Challenges of crystal structure prediction of diastereomeric salt pairs

A methodology for the computational prediction of the crystal structures and resolution efficiency for diastereomeric salt pairs is developed by considering the polymorphic system of the diastereomeric salt pair (R)-1-phenylethylammonium (R/S)-2-phenylpropanoate. To alleviate the mathematical complexity of the search for minima in the lattice energy due to the presence of two flexible entities in the asymmetric unit, the range of rigid-body lattice energy global optimizations was guided by a statistical analysis of the Cambridge Structural Database for common ion-pair geometries and ion conformations. A distributed multipole model for the dominant electrostatic interactions and high-level ab initio calculations for the intramolecular energy penalty for conformational distortions are used to quantify the relative stabilities of the p- and n-salt forms. While the ab initio prediction of the known structure of the p-salt as the most stable structure was insensitive to minor changes in the rigid-ion conformations considered, the relative stabilities of the known polymorphs and hypothetical structures of the n-salt were very sensitive. Although this paper provides a significant advance over traditional search algorithms and empirical force fields in determining the structures and relative stabilities of diastereomeric salt pairs, the sensitivity of the computed lattice energies to the fine details of the ion conformations overtaxes current computational models and renders the design of diastereomeric resolution processes by computational chemistry a challenging problem.     

The CGC enantiomer separation of 2-arylcarboxylic acid esters by using β-cyclodextrin derivatives as chiral stationary phases

Chiral 2-arylcarboxylic acid esters are important intermediates in preparation of enantioenriched 2-arylpropionic acids type Non-steroidal anti-inflammatory drugs (NSAIDs). Enantiomer separation of 2-arylcarboxylic acid esters is crucial for evaluation of the asymmetric synthesis efficiency and the enantiomer excess of chiral 2-arylcarboxylic acid derivatives. The capillary gas chromatography (CGC) enantiomer separation of 17 pairs of 2-arylcarboxylic acid esters enantiomers was conducted by using seven different β-cyclodextrin derivatives (CDs) as chiral stationary phases. It was found that for the 7 pairs of 2-phenylpropionates enantiomers, CDs with both alkyl and acyl substituents especially 2,6-di-O-pentyl-3-O-butyryl-β-cyclodextrin exhibited better enantiomer separation abilities than the other CDs examined. For the 7 pairs of 2-(4-substituted phenyl)propionates enantiomers, 2,3,6-tri-O-methyl-β-cyclodextrin possessed better enantiomer separation abilities than the other CDs. Among the 3 pairs of 2-phenylbutyrates enantiomers examined, only methyl 2-phenylbutyrate enantiomers could be separated by three CDs among the 7 CDs tested, while enantiomers of ethyl 2-phenylbutyrate and isopropyl 2-phenylbutyrate couldn't be separated by any of the 7 CDs tested. Besides the structures of CDs, the structures of 2-arylcarboxylic acid esters including different ester moieties, substituents of phenyl, and different carboxylic acids moieties in 2-arylcarboxylic acid esters also affected the enantiomer separation results greatly. The CGC enantiomer separation results of 2-arylcarboxylic acid esters on different CDs are useful for solving the enantiomer separation problem of 2-arylcarboxylic acid esters.     

Liquid Chromatographic Resolution of Enantiomeric Dipeptides on the Chiral Stationary Phase Derived from (S)-1-(6,7-Dimethyl-1-naphthyl)isobutylamine

Abstract

Liquid chromatographic resolution of fifteen enantiomeric dipeptide methyl esters as their N-3,5-dinitrobenzoyl derivatives was investigated on the chiral stationary phase (CSP) derived from (S)-1-(6,7-dimethyl-1-naphthyl)isobutylamine. The four stereoisomers present in each dipeptide derivative were observed to be separated quite well with the (R,R) isomer being eluted first. The separation factors for two enantiomeric pairs such as (R,R)/(S,S) and (R,S)/(S,R) and the elution orders are explained by two competing “opposite-sense” chiral recognition mechanisms.     

