Non-racemic Mixtures Research Articles

Computer simulation of three scenarios for the separation of non-racemic mixtures by chromatography on achiral stationary phases

With the aid of a general chromatography simulation program based on the theoretical plate model, three scenarios rationalizing the phenomenon of the separation of non-racemic mixtures into racemate and excess enantiomers by chromatography on achiral stationary phases were simulated. The separation, repeatedly observed in high-performance liquid chromatography and gas chromatography, can be explained by the formation of homo- and heterochiral self-associates ( i.e. RR, SS and RS). The kinetic calculations were performed using a Runge—Kutta routine. This program offers for the first time a general means of simulating dynamic chromatographic elution profiles involving any type of reaction occurring during chromatographic separation. Thus computer simulation of experimental elution profiles is no longer limited to first-order reactions such as enantiomerizations or isomerizations.

Self-induced nonequivalence in the 1H-NMR spectra of the (+)- and (−)-isomers of a cannabinoid ketone intermediate

The 1H-NMR spectra in deuteriochloroform of racemic and optically pure (trans)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-3- pentyl-6H-dibenzo[b,d]pyran-9(8H)-one (1) are nonsuperimposable, while nonracemic mixtures of the (+)- and (−)-isomers show two sets of signals for the phenolic and aromatic protons in ratios directly proportional to the enantiomeric composition of the mixture. This is a new example of “self-induced nonequivalence” or “diastereomeric solute-solute interaction,” a known but seldom reported phenomenon. The magnitude of the chemical shift differences are dependent on the ratios of the two enantiomers while the chemical shift δ values are concentration dependent. The overall effect was clearly observable even at a concentration of 0.01 M. In a practical sense, optical purities of samples of the cannabinoid ketone (1) are readily determined by 1H-NMR without the use of additional chiral shift reagents.

Stereospecificity of the products of the fatty acid oxygenases derived from psoriatic scales.

The principal in vivo oxygenase products of arachidonic acid and linoleic acid in psoriatic skin scales are 12-hydroxyeicosatetraenoic acid (R/S ratio = 5.7), 13-hydroxyoctadecadienoic acid (S/R = 1.9), and 9-hydroxyoctadecadienoic acid (R/S = 2.4). Definition of the enzymatic origin of these fatty acid derivatives is an important step in assessing their possible role in the pathogenesis of psoriasis. Psoriatic skin scales were incubated with radiolabeled arachidonic acid and linoleic acid and the monohydroxylated derivatives produced in vitro were characterized. The products of incubation with [3H]arachidonic acid were an enantiopure 15(S)-[3H]hydroxyeicosatetraenoic acid and a nonracemic mixture of the 12-[3H]hydroxyeicosatetraenoic acid steroisomers (R/S ratio = 4.5). An enantiopure 13(S)-[14C]hydroxyoctadecadienoic acid was produced from [14C]linoleic acid. No radiolabeled products were derived from incubations with heat-denatured scales. These results provide evidence for two distinct oxygenase activities that are preserved in psoriatic skin scales. One is that of an omega-6 oxygenase with strict (S) stereospecificity, consistent with the activity of a lipoxygenase. This enzyme activity appears to be similar to that of the 15-lipoxygenase which has been described in cultured human keratinocytes. The second activity is that of an arachidonic acid 12(R)-oxygenase that has not been observed in normal human epidermis but which appears to be expressed in psoriatic epidermis.

Investigation of Bis(α-Phenylethylamido)Methylphosphonates by NMR Spectroscopy

Abstract The influence of the relative location of chiral carbon and phosphorus atoms and the position of the aryl-group on diastereomeric anisochronity in non-racemic mixtures of enantiomers has been examined. The optical isomers of methanephosphonic acid bis(α-phenylethylamide) (I), which contain pro-chiral phosphorus atom, were synthesized by the reaction of methanephosphonic acid dichloride(II) with (+)- or (-) -α-phenylethylamine (III). The extent of chemical shift nonequivalence in 31P and 1H NMR spectra of non-racemic mixtures of RR- and SS-I was negligible. It can be explained by the absence of aryl-amino group, favouring intermolecular association, effect of SCADA1, and the long distance between the chiral center and pro-chiral phosphorus. Phosphonylation of non-racemic mixtures of (+)- and (-)-III by II proceeds stereospecifically giving mixture of RR-, SS-I, and two meso-compounds analyzed by 31P 1H NMR.

Characterization of the chirality of the monohydroxy-eicosatetraenoic acids produced by rat basophilic leukemia cells

Incubation of rat basophilic leukemia cells with exogenous arachidonic acid and permeabilizing concentrations of ethanol resulted in the production of 5-, 12-, and 15-hydroxyeicosatetraenoic acids. With chiral phase high performance liquid chromatography, it was demonstrated that the 5-hydroxyeicosatetraenoic acid had strict (S) stereospecificity while contrary to expectation, the 12- and the 15-hydroxyeicosatetraenoic acids were non-racemic mixtures of the stereoisomers with the S R ratios averaging 8.6 and 2.2, respectively. If the strict (S) stereospecificity of mammalian lipoxygenases holds true, these results suggest that the 15- and 12-hydroxyeicosatetraenoic acids may be derived from non-lipoxygenase sources. Examination of the chirality of the oxygenase products of unsaturated fatty acids may be of value in defining the enzymes which are activated in vivo in pathological states.

