Enantiomers Of Α-amino Acids Research Articles

Synthesis of chiral functionalized UiO-66-NH2@SiO2 and use of its domain-limiting effect for separating small enantiomers.

Herein, to overcome the challenges of enantiomerically separating small chiral molecules, UiO-66-NH2@SiO2 was synthesized and samples of it were functionalized using a simple post-synthetic modification strategy with (+)-diacetyl-L-tartaric anhydride (DATA) and dibenzoyl-(+)-tartaric acid (DBTA), respectively. Then, based on the domain-limiting effect from the regular micropore structure of the included metal organic frameworks, the obtained UiO-66-DATA@SiO2 and UiO-66-DBTA@SiO2 each exhibited enhanced stereoselectivity for small enantiomers and successfully achieved the separation of α-amino acid and small alkaline enantiomers. This study has provided a new concept for the design and synthesis of chiral materials for separating small-molecule enantiomers.

Unusual enantiomeric separation due to residual amines in chiral crown ether stationary phase linked by long alkyl chain

A new chiral stationary phase (CSP) in which (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid was linked to a silica gel surface through a long alkyl chain and which did not contain additional aminoundecyl groups was prepared. Generally, when enantiomers containing a primary amine group are optically resolved using a crown-ether-type CSP, a higher resolution is achieved if the surface of the CSP does not contain any residual amine. In this study, the chiral separation factor and resolution factor of a CSP with a long alkyl chain such as the aminoundecyl group were unusually low in the absence of the residual aminoundecyl groups.In this study, a chiral column was prepared by introducing a chiral selector having a long alkyl chain on the surface of silica gel to separate enantiomers of α-amino acids. Furthermore, it was confirmed that the residual-amine-containing CSP, which was easier to synthesize, facilitated more effective enantiomeric separation than the CSP without residual amines.

An enzyme Biosensor Based on Organic Transistors for Recognizing α-Amino Acid Enantiomers

The chiral recognition of α-amino acids has attracted considerable interest because different enantiomeric amino acids show differences in their biological behavior and pharmacological activity. An organic electrochemical transistor (OECT)-based biosensor modified with L-amino acid oxidases (L-AAODX) was fabricated and successfully used as a biosensor for enantioselectively discriminating α-amino acids, such as D/L-tryptophan (D/L-Trp), D/L-tyrosine (D/L-Tyr) and D/L-phenylalanine (L-Phe) with high performance because L-AAODX selectively catalyzed the oxidation of L-Trp, L-Tyr, and L-Phe along with the amplification of OECT. The biosensor showed a sensitivity of 19.67 μA/μM with a LOD of 10 nM (S/N > 3) over the range of 10 nM to 30 μM for L-Trp, 16.71 μA/μM with a LOD of 2 nM (S/N >3) over the range of 2 nM to 30 μM for L-Tyr and 15.51 μA/μM with a LOD of 10 nM (S/N > 3) over the range of 30 nM to 30 μM for L-Phe. Furthermore, the biosensor can both be used for the chiral recognition of Trp, Tyr and Phe, and distinguish L-amino acids from its interferences (e.g., Glu, UA, L-Asp, L-Lys and L-Glu) and common metal ions (K+, Na+ and Fe3+).

Liquid chromatographic separation of the enantiomers of N-fluorenylmethoxycarbonyl α-amino acids on a covalently bonded type polysaccharide-derived chiral stationary phase under fluorescence detection

The liquid chromatographic enantiomer separation of N-fluorenylmethoxycarbonyl (FMOC) α-amino acids was performed using a covalently immobilized CSP (Chiralpak IB) with cellulose...

Temperature Dependences and Enthalpic Discrimination of Homochiral Pairwise Interactions of Six α-Amino Acid Enantiomers in Pure Water

Dilution enthalpies of six α-amino acid enantiomers (l-alanine vs d-alanine, l-serine vs d-serine, and l-proline vs d-proline) in pure water were determined at T = (288.15 to 323.15) K by isothermal titration calorimetry (ITC). Homochiral enthalpic pairwise interaction coefficients (hxx) at each temperature were evaluated according to the McMillan–Mayer theory. The hxx values of α-alanine and α-proline enantiomers are all positive (hLL > hDD > 0), while those of α-serine enantiomers are all negative (hLL < hDD < 0). In both cases, the hxx values increase uniformly and gradually with elevating temperatures. A slight but significant enthalpic discrimination effect is found in the homochiral pairwise interactions of these α-amino acid enantiomers. The positive growth of hxx values indicates that increasing temperature promotes the predominance of hydrophobic interactions in the binary aqueous solutions studied.

