Racemic Mandelic Acid Research Articles

TiCl4 promoted menthyl ester chiral auxiliary mediated synthesis of chiral syn-β-amino esters and applications of a representative syn-β-amino ester

β-Amino esters were obtained in up to 78% yield with 72:28–96:4 diastereomeric ratios by the reaction of the chiral titanium enolate of menthyl esters, prepared using the TiCl 4 /Et 3 N reagent system with prochiral imines. A representative syn -β-amino ester derivative has been used for the resolution of racemic mandelic acid to obtain a sample with >99% ee in a single step. A representative syn -β-amino ester was converted to the corresponding N-deprotected amino ester using the Pd–C/HCOOH reagent system, and then to the corresponding β-amino acid using the glacial CH 3 COOH/HCl reagent system, and to the corresponding β-lactam derivative with partial epimerization by the reaction using C 2 H 5 MgBr.

Enantioselective Extraction of Racemic Mandelic Acid by Di(2‐ethylhexyl) Phosphoric Acid and Tartaric Acid Derivatives as Mixed Complex Chiral Selectors

The distribution behavior of mandelic acid (MA) enantiomers was examined in a two‐phase system containing di(2‐ethylhexyl) phosphoric acid (D2EHPA) with two tartaric acid derivatives as complex chiral selectors in n‐octanol. Factors affecting the extraction were investigated, including the structure and concentration of tartaric acid as well as the concentration of D2EHPA and D,L‐MA. The results showed that both the distribution ratio and enantioselectivity were greatly improved by using a complex chiral selector rather than using the tartaric acid derivative by itself. Finally, it was found that the formation of mixed complex chiral selectors by mixing two tartaric acid derivatives with D2EHPA can improve the capacity of enantioselective extraction.

Piracetam Co-Crystals with OH-Group Functionalized Carboxylic Acids

We report the synthesis, crystal structures, and basic physicochemical properties of six co-crystals of piracetam. Co-crystals of piracetam with l-tartaric acid, with citric acid in a 1:1 and 3:2 ratio, with racemic mandelic acid, and with l-mandelic acid, as well as a piracetam−citric acid ethanol solvate were found in a focused screening approach. Sample amounts of up to several hundred milligrams of each co-crystal were obtained from either solvent-drop grinding, solution evaporation, or crystallization from solution. Crystal structure analysis revealed that the often observed amide-carboxylic acid R22(8) synthon is rarely found in the herein reported crystal structures. The mentioned motif can be used as a target for hydrogen bonds; however, in presence of a multitude of hydrogen bond donors and acceptors it cannot serve for an anticipation of co-crystals. Compared to piracetam the piracetam−l-tartaric acid co-crystal shows improved hygroscopic properties.

Extractive Resolution of racemic mandelic acid through a bulk liquid membrane containing binary chiral carrier

A method of bulk liquid membrane (BLM) using complex of di(2-ethylhexyl) phosphoric acid (D2EHPA) and O,O'-dibenzoyl-(2R, 3R)-tartaric acid (L-(-)-DBTA) was developed for the extractive resolution of racemic mandelic acid (rac MA). The effects of resolution time, concentration of D2EHPA in the organic phase, concentration of rac MA in the feed phase, stirring speed and temperature on extractive resolution were studied. The experimental results have shown that the greatest separation factor (α) 2.74 and the enantiomeric excess value (ee, %) 46.47% were obtained when the resolution time was about 4 h, the molar concentration ratio of rac MA, D2EHPA and L-(-)-DBTA 0.05:0.2:0.3, the stirring speed 400 r min-1 and the temperature 35 ºC. The developed method is helpful for optimizing the transport of BLM systems and for large-scale production of pure enantiomer.