A combined DSC, X-ray diffraction, and molecular modelling study of chiral discrimination in the purification of enantiomeric mixtures of cis-permethrinic acid

Purification of the non-racemic enantiomeric mixtures of cis-permethrinic acid has been performed by selective precipitation of the diastereoisomeric homo-(RCPAC) and hetero-(RSCPAC) dimers of the acid. The differences between the properties of the dimers have been studied using DSC and X-ray diffraction measurements. Molecular mechanics and quantum chemical calculations have been performed in order to describe quantitatively the energy differences and intermolecular interactions formed and to shed light on the mechanism of chiral discrimination in the separation of cis-permethrinic acid isomers.

Optical purity determination, conformer populations and 1H NMR spectral simplification with lanthanide shift reagents — Part IX. A method for improved analytical precision for “DOEt”, 2,5-dimethoxy-4-ethylamphetamine

The 60 MHz 1H NMR spectra of the potent hallucinogen 2,5-dimethoxy-4-ethylamphetamine (“DOEt”), 1, have been studied in CDCl 3 at 28° with the achiral shift reagent, tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)europium(III), 2, and the chiral reagents tris[3-(trifluoromethylhydroxymethylene)- d-camphorato] europium(III), 3, and tris[3-(heptafluoropropylhydroxymethylene)- d-camphorato] europium(III), 4. Distinct enantiomeric shift differences, ΔΔδ, were observed for the amphetamine CH 3 and the adjacent CH resonances using either 3 or 4 that permit direct optical purity determinations. A novel use of an external computing integrator as an accessory to a basic NMR is described; interfacing these instruments permits improved analytical precision for the reported optical purity determinations using nonracemic mixtures of known compositions. Relative abundances of the different conformers with respect to C αC β bond rotation in the arylethylamine moiety is discussed based on coupling constants. Results are compared with the related hallucinogen, 3,4-methylenedioxyamphetamine.

Application of NMR spectroscopy of chiral association complexes. 14—chiral recognition of terpene and cyclohexene hydrocarbons by1H and13C NMR

Chiral NMR recognition of terpenic and similar hydrocarbons by Ag(fod) and optically active lanthanide shift reagents is described. Twenty-four 1H signals of eight compounds and, as a first report in the literature, eleven 13C signals of three compounds were split into signal pairs due to the respective enantiomers. Although the magnitudes of the splittings are not connected to the structure of the substrate molecules in an obvious manner, the configurations of the similar compounds camphene and epi-β-santalene were related empirically. All spectra were sufficiently resolved to allow separate integration of enantiomer signals; from the integrals the enantiomeric purities of seven non-racemic mixtures were determined with good accuracy. The shift curves made several hitherto unknown assignments feasible.

Determination of the Enantiomeric Purity by 1h NMR with Eu(tfc)3 of β‐Hetarylalanine Derivatives. Correlation Of the Enantiomeric Shift Difference with Absolute Configuration

AbstractThe best conditions (solvent, lanthanide/substrate molar ratios…) to determine the enantiomeric purity of a nonracemic mixture of R and S N‐acetyl (or benzoyl)‐β‐hetarylalanine methyl esters by 1H NMR with tris (3‐trifluoromethyl‐hydroxymethylene‐d‐camphorato)europium(III) «Eu(tfc)3» were studied. A direct correlation between configuration and chemical shift differences, ΔΔδR‐S, between the methyl singlets was observed.

ChemInform Abstract: THE COMPLEXATION OF CALCIUM(II) AND LANTHANIDE(III) CATIONS WITH THE PHOSPHATE SUBSTITUTE (CARBOXYMETHOXY)SUCCINATE (CMOS), AS STUDIED BY MAGNETIC RESONANCE SPECTROSCOPY

AbstractDie Komplexbildung zwischen Trinatrium‐carboxymethoxysuccinat und Lanthanoid(III)‐ sowie Ca(ll)‐Kationen wird mittels 1H‐NMR‐Spektroskopie untersucht.

