Formation Of Diastereomeric Complexes Research Articles

Update on chiral recognition mechanisms in separation science.

The stereospecific analysis of chiral molecules is an important issue in many scientific fields. In separation sciences, this is achieved via the formation of transient diastereomeric complexes between a chiral selector and the selectand enantiomers driven by molecular interactions including electrostatic, ion-dipole, dipole-dipole, van der Waals or π-π interactions as well as hydrogen or halogen bonds depending on the nature of selector and selectand. Nuclear magnetic resonance spectroscopy and molecular modeling methods are currently the most frequently applied techniques to understand the selector-selectand interactions at a molecular level and to draw conclusions on the chiral separation mechanism. The present short review summarizes some of the recent achievements for the understanding of the chiral recognition of the most important chiral selectors combining separation techniques with molecular modeling and/or spectroscopic techniques dating between 2020 and early 2024. The selectors include polysaccharide derivatives, cyclodextrins, macrocyclic glycopeptides, proteins, donor-acceptor type selectors, ion-exchangers, crown ethers, and molecular micelles. The application of chiral ionic liquids and chiral deep eutectic solvents, as well as further selectors, are also briefly addressed. A compilation of all published literature on chiral selectors has not been attempted.

Enantiomerization of Axially Chiral Biphenyls: Polarizable MD Simulations in Water and Butylmethylether.

In this study, we investigate the influence of chiral and achiral cations on the enantiomerization of biphenylic anions in n-butylmethylether and water. In addition to the impact of the cations and solvent molecules on the free energy profile of rotation, we also explore if chirality transfer between a chiral cation and the biphenylic anion is possible, i.e., if pairing with a chiral cation can energetically favour one conformer of the anion via diastereomeric complex formation. The quantum-mechanical calculations are accompanied by polarizable MD simulations using umbrella sampling to study the impact of solvents of different polarity in more detail. We also discuss how accurate polarizable force fields for biphenylic anions can be constructed from quantum-mechanical reference data.

The Impact of Solvent and the Receptor Structure on Chiral Recognition Using Model Acyclic Bisamides Decorated with Glucosamine Pendant Arms.

We investigated the influence of various factors (including solvent mixtures) on chiral recognition of chiral carboxylates, using the titration method under 1H NMR control. We found that strong binding carboxylates (geometrical matching) is not enough for the satisfactory differentiation of enantiomers. Moreover, solvent mixture studies indicate a significant influence of environment on the formation of diastereomeric complexes and variations among them. Our findings offer insights into the complementarity of chiral recognition processes.

A Review on Chiral Columns/Stationary Phases for HPLC

The chiral separation of pharmaceutical molecules and their precursors is one of the important areas of application of HPLC in pharmaceutical analysis for obtaining enantiomerically pure drug. The latter procedures include the use of so-called chiral selectors to enantio-selectively recognise and isolate the enantiomer. The direct approaches, i.e. those which do not derivate the compound of interest before separation, are addressed in detail, since they are now the most common approaches. The role of stereochemistry in medicinal products is being given greater emphasis to medical practice. For physicians to make conscious choice about the use of single-enantiomered medicinal products, basic knowledge is required. For few treatments single-enantiomer formulations can provide more selectivity than a combination of enantiomers in their biological purposes, enhanced therapeutic indexes and/or better pharmacokinetics. This highlights the possible biological and pharmacological variations between the two drug enantiomers and underlines the clinical experience of individual enantiomers. Particular emphases have been put on chiral separation by HPLC on chiral stationary phases (CSPs). Chiral derivatization reagents (CDRs) are optically pure reagent on reaction with drugs forms a pair of diastereoisomers that can be separated on conventional achiral phase. In Chiral mobile phase additive (CMPA) method, the stationary phase is achiral and the chiral selector is dissolved during the mobile phase. Interaction with the analyte’s enantiomer leads to the formation of transient diastereomeric complexes that are separated by their affinity towards mobile/stationary phase. Separation mechanisms and method development for chiral molecules using these phases are discussed in this review.