Enthalpic discrimination of homochiral pairwise interactions: Enantiomers of proline and hydroxyproline in (dimethyl formamide (DMF) + H2O) and (dimethylsulfoxide (DMSO) + H2O) mixtures at 298.15 K

Dilution enthalpies of two pairs of α-amino acid enantiomers, namely l-proline vsd-proline, and l-hydroxyproline vsd-hydroxyproline, in water-rich regions of dimethyl formamide (DMF)+H2O and dimethylsulfoxide (DMSO)+H2O mixtures (mass fractions of cosolvents wCOS=0 to 0.30) have been determined respectively at 298.15K by isothermal titration calorimetry (ITC). The successive values of dilution enthalpy obtained in a single run of ITC determination were used to calculate homochiral enthalpic pairwise interaction coefficients (hxx) at the corresponding composition of mixed solvents according to the McMillan–Mayer’ statistical thermodynamic approach. The sign and magnitude of hxx were interpreted in terms of solute–solute interactions mediated by solvent and cosolvent molecules, and preferential configurations of homochiral pairwise interactions (l–l or d–d pairs) in aqueous solutions. The variations of hxx with wCOS were considered to be dependent greatly on the competition equilibrium between hydrophobic and hydrophilic interactions, as well as the structural alteration of water caused by the two highly polar aprotic cosolvents (DMF and DMSO). Especially, it was found that when one of the two kinds of interactions (hydrophobic or hydrophilic interactions) preponderates over the other in solutions, enthalpic effect of homochiral pairwise interactions is always remarkable, and is characterized by a large absolute value of hxx, positive or negative, which corresponds respectively to the prevailing interactions of hydrophobicity or hydrophilicity. Interestingly, it was also found that the hxx values of l-enantiomers are generally larger than those of d-enantiomers across the whole studied composition range of mixed solvents, i.e. |hLL|>|hDD|, which is defined as enthalpic discrimination effect and attributed to the influence of preferential configuration on homochiral pairwise interactions in aqueous solutions.

Chromatographic resolution of racemic α-amino acids: Chiral stationary phase derived from modified xanthan gum

Enantiomeric resolution of α-amino acids into l-amino acid and d-amino acid via column chromatography using chiral stationary phase was performed. For this purpose, a dynamic chiral stationary phase prepared by grafting of methylmethacrylate onto xanthan gum (XG) was successfully employed in resolving various α-amino acids racemates. The peculiarities of the chromatographic behaviour of xanthan gum–graft-poly(methylmethacrylate)–amino acid interaction and the mechanism of their retention in column are discussed. The enantioselective properties of the xanthan gum–graft-poly(methylmethacrylate) in the separation of enantiomers of α-amino acids were studied using acidic solution of alanine, leucine, valine and tryptophan. The procedure is characterized by simplicity, efficiency and relatively low cost to analyze enantiomers of some amino acids.

Asymmetric Synthesis of α-Amino Acids by Reduction of N-tert-Butanesulfinyl Ketimine Esters

A highly regio- and diastereoselective reduction of various N-tert-butanesulfinyl ketimine esters with L-Selectride resulting in the formation of α-amino acids is reported. This method is quite general and also practical for the preparation of both enantiomers of aryl or aliphatic α-amino acids in high yields.

ChemInform Abstract: Enantiocontrol by Intrinsic Antiparallel Double Repulsion on Diacetone- D-glucose Template. Enantioselective Synthesis of Alanine and Chirally Deuterated Glycine.

Abstract A divergent and highly enantioselective synthetic methodology not only for both enantiomers of α-amino acids but for both chirally deuterated glycines from a single starting material was developed by making use of stereocontrol with antiparallel double repulsion on the diacetone-D-glucos-3-ulose template.