Efficient synthesis of a chiral precursor for angiotensin-converting enzyme (ACE) inhibitors in high space-time yield by a new reductase without external cofactors

A new reductase, CgKR2, with the ability to reduce ethyl 2-oxo-4-phenylbutyrate (OPBE) to ethyl (R)-2-hydroxy-4-phenylbutyrate ((R)-HPBE), an important chiral precursor for angiotensin-converting enzyme (ACE) inhibitors, was discovered. For the first time, (R)-HPBE with >99% ee was produced via bioreduction of OPBE at 1 M without external addition of cofactors. The space-time yield (700 g·L(-1)·d(-1)) was 27 times higher than the highest record.     

Efficient synthesis of optically active 1-(2-carboxymethyl-6-ethylphenyl)-1H-pyrrole-2-carboxylic acid: a novel atropisomeric 1-arylpyrrole derivative

An efficient synthesis and resolution of (±)-1-(2-carboxymethyl-6-ethylphenyl)-1H-pyrrole-2-carboxylic acid has been developed for the preparation of novel optically active atropisomers. The ee values were measured by a ¹H NMR spectroscopic method using quinidine as the chiral complexing agent. Absolute configurations of the separated enantiomers were determined using single crystal X-ray diffraction measurements of both the disodium salt and the (R)-1-phenylethylamine salt of the enantiomerically pure dicarboxylic acid, separately. The analysis of the CD spectra with the aid of TD-DFT quantum chemical calculations confirmed the assignment of configurations.     

Enantioselective determination of modafinil in pharmaceutical formulations by capillary electrophoresis, and computational calculation of their inclusion complexes

A fast capillary electrophoretic method is described for the separation and determination of the enantiomers of the novel wake-promoting agent, modafinil. Several parameters affecting the separation were studied, including the type and concentration of chiral selector, buffer pH, buffer concentration, voltage and temperature. Good chiral separation of the racemic mixture was achieved in less than 5 min with resolution factor Rs?=?2.51, using a bare fused-silica capillary and a background electrolyte (BGE) of 25 mM H₃PO₄?1 M tris solution; pH 8.0; containing 30 mg mL^?1 of sulfated-β-cyclodextrin (S-β-CD). The separation was carried out in normal polarity mode at 25 ^?C, 18 kV and using hydrostatic injection. Acceptable validation criteria for selectivity, linearity, precision, and accuracy were included. The developed method was successfully applied to the assay of enantiomers of modafinil in pharmaceutical formulations. The computational calculations for the enantiomeric inclusion complexes rationalized the reasons for the different migration times between the modafinil enantiomers.     

Enantioselective analysis of ofloxacin and ornidazole in pharmaceutical formulations by capillary electrophoresis using single chiral selector and computational calculation of their inclusion complexes

A capillary electrophoretic method for the separation of the enantiomers of both ofloxacin and ornidazole is described. Several parameters affecting the separation were studied, including the type and concentration of chiral selector, buffer pH, voltage and temperature. Good chiral separation of the racemic mixtures was achieved in less than 16 min with resolution factors Rs = 5.45 and 6.28 for ofloxacin and ornidazole enantiomers, respectively. Separation was conducted using a bare fused-silica capillary and a background electrolyte (BGE) of 50 mM H₃PO₄-1 M tris solution; pH 1.85; containing 30 mg mL⁻¹ of sulfated-β-cyclodextrin (S-β-CD). The separation was carried out in reversed polarity mode at 25 °C, 18 kV, detection wavelength at 230 nm and using hydrodynamic injection for 15 s. Acceptable validation criteria for selectivity, linearity, precision, and accuracy were studied. The limits of detection (LOD) and limits of quantitation (LOQ) of the enantiomers (ofloxacin enantiomer 1 (OF-E1), ofloxacin enantiomer 2 (OF-E2), ornidazole enantiomer 1 (OR-E1) and ornidazole enantiomer 2 (OR-E2)) were (0.52, 0.46, 0.54, 0.89) and (1.59, 1.40, 3.07, 2.70) μg mL⁻¹, respectively. The proposed method was successfully applied to the assay of enantiomers of both ofloxacin and ornidazole in pharmaceutical formulations. The computational calculations for the enantiomeric inclusion complexes rationalized the reasons for the different migration times between the ofloxacin and ornidazole enantiomers.     

