Non-racemic Mixtures Research Articles

Identification and Quantitation of Enantiomers by Capillary Electrophoresis and Circular Dichroism Independent of Single Enantiomer Standard.

Identification and quantitation of enantiomers is a critical and challenging step in the process of chiral capillary electrophoresis (CE) analysis, especially when the optically pure enantiomers are expensive or commercially unavailable. Herein, a method of CE in combination with circular dichroism (CD) spectroscopy for the identification of enantiomeric peak independent of single enantiomer standard was proposed. By comparing the theoretical CD spectrum of the single enantiomer calculated by time-dependent density functional theory (TDDFT) with the experimental CD spectrum of the enantiomeric mixture, the configuration of the dominant enantiomer in the nonracemic mixture was determined. Considering that the dominant enantiomer showed bigger peak area on the CE electrophoretogram, the enantiomeric peak was easily identified. Three kinds of enantiomers including seven chiral compounds (i.e., tryptophan, tyrosine, phenylalanine, Boc-valine, Boc-leucine, ibuprofen, and naproxen) were used to evaluate the reliability of the method. The concentration of the single enantiomer in the mixture can be further accurately quantified based on the total concentration of the mixture and the peak area ratio of a couple of enantiomers, and the accuracy was assessed by taking ibuprofen as an example. The developed CE-CD method provides an alternative tool for the analysis of nonracemic mixture with good ECD signals.

Homochirality in biomineral suprastructures induced by assembly of single-enantiomer amino acids from a nonracemic mixture

Since Pasteur first successfully separated right-handed and left-handed tartrate crystals in 1848, the understanding of how homochirality is achieved from enantiomeric mixtures has long been incomplete. Here, we report on a chirality dominance effect where organized, three-dimensional homochiral suprastructures of the biomineral calcium carbonate (vaterite) can be induced from a mixed nonracemic amino acid system. Right-handed (counterclockwise) homochiral vaterite helicoids are induced when the amino acid l-Asp is in the majority, whereas left-handed (clockwise) homochiral morphology is induced when d-Asp is in the majority. Unexpectedly, the Asp that incorporates into the homochiral vaterite helicoids maintains the same enantiomer ratio as that of the initial growth solution, thus showing chirality transfer without chirality amplification. Changes in the degree of chirality of the vaterite helicoids are postulated to result from the extent of majority enantiomer assembly on the mineral surface. These mechanistic insights potentially have major implications for high-level advanced materials synthesis.

Clomiphene citrate: the changing landscape

Ovulatory dysfunction is one of the leading causes of female infertility. Clomiphene citrate has emerged as a boon in the induction of ovulation in the human female. Clomiphene results in many adverse effects some of which are documented, and some reported spontaneously. Clomiphene citrate is a non-racemic mixture of two isomers, zuclomiphene and enclomiphene, having individual and opposite biological actions. It is accepted that cis isomer (zuclomiphene) is estrogenic and trans isomer (enclomiphene) is anti-estrogenic. Zuclomiphene does not have any ovulation-induction propertybut gets accumulated for a longer time in the human body and it has more agonistic activity than enclomiphene. Thus, Zuclomiphene may be responsible for the adverse effects by clomiphene citrate. Enclomiphene is being explored for its potential use in male as well as female infertility. Trails are underway to explore its effectiveness and safety in various disorders. This article highlights the pharmacology of Clomiphene with respect to its isomers and the potential uses of enclomiphene based on evidences available.

Chirality Sensing, Halochromism and Solvatochromism in a Conjugated Calix[4]Pyrrole

The conjugated calix[4]pyrrole tetrakis(3,5-di-t-butyl-4-oxocyclohexadien-2,5-yl)porphyrinogen (OxP) is a highly coloured macrocycle with excellent potential as a sensing element in various applications. The first of these is chiral sensing where guest binding at the macrocyclic NH groups allows for estimation of enantiomeric excesses in non-racemic mixtures of chiral analytes. This feature is permitted by the relatively weak binding of the guest resulting in its rapid exchange so that the molecule essentially acts as a probe of average solution chirality. Chirality sensing in OxP is complicated by tautomeric processes when an acid analyte is used. This has allowed us also to develop an acidity sensor for use in non-polar media. More recently, we have designed a series of OxP type molecules that undergo modulation of halochromic (sensitivity to acid) properties and the development of colour scales based on the blocking of OxP binding sites and involving allied protic tautomerization of the OxP chromophore. We will discuss the sensing properties of OxP in relation to chirality, tautomeric processes and the complicating factor of solvatochromism.