Synthesis and characterization of mesoporous silica modified with chiral auxiliaries for their potential application as chiral stationary phase

Novel chiral stationary phase (CSP) based on chiral aminoalcohol immobilized on ordered mesoporous silica SBA-15 1a and standard silica 1b and their copper complexes 1a′ and 1b′, respectively, was synthesized as potential material for chiral ligand exchange chromatography (CLEC). Microanalysis, inductively coupled plasma spectroscopy (ICP), thermo-gravimetric analysis (TGA), cross polarized magic angle spinning (CP-MAS) 13C NMR, Powder X-ray diffraction (PXRD), FTIR, N 2 adsorption isotherm, scanning electron microscopy (SEM), transmitted electron microscope (TEM) and solid reflectance UV–vis spectroscopy were used to characterize these materials. All the chiral stationary phases thus synthesized were used for the separation of different racemic compounds such as mandelic acid, 2,2′-dihydroxy-1,1′-binaphthalene BINOL) and diethyl tartrate by simple medium-pressure column chromatography. Successful enantio-separation of racemic mandelic acid was achieved with all the stationary phases but 1a and 1b gave slightly better resolution than their copper complexes 1a′ and 1b′. Remarkably these materials are stable under the given experimental conditions and can be used repeatedly for several cycles of enantioresolution. It was observed that the porosity and surface area of the stationary phase play an important role in the chiral separation.

Preparation of (R)-(−)-mandelic acid and its derivatives from racemates by enantioselective degradation with a newly isolated bacterial strain Alcaligenes sp. ECU0401

An enantioselective mandelate-degrading bacterium, Alcaligenes sp. ECU0401, was newly isolated from soil. By fed-batch culture, (R)-(-)-mandelic acid was successfully prepared in a 5-L fermenter with 32.8% isolated yield and >99.9% enantiomeric excesses (e.e.) from totally 3.04% (w/v) of racemic mandelic acid after 99 h of biotransformation. The optimal reaction pH and temperature were 6.5 and 30 degrees C, respectively. Using the resting cell as a biocatalyst for asymmetric degradation of racemic mandelic acid and chloro-substituted derivatives thereof, (R)-(-)-mandelic acid, (R)-(-)-o-chloromandelic acid, (S)-(+)-m-chloromandelic acid and (S)-(+)-p-chloromandelic acid were recovered with high analytic yields and excellent enantiomeric excesses (e.e. > 99.9%). (R)-(-)-Mandelic acid could also be obtained after 12 h of biotransformation with 41.5% isolated yield and >99.9% e.e.

Enantioselective extraction of mandelic acid enantiomers by L-dipentyl tartrate and β-cyclodextrin as binary chiral selectors

AbstractA new binary chiral selector system effective for the enantioselective extraction of racemic mandelic acid is presented. While L-dipentyl tartrate and β-cyclodextrin had a very low enantioselectivity as single selectors, a preferential extraction of D-mandelic acid to the organic phase was found in the binary selector system. Using decanol as organic solvent and pH of a phoshate buffer equal to 2.3, the distribution coefficients of D-and L-mandelic acids as high as 14.9 and 7.0, respectively, and the enantioselectivity value of 2.1 were found at optimum concentration of β-cyclodextrin.

Biocatalytic enantioconvergent separation of racemic mandelic acid

Chiral mandelate was produced by biocatalytic enantioconvergent separation of racemic mandelic acid. One pot enantioconvergent synthesis of ( R)-mandelic acid ester from racemic mandelic acid was achieved by a novel aqueous/organic two-phase system with two-enzyme process consisting of (1) lipase-catalyzed enantioselective esterification of racemic mandelic acid in organic solvent and (2) in situ racemization of unreacted isomer, ( S)-mandelic acid in aqueous phase by recombinant mandelate racemase. Lipase was screened from commercially available sources and mandelate racemase was prepared by overexpression of cloned gene originated from Pseudomonas putida in E. coli Top 10. Organic solvent was selected based on its effect on the partition characteristics for substrate and product, and enzymatic esterification and racemization. The aqueous/organic two-phase dynamic kinetic resolution (DKR) was attempted in a hollow-fiber membrane bioreactor wherein Candida antarctica lipase (CHIRAZYME L-2, Roche)-catalyzed enantioselective esterification and mandelate racemase-mediated racemization of unreacted mandelic acid were performed in ethylene dichloride and aqueous buffer, respectively. Using the novel DKR process, ( R)-mandelic ethyl ester was obtained from racemic mandelic acid in 65% isolated yield and 98%ee as the sole product.

