The role of weak hydrogen bonds in chiral recognition

Chiral recognition has been studied in neutral or ionic weakly bound complexes isolated in the gas phase by combining laser spectroscopy and quantum chemical calculations. Neutral complexes of the two enantiomers of lactic ester derivatives with chiral chromophores have been formed in a supersonic expansion. Their structure has been elucidated by means of IR-UV double resonance spectroscopy in the 3 μm region. In both systems described here, the main interaction ensuring the cohesion of the complex is a strong hydrogen bond between the chromophore and methyl-lactate. However, an additional hydrogen bond of much weaker strength plays a discriminative role between the two enantiomers. For example, the 1:1 heterochiral complex between R-(+)-2-naphthyl-ethanol and S-(+) methyl-lactate is observed, in contrast with the 1:1 homochiral complex which lacks this additional hydrogen bond. On the other hand, the same kind of insertion structures is formed for the complex between S-(±)-cis-1-amino-indan-2-ol and the two enantiomers of methyl-lactate, but an additional addition complex is formed for R-methyl-lactate only. This selectivity rests on the formation of a weak CHπ interaction which is not possible for the other enantiomer. The protonated dimers of Cinchona alkaloids, namely quinine, quinidine, cinchonine and cinchonidine, have been isolated in an ion trap and studied by IRMPD spectroscopy in the region of the ν(OH) and ν(NH) stretch modes. The protonation site is located on the alkaloid nitrogen which acts as a strong hydrogen bond donor in all the dimers studied. While the nature of the intermolecular hydrogen bond is similar in the homochiral and heterochiral complexes, the heterochiral complex displays an additional weak CHO hydrogen bond located on its neutral part, which results in slightly different spectroscopic fingerprints in the ν(OH) stretch region. This first spectroscopic evidence of chiral recognition in protonated dimers opens the way to the study of the complexes of Cinchona alkaloids involved in enantioselective catalysis. These examples show how secondary hydrogen bonds controlled by stereochemical factors govern molecular recognition processes.     

Enantioselective enolate protonation in sulfa-Michael addition to α-substituted N-acryloyloxazolidin-2-ones with bifunctional organocatalyst

Organocatalytic conjugate addition of thiols to α-substituted N-acryloyloxazolidin-2-ones followed by asymmetric protonation has been studied in the presence of cinchona alkaloid derived thioureas. Both of the enantiomers are accessible with the same level of enantioselectivity using pseudoenantiomeric quinine/quinidine derived catalysts. The addition/protonation products have been converted to useful biologically active molecules.     

Simultaneous separation of the stereoisomers of 1-amino-2-hydroxy and 2-amino-1-hydroxypropane phosphonic acids by stereoselective capillary electrophoresis employing a quinine carbamate type chiral selector

A stereoselective nonaqueous capillary electrophoresis (CE) method utilizing O-(tert-butylcarbamoyl) quinine as chiral ion-pair agent and additive to the non aqueous background electrolyte was evaluated for the simultaneous separation of the enantiomers and diastereomers of 1 -amino-2-hydroxypropane phosphonic acid besides the corresponding beta-aminophosphonic acid analogs, the stereoisomers of 2-amino-1-hydroxypropane phosphonic acid, in a single run. The separations have been carried out using the partial filling technique to avoid strong background signal from the quinine selector. It conveniently allowed the baseline separation of all eight components of interest (alpha- as well as beta-aminophosphonic acids) as N-2,4-dinitrophenyl derivatives in a single run. Moreover, the absolute configurations of all eight peaks were identified. Compared to the quinine carbamate selector, the corresponding 'pseudo-enantiomeric' O-(tert-butylcarbamoyl) quinidine selector exhibited reserved elution order and nearly identical resolutions. The proposed CE method turned out to be advantageous over stereoselective high-performance liquid chromatography (HPLC) with a quinine carbamate type stationary phase, which showed high enantioselectivity, but failed to simultaneously separate all eight components.     

