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

This review discusses all available literature on the self-disproportionation of enantiomers (SDE) of fluorine-containing compounds, resulting in a separation of racemic form from the excess enantiomer. Included are examples of the SDE via distillation, sublimation and achiral chromatography. The role of fluorine on the magnitude and preparative efficiency of the SDE, as a new, nonconventional method for optical purifications, is emphasized and critically discussed. 1 Introduction 2 General Aspects of Fluorine Influence on the Self-Disproportionation of Enantiomers 3 Self-Disproportionation of Enantiomers via Distillation 4 Self-Disproportionation of Enantiomers via Sublimation 5 Self-Disproportionation of Enantiomers via Achiral Chromatography 6 Conclusions

Review: ca. 80 refs.

This commentary discusses an important, though not widely appreciated, chiral phenomenon of molecular chirality that effectively always occurs whenever nonracemic samples are subjected to practically any physicochemical process (e.g., force field, recrystallization, sublimation, even distillation, etc.) under totally achiral conditions external to the sample itself. The phenomenon is termed as the self-disproportionation of enantiomers (SDE) and though ubiquitous, its presence may not always be readily apparent, or workers may be otherwise oblivious to its effects. In the particular case of chromatography, when the SDE is apparent, the enantiomeric excess (ee) of the chiral compound is observed to vary across an eluted peak, with anterior eluted portions either enantioenriched or enantiodepleted relative to the ee of the starting material, and conversely for the posterior eluted portions. Herein, we highlight various aspects of the SDE phenomenon as it pertains to chromatography and, in particular, the effect of scaling down chromatographic systems, the potential risk of problems that the SDE can cause, as well as opportunities for practical applications of the phenomenon, possible new occurrences of the SDE phenomenon to be searched for, and unrealized opportunities.

This tutorial review describes the self-disproportionation of enantiomers (SDE) of chiral, non-racemic compounds, subjected to chromatography on an achiral stationary phase using an achiral eluent, which leads to the substantial enantiomeric enrichment and the corresponding depletion in different fractions, as compared to the enantiomeric composition of the starting material. The physicochemical background of SDE is a dynamic formation of homo- or heterochiral dimeric or oligomeric aggregates of different chromatographic behavior. This phenomenon is of a very general nature as the SDE has been reported for different classes of organic compounds bearing various functional groups and possessing diverse elements of chirality (central, axial and helical chirality). The literature data discussed in this review clearly suggest that SDE via achiral chromatography might be expected for any given chiral enantiomerically enriched compound. This presents two very important issues for organic chemists. First, chromatographic purification of reaction products can lead to erroneous determination of the stereochemical outcome of catalytic asymmetric reactions and second, achiral chromatography can be used as a new, nonconventional method for optical purifications. The latter has tremendous practical potential as the currently available techniques are limited to crystallization or chiral chromatography. However, a further systematic study of SDE is needed to develop understanding of this phenomenon and to design practical chromatographic separation techniques for optical purification of non-racemic mixtures by achiral-phase chromatography.

Altering the mobile phase composition to enhance self-disproportionation of enantiomers in achiral chromatography

The review is devoted to self-disproportionation of enantiomers (SDE) phenomenon which has been observed for many different classes of chiral organic compounds. The SDE phenomenon occurs when the fractionation of an enantioenriched sample due the application of a physicochemical process under achiral conditions results in the variation of the proportion of the enantiomers present across the fractions, though the overall composition in terms of the sample ee remains unchanged. The SDE process can be considered in terms of separating the excess enantiomer from the racemate. The basic terminology related to SDE was described. The formation of the SDE under chromatographic conditions is the result of an association process occurring in a solution of a chiral, non-racemic compound. Information on preferred interactions leading to homo-/heterochiral supramolecules can be provided by quantum chemical calculations, NMR spectroscopy and comparison of crystal structures of the racemic and enantiomeric crystals. Several examples of the chromatographic experiments with different classes of compounds were given in two purposes 1) to highlight the possibility of application SDE during column chromatography as the method for enantiopurification of the chiral, non-racemic compounds; 2) to demonstrate that a standard workup (chromatographic purification, evaporation) can alter the stereochemical outcome of asymmetric reactions

Gas antisolvent precipitation (GAP) using dense carbon dioxide (CO2) is a novel technique for the purification or enrichment of phytochemicals by selective crystallisation. It involves dissolution of sub-critical CO2 into an organic solution of the extract for selectively reducing the solubility of the solid solutes of interest by anti-solvent effect. The recovery and enrichment of three bioactive phytochemicals, such as β-carotene, α-hydroxycitric acid, and licochalcone-A have been investigated in this paper. Initially, organic solvent (Soxhlet) extraction or supercritical CO2 extraction has been carried out for the recovery of β-carotene from mango leaves, α-hydroxycitric acid from kokum, and licochalcone-A from licorice. Subsequently, purification has been performed by the GAP process using CO2 in the pressure range of 40 to 70 bar at 298 K, followed by filtration at the same pressure and temperature, and removal of the residual solvent from the product by flushing it with CO2. High performance liquid chromatography (HPLC) analysis of the phytochemicals before and after the GAP process confirms significant enrichment of the active ingredients.