Hermaphroditic Chirality of a D2‐Symmetric Saddle‐Shaped Porphyrin in Multicomponent Spontaneous Optical Resolution: Inclusion Cocrystals with Double‐Helical Porphyrin Arrays

The dynamic dual chirality of D2-symmetric saddle-shaped porphyrin 1 decreases the stereochemical complexity of cocrystallization with racemic mandelic acid derivatives, such as BrMA, and allows spontaneous optical resolution (see picture). Each resulting cocrystal is porous and consists of one-handed double-helical porphyrin arrays in which chiral guests are enantioselectively included.

Preparation of ( S)-mandelic acids by enantioselective degradation of racemates with a new isolate Pseudomonas putida ECU1009

An enantioselective ( R)-mandelate degrading bacterium, Pseudomonas putida ECU1009, was newly isolated from soil. The degradation activity of the bacterial cells was significantly enhanced by supplementing an optimal amount of racemic mandelic acid (0.4%), benzoylformic acid (0.4%), or benzoic acid (0.2%) to the culture medium as the enzyme inducer. Using the resting cells as a biocatalyst, three kinds of ( S)-mandelic acids 1– 3 were prepared with high isolated yields and enantiomeric excesses. Moreover, in a one-pot fermentation–transformation process using 1.25% ( RS)-mandelic acid as the sole carbon/energy source for cultivation of the bacterium, ( S)-mandelic acid 1 was accumulated after 48 h of bioconversion with 46.5% yield and >99% ee.

(RS)-Benzyl mandelate

A benzyl ester of mandelic acid, C15H14O3, was obtained by the crystallization of racemic mandelic acid from benzyl alcohol followed by vacuum drying at 363 K. The structure is composed of two hydrogen-bonded chains of S or R configuration, running along the shortest crystallographic b axis. There is one mol­ecule in the asymmetric unit and each mol­ecule forms four intermolecular hydrogen bonds with two other mol­ecules of the same chirality.

Exceptional chiral recognition of racemic carboxylic acids by calix[4]arenes bearing optically pure alpha,beta-amino alcohol groups.

Calixarenes bearing optically pure alpha,beta-amino alcohol groups at their lower rim exhibit exceptional and efficient chiral recognition ability in discrimination of racemic mandelic acid, 2,3-dibenzoyltartaric acid and 2-hydroxy-3-methylbutyric acid. [structure: see text]

Influence of Solvent and the Operating Conditions on the Crystallization of Racemic Mandelic Acid

The crystallization of racemic mandelic acid is studied in unseeded batch cooling experiments in four solvent systems. Apart from the thermodynamically stable racemic compound, a metastable modification of the racemic compound is also found to initially form upon nucleation. The metastable racemate is characterized by thermal analysis (MDSC), FTIR spectroscopy, and X-ray powder diffraction (XRPD). The experiments show that the type of crystal modification that is formed upon nucleation is strongly influenced by the operating conditions such as filtration, cooling rate, and stirring rate, as well as by the solvent. The solvent effect can be related to the characteristics of the crystal structures of the two modifications, and to the hydrogen bonding properties of the solvent. The crystal structure of the metastable modification of the racemic compound is very similar to that of the pure enantiomer, which explains the similarity of the FTIR spectra, the XRPD diffraction pattern, and the thermodynamic stability.

A contribution to the mandelic acid phase diagram

Literature data on the mandelic acid phase diagram are reviewed and examined together with new own results in order to clarify the heterogeneous equilibria in the binary system of the mandelic acid enantiomers and the racemate in water. For this purpose the thermal stability and the melting and recrystallization behavior of racemic mandelic acid are studied using TG and DSC. A metastable racemic phase is prepared from the melt and solution and identified by means of DSC, XRPD and IR spectroscopy as a monotropic modification of the stable racemic compound. Problems associated with handling the metastable phase are addressed. Finally, a mandelic acid phase diagram modified by polymorphy of the racemate is suggested.

Optical Resolution of Mandelic Acid by Complexation with (S)‐(+)‐Alanine.

Racemic mandelic acid (2) was resolved efficiently by complexation with (S)-(+)-alanine (1) and the crystal structure of 2:2:1 complex of (S)-(+)-alanine (1), (R)-(-)-mandelic acid (2) and H 2 O was determined characterizing the hydrogen bond network in the solid state.