Enantiomer separation of N-protected amino acids by non-aqueous capillary electrophoresis and high-performance liquid chromatography with tert.-butyl carbamoylated quinine in either the background electrolyte or the stationary phase

A non-aqueous CE method was developed for evaluating the chiral discrimination potential of cinchona alkaloids and different kinds of carbamoylated derivatives of quinine and quinidine type chiral selectors towards acidic analytes, in particular a series of various Bz (benzoyl), DNB (3,5-dinitrobenzoyl) and DNZ (3,5-dinitrobenzyloxycarbonyl) amino acid derivatives. In this study, the enantioselectivity values obtained in non-aqueous CE with tert.-butyl carbamoylated quinine as chiral additive have been compared with the values found for the same series of selectands in HPLC using the same selector immobilized onto silica as chiral stationary phase. Similarly to the background electrolyte used in CE an ethanol-methanol mixture (60:40, v/v) containing 100 mM octanoic acid and 12.5 mM ammonia has been selected as HPLC mobile phase. Under these conditions, a good correlation (r = 0.954) between the enantioselectivities observed with the two techniques has been obtained. Thus the non-aqueous CE method can be applied as a screening tool for the rapid evaluation of the chiral discrimination potential of a large set of newly developed chiral selectors derived from quinine and related alkaloids.     

Improvement of chiral stationary phases based on cinchona alkaloids bonded to crown ethers by chiral modification

To improve the chiral recognition capability of a cinchona alkaloid crown ether chiral stationary phase, the crown ether moiety was modified by the chiral group of (1S, 2S)‐2‐aminocyclohexyl phenylcarbamate. Both quinine and quinidine‐based stationary phases were evaluated by chiral acids, chiral primary amines and amino acids. The quinine/quinidine and crown ether provided ion‐exchange sites and complex interaction site for carboxyl group and primary amine group in amino acids, respectively, which were necessary for the chiral discrimination of amino acid enantiomers. The introduction of the chiral group greatly improved the chiral recognition for chiral primary amines. The structure of crown ether moiety was proved to play a dominant role in the chiral recognitions for chiral primary amines and amino acids.     

Novel chiral stationary phases based on peptoid combining a quinine/quinidine moiety through a C9‐position carbamate group

By connecting a quinine or quinidine moiety to the peptoid chain through the C9‐position carbamate group, we synthesized two new chiral selectors. After immobilizing them onto 3‐mercaptopropyl‐modified silica gel, two novel chiral stationary phases were prepared. With neutral, acid, and basic chiral compounds as analytes, we evaluated these two stationary phases and compared their chromatographic performance with chiral columns based on quinine tert‐butyl carbamate and the previous peptoid. From the resolution of neutral and basic analytes under normal‐phase mode, it was found that the new stationary phases exhibited much better enantioselectivity than the quinine tert‐butyl carbamate column; the peptoid moiety played an important role in enantiorecognition, which controlled the elution orders of enantiomers; the assisting role of the cinchona alkaloid moieties was observed in some separations. Under acid polar organic phase mode, it was proved that cinchona alkaloid moieties introduced excellent enantiorecognitions for chiral acid compounds; in some separations, the peptoid moiety affected enantioseparations as well. Overall, chiral moieties with specific enantioselectivity were demonstrated to improve the performance of peptoid chiral stationary phase efficiently.     

Structure and Mechanism in Cinchona Alkaloid Chemistry: Overturning a 50-Year-Old Misconception

Long-standing errors of the supposedly established literature, including textbooks and data bases have been corrected: The structure of the hetero-cinchona bases in the crystal and in solution (see scheme) and the mechanism of their formation from quinine and quinidine have been elucidated.     

Conformational Analysis of Epiquinine and Epiquinidine

The conformational potential energy surfaces for the epiquinine and epiquinidine molecules were analyzed in gas phase and water solution using semiempirical and ab initio levels of theory. The results obtained showed that the main conformation of the nonactive threo epimers is distinct from those observed for the active parent compounds quinine and quinidine. This result might be used, on a qualitative way, to understand the loss of activity of the threo epimers and allow selecting important conformations to be considered in molecular modeling quantitative studies addressing the drug–receptor interactions.     