Drug encapsulation and chiral recognition in deep eutectic solvents/β-cyclodextrin mixtures

Hybrid materials resulting from the combination of Deep Eutectic Systems (DES) with well-known encapsulating agents like β-cyclodextrin (βCD) can open up new possibilities in the design of novel drug delivery systems or chiral-recognizing platforms. Here, 1:1 inclusion complexes of βCD and the tricyclic drugs amitriptyline (AMT) and cyclobenzaprine (CBZ) are studied in DES choline chloride:urea (reline) using a combination of NMR experiments. 1H complexation-induced chemical shift and intermolecular host-guest NOEs in the rotating frame (ROESY) confirm genuine drug encapsulation, and diffusion and relaxation measurements are used to study the dynamics of the guest-host inclusion complexes at the molecular level. Given the inherent chirality of AMT and CBZ, 13C NMR spectra unambiguously indicate the formation of diastereomeric inclusion complexes, demonstrating for the first time the retained enantiorecognition ability of βCD in DES. The proposed supramolecular systems combine then effectively the properties of DES and CDs.

Preparation of Enantiomerically Enriched P-Stereogenic Dialkyl-Arylphosphine Oxides via Coordination Mediated Optical Resolution

Optical resolution of several dialkyl-arylphosphine oxides was elaborated using the Ca2+ salt of (−)-O,O’-dibenzoyl-(2R,3R)-tartaric acid as the resolving agent. The conditions of crystallization and purification of the enantiomerically enriched phosphine oxides were optimized. Ethyl-phenyl-propylphosphine oxide and butyl-methyl-phenylphosphine oxide were prepared with an enantiomeric excess higher than 93%, whereas, three other dialkyl-arylphosphine oxides were obtained with an enantiomeric excess of 37–85%. It was also found that the sterically demanding alkyl chains hinder the formation of stable diastereomeric complexes, which consequently led to less efficient resolution procedures.

Electrochemical chiral interface based on the Michael addition/Schiff base reaction of polydopamine functionalized reduced graphene oxide

A novel approach for the fabrication of chiral sensing platform via the Michael addition or Schiff base reaction between functionalized graphene with polydopamine (rGO-PDA) and L-lysine (L-Lys) was first put forward. GO can be modified and reduced simultaneously via using dopamine. By utilizing catechol functional group on PDA, L-Lys combined with rGO-PDA via the Michael addition or Schiff base reaction. Michael addition reaction occurred between electrophilic conjugate system (L-Lys) and nucleophilic negative carbon ion (rGO-PDA). We firstly synthesized the L-Lys copper (II) (L-Lys-Cu) complex to protect the chiral sites on L-Lys. The terminal amino group on L-Lys-Cu will interact with rGO-PDA by Michael addition or Schiff base reaction to synthesize rGO-PDA/L-Lys copper (II) composite. The copper ions in rGO-PDA/L-Lys copper (II) composite were removed to prepare rGO-PDA-L-Lys chiral composite, which was served as electroactive materials to discriminate tryptophan (Trp) enantiomers via electrochemical method. The results showed that the rGO-PDA-L-Lys showed better affinity for D-Trp than L-Trp owing to the formation of diastereomeric complexes between enantiomer (D-Trp) and selector (L-Lys). Besides, the proposed rGO-PDA-L-Lys showed great application potential in actual samples.

Chiral Mobile-Phase Additives in HPLC Enantioseparations.

High-performance liquid chromatography (HPLC) is one of the main separation techniques for chiral drugs. Among the chiral HPLC techniques available, the chiral mobile-phase additive (CMPA) technique is a valuable method for the direct enantioseparation of chiral chemical entities. In the CMPA method, the chiral selector is dissolved in the mobile phase while the stationary phase is achiral. Interaction with the analyte enantiomers results in the formation of transient diastereomeric complexes. These complexes differ in their formation constants and/or distribution between the (achiral) stationary phase and the mobile phase resulting in an enantioseparation. This chapter describes the HPLC separation applying CMPA methods by several most useful types of chiral selectors including chiral ligand exchangers, macrocyclic antibiotics, and cyclodextrins.