Structural and computational analysis of intermolecular interactions in a new 2‐thiouracil polymorph

The crystallization and characterization of a new polymorph of 2‐thiouracil by single‐crystal X‐ray diffraction, Hirshfeld surface analysis and periodic density functional theory (DFT) calculations are described. The previously published polymorph (A ) crystallizes in the triclinic space group P , while that described herein (B ) crystallizes in the monoclinic space group P 2₁/c . Periodic DFT calculations showed that the energies of polymorphs A and B , compared to the gas‐phase geometry, were −108.8 and −29.4 kJ mol⁻¹, respectively. The two polymorphs have different intermolecular contacts that were analyzed and are discussed in detail. Significant differences in the molecular structure were found only in the bond lengths and angles involving heteroatoms that are involved in hydrogen bonds. Decomposition of the Hirshfeld fingerprint plots revealed that O…H and S…H contacts cover over 50% of the noncovalent contacts in both of the polymorphs; however, they are quite different in strength. Hydrogen bonds of the N—H…O and N—H…S types were found in polymorph A , whereas in polymorph B , only those of the N—H…O type are present, resulting in a different packing in the unit cell. QTAIM (quantum theory of atoms in molecules) computational analysis showed that the interaction energies for these weak‐to‐medium strength hydrogen bonds with a noncovalent or mixed interaction character were estimated to fall within the ranges 5.4–10.2 and 4.9–9.2 kJ mol⁻¹ for polymorphs A and B , respectively. Also, the NCI (noncovalent interaction) plots revealed weak stacking interactions. The interaction energies for these interactions were in the ranges 3.5–4.1 and 3.1–5.5 kJ mol⁻¹ for polymorphs A and B , respectively, as shown by QTAIM analysis.     

Resolution of racemic 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid with enantiopure (S)-phenylalanine N-benzylamide via diastereomeric salt formation

The resolution of racemic 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid 1, a potent chiral synthon with high pharmacological activity, was investigated with a variety of basic chiral resolving agents via diastereomeric salt formation. The findings in the optimization of resolution conditions aiming at an industrial-scale production revealed that (S)-phenylalanine benzylamide (S)-10 and 2-propanol containing ca. 4 mol % of water to (RS)-1 were the best conditions for obtaining enantiopure less-soluble diastereomeric salt, (S)-1/(S)-10/0.5H₂O (81%, 98% de, E 79%). X-ray crystallographic analysis of the salt clearly revealed that water molecules play a key role in crystallizing the enantiopure salt crystals, while stabilizing the crystal structure via three types of hydrogen-bond network associated with water molecules in addition to usual acid–base hydrogen bond.     

Stacking and separation of enantiomers by acetonitrile-salt mixtures in micellar electrokinetic chromatography

The feasibility of employing the "acetonitrile stacking" method in micellar electrokinetic chromatography (MEKC) for the on-line preconcentration and separation of enantiomers is demonstrated for the first time. The effects of various experimental parameters on the stacking and separation of three different pairs of optical isomers, i.e., two substituted naphthyl enantiomers and one dansylated-DL-amino acid, were examined. In particular, the effectiveness of the addition of acetonitrile and salt in the sample matrix to induce narrowing of the analyte bands was investigated in the presence of sodium cholate as the chiral surfactant micelle in the separation buffer. For example, it was found that the presence of both acetonitrile and 1% NaCl in the sample matrix (volume ratio = 2:1) led to a significant improvement of the peak height and resolution for the MEKC separation of a pair of R(-)/S(+)-1,1'-binaphthyl diyl hydrogen phosphate enantiomers when the injection sample size was relatively large (e.g., 12% capillary volume). Furthermore, the feasibility of combining salting-out solvent extraction (off-line) and acetonitrile stacking (on-line) as a novel approach for sample preconcentration in capillary electrophoresis was also demonstrated.     

Quantum chemical study of three polymorphs of the mononuclear spin-transition complex [Fe(DPPA)(NCS)2

The calculations of the high spin (HS) and low spin (LS) states of the [Fe(II)(DPPA)(NCS)(2)] complex have been performed at three experimentally observed geometries corresponding to three synthesized polymorphs with different spin-transition behavior. The structure optimization leads to a single molecular structure, suggesting that the existence of three geometries is not an intrinsic phenomenon but is induced by the crystal lattice. The structural difference between three forms can be reproduced by introducing the Madelung field of the crystal lattice. However, the calculations show that the differences in magnetic behavior of the three polymorphs cannot be attributed only to variations of the energy gap between two spin states.     

