Highly diastereoselective alkylation of vicinal dianions of chiral succinic acid derivatives: a new general strategy to (R)-β-arylmethyl-γ-butyrolactones

The vicinal dianions derived from chiral succinic acid derivatives, 1,4-bis[(4R,5S)-3,4-dimethyl-2-oxo-5-phenylimidazolidin-1-yl]butane-1,4-dione and 1,4-bis[(4S,5R)-3,4-dimethyl-2-oxo-5-phenylimidazolidin-1-yl]butane-1,4-dione react with arylmethyl bromides with high diastereo- and regio-selectivity to provide the corresponding chiral α-arylmethylated succinic acid derivatives; the (R)-products are converted into (R)-β-arylmethyl-γ-butyrolactones and (R)-α-arylmethyl-γ-butyrolactones.     

Practical and highly stereoselective technology for preparation of enantiopure sulfoxides and sulfinamides utilizing activated and functionally differentiated N-sulfonyl-1,2,3-oxathiazolidine-2-oxide derivatives

A simple, general, and practical technology to prepare enantiopure 1,2,3-oxathiazolidine-2-oxide derivatives using chiral aryl N-sulfonyl aminoalcohol derivatives and thionyl chloride is reported. The versatility of these novel chiral building blocks (MIOO and TMPOO), was exemplified by the expedient production of a variety of unique chiral sulfoxides and valuable chiral sulfinamides in excellent yields and enantiopurities.     

A novel approach for LC-MS/MS-based chiral metabolomics fingerprinting and chiral metabolomics extraction using a pair of enantiomers of chiral derivatization reagents

Chiral metabolites are found in a wide variety of living organisms and some of them are understood to be physiologically active compounds and biomarkers. However, the overall analysis of chiral metabolomics is quite difficult due to the high number of metabolites, the significant diversity in their physicochemical properties, and concentration range from metabolite-to-metabolite. To solve this difficulty, we developed a novel approach for chiral metabolomics fingerprinting and chiral metabolomics extraction, which is based on the labeling of a pair of enantiomers of chiral derivatization reagents (i.e., DMT-(S,R)-Pro-OSu and DMT-3(S,R)-Apy) and precursor ion scan chromatography of the derivatives. The multivariate statistics is also required for this strategy. The proposed procedures were evaluated by the detection of a diagnostic marker (i.e., d-lactic acid) using the saliva of diabetic patients. This method was used for the determination of biomarker candidates of chiral amines and carboxyls in Alzheimer's disease (AD) brain homogenates. As the results, l-phenylalanine (L-Phe) and l-lactic acid (L-LA) were identified as the decreased and increased biomarker candidates in the AD brain, respectively. Therefore, the proposed approach seems to be helpful for the determination of non-target chiral metabolomics possessing amines and carboxyls.     

Urea-tetrahydrobenzoxanthene receptors for carboxylic acids

Hydrogen-bonding receptors for carboxylic acids have been prepared based on a cis tetrahydrobenzoxanthene skeleton. X-ray diffraction study of one of these compounds revealed that the cleft is suitable for establishing strong linear hydrogen bonds with the oxygen of a water molecule. Complexes that set only three H-bonds with the guests showed no chiral recognition with amino acid derivatives. However, suitable functionalization of the receptor provided a fourth H-bond with certain amino acid derivatives, leading to significant enantioselective complexation in this case.     

Synthesis of α-chiral-β,γ-unsaturated carboxylic acid derivatives using chiral auxiliaries

We report an efficient and reliable method for the synthesis of α-chiral-β,γ-unsaturated carboxylic acid derivatives using chiral auxiliaries and vinylacetic acid. Two well-established chiral auxiliaries ((S,S)-pseudoephedrine and (R)-benzyl-oxazolidinone) were chosen to test the merits of this method. Six different electrophiles were examined in the diastereoselective alkylation with both auxiliaries. The pseudoephedrine auxiliary provided isolated yields between 61 and 85% and diastereomeric ratios all greater than 96:4. Employing the same reactions as with the pseudoephedrine derivative, the corresponding oxazolidinone auxiliary provided isolated yields between 0 and 80% with diastereomeric ratios from 80:20 to 93:7.     

Chiral nitrogen-containing calix[4]crown—an excellent receptor for chiral recognition of mandelic acid

A chiral nitrogen-containing calix[4]crown 2 bearing optically pure 1,2-diphenyl-1,2-oxyamino residue at lower rim showed excellent chiral recognition between enantiomers of mandelic acid. Using competitive ¹H NMR titration the ratio of association constants of (S)- and (R)-mandelic acid with the chiral calix[4]crown was determined to be 102, that is 98% de, which is the best result obtained from artificial receptors for the chiral recognition of mandelic acid up to now.     