Gas Antisolvent Fractionation: a New Method to Obtain Enantiopure Compounds, a Case Study on Mandelic Acid

Micronization processes involving supercritical carbon dioxide are rapid methods to produce fine particles. They also might offer the possibility of using less organic solvent than conventional crystallization methods leading to an environmentally friendlier processing. The separation capabilities of such processes are now demonstrated on the diastereomeric resolution of mandelic acid using (R)-1-phenylethanamine as a resolving agent, utilizing the batch type gas antisolvent fractionation as the separation method. A detailed study was conducted on the effects of the operational parameters pressure (12-20 MPa), temperature (35-55 °C) and co-solvent concentration (33-99 mg/ml). At 12 MPa, 35 °C and 99 mg/ml methanol concentration, a selectivity of 0.52 and a diastereomeric excess of 62% was reached. The same operational parameters were applied during the investigation of the recrystallization-based further purification of the diastereomeric salts, applying the resolving agent in molar equivalent quantity to a non-racemic mixture of mandelic acid. It has been found that the more stable (R)-1-phenylethylammonium-(R)-mandelate salt can be purified to de>98% through four additional recrystallization steps following the initial, half-molar equivalent resolution step.

Phase Diagrams to Evaluate the Opportunity for Enantiomeric Enrichment of Some Nonracemic Mixtures of Amino Acid Benzyl Esters by Crystallization as p-Toluenesulfonate Salts

A number of amino acids undergo moderate-to-high racemization when converted to benzyl ester under inadequate conditions. As they are usually recovered and purified at the end of the esterification by precipitating/crystallizing the p-toluenesulfonate salt, it is of most importance to be aware that such isolation procedures can improve but also lessen the enatiomeric excess of the product. To predict the chance of enantioenrichment by crystallization, it is necessary to define whether the enantiomers of these ester salts form conglomerates or racemic compounds in the solid state and, in case of racemic compounds, to know the enantiomeric composition of the eutectics and to verify that it is similar to the eutectic composition obtained from ternary solubility curves. We constructed the binary melting point phase diagrams of a number of amino acid benzyl ester p-toluenesulfonates showing that most of them form racemic compounds. Of these, we studied those of Ala, Phe, Leu, and Glu, in particular, demonstrating that when prepared in l form with moderate racemization the first three cannot be enantioenriched by crystallization because their l fraction is much higher at the ternary solubility eutectic than at the binary eutectic, whereas the last one can be isolated enantiopure by crystallization because its l fractions at both the ternary solubility and binary eutectics are accordingly low.

A fast, new method to enhance the enantiomeric purity of non-racemic mixtures: self-disproportionation of enantiomers in the gas antisolvent fractionation of chlorine-substituted mandelic acid derivatives

Gas antisolvent precipitation is a particle formation technique, when typically pressurized carbon dioxide is added to an organic solution resulting in immediate and high oversaturation and precipitation of fine particles. Provided that a reasonable share of the originally dissolved material remains dissolved in the carbon dioxide – organic mixed solvent, these components can be extracted during the washing phase. This method is called gas antisolvent fractionation. Gas antisolvent fractionation has been applied for the first time to enantiomeric enrichment of non-racemic mixtures, and demonstrated on the example of chlorinated mandelic acid derivatives. Due to self-disproportionation of enantiomers, the precipitated solid and the extracted fractions have different enantiomeric excesses if gas antisolvent fractionation is carried out on a non-racemic mixture. However, there is a limit in the enantiomeric excess (ee) that can be achieved correlating strongly with the atmospheric melting eutectic behavior of the compounds. Thus, if initial enantiomeric mixtures have a higher than eutectic ee, a >99% ee can be reached in the crystalline product. The strong correlation between the high-pressure experiments and the atmospheric melting eutectic behavior suggest that despite the very large oversaturation during the antisolvent precipitation, the composition of the products (i.e., the crystalline and the extracted phases) is thermodynamically determined. Technological advantages such as short operational time, or the possibility of controlling the crystal morphology suggest that the development of an efficient technique of enantiomeric purification is possible based on gas antisolvent fractionation.

