NH(4))(2)[Mo(Delta)O(2)(R-mand)(2)]x3H(2)O (1a), (NH(4))(2)[Mo(Lambda)O(2)(S-mand)(2)]x3H(2)O (1b), (NH(4))(4)[Mo(Delta)O(2)(RS-mand)(2)][Mo(Lambda)O(2)(RS-mand)(2)]x8H(2)O (2), (NH(4))(2)[W(Delta)O(2)(R-mand)(2)]x2H(2)O (3a), (NH(4))(2)[W(Lambda)O(2)(S-mand)(2)]x2H(2)O (3b) (H(2)mand=mandelic acid, C(8)H(8)O(3)), which have been characterized by elemental analyses, optical rotation, circular dichroism, IR, NMR spectroscopes and X-ray single crystal studies. The R and S chiral mandelic acids induce the formations of the enantiomeric pair of chiral complexes, which are supported by the characterizations of optical rotation and circular dichroism. The configuration of the resulted metal center could be assigned as Delta or Lambda. While the RS racemic reagent yields only mesomeric compound. The Delta(R,R)-complexes 1a and 3a are enantiomers of Lambda(S,S)-1b and 3b, respectively. Of the five complexes, Mo and W atoms are all hexa-coordinated by two cis-oxo groups and two bidentate mandelate ligands through the deprotonated alpha-alkoxyl and alpha-carboxyl groups, forming a stable five-membered chelated rings. The average Mo(VI)-O bond distances with alpha-alkoxyl and alpha-carboxyl are 1.944 and 2.210 A, respectively. Further comparison indicates that bonds of alpha-alkoxyl groups in the hydroxycarboxylato molybdenum complexes are much sensitive to the change in the oxidation state of molybdenum, which support the possible Mo activation model in FeMo-co through the protonation and cleavage of alpha-alkoxyl group in homocitrate ligand.     

Enzymatic resolution of (+/-)-epoxy-beta-cyclogeraniol, a synthetic precursor for abscisic acid analogs

Lipase-catalyzed optical resolution of (+/-)-epoxy-beta-cyclogeraniol (1), a key synthetic intermediate for epoxy-beta-ionylideneacetic acid, was achieved in high enantiomeric purity. Transesterification with vinyl acetate by using lipase P (Nagase) made enriched (-)-1, while hydrolysis of the corresponding acetate by using lipase P (Amano) afforded (+)-1 with a high E value (E = 1600).     

Structure of an O-specific polysaccharide of Proteus mirabilis 03, containing N-(2-hydroxyethyl)-D-alanine

O-Specific polysaccharide, obtained by mild acid degradation of the Proteus mirabilis 03 lipopolysaccharide, was dephosphorylated with 48% HF to give a linear polysaccharide and an amino acid, N-(2-hydroxyethyl)-D-alanine. The structure of the polysaccharide was determined by methylation, the Smith degradation and computer-assisted analysis of the 13C NMR spectra of original and dephosphorylated polymers and oligomers. The structure of the amino acid was elucidated by using 1H and 13C NMR spectroscopy and mass spectrometry (applied to the acetylated methyl ester derivative), optical rotation and CD spectrum data and comparison with the synthetic sample. The repeating unit of P. mirabilis 03 O-specific polysaccharide is shown to have the following structure: (formula; see text)     

The specific capsular polysaccharide of Streptococcus pneumoniae type 9V

The specific capsular polysaccharide produced by Streptococcus pneumoniae type 9V (American type 68) is composed of D-glucuronic acid (1 part), D-galactose (1 part), 2-acetamido-2-deoxy-D-mannose (1 part), D-glucose (2 parts), and O-acetyl (1.6 parts). Methylation, periodate oxidation, optical rotation, and nuclear magnetic resonance studies, and partial hydrolysis showed that the polysaccharide is an unbranched high molecular weight linear polymer of a partially O-acetylated pentasaccharide repeating unit having the structure indicated below. (Formula: see text).     

Stereoselective Epoxidation of 4-Bromo-1-Butene and 3-Butene-1-Ol with Three Alkene-Utilizing Bacteria

Stereoselective epoxidation of 4-bromo-1-butene and 3-butene-1-ol was carried out with three alkene-utilizing bacteria: Mycobacterium LI, Mycobacterium E3 and Nocardia IP1. The enantiomeric compositions of 4-bromo-1,2-epoxybutane and 4-hydroxy-1,2-epoxybutane were determined by optical rotation and checked by ¹H NMR using a chiral shift reagent and by ¹⁹F NMR after reaction with the Mosher reagent. The presence of a bromine atom or a hydroxyl group induced some variations in the stereochemical course of the microbial epoxidation. The epoxides were produced predominantly in the 2R-form but their enantiomeric composition depended on both the microorganism used and on the substrate studied.     

环氧丙醇酯立体专-性水解酶产生菌的筛选

从土壤中筛选出一株能拆分（Ｒ,Ｓ）－环氧丙醇丁酸酯的根霉（Ｒｈｉｚｏｐｕｓｓｐ．Ｂｃ０－０９）,该菌株所产胞外脂肪酶在水解环氧丙醇丁酸酯的反应中具有良好的立体专一性。在ｐＨ恒定７．０的条件下,以其发酵液水解底物,当转化率为５８％时,残留的（Ｒ）－环氧丙醇丁酸酯的光学纯度（对映体过量值）达９６．１％。