Enantioselective fluorescent sensor for amino acid derivatives based on BINOL bearing hexahydropyrrolo[1,2-c]imidazol-1-one units

A chiral fluorescent sensor (Ra,S,l)-3 incorporating (R)-BINOL and l-prolinamide is found efficient in enantioselective recognition of N-Cbz-protected phenylglycine. It is observed that one enantiomer of N-Cbz-protected phenylglycine can obviously increase the fluorescence intensity of (Ra,S,l)-3, while the other enantiomer does not cause much fluorescence enhancement. Such highly enantioselective response makes the sensor (Ra,S,l)-3 useful for the enantioselective fluorescence recognition of other N-Cbz-protected amino acids.     

A highly enantioselective chiral Schiff-base fluorescent sensor for mandelic acid

A chiral Schiff-base compound, 4-methyl-2,6-bis-[(2-hydroxy-1-phenylethylimino)methyl]phenol, is found to act as highly enantioselective fluorescent agent for α-hydroxycarboxylic acid, e.g., mandelic acid. It is observed that, within a certain concentration range, one enantiomer of the chiral acid can increase the fluorescence intensity of the Schiff-base compound 122-fold while the other enantiomer enhances the intensity only 42-fold. Such highly enantioselective responses towards the chiral acid make the unusual Schiff-base compound attractive as a fluorescent sensor for determining the enantiomeric composition of α-hydroxycarboxylic acids.     

Highly enantioselective fluorescent recognition of amino acid derivatives by unsymmetrical salan sensors

Novel unsymmetrical salan fluorescent sensors 2a and 2b have been designed and synthesized. The chiral recognition of N-Boc-protected amino acids by 2a and 2b has been investigated. Sensor 2a possesses higher sensitivity and enantioselectivity than sensor 2b does. Job analysis and nonlinear regression results show that 2a can form a 1:1 stoichiometric complex with a N-Boc-protected amino acid. The obtained response selectivities and the association constants indicate that 2a is a highly enantioselective and sensitive fluorescent sensor toward N-Boc-protected amino acids.     

A novel chiral terpyridine macrocycle as a fluorescent sensor for enantioselective recognition of amino acid derivatives

Terpyridine macrocycle 1 is shown to be a strong chelating agent for organic ammonium salts and also a useful chromophore in fluorescent sensing. It exhibits very good enantioselectivity (K(obs)(S)/K(obs)(R)= 3.8) in chiral discrimination of alpha-phenylglycine methyl ester hydrochloride (PhEtOMe).     

Enantioselective fluorescent recognition of chiral acids by 3- and 3,3′-aminomethyl substituted BINOLs

Benzylaminomethyl groups are introduced to the 3,3′-positions of BINOL. The resulting compounds can be used to conduct the enantioselective fluorescent recognition of mandelic acid and N-benzyloxycarbonylphenylglycine. In the presence of (S)-mandelic acid, compound (R)-2 showed over 30-fold fluorescence enhancement with the ef [ef=enantiomeric fluorescence difference ratio=(I_S−I₀)/(I_R−I₀)] up to 4.2. In the presence of d-N-benzyloxycarbonylphenylglycine, compound (RR)-4 showed up to 15-fold fluorescence enhancement with the ef up to 5.0. These high fluorescence sensitivity and enantioselectivity make compounds (R)-2 and (RR)-4 practically useful sensors for the recognition of the chiral acids in apolar solvents.     

New C2-symmetric 2,2′-bipyridine crown macrocycles for enantioselective recognition of amino acid derivatives

A series of new C₂-symmetric 2,2′-bipyridine-contaning crown macrocycles 1-4 has been developed for enantiomeric recognition of amino acid derivatives. These new macrocycles have been showed to be strong complexing agents for primary organic ammonium salts (with K up to 4.83×10⁵ M⁻¹ and −ΔG₀ up to 32.4 kJ mol⁻¹) and also useful chromophores for UV-vis titration studies. These macrocyclic hosts exhibited enantioselective binding towards the (S)-enantiomer of phenylglycine methyl ester hydrochloride (Am1) with K_(S)/K_(R) up to 2.10 (ΔΔG₀=−1.84 kJ mol⁻¹) in CH₂Cl₂ with 0.25% CH₃OH. The structure-binding relationship studies showed that the aromatic subunit and the ester group of the ammonium guests are both important for good enantioselectivity. In addition, the host-guest complexes have been studied using various NMR experiments.     

Highly enantioselective fluorescent recognition of mandelic acid derivatives by chiral salen macrocycles

Calixarene-like chiral salen macrocycles can be used for the enantioselective fluorescent recognition of mandelic acid derivatives. It was observed that one enantiomer of mandelic acid causes a 28-fold increase in the fluorescence intensity of a chiral salen macrocycle, whereas the other enantiomer causes only a 14-fold fluorescence enhancement. This highly enantioselective fluorescent response makes chiral salen macrocycles useful for the enantioselective fluorescent recognition of some mandelic acid derivatives.     

