Diastereomeric Association Research Articles

Chiral separation of rasagiline using sulfobutylether-β-cyclodextrin: capillary electrophoresis, NMR and molecular modeling study.

Pressure-assisted stereospecific capillary electrophoresis method was developed for the determination of enantiomeric purity of the antiparkinsonian agent (R)-rasagiline. The optimized method, 50mM glycine-HCl buffer pH 2, supplied with 30mM sulfobutylether-β-cyclodextrin, at 35°C, applying 12 kV in reversed polarity, and -8 mbar pressure (vacuum), short-end injection with -25 mbar × 2 s, was successful for baseline separation of rasagiline enantiomers (Rs = 3.5 ± 0.1) in a short analysis time. The method was validated according to current guidelines and proved to be reliable, linear, precise and accurate for determination of 0.15% S-enantiomer as chiral impurity in R-rasagiline sample, as well as quantification of the eutomer. Method application was tested on a commercial tablet formulation. Determination of spatial structure of diastereomeric associates was based on 1 H and 2D ROESY NMR, indicating that the aromatic moiety of the molecule can enter the cyclodextrin cavity. NMR titration and molecular modeling revealed that S-rasagiline formed a more stable inclusion complex with sulfobutylether-β-cyclodextrin, than its antipode, which is in agreement with electrophoretic results.

Selector‐Induced Dynamic Deracemization of a Selectand‐Modified Tropos BIPHEPO‐Ligand: Application in the Organocatalyzed Asymmetric Double‐Aldol‐Reaction

Stereolabile interconverting catalysts open up the possibility of directing enantioselectivity in asymmetric synthesis by formation of diastereomeric complexes with chiral auxiliaries and deracemization. However, the stoichiometrically used auxilliaries can significantly limit the potential applications of such systems. We synthesized a new BIPHEPO tropos ligand containing achiral selectands in the backbone, which forms transient diastereomeric associates with amylose-tris-3,5-dimethylphenyl carbamate as a selector and thus deracemizes. The enantiomerically enriched BIPHEPO obtained was successfully used in the organocatalytic asymmetric double aldol addition of substituted methyl ketones to form benzaldehyde. This strategy combines an on-column deracemization with the high stereoinduction of chiral biarylphosphineoxides and opens up new possibilities in the field of self-amplified asymmetric syntheses.

Capillary electrophoretic and nuclear magnetic resonance studies on the opposite affinity pattern of propranolol enantiomers towards various cyclodextrins

In the present study the migration order of the propranolol enantiomers with various native CDs and neutral and charged CD derivatives was examined in capillary electrophoresis (CE). The reversal of the enantiomer migration order was observed due to sulfation of beta-CD on its primary hydroxy groups. The structures of intermolecular selector-select and temporary diastereomeric associates in solution were elucidated based on 1D rotating frame nuclear Overhauser effect spectroscopy (1D ROESY) experiments. Major structural differences were observed between the propranolol complexes with native beta-CD and heptakis(6-O-sulfo)-beta-CD.

About the role of enantioselective selector–selectand interactions and the mobilities of diastereomeric associates in enantiomer separations using CE

It is generally accepted that the selective binding of enantiomers of the chiral analyte to a chiral selector is necessary for enantioseparations in CE, whereas the role of mobility differences between the temporary diastereomeric associates formed between the enantiomers and the chiral selector has been commonly neglected. One of the authors of this study suggested in 1997 that the mobility difference between the diastereomeric associates of two enantiomers with the chiral selector may be solely responsible for a separation of enantiomers in CE and enantioselective selector-selectand binding may be not necessarily required. Several indirect confirmations of this hypothesis have been described in the literature within the last few years but a dedicated study proving this concept has not been published yet. The present data obtained for the two chiral antimycotic drugs ketoconazole and terconazole by CE and NMR spectroscopy unequivocally support this concept.