Recognition Mechanisms of Chiral Selectors: An Overview.

Stereospecific recognition of chiral molecules plays an important role in nature as the basis of the interaction of chiral bioactive compounds with the chiral target structures. In separation sciences such as chromatographic and capillary electromigration techniques, interactions between chiral analytes and chiral selectors, i.e., the formation of transient diastereomeric complexes in thermodynamic equilibria, are the basis for chiral separations. Due to the large structural variety of chiral selectors, different structural features contribute to the overall chiral recognition process. This introductory chapter briefly summarizes the present understanding of the structural enantioselective recognition processes for various types of chiral selectors.

Chirality Effect on Cholesterol Modulation of Protein Function.

Cholesterol is a key steroidal, lipid biomolecule found abundantly in plasma membranes of eukaryotic cells. It is an important structural component of cellular membranes and regulates membrane fluidity and permeability. Cholesterol is also essential for normal functioning of key proteins including ion-channels, G protein-coupled receptors (GPCRs), membrane bound steroid receptors, and receptor kinases. It is thought that cholesterol exerts its actions via specific binding to chiral proteins and lipids as well as through non-specific physiochemical interactions. Distinguishing between the specific and the non-specific interactions can be difficult. Although much remains unclear, progress has been made in recent years by utilizing ent-cholesterol, the enantiomer of natural cholesterol (nat-cholesterol) as a probe. Ent-Cholesterol is the non-superimposable mirror image of nat-cholesterol and exhibits identical physiochemical properties as nat-cholesterol. Hence, if the biological effects of cholesterol result solely due to membrane effects, it is expected that there will be no difference between ent-cholesterol and nat-cholesterol. However, when direct binding with chiral proteins and lipids is involved, the enantiomer is expected to potentially elicit significantly different, measurable effects due to formation of diastereomeric complexes. In this chapter, we have reviewed the literature related to ent-cholesterol and its use as a probe for various biophysical and biological interactions of cholesterol.

Tetraglymes as Prochiral Host Reagents for Ammonia Borane

The molecular structure of the complex of ammonia borane (AB) with acyclic ether tetraglyme Me(OCH2CH2)4OMe (1), 1·(AB)2 was determined by single‐crystal X‐ray structure analysis for the first time. The crystal structure features two AB molecules, bonded by dihydrogen bonds, per one tetraglyme unit. The intermolecular BH···HN distances of 1.94 Å are shorter than those in the solid ammonia borane (2.02–2.32 Å). A comparison of the hydrogen and dihydrogen bonds in 1·(AB)2 and in the complexes of AB with crown‐ethers (CE) was carried out. The complex formation with both the CE and the acyclic polyether 1 activates the B–H bond in AB via N–H···O hydrogen bonds and therefore increases the reducing activity of AB. Supposedly, the structure of 1·(AB)2 is related to the initial steps of the AB activation in a polyether solution. The effect of the substituents on the complexation of the substituted derivatives of 1 comes down to a structural adjustment minimizing steric repulsion. Computations reveal that the complexation of diastereomeric disubstituted glymes with AB leads to the formation of diastereomeric complexes that differ noticeably in stability. This is a prerequisite for inducing stereoselectivity, which makes such complexes attractive for potential synthetic applications.

Last ten years (2008-2018) of chiral ligand-exchange chromatography in HPLC: An updated review.