Fluorescent cyclodextrins bearing metal binding sites and their use for chemo- and enantioselective sensing of amino acid derivatives

Ditopic receptors based on cyclodextrins bearing a metal binding site were used as enantioselective fluorescence sensors, which were able to generate different responses in the presence of d- or l-amino acids. The performances of the selectors as a function of their structure were evaluated, and the same analysis was extended to other analytes. In this work, this approach is used for the enantiomers of a series of amino acid derivatives and in particular of 2-aminocaprolactam. The results showed that the ability of these sensors to perform enantiomeric analysis can be extended to other analytes of interest in organic synthesis such as amino acid amides and α-aminolactams.     

Highly enantioselective fluorescent recognition of α-amino acid derivatives

Bisbinaphthyl-based macrocycles are found to carry out enantioselective fluorescent recognition of α-amino acid derivatives. It is observed that one enantiomer of a N-protected phenyl glycine can increase the fluorescence intensity of the binaphthyl fluorophores by over 4-fold but the other enantiomer does not cause much fluorescence enhancement. This highly enantioselective fluorescent response makes the binaphthyl macrocycles practically useful for the enantioselective fluorescent recognition of the amino acid substrate.     

胆甾类分子钳对氨基酸衍生物的对映选择性识别

用差紫外光谱滴定法考察了以脱氧胆酸作spacer的手性分子钳1～3对一系列α-氨基酸甲酯的对映选择性识别性能。结果表明,分子钳1和2与客体氨基酸甲酯形成1:1型超分子配合物,并显示较好的手性识别能力。分钳3对所考察的氨基酸甲酯均没有明显的识别作用。讨论了主-客体间尺寸/形状匹配、几何互补等因素对形成超分子配合物的影响,并利用计算机模拟作辅助手段对实验结果和现象进行了解释。     

Chemoselective and enantioselective analysis of proteinogenic amino acids utilizing N-derivatization and 1-D enantioselective anion-exchange chromatography in combination with tandem mass spectrometric detection

D-Amino acid analysis in biological samples still poses a challenge to analytical chemists. In higher developed species trace amounts of d-amino acids have to be detected in vast excesses of the corresponding L-enantiomers. This method utilizes an easy-to-carry-out derivatization step on the amino group with an iron ferrocenyl propionate hydroxy succinimide ester followed by one-dimensional enantioselective anion exchange chromatography with cinchona alkaloid based chiral stationary phases (CSPs). MS detection is carried out in the highly sensitive SRM (selected reaction monitoring) mode, which allows a chemoselective differentiation of amino acid derivatives as well as their enantioselective separation in one step. Application of this method allows LOD (limits of detection) in the low μmol L(-1) range and baseline enantioseparation for all proteinogenic amino acids except for Pro, Arg and His. The D-enantiomers of isomeric Leu and Ile were separated chromatographically and pose an example for the complementary selectivities of LC and MS. A successful application of this procedure to unprocessed human urine indicated the eligibility to analyse biological samples.     

Chiral separation of enantiomers of amino acid derivatives by high-performance liquid chromatography on a norvancomycin-bonded chiral stationary phase

A novel norvancomycin-bonded chiral stationary phase (NVC-CSP) was synthesized by using the chiral selector of norvancomycin. The chiral separation of enantiomers of several dansyl-amino acids by high-performance liquid chromatography (HPLC) in the reversed-phase mode is described. The effects of some parameters, such as organic modifier concentration, column temperature, pH and flow rate of the mobile phase, on the retention and enantioselectivity were investigated. The study showed that ionic, as well as hydrophobic interactions were engaged between the analyte and macrocycle in this chromatographic system. Increasing pH of buffers usually improved the chiral resolution for dansyl--amino-n-butyric acid (Dns-But), dansyl-methionine (Dns-Met) and dansyl-threonine (Dns-Thr), but not for dansyl-glutamic acid (Dns-Glu) which contains two carboxylic groups in its molecular structure. The natural logarithms of selectivity factors (ln ) of all the investigated compounds depended linearly on the reciprocal of temperature (1/T), most processes of enantioseparation were controlled enthalpically. Interestingly, the process of enantioseparaton for dansyl-threonine was enthalpy-controlled at pH of 3.5, while at pH of 7.0, it was entropy-controlled according to thermodynamic parameters Δ_R,SΔH° and Δ_R,SΔS° afforded by Van’t Hoff plots. In order to get baseline separation for all the solutes researched, norvancomycin was also used as a chiral mobile phase additive. In combination with the NVC-CSP, remarkable increases in enanselectivity were observed for all the compounds, as the result of a “synergistic” effect.     

Carboxylic fused furans for amino acid fluorescent labelling

Four carboxylic fused furans are presented as new fluorescent labels for the amino and hydroxyl functions of organic molecules. Various representative l-amino acids were chosen as models, labelled at their N-terminus and also at their side-chain. Fluorescent derivatives were obtained in high yields, and their absorption and emission properties were studied.     