Synthesis of noval chiral tridentate amino alcohols as chiral solvating agents under ball-milling conditions

A new family of chiral solvating agents based on chiral didentate amino alcohols and chloromethyl pyridine derivatives were synthesized by ball milling in solvent free condition. The new chiral tridentate amino alcohols were tested as chiral NMR solvating agents for the Ts-derivatives of amino acids, other several acids and pyrazole drugs. For the Ts-derivatives of amino acids studied herein, chiral tridentate amino alcohol 3a could be used for the assignment of the absolute configurations of their racemes through the chemical shift non-equivalences of their CH₃ (Ts) protons with certain confidence.     

Enantioselective γ-addition reaction of rhodanines to allenoates catalyzed by chiral phosphine-carbamate

Phosphine-catalyzed enantioselective γ-additions of rhodanines to allenoates have been developed for the first time. With the employment of chiral cyclohexane-based phosphines, a wide range of substituted rhodanine derivatives containing tertiary chiral centers were constructed in good yields and high enantioselectivities.     

Impact of amines as co-modifiers on the enantioseparation of various amino acid derivatives on a tert-butyl carbamoylated quinine-based chiral stationary phase

A tert-butyl carbamoylated quinine-based chiral stationary phase (CSP) for direct enantiomer separation of various natural and unnatural amino acid derivatives was studied. The influence of functional groups in the amino acid side chains upon the enantioseparation is discussed with the aim of realizing contributions to their overall chiral recognition. The effects of various amines as co-modifiers upon retention and overall enantioselectivity of amino acid derivatives in polar organic solvents was systematically investigated. In general, retention times decreased with increasing amine concentrations without a distinct alteration of enantioselectivity. All analytes were rapidly resolved on the CSP with the methanol-based mobile phase containing 87 mM acetic acid and 7 mM triethylamine.     

Chirality induction of polyaniline derivatives through chiral complexation

Chirality induction of π-conjugated polyaniline derivatives was achieved by chiral complexation with chiral palladium(II) complexes. The crystal structure of the chiral conjugated complex with a model compound of the polyaniline, N,N-bis(4^′-dimethylaminophenyl)-1,4-benzoquinonediimine, revealed a chiral propeller twist conformation of the π-conjugated moiety.     

Chiral oxazoline route to enantiomerically pure biphenyls: magnesio and copper mediated asymmetric hetero- and homo-coupling reactions

A series of chiral biphenyls were prepared via asymmetric reactions involving chiral oxazolines. One series of chiral biphenyls was reached by the magnesium mediated coupling of aryl bromides (via their Grignard reagents) with o-methoxyaryl oxazolines. In this case only the o-methoxy group was replaced by the ArMgBr. The initially formed biphenyl adducts were obtained in de's as high as 92:8. These adducts could be manipulated to various other chiral biphenyls. Another series of chiral biphenyls were obtained via an asymmetric Ullmann reaction, which was shown to be thermodynamically controlled. The de's of this copper mediated process were also in the range of 90% and could be utilized to reach various derivatives. Racemization, thermal stability, and atropisomerization characteristics were also studied.     

Enantiomer separation and indirect chromatographic absolute configuration prediction of chiral pirinixic acid derivatives: Limitations of polysaccharide-type chiral stationary phases in comparison to chiral anion-exchangers

Chiral α-arylthiocarboxylic acids with different substitution patterns, representing new pirinixic acid derivatives with dual PPARα/γ agonistic activities, have been separated into enantiomers on tert-butylcarbamoylquinine and quinidine based chiral anion-exchangers and amylose tris(3,5-dimethylphenylcarbamate) coated silica on analytical and preparative scale. Absolute configurations of individual enantiomers were assigned chromatographically via elution orders on the chiral anion-exchangers and were confirmed by stereoselective syntheses via Ewans auxiliaries that have lead to enantiomeric products with known absolute configurations. The results of both methods were in full agreement. Moreover, the receptor stereoselectivity in PPARα transactivation activities was consistent within the test set of structurally related compounds. Limited correlation (between elution order and substitution) was observed within the set of α-arylthiocarboxylic acids on the amylose tris(3,5-dimethylphenylcarbamate) based chiral stationary phase (CSP), in particular the elution order changed with remote substitution. This clearly demonstrates the risks of chromatographic absolute configuration assignments by prediction from one structural analog to another one, especially with CSPs such as polysaccharide CSPs that are recognized for their broad applicability due to multiple binding and chiral recognition modes. It is therefore of utmost importance that such chromatographic absolute configuration predictions by extrapolation to structural analogs are combined with orthogonal methods for verification of the results.     