Chiral ligand-exchange chromatography is one of the elective strategies for the direct enantioresolution of small chelating compounds: amino acids, diamines, amino alcohols, diols, small peptides, etc. Unlike other methods, the interaction between chiral selector and analyte enantiomers is mediated by a cation, thus producing diastereomeric ternary complexes. Two main approaches are conventionally applied in chiral ligand-exchange chromatography. The first relies upon chiral stationary phases where the chiral selector is either covalently immobilized or physically adsorbed onto suitable packing materials (coated phases). In the second approach, chiral molecules are added to the eluent, thus generating chiral eluent systems. Among the advantages of chiral ligand-exchange chromatography, the generation of UV/vis-active metal complexes, and the use of commercially available or easy-to-synthesize chiral selectors, in combination to rather inexpensive achiral columns for coated phases and chiral eluents, are noteworthy. Besides amino acids and amino alcohols, other species have proven suitable for chiral ligand-exchange chromatography applications. Recently, the use of either chiral ionic liquids or micellar liquid chromatography systems as well as the successful off-column formation of diastereomeric complexes have expanded the selectivity profiles and application fields. All of these issues are touched in the review, shedding light to the contributions appeared in the last decade.

The resolution of acyclic P-stereogenic phosphine oxides via the formation of diastereomeric complexes: A case study on ethyl-(2-methylphenyl)-phenylphosphine oxide.

As an example of acyclic P-chiral phosphine oxides, the resolution of ethyl-(2-methylphenyl)-phenylphosphine oxide was elaborated with TADDOL derivatives, or with calcium salts of the tartaric acid derivatives. Besides the study on the resolving agents, several purification methods were developed in order to prepare enantiopure ethyl-(2-methylphenyl)-phenylphosphine oxide. It was found that the title phosphine oxide is a racemic crystal-forming compound, and the recrystallization of the enantiomeric mixtures could be used for the preparation of pure enantiomers. According to our best method, the (R)-ethyl-(2-methylphenyl)-phenylphosphine oxide could be obtained with an enantiomeric excess of 99% and in a yield of 47%. Complete racemization of the enantiomerically enriched phosphine oxide could be accomplished via the formation of a chlorophosphonium salt. Characterization of the crystal structures of the enantiopure phosphine oxide was complemented with that of the diastereomeric intermediate. X-ray analysis revealed the main nonbonding interactions responsible for enantiomeric recognition.

Preparation of enantiopure 1‐isopentyl‐3‐methyl‐3‐phospholene 1‐oxide via the formation of diastereomeric complexes

AbstractThe resolution of 1‐isopentyl‐3‐methyl‐3‐phospholene 1‐oxide via the formation of diastereomeric complexes using TADDOL derivatives or the Ca2+‐salts of tartaric acid derivatives was studied. Both enantiomers of the 1‐isopentyl‐3‐phospholene oxide were prepared in an enantiopure form with (R,R)‐spiro‐TADDOL, or with the acidic Ca2+‐salt of O,O′‐dibenzoyl‐(R,R)‐tartaric acid. The absolute configuration of the 1‐isopentyl‐3‐phospholene oxide enantiomer with negative optical rotation was also substantiated by a study involving CD spectroscopy and theoretical calculations.

Resolution of Racemic Mixtures by Phase Transition of PEGylated Resolving Agents.

A novel, efficient, and simple method for the resolution of racemic mixtures is presented in which PEGylated resolving agents are subjected to diastereomeric complex formation in alcohols. The resulting complexes then undergo temperature-assisted phase transition, affording a precipitate that is enriched in one enantiomer and separable by filtration. In an aqueous solution, phase transition can be caused by the methods used in the precipitation of poly(ethylene glycol) (e.g., addition of ammonium sulfate). A number of racemic amines have been successfully resolved using this method. The first cycle of resolution affords the amines with an optical purity of 72–85% from their corresponding racemic mixture in good yields (78–90%). An additional cycle improved the optical purity to 87–95%. The PEGylated resolving agents can be recovered and reutilized without the loss of resolution efficiency.

