The separation of racemic crystals into enantiomers by chiral block copolymers

A series of chiral double hydrophilic block copolymers (DHBCs) was synthesized and employed as additives in the crystallization of calcium tartrate tetrahydrate (CaT). We found that appropriate polymers can slow down the formation of the thermodynamically most stable racemic crystals as well as the formation of one of the pure enantiomeric crystals so that chiral separation by crystallization occurs even when racemic crystals can be formed. In addition, the presence of DHBCs results in major modifications of crystal morphology, creating unusual morphologies of higher complexity. Our study demonstrates the potential application of chiral DHBCs in the control of chirality throughout crystallization, in particular for racemic crystal systems, and also shows that enantiomeric excess of one enantiomer can be maximized by the kinetic control of crystallization.     

Gas-chromatographic identification of products formed in iodination of methyl phenols by retention indices

Iodination reaction followed by conversion of iodine-substituted methylphenols to the corresponding trifl uoroacetates was suggested for improving the sensitivity of the gas-chromatographic determination of phenol and its methyl-substituted derivatives (al isomers of mono- and diethylphenols, 2,3,5-, 2,3,6-, and 3,4,5-trimethylphenols) in aqueous media. Acylation products of iodo methylphenols (104 compounds) were identified by linear-logarithmic retention indices on a standard nonpolar polydimethylsiloxane stationary phase, and the pattern of their variation with the number and nature of substituents were characterized. A procedure for identification of methyl-substituted phenols in water in their gas-chromatographic determination with an electron-capture detector was developed.     

Discrimination of the enantiomers of biphenylic derivatives in micellar aggregates formed by chiral amidic surfactants

The chirality of micellar aggregates formed by surfactants derived from l-proline was investigated by using two chiral biphenylic derivatives as probes of chirality. The investigation carried out by ¹H NMR, circular dichroism, and HPLC on chiral phase demonstrates that chiral recognition may occur in sites of the aggregates far from the head-group stereogenic centers and it is due to interaction with a whole region of the aggregate rather than with a single monomer in the aggregate. Subtle changes of the structure of the monomer influence the aggregation properties of the surfactants and its expression of chirality.     

Palladium-catalyzed reaction of boronic acids with chiral and racemic alpha-bromo sulfoxides

Palladium-catalyzed cross-coupling reactions of racemic alpha-bromo sulfoxides with boronic acids are carried out in either aqueous or nonaqueous medium with formation of a new C sp(3)-C sp(2) bond. The arylation of chiral alpha-bromo sulfoxides occurs without racemization. The cross-coupling reaction is general and gives high yields with arylboronic acids substituted with either donor or acceptor groups but gives poor results with heteroarylboronic acids. The best yields are obtained using degassed solvents and CsF instead of aqueous base. The use of aqueous base and the presence of oxygen favor the homocoupling side reaction.     

Kinetic resolution of racemic alcohols with chiral carboxylic acids and dicyclohexylcarbodiimide

The DCC-esterification method has been used to kinetically resolve racemic mixtures of alcohols. With simple chiral carboxylic acids, such as O-aryl lactic acids, in the presence of various basic catalysts, mixtures of the enantiomerically enriched alcohols (e.e. <50%) and the corresponding esters (d.e.<70%) have been obtained.     

A trans-tetrahydrobenzoxanthene receptor for the resolution of racemic mixtures of sulfonylamino acids

An enantioselective cleft-type receptor for sulfonylamino acids has been prepared and its use for the resolution of the amino acid racemic mixture is shown.     

HPLC separation of the enantiomers of racemic benzergoline derivatives on a chiral binaphthalene covalently bonded to silica gel

A novel chiral stationary phase (CSP) derived from the atropisomeric enantiomer S-3,3′-dicarboxy-2,2′-dihydroxy-1,1′-binaphthyl (S-DDBN) has been synthesized and its use for the separation of enantiomers demonstrated. The chiral selector is covalently bonded to amino-functionalized silica gel, thus enabling the use of alcohols as mobile phases. Good chiral discrimination was obtained for the pharmacologically interesting class of benzergoline derivatives which act as selective dopamine D₁ receptor agonists. This paper reports the successful separtion of fifteen structurally related benzergoline racemates with separation factors up to 3.5. The influence of small differences in molecular structure on chiral discrimination was examined.     