Chromatographic separation of enantiomers of non-protein α-amino acids after derivatization with Marfey’s reagent and its four variants

Some non-protein alpha-amino acids were derivatized with 1-fluoro-2,4-dinitrophenyl-5-L-alaninamide (Marfey's reagent, MR, FDNP-L-Ala-NH(2),) and four of its structural variants FDNP-L-Phe-NH(2), FDNP-L-Val-NH(2), FDNP-L-Leu-NH(2) and FDNP-L-Pro-NH(2). The resultant diastereomers were separated by normal and reversed phase thin layer chromatography (TLC) and reversed phase HPLC. In normal phase TLC, best resolution was obtained with solvent combination of phenol-water (3:1) while in reversed phase TLC mixtures of acetonitrile with triethylammonium phosphate buffer were found successful for resolution of diastereomers. The separation behavior of diastereomers prepared with different reagents was compared. The diastereomers of most of the amino acids prepared with FDNP-L-Leu-NH(2) were best separated while those prepared with FDNP-L-Pro-NH(2) failed to separate in most of the cases. The diastereomers were also separated on a reversed phase C(8) column with gradient elution using mixture of aqueous-trifluoroacetic acid (TFA) and acetonitrile and with detection at 340 nm. The effects of TFA concentration, flow rate and run time on HPLC separation were studied.

Enantioseparation of N-fluorenylmethoxycarbonyl α-amino acids on polysaccharide-derived chiral stationary phases by reverse mode liquid chromatography

The enantioseparation of N-protected fluorenylmethoxycarbonyl ( N-FMOC) α-amino acids was carried out on three polysaccharide-derived chiral stationary phases, such as cellulose tris(3,5-dimethylphenylcarbamate) (Chiralcel OD), amylose tris(3,5-dimethyl-phenylcarbamate) (Chiralpak AD) and cellulose tris(4-methylbenzoate) (Chiralcel OJ), and the influence of acetonitrile composition and pH of the eluents on the enantioseparation in reverse mode chromatography was examined. The best separation of the enantiomers was achieved with 40% acetonitrile in 50 mM phosphate buffer at pH 2. However, increasing the composition of acetonitrile to 50% on Chiralcel OD yielded a considerable decrease of retention time with minimum loss of resolution. The elution order of N-FMOC α-amino acid enantiomers on Chiralcel OD and OJ were quite different, indicating that both phases could be used in a complementary manner for the separation of the enantiomers of N-FMOC α-amino acids. The positive relationship between the capacity factor of N-FMOC α-amino acids and the hydrophobicity of amino acids indicated that hydrophobicity plays an important role on the retention of the N-FMOC α-amino acids in the reverse mode.

High-performance liquid chromatography of α-amino acid enantiomers on eremomycin-modified silica

The chromatographic behavior of enantiomers of α-amino acids was studied on new chiral stationary phases based on silica gel with macrocyclic glycopeptide antibiotic eremomycin and its aglycone immobilized on the surface. The retention of adsorbates and enantioselectivity of their separation were studied as functions of the structure of the side group of α-amino acids, eluant pH, concentration of organic modifier in the eluant, and temperature. The mechanism of the chiral recognition of α-amino acid enantiomers is discussed.

Synthesis of New Chiral Crown Ethers Incorporating Two Different Chiral Units and 'Matched/Mismatched' Effect of the Two Chiral Units on the Chiral Recognition