Subtle Crossover from C−H···O to SO···CO Short Contacts in the Association of Diastereomers of 2,4(6)-Di-O-benzoyl-6(4)-O-[(1S)-10-camphorsulfonyl]-myo-inositol 1,3,5-Orthoformate upon Formation of Pseudopolymorphs

Diastereomers of 2,4(6)-di-O-benzoyl-6(4)-O-[(1S)-10-camphorsulfonyl]-myo-inositol 1,3,5-orthoformate associate via weak interactions to form “head-to-head” dimers in their crystals. Molecular association through C−H···O short contacts do not leave any void for the guest inclusion, while association through SO···CO bridging produces pseudopolymorphs. Three crystalline modifications are observed for the title compound: form I, monoclinic P21, without any guest solvent, and solvated forms II and III, that belong to monoclinic space groups P21 and C2, respectively. A majority of solvates, which include pyridine, dichloromethane, benzene, tetrahydrofuran, and cyclohexanone as guests, belong to form III. All these guests have 2-fold symmetry axes (C2) with their electron count within 40−62 electrons; guest selectivity experiments indicate that planar aromatic guests (pyridine, benzene) bind better to the host molecules as compared to nonplanar guests (dioxane, cyclohexanone). The molecular packing that is created thorough channels in the crystal (avoiding interpenetration of the layers) are of interest because of their potential application in molecular separation by forming selective inclusions. The diastereomeric association via SO···CO dipolar short contacts, a consistent feature observed in all the solvates, is thought to have relevance in the binding of sulfonyl drugs to the CO moieties of the receptor proteins.

Differentiations of Enantiomers via Their Diastereomeric Association Complexes—There Are Two Ways of Shaking Hands

The intermolecular interactions of one enantiomer with a chiral auxiliary molecule and the interactions of the other enantiomer with the auxiliary are considered. Different functions of the latter give rise to the following well-known aspects of organic stereochemistry that are characterized in the present article: (i) preparative separation of enantiomers via crystallization of diastereomeric salts; (ii) analysis of enantiomers by NMR spectroscopy; (iii) separation of enantiomers by chromatography; (iv) biological activities of enantiomers; and (v) reactivities of enantiomers in enzymatic resolution. The common basis of these aspects is the formation of two diastereomeric association complexes that may differ with respect to their physical and chemical properties. The following practical applications of this phenomenon are briefly described: the small- and large-scale preparation of the enantiomers of organic compounds; the analysis of chiral nonracemic mixtures by chromatography and by NMR spectroscopy; and the growing use of drugs in the form of one of the enantiomers. It is proposed to emphasize the similarity of the association-based differentiations. This goal can be attained by giving a corresponding lecture in the second or third year of university chemistry.

Enantiomer separations in capillary electrophoresis in the case of equal binding constants of the enantiomers with a chiral selector: commentary on the feasibility of the concept.

It is generally acknowledged that enantiomer separations in capillary electrophoresis are based on differences in the affinities of the analyte enantiomers toward the chiral selector expressed as equilibrium constants of the resulting temporary diastereomeric associates. However, as can be derived from theoretical considerations, a separation of enantiomers by CE is in principle also possible solely based on differences in the mobilities of the temporary diastereomeric complexes per se, when equal binding constants between analyte enantiomers and the chiral selector are assumed and observed.

Preparation, conformational analysis and behaviour as chiral solvating agents of 9-anthrylpentafluorophenylmethanol enantiomers: study of the diastereomeric association

The synthesis, structure and behaviour as chiral solvating agents of the enantiomers of 9-anthrylpentafluorophenylmethanol is reported.

Preparation and behavior of ( R)- and ( S)-2,2,2-trifluoro-1-(1-pyrenyl)ethanol as chiral solvating agents: study of the diastereomeric association by Job's plots, intermolecular NOE and binding constants

Racemic 2,2,2-trifluoro-1-(1-pyrenyl)ethanol 2, was prepared and the ( R)- and ( S)-enantiomers obtained by preparative chiral HPLC. The behavior of these compounds as chiral solvating agents is studied with mixtures of several enantiomeric aromatic alcohols and amines. The non-linear distribution of aromatic rings in the pyrene appears to enhance the enantiodiscrimination capacity.