(R)-mandelic acid (S)-alanine hemihydrate.

Crystals of the title complex, C(3)H(7)NO(2).C(8)H(8)O(3).0.5H(2)O, were obtained from an aqueous solution containing racemic mandelic acid and (S)-alanine. The unit cell includes two independent molecular complexes and one water molecule. The structure formed by (R)-mandelic acid and (S)-alanine in a 1:1 molar ratio shows the successful optical separation of racemic mandelic acid. Strong hydrogen bonding, with a rather short O...O separation of 2.494 (3) A, is observed between the carboxyl and carboxylate groups. A structural comparison suggests that the strong hydrogen bonding affects the neighbouring covalent bond.

Optical Resolution of Mandelic Acid by Complexation with (S)-(+)-Alanine

Racemic mandelic acid (2) was resolved efficiently by complexation with ( S)-(+)-alanine (1) and the crystal structure of 2:2:1 complex of ( S)-(+)-alanine (1), ( R)-(-)-mandelic acid (2) and H2O was determined characterizing the hydrogen bond network in the solid state.

Mechanism of optical resolutions via diastereoisomeric salt formation. Part 6. Thermoanalytical investigation of the optical resolution of racemic mandelic acid with S-(+)-2-benzylamino-butanol

The optical resolution of racemic mandelic acid (I) by S-2-benzylamino-butanol (II) was performed in water, ethyl acetate, and water saturated ethyl acetate. It was found that the efficiency of the resolution is three times higher in water saturated ethyl acetate than in either water or ethyl acetate. The salt mixtures produced during the resolutions and the pure diastereoisomeric salts were analyzed by TG, DSC and X-ray powder diffraction measurements. The R-(-)-I×S-(+)-II salt has the higher melting point and heat of fusion value which indicates that this is the more stable salt. Though the general assumption is that diastereoisomeric salt pairs of successful optical resolutions form eutectic systems, the R-mandelic acid-S-2-benzylamino-butanol and the S-mandelic acid-S-2-benzylamino-butanol system was found to behave in a different way. Melting did not start at or near the estimated eutectic temperature. The difference can be explained either by miscibility in the solid phase (solid solution) or by a blocked interaction between the crystals of the two solid salts. This unusual behaviour of the salt pair should be responsible for the unusual difference in the efficiency of the resolutions performed in different solvents

Chromatographic resolution of organic acids using the Kromasil-CHI-TBB chiral stationary phase

Derivatives of racemic mandelic and tropic acids have been separated directly on a t-butylbenzoylated tartaric acid-based chiral stationary phase (CSP) (Kromasil-CHI-TBB) on both analytical and preparative scales. The resolution of the enantiomers of the model compound, rac-3-methoxytropic acid, was optimized by changing the nature and the composition of the mobile phase. The dominating interaction between the CSP and these hydroxy acids was found to be hydrogen-bonding. Consequently, retention of the analytes on the CSP decreased with increasing polarity of the mobile phase modifier. The separation of the enantiomers was strongly influenced by the π-donating and π-accepting ability of the aryl moiety, and strong electron-withdrawing substituents in the aryl group e.g.,—CF3 result in a loss of chiral recognition. However, the CSP can discriminate between the two enantiomers only when both the aryl moiety and the carboxylic function are directly bonded to the asymmetric carbon atom. The Kromasil-CHI-TBB column displays broad selectivity for the enantiomers of mandelic and tropic acid derivatives, which are relatively simple structures and not easily resolved. Even though the α-values are moderate, the high efficiency of the column facilitates the use of the CSP for the preparative scale chiral separation of a number of these compounds. Chirality 11:420–425, 1999. © 1999 Wiley-Liss, Inc.

Investigation of Cyclodextrin Complexes of Mandelic acid

The inclusion complexes of both optically active and racemic mandelic acids with α-, (β- and γ-cyclodextrins were prepared by using a liophylisation technique. The compounds formed were investigated by thermoanalytical methods (TG, DSC and EGD) which were completed with FT-IR spectroscopic measurements, scanning electron microscopic observations, and dissolution rate determinations. The inclusion complex formation between all guests and hosts were proven using the thermoanalytical and FT-IR spectroscopic methods.