Synthesis of a pair of novel receptors and their properties of enantioselective recognition for amino acid zwitterions

A pair of artificial enantiotopic receptors la and lb composed of ( S, S) or (R,R) chiral bicyclic guanidinium, azacrown ether and (t-butyldiphenylsilyloxy) methyl group for amino acid zwitterions have been synthesized. The liquid-liquid competition extraction experiments and 1H NMR studies indicate that the receptor 1a with (S, S) configuration and lb with (R,R) configuration selectively recognize L- and Z)-aromatic amino acids respectively.     

Highly enantioselective synthesis of a fluorescent amino acid

A high enantiomeric excess (>99.5%) synthesis of 2-amino-3-(7-methoxy-4-coumaryl) propionic acid ( Amp) is described. The two step synthesis route of this non-proteinogenic amino acid includes an oxazinone derivative as glycine enolate, which is alkylated with the fluorogenic group.     

Novel chiral imidazole cyclophane receptors: synthesis and enantioselective recognition for amino acid derivatives

Novel chiral imidazole cyclophane receptors were synthesized by highly selective N-alkylation of the imadazolyl 1N-position of the bridged histidine diester 2 with the dibromide in the presence of NaH; these receptors exhibit good chiral recognition toward the enantiomers of L- and D-amino acid derivatives (up to KD/KL = 3.52, delta delta G0 = -3.11 kJ mol-1) in CHCl3 at 25.0 degrees C.     

The application of functional silica nanoparticles to fulfill the rapid and improved enantioselective capillary electrophoresis separation of amino acid derivatives

In this study, diamino moiety functionalized silica nanoparticles with the size of 118 ± 12 nm were successfully synthesized and directly introduced into a chiral capillary electrophoresis system to improve the enantioseparation of 9‐fluorenyl methoxycarbonyl derivatized amino acids using norvancomycin as chiral selector. Under acidic background electrolyte conditions, functional silica nanoparticles can be readily adsorbed onto the inner surface of bare silica capillary column through electrostatic interaction to form a dynamic coating, resulting in a reversed anodic electro‐osmotic flow (i.e. from cathode to anode). As expected, chiral amino acid derivatives (usually negatively charged) can be rapidly separated under co‐electro‐osmotic flow conditions in the current separation system. Furthermore, the column performance and detection sensitivity for the enantioseparation were also obviously improved because the adsorption of chiral selector of norvancomycin to the capillary wall was greatly suppressed. Some important factors influencing the separation, such as the coating thickness, background electrolyte concentration, functional silica nanoparticles concentration, and the organic modifier were also investigated and the optimized separation conditions were obtained.     

Solvent effect on the conformational behaviour of amino acid and oligopeptide derivatives

The solvent effect on acetyl amino acid methyl esters and C- and N-protected di- and tripeptide derivatives has been studied in deuterium oxide (D₂O), 1.1.1.3.3.3-hexafluoroisopropanol (HFiP), dimethyl sulfoxide (DMSO) and methylene chloride (CH₂Cl₂). The interpretation is based on the amide I region. For the amino acid derivatives the relative shift of the amide I signal clearly indicates the strength of the interaction with the solvent molecules. However, in HFiP and DMSO solutions the occurrence of two overlapping signals for the amide I and the ester carbonyl signal, respectively, indicates the existence of two major conformers. Knowing the solvent effects on the small amino acid esters allows the assignment of the signals in di- and tripeptide derivatives. Although the identification of turn structures in these flexible molecules is not possible, the band positions and intensity of the deconvoluted amide I region clearly shows that certain conformers can be stabilised. It can be concluded that the band profile in the amide I region is determined by the number of amino acid residues linked in the molecule, the bulkiness of the side chains and their sequence and to a major extend by the solvent properties.     

Retention prediction of o-phthalaldehyde amino acid derivatives in reversed-phase liquid chromatography

Summary Retention prediction of o-phthalaldehyde amino acid derivatives in reversed-phase liquid chromatography has been investigated. The retention of all derivatives could be predicted within about 10% relative error under the appropriate separation conditions in both isocratic and gradient-elution modes.     

手性芳酰胺类分子钳对氨基酸衍生物的对映选择性识别

在微波辐射条件下,以联苯二甲酸为间隔基,L-氨基酸甲酯为手臂,合成了3个新型芳酰胺手性分子钳。这些化合物的结构经1HNMR,IR,MS和元素分析确证。利用差紫外光谱滴定法考察了其与D/L氨基酸甲酯的对映选择性识别性能。结果表明,分子钳2a~2c对所考察的氨基酸甲酯均具有识别能力,其对D-氨基酸甲酯的识别优于对L-氨基酸甲酯的识别。从主客体间的大小形状匹配及几何互补关系等方面对这些受体的识别能力及对映选择性进行了讨论。