Molecular modeling of salt (lithium chloride) effects on the enantioselectivity of diethylzinc addition to benzaldehyde in the presence of chiral beta-amino alcohols

Beta-amino alcohols (S,S,S)-1 and (R,R,S)-1, derived from cyclohexene oxide and containing alpha-phenylethyl auxiliaries, were examined as chiral promoters in the addition of diethylzinc to benzaldehyde. In agreement with literature precedent, the N-alpha-phenylethyl chiral auxiliary had no significant impact on enantioinduction, which is determined by the configuration of the framework's C(OH), with unlike induction. Contrary to some literature reports, stereoinduction by lithium salt derivatives of (S,S,S)-1 and (R,R,S)-1 was lower than that obtained with the free amino alcohol. Remarkable lithium chloride salt effects were observed in the reaction. In particular, an opposite chiral induction was found with (S,S,S)-1-Li(2) as ligand and in the presence of "inert" salt. N-Alkylated derivatives (S,S,S)-3-7 proved to be more efficient ligands, providing higher yields and enantioselectivities in the formation of carbinols (R)- or (S)-2. BP86/DN**//PM3 theoretical calculations proved remarkably successful in reproducing the experimental observations and permitted expansion of Noyori's catalytic cycle [J. Am. Chem. Soc. 1995, 117, 6327] to understand the relevant N-substitution and medium salt effects that determine the enantioselection in this catalytic asymmetric reaction.     

(S)-(+)-2-octanol as a chiral oil core for the microemulsion electrokinetic chromatographic separation of chiral basic drugs.

The enantiomeric separation of basic drugs was successfully demonstrated by using a novel chiral microemulsion electrokinetic chromatography (MEEKC). An interesting finding was that the chiral oil core ((S)-(+)-2-octanol) within the microemulsion droplets appeared to play an important role in the chiral separation mechanism. In addition, the enantioselectivity of the analyte-selector complex could be influenced by methanol, through an interaction with the complex. The chiral resolution (R(s)) and partition coefficient were strongly influenced by the concentration of methanol, pH, the concentration of chiral oil and the concentration of a cosurfactant. Under the optimized microemulsion conditions, the baseline separation of (+/-)-ephedrine (R(s) = 2.7), and the partial separations of (+/-)-norephedrine (R(s) = 1.3), (+/-)-synephrine (R(s) = 1.4) and (+/-)-propranolol (R(s) = 1.3), could be achieved.     

Direct observation of enantiomer discrimination of epoxides by chiral salen complexes using ENDOR

Electron nuclear double resonance (ENDOR) spectroscopy was used to investigate the weak enantioselective binding between chiral salen complexes [VO(1)] ((R,R)- and (S,S)-vanadyl N,N'-bis(3,5-di-tert-butylsalcylidene)-1,2-cyclohexanediamine) and chiral epoxides (e.g., (R)-/(S)-propylene epoxide, 5) in frozen (10 K) solution. Differences in epoxide binding by enatiomers of [VO(1)] was evidenced by changes to the 1H epoxide derived peaks in the ENDOR spectra, such that (R,R)-[VO(1)] + (R)-5 and (R,R)-[VO(1)] + (S)-5 yield noticeably different spectra. These changes were assigned to the small structural differences between the diastereomeric metal-epoxide adducts. Simulation of the spectra revealed differences in the VO...1Hepoxide distances for the diastereomeric pairs, which was confirmed by a complementary set of density functional theory (DFT) calculations. While the epoxide molecule is very weakly coordinated, ENDOR measurements of the racemic complex in racemic epoxide nevertheless indicated the preferential coordination of the (R)-5 to (R,R)-[VO(1)] (likewise (S)-(5) to (S,S)-[VO(1)]), which is favored over the binding of (S)-5 epoxide to (R,R)-[VO(1)] (and likewise (R)-5 epoxide to (S,S)-[VO(1)]). This demonstrates the unique power of the ENDOR technique to resolve weak chiral interactions for which EPR spectroscopy alone lacks sufficient resolution.     