2′-Aminoanalogues of the cruciferous phytoalexins spirobrassinin, 1-methoxyspirobrassinin and 1-methoxyspirobrassinol methyl ether: Synthesis and anticancer properties

A method for the synthesis of new 2′-aminoanalogues of spiroindoline phytoalexins is reported. 2′-Aminonalogues of spirobrassinin, 1-methoxyspirobrassinin and 2,2′-diamino analogues of 1-methoxyspirobrassinol methyl ether were prepared by substitution of the methylsulphanyl group on the dihydrothiazole ring of corresponding phytoalexins. Final products were obtained by heating the phytoalexins with aniline or substituted aniline in the absence of solvent at 120 or 140 °C. By replacement of the SCH3 moiety of (S)-(−)- or (R)-(+)-spirobrassinin, enantiomers of 2′-aminoanalogues of spirobrassinin were also synthesized. Determination of their enantiomeric compositions using HPLC with chiral stationary phase revealed partial enantiomeric enrichment. The occurence of a SIDA effect of our 2′-aminonalogue of spirobrassinin was evaluated by examination of a non-racemic mixture in non-polar C6D6. Complete enantioresolution and distinct signals for two enantiomers were observed for a number of 1H and 13C NMR resonances. New synthesized compounds were supplied for testing the antiproliferative effect on a panel of six human cancer cell lines. 2′-Aminoanalogue with CF3 functionality exhibited more significant inhibitory effects than natural phytoalexins spirobrassinin.

Chromatographic Enantioseparations in Achiral Environments: Myth or Truth?

Direct chromatographic enantioseparations are among the most important practical tasks of chromatography. The accepted rules and concepts of stereochemistry anticipated one type of chromatographic systems applicable only to such enantioseparations consisting either of chiral stationary phase, or chiral selector present in mobile phase. In such a model of chromatographic system, both racemic and non-racemic mixtures could be enantioseparated. Over the years, however, reports on successful chiral enantioseparations in non-chiral chromatographic systems have cumulated as well. To adapt the initial model to novel experimental evidence, an assumption had to be added stating that these were only non-racemic mixtures (and not racemic ones), which could be enantioseparated in achiral chromatographic systems, by granting them an inevitable chirality from the enantiomeric excess of a more abundant enantiomer. There still exists an overlooked portion of experimental evidence for successful enantioseparations of racemic mixtures in the non-chiral chromatographic systems, which cannot be explained by the accepted model. Facing this incompatibility between the model and practical results, we reflect on how to reconcile these two by questioning the possibility of pinpointing a true racemate with the help of our imperfect analytical tools.

Hierarchical Ordering in Adsorbed Overlayers of Chiral Tripod Molecules with Directional Interactions

Chiral molecules can adopt mirror-image configurations when adsorbed on solid substrates, and due to this unique property they can self-assemble into 2D mixed superstructures with complex geometries. In this contribution, we use the Monte Carlo simulation method to study the surface-confined organization of model chiral tripod molecules equipped with terminal centers providing directional short-range intermolecular interactions. These centers, representing functional groups, are the main source of chirality of the considered molecular units which are modeled as rigid planar structures comprising a few interconnected segments. Our simulations embrace enantiopure adsorbed systems, racemic overlayers, as well as nonracemic mixtures, and they are performed for two C3-symmetric tectons differing in size. The obtained results, including structural and thermodynamic characteristics, demonstrate that the pattern formation in the modeled systems is highly sensitive to the composition of the adsorbed overlayer, lea...

ChemInform Abstract: Enantioseparations in Achiral Environments and Chromatographic Systems

AbstractReview: [109 refs.