Chromatographic behavior of nonracemic mixtures, viz., mandelic acid and stilbene oxide as analytes has been studied in detailed by enantiomer self-disproportionation on achiral ordered mesoporous material M41S and regular silica gel as stationary phases. Enantiomer self-disproportionation gave enhanced separation of analytes. The extent and magnitude of enantiomer self-disproportionation is dependent on the optical purity of the starting non-racemic molecules, presence of intermolecular hydrogen bonding/pi-pi interactions and the nature of eluents used. The present study and previous literature data suggest that percentage ee of a nonracemic mixture needs to be determined before any chromatographic purification is taken up as enantiomer self-disproportionation phenomenon could occur during purification. The data show that enantiomer self-disproportionation of nonracemic mixtures can be harnessed for its enantioenrichment on inexpensive achiral stationary phases.

NMR spectral enantioresolution of spirobrassinin and 1-methoxyspirobrassinin enantiomers using ( S)-(−)-ethyl lactate and modeling of spirobrassinin self-association for rationalization of its self-induced diastereomeric anisochromism (SIDA) and enantiomer self-disproportionation on achiral-phase chromatography (ESDAC) phenomena

The purpose of this review is to highlight the necessity of conducting tests to gauge the magnitude of the self-disproportionation of enantiomers (SDE) phenomenon to ensure the veracity of reported enantiomeric excess (ee) values for scalemic samples obtained from enantioselective reactions, natural products isolation, etc. The SDE always occurs to some degree whenever any scalemic sample is subjected to physicochemical processes concomitant with the fractionation of the sample, thus leading to erroneous reporting of the true ee of the sample if due care is not taken to either preclude the effects of the SDE by measurement of the ee prior to the application of physicochemical processes, suppressing the SDE, or evaluating all obtained fractions of the sample. Or even avoiding fractionation altogether if possible. There is a clear necessity to conduct tests to assess the magnitude of the SDE for the processes applied to samples and the updated and improved recommendations described herein cover chromatography and processes involving gas-phase transformations such as evaporation or sublimation.

Self-disproportionation of enantiomers of 3,3,3-trifluorolactic acid amides via sublimation

Sub-micrometer-sized particles of poly(L-lactic acid) may be formed by using near-critical or supercritical carbon dioxide as an antisolvent to precipitate poly(L-lactic acid) from droplets of methylene chloride solution sprayed into a carbon dioxide continuous phase. Particle sizes may be controlled by varying the density of the carbon dioxide; at constant temperature in the supercritical region, higher carbon dioxide densities yield larger particles. Two methods (one batch and one continuous) for introducing the poly(L-lactic acid) solutions into carbon dioxide are demonstrated. Although the two methods use very different mechanisms for forming the droplets, similar particle sizes are observed as a function of carbon dioxide density. We suggest that mass transport, rather than jet breakup and hydrodynamics, controls particle sizes in the near-critical and supercritical regions.

This review describes self-disproportionation of enantiomers (SDE) of non-racemic mixtures, subjected to distillation, sublimation, or chromatography on achiral stationary phase using achiral eluent, which leads to the substantial enantiomeric enrichment and corresponding depletion in different fractions, as compared to the enantiomeric composition of the starting material. This phenomenon is of a very general nature as SDE has been reported for different classes of chiral organic compounds bearing various functional groups and possessing diverse elements of chirality. The literature data discussed in this review clearly suggests that SDE is typical for enantiomerically enriched chiral organic compounds and special care should always be taken in evaluation of the stereochemical outcome of enantioselective reactions as well as determination of enantiomeric ratios of non-racemic mixtures of natural products after any purification process. The role of molecular association of enantiomers on the magnitude and preparative efficiency of SDE, as a new, nonconventional method for enantiomerc purifications, is emphasized and discussed.

Use of supercritical fluid (SCF) processing technologies in the pharmaceutical industry has seen remarkable growth as an alternate technology for the preparation of micro- and nano-sized particles. Carbon dioxide, having low critical temperature (31.2 °C) and pressure (73.8 bar or 7.4 Mpa) and being nonflammable, nontoxic, and environmentally safe, is the choice of SCF for processing of pharmaceuticals including heat-sensitive materials such as biologicals. Depending on how SCF is used in the technology, a number of variations have emerged to meet the needs of the compound and the product design. For example, SCF can act either as a solvent, an antisolvent, or as a solute. The superior solvent characteristics of SCF stem from its physical properties where it behaves like a gas and liquid at the same time. The high diffusivity and low viscosity coupled with low surface tension helps in solubilizing the organic compounds. SCF technologies can be grouped into several categories based on the particle growth mechanism and their collection environment. Rapid expansion of supercritical solutions, gas antisolvent (GAS) precipitation, supercritical antisolvent (SAS) precipitation, precipitation with compressed fluid antisolvent (PCA), solution-enhanced dispersion by SCF (SEDS), and precipitation from gas-saturated solutions (PGSS) are the main variants of SCF technologies. These techniques have successfully produced micro- and nanoparticles as well as amorphous solid dispersions (ASDs). In addition to being a stand-alone processing technology, SCF has been frequently used as a processing aid in the manufacture of the ASD, for instance, as temporary plasticizer in the melt extrusion process to reduce the processing temperature, melt viscosity, or to impart porosity. The premise of this chapter is to examine the potential of SCF in producing amorphous dispersions and to identify the opportunities for future development.

A question of policy: should tests for the self-disproportionation of enantiomers (SDE) be mandatory for reports involving scalemates?