Chiral crown ethers have been widely applied as chiral selectors in differentiating the two enantiomers of racemic compounds containing a primary amino group. Especially chiral crown ethers have been quite useful as chiral selectors of liquid chromatographic chiral stationary phases (CSPs) for the recognition of the two enantiomers of racemic primary amino compounds. Among a large number of chiral crown ethers, two types have been most successfully utilized as liquid chromatographic CSPs. The first type is chiral crown ethers incorporating chiral 1,1'-binaphthyl unit, which were first developed by Cram. Especially, chiral crown ethers such as bis-(1,1'-binaphthyl)-22-crown-6 immobilized on silica gel or polystyrene were used as CSPs in separating the enantiomers of racemic α-amino acids and their derivatives in the late 1970s by Cram and coworkers. Afterward, chiral crown ethers related to (3,3'-diphenyl-1,1'binaphthyl)-20-crown-6 (1, Fig. 1) dynamically coated on octadecyl silica gel or covalently bonded to silica gel were developed as liquid chromatographic CSPs and successfully utilized in the resolution of racemic α-amino acids and other racemic compounds containing a primary amino group. The second type of chiral crown ether successfully utilized as a chiral selector of CSPs is the one incorporating two tartaric acid units, (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (2, Fig. 1), which was first synthesized by Lehn and coworkers. Initially, (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (2) was utilized as a chiral selector for the chiral separation by capillary electrophoresis. The use of (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (2) was then extended as a chiral selector of liquid chromatographic CSPs. Liquid chromatographic CSPs based on (+)-(18crown-6)-2,3,11,12-tetracarboxylic acid (2) were very successful in the resolution of various racemic primary amino compounds or racemic non-primary amino compounds. In addition, (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid (2) was utilized as an NMR chiral solvating agent. However, chiral crown ethers incorporating both chiral 3,3'-diphenyl-1,1'-binaphthyl and tartaric acid unit have never been known to the best of our knowledge. Chiral crown ethers incorporating both chiral 3,3'-diphenyl-1,1'binaphthyl and tartaric acid unit are expected to show characteristics somewhat different from chiral crown ether 1 or 2 in the chiral recognition. In this study, we wish to report the synthesis of novel chiral crown ethers incorporating both chiral 3,3'-diphenyl-1,1'-binaphthyl and tartaric acid unit and their applications as chiral selectors of liquid chromatographic CSPs. We prepared actually two diastereomeric chiral crown ethers, (R,R,R)-3 and (R,S,S)-3 (Fig. 2), incorporating both (R)-3,3'-diphenyl-1,1'-binaphthyl and (R,R)or (S,S)-tartaric acid unit as chiral barriers. Combination of the two different chiral units as chiral barriers is expected to endow the two diastereomeric chiral crown ethers with characteristic chiral recognition ability according to the stereochemistry of the two chiral units. Synthesis of the two diastereomeric chiral crown ethers was successfully performed as shown in Scheme 1. Diols (R,R)-4 and (S,S)-4 prepared from commercially available (R,R)and (S,S)-N,N,N',N'-tetramethyltartaramide respectively via the known procedure were converted into their tosyl derivatives, (R,R)-5 and (S,S)-5. Tosylation of (R,R)-4 or (S,S)-4 was most successful when a small amount of 4(dimethylamino)pyridine (DMAP) was added to the reaction mixture. The cyclization of tosyl derivative (R,R)-5 or (S,S)-

Chiral high-performance liquid chromatography analysis of α-amino acid mixtures using a novel SH reagent— N- R-mandelyl- l-cysteine and traditional enantiomeric thiols for precolumn derivatization

Several chiral thiols, i.e. traditionally used enantiomerically pure SH reagents and novel N- R-mandelyl- l-cysteine ( R-NMC) containing additional chiral center, have been applied as co-reagents in precolumn derivatization with o-phthalaldehyde for enantiomeric HPLC analysis of individual α-amino acids and their mixtures. The R-NMC-derived isoindoles as well as adducts with other thiols have a characteristic absorption maximum at 340 nm, and are highly fluorescent allowing detection of 10 μg/l of an amino acid. Investigated 19 amino acids were analyzed separately and in a mixture by a gradient HPLC after precolumn derivatization. The chromatographic behavior of formed isoindoles substantially differs for each of the thiols used for modification. In contrast to traditional enantiomeric thiols application of diastereomeric R-NMC provides higher resolution for α-amino acid enantiomers, with l, d-elution order (except for Arg). Combined use of R-NMC and other thiol enlarges the possibilities of this method, allowing accurate chiral analysis of complex amino acid mixtures.

Highly Enantioselective Decarboxylative Protonation of α-Aminomalonates Mediated by Thiourea Cinchona Alkaloid Derivatives: Access to Both Enantiomers of Cyclic and Acyclic α-Aminoacids

Thiourea derived cinchona alkaloids promote the asymmetric decarboxylative protonation of cyclic, acyclic, or bicyclic alpha-aminomalonate hemiesters under mild and metal-free conditions to afford enantioenriched aminoesters in high yields and enantioselectivities up to 93%. Both enantiomers of the aminoesters have been synthesized with the same selectivity when using organic base 3 and its pseudoenantiomer 6 derived from quinine.