Distinction of clenbuterol intake from drug or contaminated food of animal origin in a controlled administration trial – the potential of enantiomeric separation for doping control analysis

ABSTRACTThe differentiation of clenbuterol abuse and unintentional ingestion from contaminated meat is crucial with respect to the valuation of an adverse analytical finding in human sports doping control. The proportion of the two enantiomers of clenbuterol may serve as potential discriminating parameter. For the determination of the individual enantiomers, specific methods were developed and validated for the different matrices under investigation based on chiral chromatography coupled to tandem mass spectrometry. Data are presented from the administration to humans of clenbuterol from a pharmaceutical preparation, and from cattle meat and liver containing residues. A shift in the proportion of the enantiomers in cattle meat is detected and this signature is also found in human urine after ingestion. Thus, an altered enantiomeric composition of clenbuterol may be used to substantiate athletes’ claims following adverse analytical findings in doping control. However, in meat, the enantiomeric composition was found to be highly variable. Species as well as tissue dependent variances need to be considered in interpreting enantiomer discrimination. Analysis of post administration urines from a controlled experiment comparing the administration of racemic clenbuterol from a registered pharmaceutical preparation and the administration of residue-containing meat and liver (nonracemic mixture) from treated animals is reported. Furthermore doping control samples from Mexican U17 World Championship 2011 of the Fédération Internationale de Football Association (FIFA), with adverse analytical findings for clenbuterol, were re-analysed.

Enantioseparations in Achiral Environments and Chromatographic Systems

AbstractSince the very first resolution of racemic tartaric acid by Pasteur, the importance of resolution and methodology has been on a path of continuous understanding and expansion. The science and chemistry of achieving such targets has changed a lot. The advent of chromatography changed the direction by involving synthetic, semisynthetic, or naturally occurring chiral materials for a direct approach to resolution, where rapid and reversible association occurs to form diastereomers with different stabilities and partition coefficients responsible for overall enantioseparation. It has now reached a stage where the separation of excess enantiomers from nonracemic mixtures has been achieved in a totally achiral environment, which does not appear to be in line with the prevalent concepts of basic stereochemistry. Caution should be exercised when enantiomerically enriched mixtures – obtained by enantioselective synthesis – are chromatographed for purification in preparative organic synthesis.

Can enantiomers be separated in achiral chromatographic systems?

Consideration of chromatography of a nonracemic mixture on an achiral sorbent from a stereochemical point of view allows the claim that partial separation of the excess enantiomer zone from the racemate zone is possible only with analytes capable of self-associating under the conditions of the chromatographic column. It is from these positions that features of this process can be explained and conditions for its maximal proceeding formulated.

Evidence for the effect of sorption enantioselectivity on the availability of chiral pesticide enantiomers in soil

Although enantioselective sorption to soil particles has been proposed as a mechanism that can potentially influence the availability of individual chiral pesticide enantiomers in the environment, environmental fate studies generally overlook this possibility and assume that only biotic processes can be enantioselective, whereas abiotic processes, such as sorption, are non-enantioselective. In this work, we present direct evidence for the effect of the enantioselective sorption of a chiral pesticide in a natural soil on the availability of the single pesticide enantiomers for transport. Batch sorption experiments, with direct determination of the sorbed amounts, combined with column leaching tests confirmed previous observations that from non-racemic aqueous solutions the sorption of the chiral fungicide metalaxyl on the soil appeared to be enantioselective, and further demonstrated that the enantiomer that was sorbed to a greater extent (R-metalaxyl, Kd = 1.73 L/kg) exhibited retarded leaching compared to its optical isomer (S-metalaxyl, Kd = 1.15 L/kg). Interconversion and degradation of the pesticide enantiomers, which are potential experimental artifacts that can lead to erroneous estimates of sorption and its enantioselectivity, were discarded as possible causes of the observed enantioselective behavior. The results presented here may have very important implications for a correct assessment of the environmental fate of chiral pesticides that are incorporated into the environment as non-racemic mixtures, and also of aged chiral pesticide residues that have been transformed from racemic to non-racemic by biologically-mediated processes.