Comparison of two methods for the gas chromatographic determination of thermodynamic parameters of enantioselectivity

The thermodynamic parameters responsible for the formation of diastereomeric associates between enantiomers of methyl lactate and two Lipodex E columns [with 5.37% or 10.08% of octakis(3- O-butanoyl-2,6-di- O-pentyl)-γ-cyclodextrin in SE 54] were calculated using two different methods. Method A was based on the direct determination of Δ(Δ G R, S 0) from experimental values of the chiral separation factor α obtained at different temperatures for the separation of the enantiomers of methyl lactate on two Lipodex E columns. Method B relies on the determination of the relative retention of the enantiomers of methyl lactate in respect to an inert reference standard on a reference column containing only the solvent and that of the enantiomers of methyl lactate to the same reference standard on the reactor column containing the cyclodextrin derivative in the solvent S. SE 54 was used as solvent for Lipodex E and n-heptane, n-octane and n-nonane were used as reference standards. Obtained results for Δ R,S (Δ G 0) show that the data calculated by Method A are too small and are dependent on the concentration of the chiral selector in the diluted stationary phase. Since the dependence of ln α on 1/ T for methyl lactate enantiomers on Lipodex E columns was nonlinear, it was not possible to calculate Δ R,S (Δ H 0) and Δ R,S (Δ S 0) values by this method. Results obtained by Method B are essentially independent on the choice of reference compound and the concentration of the chiral selector in the mixed stationary phase.

Organic Reactions in the Solid State: Reactions of Enclathrated 3,4-Epoxycyclopentanone (=6-Oxobicyclo[3.1.0]hexan-3-one) in Tri-o-thymotide and Absolute Configuration of 4-Hydroxy- and 4-Chlorocyclopent-2-en-1-one

Several aspects of the heterogeneous actions of aqueous and gaseous HCl on the chemical behavior of 3,4‐epoxycyclopentanone (=6‐oxabicyclo[3.1.0]hexan‐3‐one; 1) included in the asymmetric cages of tri‐o‐thymotide (TOT) clathrates belonging to space groups P3₁21 are described, showing specific features strikingly at variance with those observed in liquid solutions. In a first step, the substrate underwent an acid‐promoted allylic isomerization, as already observed in our previous investigations, to give optically active 4‐hydroxycyclopent‐2‐en‐1‐one (2). In a consecutive step, a displacement of the OH group was accomplished by the Cl⁻ anion to afford the corresponding chloro compound 3. Polymorphism was encountered in the preparation of TOT/1 clathrates. Recrystallization of TOT in the pure guest 1 yielded micro‐twinned crystals belonging to the P3₁ space group (host/guest ratio 1 : 1), whereas the expected P3₁21 lattice grew from a mixture of TOT, 1, and MeOH. The structural determination of TOT/1 was carried out by X‐ray diffraction (Fig. 1). Kinetic measurements were achieved that shed light on some striking features of this type of heterogeneous reactions for solid‐liquid and solid‐gas systems. Several reactions of pure clathrate antipodes (+)‐TOT/1 with gaseous HCl were carried out under various conditions; concentration and enantiomer‐excess(ee) determinations of the products 2 and 3 allowed to establish a larger ee for 3, thus demonstrating the influence of the host‐guest diastereomeric association on the progression of the reaction. The correlation of optical activities of the host and products for the global reaction disclosed the sequence (+)‐(M)‐TOT/1→(−)‐2→(−)‐3. A new way for the preparation of 2 was devised. It was further demonstrated that the X‐ray structure analysis of the chiral clathrate (M)‐TOT/(+)‐2 (Fig. 4) associated with chiroptical measurements was an efficient and straightforward method to determine the absolute (+)‐(R)‐configuration of the guest. The enantioselectivity of the TOT clathrate for 2 was established by two different methods which allowed the appraisal of an accurate revised value of the specific rotation of 2. The enclathration of 3 occurred exclusively in the orthorhombic centrosymmetric host lattice Pbca, thus prohibiting the X‐ray structural determination of the guest absolute configuration. The problem of finding a pathway to the intended enantiomer enrichment of 3 was worked out through the action of aqueous HCl on microcrystalline (+)‐TOT/(−)‐(S)‐2 that gave an optically active mixture of unreacted 2 with 3 as sole product. The pure optically active 3 was isolated by subsequent TLC. The resolution of 3 was achieved by GC over a chiral column and its (unknown) specific rotation measured. The absolute configuration of 3 was established by the measurement of the enantiomer purity of the optically active mixture 3 obtained after the total conversion of (−)‐(S)‐2 in the presence of thionyl chloride in Et₂ O, dioxane, and benzene. It was deduced that the (−)‐3 enantiomer had the (S)‐configuration.