Multicomponent diversity and enzymatic enantioselectivity as a route towards both enantiomers of α-amino acids—a model study

A model study on a new, enantioconvergent method for the synthesis of chiral, nonracemic α-amino acids is presented. α-Acetoxyamides obtained in a Passerini multicomponent reaction are selectively hydrolyzed by Wheat Germ lipase. Studies on conversion of the thus obtained, enantiomerically enriched α-hydroxyamides into α-aminoamides are presented. Products of these reactions are then hydrolyzed to give α-amino acids.

Dual-mode of Reversed and Normal-phase Liquid Chromatographic Enantiomer Separation on Coated Cellulose Derived Chiral Stationary Phases

For their broad applicability of enantiomer separation of a number of chiral compounds, many chiral stationary phases (CSPs) based on polysaccharide derivatives have been developed and extensively used. Among these CSPs, cellulose tris(3,5-dimethylphenylcarbamate) derived CSP (Chiralcel OD or Chiralcel OD-H) and cellulose tris(4methylbenzoate) derived CSP (Chiralcel OJ or Chiralcel OJH) have proven to be highly useful CSPs. These type CSPs are usually prepared with coating or adsorbing the polysaccharide derivatives of the chiral selectors on a silica matrix. It has been used with a limited range of solvents and, therefore, it has been mainly employed with normal phase eluents, such as hexane/2-propanol mixtures. Compared to normal-phase enantiomer separation, however, reversedphase enantiomer separation using aqueous mobile phases may often provide advantages. Especially, it is important for samples that have problems for analysis under normal phase conditions because of their solubility and intrinsic aqueous biological samples or synthetic analytes with aqueous solvents. Since these coated cellulose derived CSPs like Chiralcel OD and Chiralcel OJ have been applied with normal phase eluents, only a few of results for enantiomer separation using aqueous mobile phases on these CSPs have been reported. The first attempt of reversed-phase enantiomer separation on the polysaccharide derived CSP has been reported by Ikeda et al. Four chiral drug analytes have been enantioseparated with good separation factors (α = 1.101.61) on Chiralcel OD using aqueous buffer-acetonitrile solutions. The second report on enantiomer separation of one hydantoin biological analyte of a major metabolite of phenytoin on Chiralcel OJ using aqueous ethanolic solution (Rs = 2.2) has been published by Eto et al. Also, the enantiomer resolution of four drug analytes on Chiralcel OJ using aqueous acetonitrile solution has been performed by Ishikawa et al. A series of quaternary tropane alkaloids have been resolved with good separation factors on Chiralcel OD using aqueous ion pair mobile phases and normal phases by Hempe et al., respectively. Weinz and his co-workers have reported on enantiomer resolution of only two biological samples of glutethimide and its analog analytes on Chiralcel OD using aqueous acetonitrile solution (α = 1.21, 1.14). In this study, we present enantiomer resolution of Nfluorenylmethoxycarbonyl (FMOC) α-amino acids on Chiralcel OJ-H and Chiralcel OD-H under the dual-mode of reversed as well as normal phase conditions. This is the first report on both reversed and normal phase liquid chromatographic enantiomer separation using Chiralcel OJ-H and Chiralcel OD-H, coated cellulose based CSPs. Table 1 and 2 show liquid chromatographic results for the separation of the enantiomers of N-FMOC α-amino acids on Chiralcel OJ-H and Chiralcel OD-H under reversed and normal phase conditions. In general, the enantioselectivities on these two CSPs for the resolution of N-FMOC α-amino acids under reversed phase condition of 40% acetonitrile in 50 mM phosphate buffer are lower than those under normal

Direct Chiral Separation of N-Fluorenylmethoxycarbonyl α-Amino Acids by HPLC for Determination of Enantiomeric Purity