The resolution and application of P-stereogenic phosphine oxides

GRAPHICAL ABSTRACT

New chiral oxo-bridged calix[2]arene[2]triazine for the enantiomeric recognition of α-racemic carboxylic acids

The enantiomeric excess is a key parameter for chemical and pharmaceutical industries for its ability to determine the activity and therapeutic action of chiral compounds. The determination of the enantiomeric excess using nuclear magnetic resonance is generally based on the formation of diastereomeric complexes. Herein we report novel chiral oxo-bridged calix[2]arene[2]triazine derivatives, which were synthesized from (1S,2R)-(−)-1-amino-2-indanol or (1S,2R)-(+)-2-amino-1,2-diphenylethanol. The structures of these compounds were established by various spectroscopic methods. Their enantiomeric recognition abilities towards the enantiomers of α-racemic carboxylic acids were examined by using 1H NMR spectroscopy. The ΔΔδ values of α-H signals were appropriate to give a good baseline resolution for most of the tested analytes, which ranged from 0.005 to 0.053ppm. The α-hydroxy acids, especially those containing aromatic group such as mandelic acid, α-methoxyphenylacetic acid, showed a bigger ΔΔδ value in comparison to the other carboxylic acids.

Chiral separation of new designer drugs (Cathinones) on chiral ion-exchange type stationary phases

We present the enantioseparation of new designer drugs from the cathinone family on structurally different chiral ion-exchange type stationary phases. A novel strong cation-exchange type chiral stationary phase was synthesized and its performance compared with previously reported ion-exchange type chiral stationary phases. The influence of structural elements of the chiral selectors on their chromatographic performance was studied and the possibilities of tuning chromatographic parameters by varying the polarity of the employed mobile phases were determined. Evidence is provided that a change in mobile phase composition strongly influences the solvation shell of the polarized and polarizable units of the selectors and analytes, as well as ionizable mobile phase additives. Furthermore, the structural features of the selectors (e.g. the size of aromatic units and their substitution pattern) are shown to play a key role in the effective formation of diastereomeric complexes with analytes. Thus, we have achieved the enantioseparation of all test analytes with a mass spectrometry-compatible mobile phase with a chiral strong cation-exchange type stationary phase.

Chiral (2-cyanophenoxy)methyl-15-crown-5 in diastereomeric discrimination of amino acid esters according to the data of electrospray ionization mass spectrometry

The ability of [(2-cyanophenoxy)methyl]-15-crown-5 lariat ether enantiomers to diastereomeric discrimination with respect to hydrochlorides of 1-phenylethylamine and methyl esters of alanine, phenylalanine, and phenylglycine was studied by electrospray ionization mass spectrometry. The mentioned crown ether is available in non-racemic form owing to the procedure of preferential crystallization of enantiomers of its precursor. The quantitative estimation of the differences in the formation of diastereomeric complexes between the crown ether and the guests was performed by two independent methods: application of the guests with isotopic markers and using an additive of achiral amine-displacer. Both approaches indicate the existence of a moderate chiral discrimination: The (S)-enantiomer of the crown ether binds prevailingly the (S)-enantiomer of the guest, and vice versa.

A Case Study on the Resolution of the 1‐i‐Butyl‐3‐methyl‐3‐phospholene 1‐Oxide via Diastereomeric Complex Formation Using TADDOL Derivatives and via Diastereomeric Coordination Complexes Formed from the Calcium Salts of O,O′‐Diaroyl‐(2R,3R)‐tartaric Acids

ABSTRACTThe resolution of 1‐i‐butyl‐3‐methyl‐3‐phospholene 1‐oxide was studied applying TADDOL [(−)‐(4R,5R)‐4,5‐bis(diphenylhydroxymethyl)‐2,2‐dimethyldioxolane], spiro‐TADDOL [(−)‐(2R,3R)‐α,α,α′,α′‐tetraphenyl‐1,4‐dioxaspiro[4.5]decan‐2,3‐dimethanol], or the acidic and neutral Ca2+ salts of (−)‐O,O′‐dibenzoyl‐ and (−)‐O,O′‐di‐p‐toluoyl‐(2R,3R)‐tartaric acid as the resolving agent. The absolute configuration of the P‐asymmetric center was determined by circular dichroism spectroscopy and related quantum chemical calculations. In one instance, the single crystal of the diastereomeric complex incorporating i‐butyl‐3‐phospholene oxide and spiro‐TADDOL was subjected to X‐ray analysis, which suggested a feasible hypothesis for the efficiency of the resolution process under discussion that may be an example for the “solvent‐inhibited” resolution.