Diastereomeric electron-donor-acceptor complexes

An electron-donor acceptor (EDA) interaction has been assumed to contribute, besides hydrogen bonding, to the formation of certain diastereomeric complexes [1]. We have now shown, for different molecular systems, the existence of diastereomeric complexes which seem to be held together by EDTA attraction exclusively. Among others, carbazole derivatives were chosen as π-donors and fluorenone derivatives as π-acceptors [2] ( e.g. Fig. 1). The 1H NMR signals of racemic ▪ Fig. 1. 1H NMR in [D 6] acetone of a racemic donor in the presence of 1.10 equivalents of (R, S)- or (R)-acceptor, respectively. Δδ: Shift difference between protons of (+)- and (−)-donor, determined from splittings or estimated from linewidths. donors show additional splittings Δδ in the presence of optically active acceptors (Fig. 1, bottom) which are absent (Fig. 1, top), if racemic acceptors are applied [2]. Similarly, the signals of racemic acceptors are split in the presence of optically active donors. In some cases, assignments of individual lines to specific diastereomeric complexes have been achieved by using a nonracemic mixture of one component and a pure enantiomer of the other component [3]. The comparison of 1H NMR shifts δ for the mixtures with those of the pure components [4] as well as the temperature dependence [2] of δ for the mixture provide further evidence of association. These relative shifts are caused predominantly by the diamagnetic anisotropy of the partner in the complex. They enabled us to proposed a model for the orientation (Fig. 2) of the components for some of the complexations studied. The magnitudes of the above splittings Δδ ( e.g. Fig. 1) give some support to this proposal. ▪ Fig. 2. Average diastereomeric 1:1 complexes between (R)-2-(N-carbazolyl)-propionic esters and (±)-2-(2,4,5,7-tetranitro-9-fluorenylideneaminoxy)-propionic esters. Results [5] with chiral or prochiral cations and optically active anions will be mentioned. In this case, similar 1H NMR effects are brought about by cationanion attraction. Possible application for the measurement of enantiomeric purity [6] will be discussed.

ChemInform Abstract: ASYMMETRIC SYNTHESIS OF β‐LACTAMS

Abstract(II) entstehen Mischungen der Addukte tion wird diskutiert, Zwischenstufen und Aus den Ketenen (I) und den Carbodiimiden (III) und (IV).

Asymmetric synthesis of β-lactams

Cycloaddition of chiral carbodi-imides to prochiral ketens yields diastereoisomeric, non-racemic mixtures of 2-iminoazetidin-4-ones, the formation of one of the diastereoisomers being preferred; the composition of these mixtures was determined.

An NMR study of optical isomers in solution

NMR 31P-{ 1H} spectra of stereoisomeric N - [S - (methylethoxyphosphinyl) - thioglycolyl]valines in solution to reveal association of the molecules, and interaction of the chiral centres. Under fast inter-associate exchange in achiral media, these interactions lead to the following: (i) The chemical shift of the racemic mixture of enantiomers deviates from the shift of the individual species; (ii) the spectra of non-racemic mixtures are doublets; (iii) there are 2 n lines in the spectrum of a mixture containing unequal concentrations of stereoisomers with n asymmetric centres. The integrated intensity ratio is equal to the concentration ratio in all cases. The concept of statistically controlled associate diastereomerism (SCAD) is introduced and the respective formalism is given to describe the spectral effects accompanying variations of temperature and concentration. It is also shown applicable to more complicated cases involving ion exchange of chiral fragments between stereoisomers.

Chemistry of the Podocarpaceae. LII. Demethylation involving partial inversion of cofiguration at two remote centres

Treatment of optically pure (+)-12-methoxypodocarpa-8,11,13-triene (2) with HI/HBr/HOAc and a trace of H3PO2 gives, as the major product, a non-racemic mixture of (+)-podocarpa-8,11,13-trien-12-ol (3) and its enantiomer (14).

Non-racemic mixture model: a computational approach.

The behavior of a slight chiral bias in favor of l-amino acids over d-amino acids was studied in an evolutionary mathematical model generating mixed chiral peptide hexamers. The simulations aimed to reproduce a very generalized prebiotic scenario involving a specified couple of amino acid enantiomers and a possible asymmetric amplification through autocatalytic peptide self-replication while forming small multimers of a defined length. Our simplified model allowed the observation of a small ascending but not conclusive tendency in the l-amino acid over the d-amino acid profile for the resulting mixed chiral hexamers in computer simulations of 100 peptide generations. This simulation was carried out by changing the chiral bias from 1% to 3%, in three stages of 15, 50 and 100 generations to observe any alteration that could mean a drastic change in behavior. So far, our simulations lead to the assumption that under the exposure of very slight non-racemic conditions, a significant bias between l- and d-amino acids, as present in our biosphere, was unlikely generated under prebiotic conditions if autocatalytic peptide self-replication was the main or the only driving force of chiral auto-amplification.

Crystallization of Non-Racemic Mixtures of the Isomers of Serine

IF the enantiomorph (unlabelled) of a labelled isomer is available, the maximum contamination of the particular labelled compound by its enantiomorph may be assessed by a crystallization method. Repeated crystallization of a mixture of enantiomorphs in which one (unlabelled) is present in large excess of the other (labelled) would be expected to lead to a purification of the more abundant isomer; hence, the presence of isotope in the purified abundant isomer should represent contamination of the labelled antipode. Thus, when enzymatically prepared1,2 D-glutamic acid-2-14C was diluted about 2,000-fold with carrier L-glutamic acid and the mixture crystallized, via the hydrochloride and the free amino-acid, to constant specific activity, it could be calculated that the maximum amount of contaminant L-glutamic acid-2-14C was less than 1 per cent3.