Separation of multicomponent mixtures of 2,4-dinitrophenyl labelled amino acids and their enantiomers by capillary zone electrophoresis

The use of capillary zone electrophoresis (CZE) for the separation of a group of 33 2,4-dinitrophenyl labeled amino acids (DNP-AA), including DNP-AA racemates, DNP-L-AA enantiomers and achiral DNP-AAs, was investigated. Alpha-, beta- and gamma-cyclodextrins (CDs) and their derivatives (hydroxypropyl derivatives of alpha-, beta- and gamma-CDs, polymeric beta-CD and 6A-methylamino-beta-cyclodextrin (MA-beta-CD)) served as complexing agents and chiral selectors in this investigation. Although native alpha- and gamma-CDs and their derivatives influenced the effective mobilities of the studied DNP-AAs in different ways, they generally failed to resolve enantiomers of the individual DNP-AAs. On the other hand, beta-CD and all of its derivatives were found to be effective in this respect. Of these, the best results were achieved with a positively charged MA-beta-CD and this chiral selector resolved enantiomers of ten DNP-AA racemates available for this study. However, a complete resolution of these enantiomers in one CZE run required that the effect of the chiral selector be complemented by complexing effects of polyvinyl pyrrolidone (PVP) or gamma-CD. Complexing and chiral recognition capabilities of MA-beta-CD combined with complexing effects of gamma-CD and PVP provided separating conditions suitable for the CZE separations of multicomponent mixtures of DNP-AAs with preserved resolutions of the enantiomers. For example, a mixture consisting of 43 DNP-AA constituents was resolved using an MA-beta-CD/gamma-CD combination with three peak overlaps.     

Separation of the enantiomers of pyrethroic acids and their esters by high-performance liquid chromatography on a polysaccharide-derived chiral stationary phase

Summary The liquid-chromatographic separation of the enantiomers of pyrethroic acids and their esters has been investigated on a polysaccharide-derived chiral stationary phase (CSP), Chiralpak AS. Good separation of the enantiomers of underivatized pyrethroic acids was achieved on the column, and the enantiomers of pyrethroic acid methyl and ethyl ester derivatives were also resolved.     

Planar chiral indoles: synthesis and biological effects of the enantiomers

The paracyclophanyl triflates (R)-4 and (S)-4, which were obtained from racemic precursors through enzymatic-kinetic resolution, could be employed as key intermediates for the synthesis of planar chiral [2.2](4,7)indoloparacyclophanes. Subjecting the double-layered test compounds (R)-8 and (S)-8 to in vitro ligand-binding experiments displayed stereoselective receptor recognition.     

Kinetic method for the simultaneous chiral analysis of different amino acids in mixtures

The kinetic method has been extended to enantiomeric excess (ee) determinations on amino acids present in mixtures. Singly charged trimeric clusters [Cu(II)(ref*)(2)(A(m)) - H](+) are readily generated by electrospraying solutions containing Cu(II), a chiral reference ligand (ref*), and the amino acids (analytes A(m), m = 1-3). A trimeric cluster ion for each amino acid is individually mass-selected and then collisionally activated to cause dissociation by competitive loss of either the reference ligand or the analyte. For each analyte in the mixture, as shown from separate experiments, the logarithm of the ratio of the fragment abundances for the complex containing one enantiomer of this analyte expressed relative to that for the fragments of the corresponding complex containing the other enantiomer is linearly related to the enantiomeric composition of the amino acid. Formation and dissociation of each trimeric complex ion are shown to occur independently of the presence of other analytes. Chiral selectivity appears to be an intrinsic property and the chiral selectivity R(chiral(m)) measured from the mixture of analytes is equal to R(chiral) measured for the pure analyte. The sensitive nature of the methodology and the linear relationship between the logarithm of the fragment ion abundance ratio and the optical purity, characteristic of the kinetic method, allow the determination of chiral impurities of less than 2% ee in individual compounds present in mixtures by simply recording the ratios of fragment ion abundances in a tandem mass spectrum.     