Article

Sterically hindered N-(o-aryl)-rhodanines (a) (N-(o-aryl)-2-thioxo-4-thiazolidinones) have been synthesized and the N-(o-tolyl) and N-(o-chlorophenyl) derivatives have been converted to their dioxo analogs (b) (N-(o-aryl)-2,4-thiazolidine- diones). The chirality of the compounds in their conformational ground states was proved by detection of the diastereotopic protons or methyl groups at C-5 of the heteroring using 1H and 13C NMR spectroscopy. In the presence of the optically active auxiliary (S)-(+)-1-(9-anthryl)-2,2,2-trifluoroethanol the enantiomers of the racemic mixtures formed diastereomeric association complexes via H-bonding.Key words: chirality, chiral auxiliary, rotational isomerism, N-(o-aryl)-rhodanines, N-(o-aryl)-2,4-thiazolidinediones, 1H and 13C NMR.

Enantioseparation of N-protected ?-amino acid derivatives by liquid-liquid extraction technique employing stereoselective ion-pair formation with a carbamoylated quinine derivative

Two-phase liquid-liquid extraction experiments were undertaken to study the enantioselective transport of the chiral N-protected α-amino acid derivatives from an aqueous buffer solution into an organic phase employing highly lipophilic carbamoylated quinine as chiral selector and phase transfer carrier, respectively. The chiral separation, derived from enantioselective ion-pair formation and differential solubility in the aqueous and organic phases of diastereomeric associates thus formed has been shown to be primarily dependent on the structure of the selectand, the nature of the organic solvent, the molar ratio of a given chiral selector to selectand in the two phases, and the pH of the aqueous phase. Extracted enantiomers were recovered by back-extraction using a relatively polar acidic medium in which the selector is barely insoluble. Thus, the enantiomeric purity of N-(3,5-dinitrobenzoyl)-leucine exceeded 95% enantiomeric excess with 70% overall yield with a single extraction and back-extraction step. Chirality 9:268–273, 1997. © 1997 Wiley-Liss, Inc.

Determination of the enantiomeric ratio of organic ammonium halides or alkali carboxylates by NMR spectroscopy

The enantiomeric ratio of chiral ammonium halides or alkali carboxylated can be determined by mixing the salt with an optically active carboxylate or ammonium halide, respectively (eq 1), and investigating the diastereomeric associates by 1 H- or 13 C-NMR

Enantiomers and barriers to racemization of sterically hindered N‐aryl‐ and N‐heteroarylpyrroles

AbstractThe N‐aryl‐ and N‐heteroaryl‐2,5‐dimethylpyrrole‐3‐carbaldehydes 2–8 have been synthesized by condensation of hexane‐2,5‐dione with the appropriate amine and subsequent Vilsmeier‐Haack formylation of the pyrrole ring. Diastereomeric association complexes of the racemic pyrrole 8 were studied by pmr chemical shifts and the splittings induced by (+)‐1‐(9‐anthryl)‐2,2,2‐trifluoroethanol. Enrichment of the enantiomers M and P of 2 and 6 was achieved by liquid chromatography on triacethylcellulose. The barrier to partial rotation about the C‐N bond in 6 was determined by thermal racemization and its lower limits in 2 and 8 were estimated.

Chiral recognition in gas chromatographic resolution of amino acid enantiomers

Studies of selectivity of hydrogen bond formation in chiral solute-solvent systems have been performed by1H and13C nuclear magnetic resonance techniques. These data are correlated with the results of gas chromatographic investigations of the same systems. Interactions between the optically active solvent(N-(N-benzoyl-L-amino acid)-anilide) and optically active solute(N-trifluoroacetyl-L-alanyl isopropyl ester) were examined. NMR evidence indicated that hydrogen bonding interaction occurred between two N-H portion and on peptidyl carbonyl portion in stationary phase and solute molecule on three points. The association constants of solvent-solute interaction were calculated and the structure of the diastereomeric association complex between N-(N-benzoyl-L-valyl)-anilide and N-TFA-L-alanyl isopropyl ester was proposed.