Mechanism of Optical Resolutions via Diastereoisomeric Salt Formation. Part 7 Role of the solvents in the optical resolution of α-phenylethylamine by 2R,3R-tartaric acid

The optical resolution of α-phenylethylamine (1) by 2R,3R-tartaric acid (2) was studied in different solvents, the precipitated salts were subjected to thermoanalytical measurements and X-ray powder diffraction. The most efficient resolution can be accomplished by using methanol, the precipitate, an unsolvated salt containing the S-(-)-1⋅2R,3R-(+)-2 salt in abundance, is not a simple mixture of the diastereoisomeric salt pair, but a new modification. In water, ethanol and acetonitrile a reversed, but less effective resolution can be accomplished by precipitation of a hydrate which contains the R-(+)-1 in abundance. The precipitates from water and ethanol also proved to be new modifications. Only the precipitate from acetonitrile is the mixture of the diastereoisomeric salt pair, which can be expected in fractional crystallization of an eutectic forming diastereoisomeric salt pair. The number of different modifications found by changing the solvent in case of this particular salt pair seems surprisingly high, but may occur for other diastereoisomeric salt pairs, too. The existing but not investigated polymorphism can be the explanation for the sometimes very poor reproducibility of the preparative resolutions. This revised version was published online in July 2006 with corrections to the Cover Date.     

Chiral separation of 12 pairs of enantiomers by capillary electrophoresis using heptakis‐(2,3‐diacetyl‐6‐sulfato)‐β‐cyclodextrin as the chiral selector and the elucidation of the chiral recognition mechanism by computational methods

Chiral separation of 12 pairs of basic analyte enantiomers including oxybutynin, bambuterol, tradinterol, clenbuterol, clorprenaline, terbutaline, tulobuterol, citalopram, phencynonate, fexofenadine, salbutamol, and penehyclidine was conducted by capillary electrophoresis using a single‐isomer anionic β‐cyclodextrin derivative, heptakis‐(2,3‐diacetyl‐6‐sulfato)‐β‐cyclodextrin as the chiral selector. Parameters influencing separation were studied, including background electrolyte pH, heptakis‐(2,3‐diacetyl‐6‐sulfato)‐β‐cyclodextrin concentration, buffer concentration, and separation voltage. A background electrolyte consisting of 50 mM Tris‐H₃PO₄ and 6 mM heptakis‐(2,3‐diacetyl‐6‐sulfato)‐β‐cyclodextrin at pH 2.5 was found to be highly efficient for the separation of most enantiomers, with other conditions of normal polarity mode at 10 kV, detection wavelength of 210 nm using hydrodynamic injection for 3 s. Under the optimal conditions, baseline resolution (>1.50) for 11 pairs of enantiomers and somewhat lower resolution for penehyclidine enantiomers (1.17) were generated. Moreover, the possible mechanism of separation of clenbuterol, oxybutynin, salbutamol, and penehyclidine was investigated using a computational modeling method.     

Solvent control of optical resolution of 2-amino-1-phenylethanol using dehydroabietic acid

The optical resolution of 2-amino-1-phenylethanol (2-APE) by the solvent switch method was investigated using dehydroabietic acid (DAA), a natural chiral acid obtained as one of the main components of disproportionated rosin. The solvent dependency of optical rotation measurements of 2-APE, DAA and the diastereomeric salts suggested solvent control of optical resolution. Both (R)- and (S)-2-APE were resolved, as the first success for aminoalcohols, only by changing the resolving solvents: (S)-2-APE was obtained in high optical purity by a single crystallization operation with polar solvents (epsilon > 50), whereas the efficiency was lower for (R)-2-APE using less polar solvents (20 < epsilon < 40). The results were compared and discussed with reference to the crystal structures of the diastereomeric salts.     