ChemInform Abstract: Enantioselective Synthesis of (+)‐Petromyroxol, Enabled by Rhodium‐Catalyzed Denitrogenation and Rearrangement of a 1‐Sulfonyl‐1,2,3‐triazole.

Petromyroxol is a nonracemic mixture of enantiomeric oxylipids isolated from water conditioned with larval sea lamprey. The (+)-antipode exhibits interesting biological properties, but only 1 mg was isolated from >100 000 L of water. Recently, transition-metal-catalyzed denitrogenation of 1-sulfonyl-1,2,3-triazoles has emerged as a powerful strategy for the synthesis of value-added products, including efficient diastereocontrolled construction of tetrahydrofurans. This methodology enabled the rapid development of the first synthesis of (+)-petromyroxol in 9 steps and 20% overall yield from a readily accessible starting material.

Enantioselective Synthesis of (+)-Petromyroxol, Enabled by Rhodium-Catalyzed Denitrogenation and Rearrangement of a 1-Sulfonyl-1,2,3-Triazole

Petromyroxol is a nonracemic mixture of enantiomeric oxylipids isolated from water conditioned with larval sea lamprey. The (+)-antipode exhibits interesting biological properties, but only 1 mg was isolated from >100 000 L of water. Recently, transition-metal-catalyzed denitrogenation of 1-sulfonyl-1,2,3-triazoles has emerged as a powerful strategy for the synthesis of value-added products, including efficient diastereocontrolled construction of tetrahydrofurans. This methodology enabled the rapid development of the first synthesis of (+)-petromyroxol in 9 steps and 20% overall yield from a readily accessible starting material.

Self‐Discriminating Termination of Chiral Supramolecular Polymerization: Tuning the Length of Nanofibers

AbstractDirecting the supramolecular polymerization towards a preferred type of organization is extremely important in the design of functional soft materials. Proposed herein is a simple methodology to tune the length and optical chirality of supramolecular polymers formed from a chiral bichromophoric binaphthalene by the control of enantiomeric excess (ee). The enantiopure compound gave thin fibers longer than a few microns, while the racemic mixture favored the formation of nanoparticles. The thermodynamic study unveils that the heterochiral assembly gets preference over the homochiral assembly. The stronger heterochiral binding over homochiral one terminated the elongation of fibrous assembly, thus leading to a control over the length of fibers in the nonracemic mixtures. The supramolecular polymerization driven by π–π interactions highlights the effect of the geometry of a twisted π‐core on this self‐sorting assembly.

Self-discriminating termination of chiral supramolecular polymerization: tuning the length of nanofibers.

Directing the supramolecular polymerization towards a preferred type of organization is extremely important in the design of functional soft materials. Proposed herein is a simple methodology to tune the length and optical chirality of supramolecular polymers formed from a chiral bichromophoric binaphthalene by the control of enantiomeric excess (ee). The enantiopure compound gave thin fibers longer than a few microns, while the racemic mixture favored the formation of nanoparticles. The thermodynamic study unveils that the heterochiral assembly gets preference over the homochiral assembly. The stronger heterochiral binding over homochiral one terminated the elongation of fibrous assembly, thus leading to a control over the length of fibers in the nonracemic mixtures. The supramolecular polymerization driven by π-π interactions highlights the effect of the geometry of a twisted π-core on this self-sorting assembly.

Chiral recognition in electron scattering by S- and R-2-butanol

Experiments are described involving the low-energy scattering of electrons from the two optical enantiomers S- and R-2-butanol. Using a synchrotron radiation photoionisation source on the ASTRID storage ring, scattering spectra are reported between a few meV and 140 meV at an electron energy resolution of 1.6 meV. These data show electron dichroism at 35 meV, for scattering into the backward hemisphere, with a cross-section of 202.1 ± 8.0 Å2 (4σ) and 182.8 ± 9.0 Å2 (4σ) for S- and R-, respectively, with the racemic mixture lying at the average value. No dichroic effect could be detected in the integral cross-section within the accuracy of the experiment. A brief qualitative discussion is given of a possible electron dissociative attachment mechanism for the creation of homochirality in space, including a new feature involving feedback through enhancement of electron polarisation through scattering from non-racemic mixtures of enantiomers.