Asymmetric chelated Claisen rearrangements in the presence of chiral ligands--scope and limitations

Claisen rearrangements of glycine crotyl ester enolates in the presence of chelating metal salts and chiral ligands provide ,-unsaturated amino acids in a highly stereoselective fashion. Best results are obtained with electron withdrawing protecting groups, isopropylates of aluminum and magnesium, and the cinchona alkaloids as chiral ligands. While the use of quinine gives rise to the (2R)-configured amino acids, quinidine provides the opposite enantiomer. The different enantiomers can also be obtained by using only one of the chiral ligands by simply changing the reaction conditions. A mechanistic rational for the stereochemical outcome of the reaction is given, which is supported by several experiments.     

Application of multivariate methods to the simultaneous Fourier Transform Infrared (FT-IR) spectrometric determination of stereo-isomers; quinine and quinidine

The two stereo-isomers; quinine and quinidine have been determined in their mixtures in the IR region using chemometric multivariate methods, principal component regression (PCR) and partial least squares (PLS). A training set of thirty synthetic binary mixture solutions in the possible combinations containing 0.0 - 4.0 and 4.0 - 0.0% w/v quinine and quinidine, respectively in chloroform was used to develop the multivariate calibrations. A validation set containing thirty synthetic binary mixtures of variable ratios in the range of 0.2 - 4.0 and 4.0 - 0.2% w/v for quinine and quinidine, respectively in chloroform was used to validate the developed calibrations. The results of analysis of the validation synthetic mixtures were found to be 100.5+/-0.44% (R.S.D.%=0.44) and 100.5+/-0.38% (R.S.D.%=0.38) for quinine and 100.1+/-0.67% (R.S.D.%=0.67) and 100.1+/-0.68% (R.S.D.%=0.68) for quinidine using PCR and PLS models, respectively.     

Quinidine oxidative metabolism. Identification and biosynthesis of quinidine 10,11-dihydrodiol stereoisomers

The isocratic reversed phase high performance liquid chromatographic method proposed for quinidine metabolic studies facilitates particularly the separation of 10(R) and (S) isomers of quinidine 10,11-dihydrodiols. The finding of each of these forms following a new synthetic pathway allows us to identify and quantify them in biological fluids. These two isomers have especially been observed in rat bile and hepatocyte secretions. The metabolic inducing effect of phenobarbital on the oxidative metabolism of quinidine is verified in rat isolated hepatocytes. Simultaneous secretion of the two dihydrodiols is also verified in human urine by a gas chromatography/mass spectrometry procedure.     

Enantioseparation of chiral sulfonates by liquid chromatography and subcritical fluid chromatography

Tert‐butylcarbamoyl‐quinine and ‐quinidine weak anion‐exchange chiral stationary phases (Chiralpak® QN‐AX and QD‐AX) have been applied for the separation of sodium β‐ketosulfonates, such as sodium chalconesulfonates and derivatives thereof. The influence of type and amount of co‐ and counterions on retention and enantioresolution was investigated using polar organic mobile phases. Both columns exhibited remarkable enantiodiscrimination properties for the investigated test solutes, in which the quinidine‐based column showed better enantioselectivity and slightly stronger retention for all analytes compared to the quinine‐derived chiral stationary phase. With an optimized mobile phase (MeOH, 50 mM HOAc, 25 mM NH₃), 12 of 13 chiral sulfonates could be baseline separated within 8 min using the quinidine‐derivatized column. Furthermore, subcritical fluid chromatography (SubFC) mode with a CO₂‐based mobile phase using a buffered methanolic modifier was compared to HPLC. Generally, SubFC exhibited slightly inferior enantioselectivities and lower elution power but also provided unique baseline resolution for one compound.     