Stereocontrolled polymerization of racemic lactide with chiral initiator: combining stereoelection and chiral ligand-exchange mechanism

New opportunities, provided by the 2,2'-[1,1'-binaphthyl-2,2'-diylbis(nitrylomethilidyne)]diphenol (SB(OH)2)/Al(OiPr)3/racemic lactide (rac-LA) polymerization system, employing a combination of stereoelection with (S) and (R) ligand-exchange mechanism at Al-alkoxide active centers were explored. The stereoelectivity was comparable to that determined for the process with an additional synthetic step of isolation and purification of the SBO2Al-OiPr alkoxide. The resultant poly(rac-LA) had a gradient stereocopolymer structure and exhibited enhanced thermal stability due to a stereocomplex formation (Tm = 210 degrees C). This is the highest melting temperature reported until now for poly(lactide) (PLA) prepared directly from rac-LA.     

Liquid chromatographic separation of the enantiomers of beta-amino acids on a ligand exchange chiral stationary phase

A liquid chromatographic ligand exchange chiral stationary phase (CSP) derived from (S)-leucinol was applied in the separation of the enantiomers of 12 beta-amino acids. The resolution was quite successful especially for the enantiomers of beta-amino acids containing aromatic functional group in the side chain. The chromatographic resolution behaviors were dependent on the organic modifier and Cu(II) concentration in aqueous mobile phase and the column temperature.     

Efficient synthesis of racemic and chiral alkenyl sulfoxides by palladium-catalyzed Suzuki coupling

Alkenyl sulfoxide derivatives are obtained in high yields through a palladium-catalyzed Suzuki/Miyaura cross-coupling reaction of racemic and chiral 1-halo sulfoxides with aryl and alkenyl boronic acids. Chiral substrates react with no loss of optical purity and high optical yields. The reaction takes place with different palladium catalysts, such as Pd(PPh₃)₄ or Pd(OAc)₂/DABCO. Although nitrogen ligands like DABCO lead to an active palladium catalyst, they are less effective than the phosphine ones.     

Separation of the two enantiomers of naproxcinod by chiral normal-phase liquid chromatography

A normal-phase enantioselective high-performance liquid chromatographic method was developed for the enantiomeric resolution of naproxcinod, the most advanced cyclooxygenase-inhibiting nitric oxide donator of anti-inflammatory drugs designed for treatment of osteoarthritis. The enantiomers of naproxcinod were resolved on a Chiralpak AD-H (250 × 4.6 mm, 5 μm) column using a mobile phase system containing n-hexane and 2-propanol (95:5, v/v). The resolution between the enantiomers was found to be more than 2.0. The limit of detection and limit of quantitation of (R)-enantiomer were found to be 5 and 15 ng/mL, respectively, for 20 μL injection volume. The sample solution and mobile phase were found to be stable for at least 48 h. The final optimized method was successfully applied to separate (R)-enantiomer from naproxcinod and was proven to be reproducible and accurate for the quantitative determination of (R)-enantiomer in bulk drugs.     

The even-handed approach: strategies for the deployment of racemic chiral catalysts

Asymmetric catalysis is predominantly associated with the use of enantiomerically pure chiral ligands and catalysts. Although racemic chiral catalysts have been employed quite extensively in polymerization, their utility in mainstream organic synthesis and catalyst development has arguably been rather overlooked. This Minireview collates various themes for the strategic application of racemic ligands and catalysts, ranging from the estimation of selectivity and determination of enantiomeric excess, through to control of regio- and stereochemical outcomes, and mechanistic studies. What emerges is a clear picture that, in isolation or in concert with enantiopure catalysts, the "even-handed" approach has much to offer.