Efficient Enantiomer Separation Research Articles

Research progress of stationary phase of gas chromatography based on chiral organic frameworks

Enantiomers typically show different pharmacological, toxicological, and physiological properties. Thus, the preparation of enantiopure compounds is of great significance for human health and sustainable development. Compared with asymmetric catalysis, enantiomeric separation is simpler, faster, and more efficient; as such, it has become the preferred method for obtaining pure enantiomers. At present, enantiomeric separation methods mainly include chromatography, nanochannel membrane separation, selective adsorption, and recrystallization. In particular, gas chromatography (GC) plays an important role in enantioseparation because of its high sensitivity, excellent reproducibility, and outstanding processing capacity for various enantiomers. The stationary phase is key to the separation efficiency of GC, and more efficient, stable, and cost-effective materials that could serve as stationary phases are constantly being explored. Organic frameworks, such as covalent organic frameworks (COFs), metal-organic frameworks (MOFs), porous organic cages (POCs), metal-organic cages (MOCs), and hydrogen-bonded organic frameworks (HOFs), possess large specific surface areas, high porosities, tunable pore sizes, and easy functionalization, rendering them promising candidates for the separation of mixed analytes. Research has shown that the use of organic frameworks as stationary phases for GC results in excellent column efficiency and high resolution for various analytes, including n-alkanes, n-alcohols, polycyclic aromatic hydrocarbons, positional isomers, and organic fluorides. Furthermore, organic frameworks can be prepared as chiral stationary phases for GC by the intelligent introduction of a chiral moiety, thereby enabling the efficient separation of enantiomers. Synthetic strategies for chiral organic frameworks are primarily categorized as post-synthesis or bottom-up approaches. In general, the post-synthesis strategy can introduce various chiral sites to the framework; however, the distribution of chiral sites may not be uniform, and the ordered framework may be destroyed during the post-synthesis process. The bottom-up strategy allows for the uniform and precise distribution of chiral sites in the framework, but the synthesis of chiral monomers and the constraint between asymmetry and crystallinity limit its development. Chiral induction has been proposed as an alternative strategy for synthesizing chiral organic frameworks. The use of this strategy has led to the successful preparation of organic frameworks with abundant chiral sites and excellent crystallinity. Dynamic coating and in situ growth are the main approaches used to transform the as-prepared chiral organic frameworks into stationary phases. Notably, the in situ growth approach can yield chiral COF/MOF-coated capillary columns that provide high resolution for the separation of enantiomers with excellent repeatability and reproducibility. Nevertheless, owing to the slightly complex pretreatment process and the difficulty of synthesizing chiral organic frameworks, the in situ growth approach has not yet been widely applied. Owing to their excellent solvent processing performance, POCs, MOCs, and HOFs can be easily coated on the inner walls of columns to form membranes via dynamic or static coating. A series of enantiomers have been successfully separated and analyzed by immobilizing chiral COFs, MOFs, POCs, MOCs, and HOFs on GC capillary columns, demonstrating the great potential of chiral organic frameworks for enantiomeric separation. In general, the mechanisms by which chiral organic frameworks recognize enantiomers could be mainly categorized as van der Waals interactions, hydrogen bonding, π-π interactions, and size-exclusion effects. While molecular simulations can offer some insights into these recognition mechanisms, clarifying these mechanisms based on effective characterization remains challenging. In summary, organic frameworks show outstanding advantages for enantiomer separation. Given breakthroughs in synthetic strategies for chiral organic frameworks and the in-depth study of chiral recognition mechanisms, chiral organic frameworks may be expected to become an important aspect in the field of chiral materials, further realizing the large-scale analysis and production of chiral analytes. A total of 64 references, most of which are from the American Chemical Society, Springer Nature, Wiley Online Library, and Elsevier databases, are cited in this review.

Enantioseparation and molecular modeling study of chiral amines as three naphthaldimine derivatives using amylose or cellulose trisphenylcarbamate chiral stationary phases.