N-Protected α-amino acids have been widely used as important chiral building blocks in the fields of pharmaceutical chemistry and biochemistry. The fluorenylmethoxycarbonyl (FMOC) group is one of the most commonly used protecting groups for α-amino acids and provides the advantages of high sensitivity in fluorescence detection. Especially, the FMOC protecting group is attractive, because it is frequently used for amino protecting groups in solid phase synthesis and combinatorial chemistry. Owing to the importance of optical purity of N-FMOC α-amino acids, convenient and accurate methods to determine the enantiopurity of these compounds have been required and developed. Several methods for the liquid chromatographic separation of the enantiomers of N-FMOC α-amino acids have been reported using CSPs derived from cyclodextrin, macrocyclic antibiotics and cellulose derivatives as well as small molecules derived brush-type CSPs. Although the enantioseparation of some FMOC secondary amino acids has been performed on 1-naphthylethyl carbamoylated βcyclodextrin bonded CSP with good resolution, most FMOC α-amino acids enantiomers have not been resolved on βand γ-cyclodextrin bonded CSPs. It has been reported that nine N-FMOC α-amino acids enantiomers were separated on macrocyclic antibiotics derived CSP. Brushtype CSPs derived from α-amino acids and cinchona derivatives including Whelk-O CSP have been employed to resolve some FMOC α-amino acids enantiomers. Also, the enantioresolution of two FMOC α-amino acid type enantiomers has been reported on cellulosic-type CSP under reversed-phase conditions. For resolution of N-FMOC αamino acids, however, polysaccharide-derived CSPs have not been applied under normal phase conditions and the enantiomer separation of a series of these analytes has not been well investigated. In this study, the liquid chromatographic resolution of N-FMOC protected α-amino acids for determination of their enantiomeric purity was performed on polysaccharide-derived CSPs, Chiralcel OD and Chiralpak AD under normal phase conditions. Table 1 and Table 2 show liquid chromatographic results for the separation of the enantiomers of N-FMOC α-amino acids on Chiralcel OD and Chiralpak AD. Chiralcel OD and/ or Chiralpak AD afford fairly good enantioselectivities for the resolution of N-protected FMOC α-amino acids under normal phase conditions. Chiralcel OD affords comparable or better enantioselectivities for the resolution of N-FMOC α-amino acids than Chiralpak AD except N-FMOC protected glutamine and tyrosine analytes (entries 7 and 17). All investigated N-FMOC α-amino acids enantiomers were base-line separated on Chiralcel OD or Chiralpak AD. For example, while N-FMOC glutamine, norvaline, phenylalanine and tyrosine enantiomers were partially separated on Chiralcel OD (Rs 1.48). Therefore, Chiralcel OD and Chiralpak AD might be complementarily used for the separation of the enantiomers of N-FMOC α-amino acids. The consistent elution order of the resolved N-FMOC α-amino acids is not observed on Chiralcel OD and Chiralpak AD. As shown in Table 1, the elution of the (D)isomers prior to the (L)-isomers for resolution of N-FMOC α-amino acids examined except five analytes is observed on Table 1. Enantiomer Separation of N-FMOC Protected α-Amino Acids on Chiralcel OD

A Stereodivergent Approach to Amino Acids, Amino Alcohols, or Oxazolidinones of High Enantiomeric Purity

(-)-Menthone, an inexpensive chiral auxiliary, was used to prepare both enantiomers of alpha-amino acids, amino alcohols, or oxazolidinones. The sequence includes the S(N)2' displacement by a cuprate reagent and a Curtius rearrangement as key steps.

Preparation and application of a new ligand exchange chiral stationary phase for the liquid chromatographic resolution of α-amino acid enantiomers

A new liquid chromatographic ligand exchange CSP has been prepared by covalently bonding ( S)- N, N-carboxymethyl undecyl leucinol monosodium salt onto silica gel and employed in resolving various α-amino acids. The new CSP was quite good in resolving various α-amino acids and the resolution results were dependent on the type and content of organic modifier in the mobile phase. From these results, a chiral recognition model using a lipophilic interaction between the tethering alkyl group of the CSP and the substituent at the chiral center of α-amino acids was proposed. The liquid chromatographic resolution of α-amino acids on the new CSP was also found to be dependent on the Cu(II) concentration in the mobile phase and the column temperature.