Noncovalent interactions between ([18]crown-6)-tetracarboxylic acid and amino acids: electrospray-ionization mass spectrometry investigation of the chiral-recognition processes

Chiral recognition of enantiomers by host compounds is one of the most challenging topics in modern host-guest chemistry. Amongst the well-established methods, mass spectrometry (MS) is increasingly used nowadays, due to its low detection limit, short analysis time, and suitability for analyzing mixtures and for studying chiral effects in the gas phase. The development of electrospray-ionization (ESI) techniques provides an invaluable tool to study, in the gas phase, diastereoisomeric complex ions prepared from enantiomer ions and a chiral selector. This paper reports on an ESIMS and ESIMSMS study of the molecular mechanisms that intervene in the chiral-recognition phenomena observed between amino acids and a chiral crown ether. The modified crown ether, namely (+)-([18]crown-6)-2,3,11,12-tetracarboxylic acid, is used as the chiral selector when covalently bound on a stationary phase in liquid chromatography. This study was stimulated by the fact that, except with threonine and proline, consistent elution orders were observed, which indicates that the D enantiomers interact more strongly with the chiral selector than the L enantiomers. For proline, the lack of a primary amino group is likely to be responsible for the nonresolution of the two forms, whereas the second stereogenic center on threonine could explain the reversed elution order. In light of those observations, we performed mass spectrometry experiments to understand more deeply the enantiomeric recognition phenomena, both in solution by the enantiomer-labeled guest method and in the gas phase by gas-phase ligand-exchange ion/molecule reactions. The results have been further supported by quantum chemical calculations. One of the most interesting features of this work is the identification of a nonspecific interaction between proline and the crown ether upon ESIMS analysis.     

Crystal Structure of Quinine: The Effects of Vinyl and Methoxy Groups on Molecular Assemblies of Cinchona Alkaloids Cannot Be Ignored

Quinine, one of Cinchona alkaloids, has been of great interest from medical, synthetic, and supramolecular viewpoints. However, unaccountably, the guest‐free (GF) crystal of quinine containing no solvent or other molecules has not been reported for nearly three decades, although GF crystals of other Cinchona alkaloids, such as quinidine, cinchonidine, and cinchonine, are already known. In this study, we successfully revealed the crystal structure of quinine, which belongs to the P2₁ space group with the cell parameters of a=6.0587(1), b=19.2492(5), c=22.2824(7) Å, β=92.1646(11)°, and V=2596.83(12) ų. Interestingly, the crystal has three crystallographically independent molecules in the cell (Z′=3) that are connected through a N(quinoline)???H? O hydrogen bond to form a pseudo three‐two‐fold (3₂) double‐helical motif. The helical motif is completely different from those observed in GF crystals of other Cinchona alkaloids. Hierarchical comparison on the crystal structures of a series of Cinchona alkaloids including quinine clearly demonstrated that only small structural differences of a molecule, particularly the position of the vinyl group, cause a significant variety of assembly manner in the crystalline state. There have been no reports systematically demonstrating such steric effect in crystals of Cinchona alkaloids, and, therefore, the present system contributes to the design of desired functional crystal structures.     

TRANSFER MECHANISM OF QUININE DRUG ACROSS THE OIL/WATER (O/W) INTERFACE

The transfer phenomena of quinine drug at the aqueous 1,2- dichloroethane (DCE)interface have been studied by the current- scanning polarography. The relationships be-tween the wave height and pH of aqueous phase, concentration of quinine as well as therate of water drop are discussed. The effect of supporting electrolyte, buffer solution andthe nature of organic solvent on the polarographic wave is studied. The transfer char-acteristics of quinine in aqueous phase and in organic phase are compared, The mono- pro-tonated and diprotonated quinines can both transfer at the interface so as to produce twopolarographic waves. The transfer process of quinine at the interface is simultaneouslycontrolled by diffusion and reestablishment of the disturbed protonated equilibrium ofquinine. A further investigation is made by chronopotentiometry. On the basis of thetheoretical analysis, the formulae of the limiting current are derived and discussed. Thetheoretical results are in agreement with the experimental ones.     