This study describes the enantioseparation of three chiral amines as naphthaldimine derivatives, using normal phase HPLC with amylose and cellulose tris(3,5-dimethylphenylcarbamate) chiral stationary phases (CSPs). Three chiral amines were derivatized using three structurally similar naphthaldehyde derivatizing agents, and the enantioselectivity of the CSPs toward the derivatives was examined. The degree of enantioseparation and resolution was affected by the amylose or cellulose-derived CSPs and aromatic moieties as well as a kind of chiral amine. Especially, efficient enantiomer separation was observed for 2-hydroxynapthaldimine derivatives on cellulose-derived CSPs. Molecular docking studies of three naphthaldimine derivatives of leucinol on cellulose tris(3,5-dimethylphenylcarbamate) were performed to estimate the binding energies and conformations of the CSP-analyte complexes. The obtained binding energies were in good agreement with the experimentally determined enantioseparation and elution order.

Homochiral Metal-Organic Framework Based Mixed Matrix Membrane for Chiral Resolution.

Efficient separation of enantiomers is critical in the chemical, pharmaceutical, and food industries. However, conventional separation methods, such as chromatography, crystallization, and enzymatic kinetic resolution, require high energy costs and specific reaction conditions for the efficient purification of one enantiomer. In contrast, membrane-based processes are continuous processes performed with less energy than conventional separation processes. Enantioselective polymer membranes have been developed for the chiral resolution of pharmaceuticals; however, it is difficult to generate sufficient enantiomeric excess (ee) with polymer membranes. In this work, a homochiral filler of L-His-ZIF-8 was synthesized by the ligand substitution method and mixed with polyamide(imide) (i.e., Torlon®) to fabricate an enantioselective mixed-matrix membrane (MMM). The enantio-selective separation of R-1-phenylethanol over S-1-phenylethanol was demonstrated with a 25 wt% loaded L-His-ZIF-8/Torlon® MMM in an organic solvent nanofiltration (OSN) mode.

A Nanoporous Supramolecular Metal-Organic Framework Based on a Nucleotide: Interplay of the π···π Interactions Directing Assembly and Geometric Matching of Aromatic Tails.

Self-assembly is the most powerful force for creating ordered supramolecular architectures from simple components under mild conditions. π···π stacking interactions have been widely explored in modern supramolecular chemistry as an attractive reversible noncovalent tool for the nondestructive fabrication of materials for different applications. Here, we report on the self-assembly of cytidine 5’-monophosphate (CMP) nucleotide and copper metal ions for the preparation of a rare nanoporous supramolecular metal-organic framework in water. π···π stacking interactions involving the aromatic groups of the ancillary 2,2’-bipyridine (bipy) ligands drive the self-assemblies of hexameric pseudo-amphiphilic [Cu6(bipy)6(CMP)2(µ-O)Br4]2+ units. Owing to the supramolecular geometric matching between the aromatic tails, a nanoporous crystalline phase with hydrophobic and hydrophilic chiral pores of 1.2 and 0.8 nanometers, respectively, was successfully synthesized. The encoded chiral information, contained on the enantiopure building blocks, is transferred to the final supramolecular structure, assembled in the very unusual topology 8T6. These kinds of materials, owing to chiral channels with chiral active sites from ribose moieties, where the enantioselective recognition can occur, are, in principle, good candidates to carry out efficient separation of enantiomers, better than traditional inorganic and organic porous materials.

Thin Films of Homochiral Metal–Organic Frameworks for Chiroptical Spectroscopy and Enantiomer Separation

Chiral nanoporous solids are a fascinating class of materials, allowing efficient enantiomer separation. Here, we review the status, applications, and potential of thin films of homochiral metal–organic frameworks (MOFs). Combining the advantages of MOFs, whose well-defined, crystalline structures can be rationally tuned, with the benefits of thin films enables new opportunities for the characterization of the enantioselectivity, e.g., via chiroptical spectroscopy and straightforward molecular uptake quantifications. By incorporating photoresponsive molecules in the chiral MOF films, the enantioselectivity of the material can be dynamically remote-controlled. The most promising application of MOF films is their use as membranes, where the enantioselective separation of chiral molecules is demonstrated and parameters for further improvements are discussed.