Synthesis and characterization of <Emphasis Type="Italic">D</Emphasis>-/<Emphasis Type="Italic">L</Emphasis>-methionine grafted PEDOTs for selective recognition of 3,4-dihydroxyphenylalanine enantiomers

Two pairs of amino-acid functionalized poly(3,4-ethylenedioxythiophene) (PEDOT) derivatives, namely, poly(N-(tert-butoxycarbonyl)-L-methionyl (3,4-ethylenedioxythiophene-2’-yl)methylamide) (L-PEDOT-Boc-Met) and poly(N-(tert-butoxycarbonyl)-D-methionyl (3,4-ethylenedioxythiophene-2’-yl)methylamide) (D-PEDOT-Boc-Met); poly(L-methionyl (3,4-ethylenedioxythiophene-2’-yl)methylamide) (L-PEDOT-Met) and poly(D-methionyl (3,4-ethylenedioxythiophene-2’-yl)methylamide) (D-PEDOT-Met) were synthesized via chemical oxidative polymerization of corresponding monomers. The structural characterization, spectroscopic properties and thermal stability of these monomers and polymers were systematically explored by FTIR spectra, Raman spectra, XRD spectra, UV-Vis spectra and thermogravimetric analysis. As chiral electrode materials, these polymers were employed to successfully recognize 3,4-dihydroxyphenylalanine (DOPA) enantiomers by cyclic voltammetry (CV) in sulphuric acid solution. The measurement results reveal that the tendency was hetero-chiral interaction between L-PEDOT-Met/PVA/GCE and D-DOPA, D-PEDOT-Met/PVA/GCE and L-DOPA, respectively. Also, the mechanism of chiral discrimination was discussed. All the results implied that the combination of electrochemical molecular recognition technology and chiral PEDOT materials can be a promising approach for chiral recognition and may open new opportunities for facile, biocompatible, sensitive and robust chiral assays in biochemical applications.     

Application of deuterated THENA for assigning the absolute configuration of chiral secondary alcohols

The structure of a constrained bicyclic chiral derivatizing agent (CDA), 1,2,3,4-tetrahydro-1,4-epoxynaphthalene-1-carboxylic acid, THENA 1, was modified by replacing both exo-methylene protons with deuterium atoms. The modified CDA, THENA-d₂2, could be used to assign the absolute configuration of chiral secondary alcohols with good reliability. Compared with THENA, the multiplicity of the methylene proton signals in the ¹H NMR spectra of THENA-d₂ derivatives is less complicated and the new CDA thus offers simpler NMR spectra for data interpretation.     

Synthesis of novel chiral imidazolium stationary phases and their enantioseparation evaluation by high-performance liquid chromatography

Two novel chiral stationary phases (CSPs) were prepared by bonding chiral imidazoliums on the surface of silica gel. The chiral imidazoles were derivatized from chiral amines, 1-phenylethylamine and 1-(1-naphthyl)ethylamine. The obtained CSPs were characterized by Fourier Transform Infrared (FT-IR) spectroscopy and elemental analysis (EA), demonstrating the bonding densities of CSP 1 and CSP 2 were 0.43 mmol g⁻¹ and 0.40 mmol g⁻¹, respectively. These two CSPs could be used to availably separate 8 pharmaceuticals, 7 mandelic acid/its derivatives, 2 1-phenylethylamine derivatives, 1 1,1′-bi-2-naphthol, and 1 camphorsulfonic acid in high-performance liquid chromatography (HPLC). It is found that CSP 1 could effectively enantioseparate most chiral analytes, especially the acidic components, while CSP 2 could enantiorecognize all chiral analytes, although a number of components did not achieve baseline separation. Additionally, the effects of mobile phase composition, mobile phase pH and salt content, chiral selector structures, and analyte structures on the enantiorecognitions of the two CSPs were investigated. It is found that high acetonitrile content in mobile phases was conducive to enantiorecognition. Mobile phase pH and salt content could alter the retention behaviors of different enantiomers of the same chiral compound, resulting in better enantioresolution. Moreover, both chiral selector structures and substituted groups of analytes played a significant role in the separation of chiral solutes.     

Enantiomer assays of amino acid derivatives using tertiary amine appended trans-4-hydroxyproline derivatives as chiral selectors in the gas phase