Synergic extraction of metals with α-acyl-d-camphor and optically active lewis bases

Solvent extraction of europium (III), zinc (II) cobalt (II) with α-acyl-d-camphor and optically active isomers of quinine and quinidine was studied in order to obtain information on chirality recognition based on adduct formation between a chiral metal chelate and optically active isomers. It was possible to differentiate clearly between the adduct formation of quinine and that of quinidine in the synergic extraction of cobalt and europium with 3-heptafluorobutyryl- d-camphor and cobalt with 3-trifluoroacetyl-d-camphor.     

Application of site-selective ion–molecule reactions to the analysis of the cinchona alkaloids

Functional group interactions within biologically relevant molecules are among the most influential yet least understood factors in determining their reactive behaviors. Reactions of dimethyl ether ions, which have previously been shown to be site-selective, with four cinchona alkaloids, cinchonine, cinchonidine, quinine and quinidine, have been examined. These reactions are each shown to produce qualitatively similar spectra for the stereoisomeric pairs cinchonidine–cinchonine and quinidine–quinine, but small variations in the relative abundances of the products indicate that some stereoselectivity can be observed. The site selectivity of each of the reagents was investigated by observing the reactions occurring with model subunits of the alkaloids.     

Enantioselective sulfa-Michael addition of thioacids to α,β-unsaturated ketones with bifunctional organocatalyst

Organocatalytic conjugate addition of thioacids to α,β-unsaturated ketones has been studied in the presence of cinchona alkaloid derived urea catalyst. Both the enantiomers of products are accessible with the same level of enantioselectivity using pseudoenantiomeric quinine/quinidine derived catalysts. The catalytic process provides optically active thioesters with high chemical yields (up to 99%) and useful enantioselectivity (up to 83% ee). The reaction was performed with 1 mol % of catalyst in toluene at room temperature. A transition state model has been proposed to explain the stereochemical outcome of the reaction.     

Empirical development of a binary adsorption isotherm based on the single-component isotherms in the framework of a two-site model

The adsorption behavior of mixtures of the enantiomers of 2,2,2-(trifluoro)-1-(9-anthryl)-ethanol (TFAE) on a quinidine carbamate bonded stationary phase was studied as an example of competitive binary adsorption on a Pirkle-type chiral adsorbent. A model of the adsorption isotherms is proposed and discussed. Binary adsorption isotherms derived by combination of the single-component isotherms of the two enantiomers in the framework of the classical bi-Langmuir model allow the correct prediction of the retention times of the elution bands of the components of binary mixtures but fail properly to predict the separation of the two enantiomers. Use of a quadratic model was needed to improve the agreement between calculated and experimental chromatograms of binary mixtures. The existence of a third type of adsorption sites besides the high-energy enantioselective and the low-energy nonselective sites was assumed. These sites have a low interaction energy, exhibit some affinity toward (S)-TFAE, but none toward (R)-TFAE.     

Enantioseparation of anionic analytes by non-aqueous capillary electrophoresis using quinine and quinidine derivatives as chiral counter-ions

A non-aqueous capillary electrophoretic method developed for the enantioseparation of N-protected amino acids has been applied to the investigation of five new quinine and quinidine derivatives as chiral selectors: 1-adamantyl carbamoylated quinine, 3,4-dichlorophenyl carbamoylated quinidine, allyl carbamoylated dihydroquinine, allyl carbamoylated dihydroquinidine and 1-methyl quininium iodide. The composition of the background electrolyte was 12.5 mM ammonia, 100 mM octanoic acid in an ethanol-methanol (60:40 v/v) mixture containing a 10 mM concentration of the chiral selector. Under these conditions, the enantioseparation of a series of various benzoyl, 3,5-dinitrobenzoyl and 3,5-dinitrobenzyloxycarbonyl amino acid derivatives was studied with respect to selectand-selector relationship and enantioselectivity.