A high-performance chiral selector derived from chitosan (p-methylbenzylurea) for efficient enantiomer separation

N-Methoxycarbonyl chitosan was prepared by selectively modifying the amino group at the 2-position of chitosan with methyl chloroformate, which was further functionalized with p-methylbenzylamine to produce chitosan (p-methylbenzylurea). Then, the hydroxyl groups at the 3- and 6-positions of the glucose skeleton were modified with various phenyl isocyanates, affording a series of chitosan 3,6-bis(arylcarbamate)-2-(p-methylbenzylurea)s, which were characterized and proposed as chiral selectors for enantiomer separation. Nineteen racemates, most of which are drugs or intermediates for drugs, were selected as the model analytes to evaluate the enantioseparation performance. The structure-performance relationship of the chiral selectors was investigated in detail. It was found that the methyl-substituted chiral selectors possessed more preferable enantioseparation performance compared with the chloro-substituted ones, and the chiral selectors containing a methyl substituent at the 4-position of the benzene ring showed the best chiral recognition and separation ability with 17 racemates being recognized and 13 racemates being baseline separated. The prepared chiral separation materials derived from these chiral selectors exhibited favorable solvent tolerance towards ethyl acetate, acetone, chloroform and a low proportion of tetrahydrofuran in normal phase. To sum up, this work provided a useful reference for the design and preparation of high-performance chiral separation materials for efficient enantiomer separation.

Daring the Challenge and Thinking Big: The Value of Early Process RD.

The production of the L/T channel blocker ACT-280778 required the enantiomerically pure 5-phenylbicyclo[2.2.2]oct-5-en-2-one (1) as key building block. As the published routes towards 1 are very low yielding (<0.5% yield) and comprise many steps that are not acceptable for scale-up, a series of processes to 1 was developed to match the increasing requirements from first kg-batches to clinical supplies. The three routes are characterized by an individual asset. (1) The first route contains a scale-up of a Diels-Alder reaction with highly reactive reagents and afforded 90 kg enantiomerically pure 1. To mitigate safety risks, a flow reactor was developed for the high-temperature Diels-Alder reaction. This route relied on an efficient enantiomer separation on a ¼-ton scale by HPLC. (2) A Crystallization Induced Diastereomer Transformation (CIDT) during an intramolecular aldol reaction was the pivotal step of a first enantioselective route that starts with the Shibasaki reaction. (3) The 2(nd) enantioselective route represents a rare example of organocatalysis on scale and allowed to skip six out of nine steps with a significant impact on the cost of goods. This simple way to 1 opened up a short synthesis of Hayashi's chiral diene ligands (bod*) that were so far lacking an affordable access. Some of these novel C1-symmetrical dienes have shown very high enantioselectivities in Rh-catalyzed additions of arylboronates.

ChemInform Abstract: Structure Control of Polysaccharide Derivatives for Efficient Separation of Enantiomers by Chromatography

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Structure Control of Polysaccharide Derivatives for Efficient Separation of Enantiomers by Chromatography

Structure Control of Polysaccharide Derivatives for Efficient Separation of Enantiomers by Chromatography

Efficient separation of enantiomers by preferential crystallization in two coupled vessels

AbstractThe focus of this work is to study the enantioseparation of conglomerate forming systems using an innovative configuration for preferential crystallization. Two batch crystallizers are coupled by an exchange of their liquid phases. In each vessel one of the two enantiomers is seeded initially and crystallizes subsequently. Compared with conventional single batch crystallization the exchange of the crystal free liquid phases between two crystallizers leads to an increase of the concentrations of the preferred enantiomers and therefore to an increase of the driving forces for the crystallization. This enhances the productivity of the process compared with the conventional operation. © 2009 American Institute of Chemical Engineers AIChE J, 2009

Optical resolution of N-formylphenylalanine succeeds by crystal growth rate differences of diastereomeric salts

Optical resolution of racemic-phenylalanine through its N-formyl derivative with a 1-phenylethylamine resolving agent is an effective procedure. Differential scanning calorimetry, single crystal X-ray diffraction and optical microscopy were used in the investigation of the resolution process. It was found that the thermodynamic properties of the given system would not allow the efficient enantiomer separation. Kinetic effects during the crystal formation have been discovered by the comparison of the crystal morphologies of the two diastereomers. The crystal structure of the less soluble diastereomer ( S)-(−)-1-phenylethylammonium ( S)-(+)- N-formylphenylalaninate salt has been determined and discussed.