A pair of pseudo-enantiomers, tertiary amine appended trans-4-hydroxyproline derivatives were designed, synthesized, and evaluated as chiral selectors for enantiomer analysis of DNB-amino acid and their amides, in single-stage electrospray ionization/mass spectrometric experiments. The chiral selectors were designed to remove the interaction of the hydroxyl group of trans-4-hydroxyproline as well as separate the ionization site from the sites required for effective chiral recognition. Addition of a chiral analyte to a solution containing two pseudo-enantiomeric chiral selectors, affords selector-analyte complexes in the electrospray ionization mass spectrum where the ratio of these complexes is dependent on the enantiomeric composition of the analyte. The relationship between the ratio of the selector-analyte complexes in the electrospray ionization mass spectrum and the enantiomeric composition of the analyte can be used to relate the extent of the measured enantioselectivity and for quantitative enantiomeric composition determinations. Effects of acid modifiers (ammonium chloride, acetic acid, formic acid and hydrochloric acid) and instrument conditions on the selector-analyte ion intensity and the enantioselectivity (α_MS) were investigated. The largest α_MS was observed using ammonium chloride at a concentration around 0.5-1 mM at desolvation temperature of 150 °C. Capillary voltage has little effects on α_MS values. The sense of chiral recognition by MS is consistent with what is observed chromatographically. Quantitative enantiomeric composition determinations for N-(3,5-dinitrobenzoyl) leucinyl butylamide were performed. A comparison to the enantioselectivities towards a scope of analytes observed by chiral HPLC using a 3,5-dimethylanilide-proline-derived chiral stationary phase, is presented.     

Application of tetraoxadiaza-crown ether derivatives as chiral selector modifiers in capillary electrophoresis

Two new diaza-crown ether derivatives (R-1, RS-1) have been synthesized from 1,4,10,13-tetraoxa-7,16-diazacyclooctadecane and tested as potential chiral selectors in capillary electrophoresis (CE) for the chiral separation of five amino acid derivatives. The individual use of the selectors did not lead to chiral differentiation. However, they enhanced the enantioselective effect of different cyclodextrins in dual selector systems. In this paper, we report the effect of different substituted diaza-crown ether derivatives on the separation results obtained in dual systems with cyclodextrins.     

Chiral calix[4]arenes bearing α-hydroxy amide units as membrane carriers for amino acid methyl esters

Novel chiral calix[4]arene derivatives functionalized at the lower rim have been prepared from the reaction of p-tert-butylcalix[4]arene diamine or acylhydrazine derivative with mandelic acid or hydroxyisovaleric acid. The structures of these receptors were characterized by FTIR, ¹H, ¹³C and 2D COSY NMR spectroscopy and elemental analysis. The transport of amino acid derivatives (phenylalanine, phenylglycine and tryptophan methyl ester hydrochlorides) was studied through bulk liquid membrane in the presence of chiral calix[4]arene derivatives. The receptors have been found to act as carriers for transport of aromatic amino acid methylesters from the aqueous source phase to the aqueous receiving phase. The transport rate and L/D selectivity of amino acid esters studied depend strongly upon the structure of the chiral receptors and guests. The best enantioselectivity was obtained in the case of phenylglycine methyl ester for all chiral carriers.     

The Resolution of Enantiomeric Ibuprofen on Chiral Stationary Phases Containing N-Arylcarbamoyl Derivatives of Phenylglycine

A series of fourteen anilide derivatives of ibuprofen were resolved on six chiral stationary phases (CSPs) derived from N-arylcarbamoyl derivatives of (S)-phenylglycine. Excellent chiral resolutions were achieved on these CSPs. The ionic-type CSPs showed better chiral recognition abilities than the corresponding covalent-type CSPs, and the CSP bearing two chiral centers has better performance than the CSPs bearing only one chiral center. The highest separation factor was achieved using the ionic-type CSP bearing two chiral centers for the resolution of the 3,5-dinitroanilide derivative of ibuprofen. This result is better than those reported in literature for the resolution of ibuprofen on the CSPs derived from amino acids, According to the chromatographic behaviors, the hydrogen bonding interaction, the π-π interactions provided by the phenyl groups in CSPs bearing one chiral center, and the phenylethylcarbamoyl moiety in CSPs bearing two chiral centers dominate the chiral recognition.     

多糖类氨基甲酸酯衍生物的区域选择性合成及其手性识别

通过糖单元6-位羟基的保护和去保护,运用区域选择性方法合成了6种新型多糖类氨基甲酸酯衍生物,分别为纤维素/直链淀粉-[2,3-二(3,5-二甲基苯基)-6-环己基]氨基甲酸酯、[2,3-二(3,5-二氯苯基)-6-环己基]氨基甲酸酯及[2,3-二(4-氯苯基)-6-环己基]氨基甲酸酯,并将其涂敷在氨丙基硅胶的表面制备HPLC手性固定相.利用1H-NMR与FTIR光谱技术对所合成衍生物进行结构表征和分析,并应用HPLC法评价其对于9种手性化合物的手性识别能力.通过与以手性识别能力高而著称且含有单一取代基的纤维素/直链淀粉-三(3,5-二甲基苯基氨基甲酸酯)等手性固定相的对比分析表明,所合成新型手性固定相对于某些对映体显示出更优的手性识别能力.由进一步分析表明,糖单元2-、3-和6-位取代基的性能对于纤维素和直链淀粉氨基甲酸酯类衍生物的手性识别能力均具有较大影响.