Gas Chromatographic Separation of Enantiomers on Optically Active Metal‐Complex‐Free Stationary Phases. New Analytical Methods (24)

AbstractIf a stationary phase A employed in gas chromatography possesses a chemical affinity for substance B, which is to be separated, then the retention behavior is not only determined by the normal physical equilibrium between the gas and liquid phases but also by the chemical equilibrium A + B ⇋ AB. If A and B are chiral and A is present in optically active form while B is a racemic mixture, then it is possible to achieve a gas chromatographic enantiomer resolution without the isolation of diastereomers: the energetically different diastereomeric associates AR BR and AR BS are formed rapidly and reversibly. This enantiospecific resolution principle was first demonstrated in 1966 by the quantitative resolution of racemic amino acid derivatives on optically active peptide phases in analogy to the well‐known stereospecificity of enzymes. The anchoring of the chiral resolving agent to thermally stable polysiloxanes together with the employment of high resolution capillary columns and the use of appropriate derivatization strategies has led to the development of enantiomer resolution into a routine modern method for many classes of substances. The demonstration of enantiospecificity in the gas chromatographic separation process is of fundamental interest, and its systematic study can result in a significant contribution to the understanding of the molecular mechanism of “chiral recognition”. The gas chromatographic separation of enantiomers has also proven to be an accurate and sensitive method for the determination of the enantiomeric composition of natural products and products of enantioselective transformations (asymmetric syntheses, “chiral pool” transformations, kinetic resolutions, biomimetic reactions) and for the quantification of racemization, e.g. in the synthesis and hydrolysis of peptides. In any research program devoted to the phenomenon of chirality, the gas chromatographic separation of the enantiomers of volatile compounds constitutes an indispensable modern instrumental technique.

Application of NMR spectroscopy of chiral association complexes. 13—electron donor–acceptor complexes between racemic carbazolo[3,4‐c]carbazoles and an optically active acceptor

AbstractStrong electron donor–acceptor (EDA) association between carbazolo[3,4‐c]carbazoles and an optically active tetranitrofluorenone derivative was detected by UV–visible spectroscopy and by 1H NMR shifts. 1H NMR splittings at low temperatures are due to diastereomeric association complexes and, thus, prove the chirality of carbazolocarbazoles.

Liquid chromatographic resolution of enantiomers on normal-phase chiral amide-bonded silica gel : Retentions of optically active a-Amino acid derivatives on N-Acyl homologues of l-Valylaminopropylsilanized silica phases

In order to develop a chiral stationary phase for the direct resolution of optical isomers in liquid chromatography, new chemically bonded phases, involving less specific and milder diastereomeric association with the solute molecule than with previously known phases, were prepared. N-Acyl homologues of l-valylaminopropylsilanized packing materials containing chiral amide bonds were synthesized from microparticulate silica gel. Racemic N-acetyl- a-amino acid and benzyloxycarbonyldipeptide esters were resolved into their antipodes in a normal-phase system using high-efficiency columns packed with a slurry of the new chiral materials. The retention mechanism was confirmed from the relationship between the capacity ratio and the binary solvent composition. The conformations and the steric fitting of the graft moiety and the solute molecule were discussed by examining space-filling models.

Separation of amino acid enantiomers by gas chromatography with an optically active stationary phase (N-TFA-L-valyl-L-leucine cyclohexyl ester)

The resolution of amino acid enantiomers by gas chromatography on optically active stationary phases has been explained by the formation of hydrogen bonded diastereomeric association complexes. Structural considerations involving these complexes have led to the synthesis of a new phase, TFA-L-valyl-L-leucine cyclohexyl ester. Relative retention times and resolution factors have been determined for each enantiomeric pair of eleven amino acids and glycine. Investigations have uncovered some trends in resolution factors and relative retention times for amino acids on different dipeptide phases. These patterns led to an explanation for the difficulties found in resolving D, L-proline. Structural differences about the α-carbon in the dipeptide phase influence the elution pattern of TFA-amino acid isopropyl esters from the column. Particularly strong effects are found in the elution patterns of hydroxy amino acids on different dipeptide phases.