Chiral Separations of Ibuprofen and Propranolol by TLC. A Study of the Mechanism and Thermodynamics of Retention

In contrast with gas and column liquid chromatography, both of which enable very efficient separation of enantiomers, thin‐layer chromatography (TLC) has never proved particularly successful in the same field. This can be regarded as puzzling because although the performance of TLC is substantially lower than that of the instrumental modes of chromatography, it still seems efficient enough to ensure even difficult separations of pairs of analytes. There is a steady demand for simple, inexpensive, and successful chiral separations, preferably executed with the aid of TLC. The best proof of this is a few documented and promising attempts reported by reliable laboratories in developing countries. Some of these reports, however, describe experiments performed with glass plates coated in the laboratory, which gives rise to questions regarding the accuracy and repeatability of the results obtained. Similar concerns are evoked by traditional visualization of the outcome of a separation by use of dyeing agents, rather than by densitometry (which furnishes concentration profiles of the bands and the possibility of in‐situ identification also). In this study, we have repeated chiral separations of two widely used drugs, ibuprofen and propranolol, adapting working conditions reported elsewhere to a system based on standardized and commercially available chromatographic plates. We also performed detection and identification on the developed chromatograms by means of densitometry. In our experiments with the modified chromatographic procedures, the results obtained proved at least as good as those reported in the original papers and occasionally somewhat better. For both ibuprofen and propranolol, preliminary thermodynamic evaluation of the standard chemical potentials of adsorption (Δμa) for each of the two enantiomers considered was also performed. The results obtained look promising and realistic; it seems that adsorption TLC can be used in the future for thermodynamic assessment of the racemization process.

Enantiomer separation by pressure-supported electrochromatography using capillaries packed with a permethyl-β-cyclodextrin stationary phase

Efficient enantiomer separation by pressure-assisted, micro-packed capillary electrochromatography (CEC) has been carried out using a permethyl-β-cyclodextrin-modified silica support (PM–β-CD–silica). When comparing this method with micro-packed-high-performance liquid chromatography in the single-column-mode, CEC displays higher column efficiencies (about three times higher theoretical plate numbers at comparable elution times). The pressure support (about 10 bar), applied to avoid bubble formation, has a negligible influence on elution times in CEC. The influence of the type and composition of organic modifiers is described.

Study of the mechanism of optical resolutions via diastereoisomeric salt formation

Racemic malic acid (I) was resolved by R-α-phenylethylamine(II). The S-(−)-I.R-(+)-II diastereoisomer was in excess in the precipitated salt. DSC curves and X-ray powder diffractograms proved that the diastereoisomeric salt mixture precipitated during the resolution was isomorphous with the optically pure S-(−)-I.R-(+)-II salt. The diastereoisomeric salt mixture containing the R-(−)-I.R-(+)-II salt in abundance bound crystal solvate (water or methanol) when produced by the total evaporation of the mother liquor, while the optically pure R-(−)-I.R-(+)-II salt crystallized without solvate. It is generally assumed that solid solution formation takes place when the two diastereoisomers are alike and the high similarity results in less efficient enantiomer separation. This paper demonstrates that efficient resolution can be accomplished in case of solid solution formation too. The diastereoisomeric salt mixtures can crystallize in isomorphic form even when the physico-chemical properties of the optically pure diastereoisomeric salts are quite different.

Physico-chemical investigation of the diastereoisomeric salt pair formed by α-phenyl-ethyl-amine and R-1-phenylethyl-succinamic acid

The diastereoisomeric salt pair formed between α-phenyl-ethyl-amine and R-1-phenylethylsuccinamic acid were investigated by physico-chemical methods. Melting and solubility phase diagrams were determined, the coincidence of the eutectic points of the two phase diagrams were demonstrated. The large difference in physico-chemical properties of the salt pair explains the efficient enantiomer separation.