Super/Subcritical Fluid Chromatography Separations with Four Synthetic Polymeric Chiral Stationary Phases

New synthetic polymeric chiral selectors were developed recently as chiral stationary phases. They were tested with supercritical fluid mobile phases made of CO₂ plus an alcohol modifier and 0.2% v/v trifluoroacetic acid. The polymeric N,N′-(1S,2S)-1,2-cyclohexanediyl-bis-2-propenamide (P-CAP), the polymeric N,N′-[(1R,2R)]-1,2-diphenyl-1,2-ethanediyl] bis-2-propenamide (P-CAP-DP), the polymeric trans-9,10-dihydro-9,10-ethanoanthracene-(11S,12S)-11,12-dicarboxylic acid bis-4-vinylphenylamide (DEABV) and the polymeric N,N′-[(1R,2R)-1,2-diphenyl-1,2-ethanediyl] bis-4-vinylbenzamide (DPEVB) were bonded to 5 μm silica particles and used to prepare four columns that were tested with a set of 88 chiral compounds with a wide variety of chemical functionalities. All 88 test compounds were separated on one or more of these “related” polymeric CSPs. Forty-three enantiomeric pairs were separated in SFC conditions by only one of the CSPs. Twenty pairs were separated by two CSPs and 18 and 7 enantiomeric pairs were separated by 3 and all 4 CSPs, respectively. The three P-CAP, P-CAP-DP and DEABV CSPs have equivalent success being able to separate 49 enantiomeric pairs of the studied set with respectively 12, 14 and 20 at baseline (R _s  > 1.5). The DPEVB CSP was significantly less efficient separating only 18 chiral compounds with only one at baseline. The great advantage of the SFC mobile phases is the rapid separation, witch most achieved in less than 5 min.     

A quadruple helicene with a rubicene core: synthesis,structural analyses and properties

We report the synthesis of a quadruple helicene with a rubicene core R1 by a Scholl reaction.Among the 10 stereoisomers including 4 pairs of enantiomers and 2 meso isomers,only 2 pairs of enantiomers and 1 meso isomer have been isolated.The sample structures were unambiguously determined by X-ray crystallography to be(P,P)₆-(P,P)₅/(M,M)₆-(M,M)₅-R1-A,which has a propeller-shaped structure,and(M,M)₆-(P,P)₅/(P,P)₆-(M,M)₅-R1-B and(M,P)₆-(P,M)₅-R1-C,which have saddle-shaped structures.The chiral resolutions of R1 were carried out by chiral HPLC,revealing two pairs of chiral stereoisomers(P,P)₆-(P,P)₅/(P,P)₆-(M,M)₅,(M,M)₆-(P,P)₅/(M,M)₆-(M,M)₅ as well as a meso isomer(M,P)₆-(P,M)₅,which were further characterized by CD spectroscopy and time-dependent density functional theory(TD-DFT)calculations.Surprisingly,the UV-vis absorption and emission spectra of these resolved stereoisomers and unresolved R1 were almost identical.In addition,the chemical oxidation of R1 led to the formation of radical cations and dications at room temperature.     

Reactivity of activated versus nonactivated 2-(bromomethyl)aziridines with respect to sodium methoxide: a combined computational and experimental study

The difference in reactivity between the activated 2-bromomethyl-1-tosylaziridine and the nonactivated 1-benzyl-2-(bromomethyl)aziridine with respect to sodium methoxide was analyzed by means of DFT calculations within the supermolecule approach, taking into account explicit solvent molecules. In addition, the reactivity of epibromohydrin with regard to sodium methoxide was assessed as well. The barriers for direct displacement of bromide by methoxide in methanol are comparable for all three heterocyclic species under study. However, ring opening was found to be only feasible for the epoxide and the activated aziridine, and not for the nonactivated aziridine. According to these computational analyses, the synthesis of chiral 2-substituted 1-tosylaziridines can take place with inversion (through ring opening/ring closure) or retention (through direct bromide displacement) of configuration upon treatment of the corresponding 2-(bromomethyl)aziridines with 1 equiv of a nucleophile, whereas chiral 2-substituted 1-benzylaziridines are selectively obtained with retention of configuration (via direct bromide displacement). Furthermore, the computational results showed that explicit accounting for solvent molecules is required to describe the free energy profile correctly. To verify the computational findings experimentally, chiral 1-benzyl-2-(bromomethyl)aziridines and 2-bromomethyl-1-tosylaziridines were treated with sodium methoxide in methanol. The presented work concerning the reactivity of 2-bromomethyl-1-tosylaziridine stands in contrast to the behavior of the corresponding 1-tosyl-2-(tosyloxymethyl)aziridine with respect to nucleophiles, which undergoes a clean ring-opening/ring-closure process with inversion of configuration at the asymmetric aziridine carbon atom.