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.     

Preparation and Enantioseparation Property of Chiral Stationary Phases Based on Cellulose Tris(3,5-dimethylbenzoate)——A New Way to Prepare Polysaccharide-coating Type Chiral Stationary Phases

A new method to prepare polysaccharide-coating type chiral stationary phases （CSPs） was developed in this work. As a typical example, naked silica gel was coated by cellulose, which was then derivatized with 3,5-dimethylbenzoyl chloride to afford cellulose tris（3,5-dimethylbenzoate）-silica gel （CTDBS） complex. The silanols on CTDBS were end-capped with 3- aminopropyltriethoxysilane to obtain CSP 1. The amino groups on CSP 1 were further end-capped with 3,5-dimethylbenzoyl chloride to give CSP 2. The silanols on CTDBS were end-capped with methyltrimethoxysilane to yield CSP 3. CSPs 1-3 were characterized by FTIR, solid-state 13C-NMR and elemental analysis. The enantioseparation abilities of CSPs 1-3 were evaluated with structurally various chiral analytes. The enantioseparation results demonstrated that the end-capping moieties on CSPs 1 and 2 significantly affected enantioseparation. In addition, the effect of the structures of chiral analytes and end- capping moieties on the retention factors and the resolutions was discussed.     

Sulfated and sulfonated polysaccharide as chiral stationary phases for capillary electrochromatography and capillary electrochromatography–mass spectrometry

The applications of polysaccharide phenyl carbamate derivatives as chiral stationary phases (CSPs) for capillary electrochromatography (CEC) are often hindered by longer retention times, especially using a normal-phase (NP) eluent due to very low electroosmotic flow (EOF). Therefore, in this study, we propose an approach for the aforementioned problems by introducing two new types of negatively charged sulfate and sulfonated groups for polysaccharide CSPs. These CSPs were utilized to pack CEC columns for enantioseparation with a NP eluent. Compared to conventional cellulose tris(3,5-dimethylphenyl carbamate) or CDMPC CSPs, the sulfated CDMPC CSP (sulfur content 4.25%, w/w) shortened the analysis time up to 50% but with a significant loss of enantiomeric resolution (∼60%). On the other hand, the sulfonated CDMPC CSP (sulfur content 1.76%, w/w) not only provided fast throughput but also maintained excellent resolving power. In addition, its synthesis is much more straightforward than the sulfated one. Furthermore, we studied several stationary phase parameters (CSP loading and silica gel pore size) and mobile phase parameters (including type of mobile phase and its composition) to evaluate the throughput and enantioselectivity. Using the optimized conditions, a chiral pool containing 66 analytes was screened to evaluate the enantioselectivity under three different mobile phase modes (i.e., NP, polar organic phase (POP) and reversed-phase (RP) eluents). Among these mobile phase modes, the RP mode showed the highest success rate, whereas some degree of complementary enantioselectivity was observed with NP and POP. Finally, the feasibility of applying this CSP for CEC–MS enantioseparation using internal tapered column was evaluated with NP, POP and RP eluents. In particular, the NP-CEC–MS provided significantly enhanced sensitivity when methanol was replaced with isopropanol in the sheath liquid. Using aminoglutethimide as model chiral analyte, all three modes of CEC–MS demonstrated excellent durability as well as excellent reproducibility of retention time and enantioselectivity.     

Evaluation of the chiral recognition properties as well as the column performance of four chiral stationary phases based on cellulose (3,5-dimethylphenylcarbamate) by parallel HPLC and SFC

The performance of four commercially available cellulose tris(3,5-dimethylphenylcarbamate) based chiral stationary phases (CSPs) was evaluated with parallel high performance liquid chromatography (HPLC) and super critical fluid chromatography (SFC). Retention, enantioselectivity, resolution and efficiency were compared for a set of neutral, basic and acidic compounds having different physico-chemical properties by using different mobile phase conditions. Although the chiral selector is the same in all the four CSPs, a large difference in the ability to retain and resolve enantiomers was observed under the same chromatographic conditions. We believe that this is mainly due to differences in the silica matrix and immobilization techniques used by the different vendors. An extended study of metoprolol and structure analogues gave a deeper understanding of the accessibility of the chiral discriminating interactions and its impact on the resolution of the racemic compounds on the four CSPs studied. Also, a clear difference in enantioselectivity is observed between SFC and LC mode, hydrogen bonding was found to play an important role in the differential binding of the enantiomers to the CSPs.     

Novel chiral stationary phases based on peptoid combining a quinine/quinidine moiety through a C9‐position carbamate group

By connecting a quinine or quinidine moiety to the peptoid chain through the C9‐position carbamate group, we synthesized two new chiral selectors. After immobilizing them onto 3‐mercaptopropyl‐modified silica gel, two novel chiral stationary phases were prepared. With neutral, acid, and basic chiral compounds as analytes, we evaluated these two stationary phases and compared their chromatographic performance with chiral columns based on quinine tert‐butyl carbamate and the previous peptoid. From the resolution of neutral and basic analytes under normal‐phase mode, it was found that the new stationary phases exhibited much better enantioselectivity than the quinine tert‐butyl carbamate column; the peptoid moiety played an important role in enantiorecognition, which controlled the elution orders of enantiomers; the assisting role of the cinchona alkaloid moieties was observed in some separations. Under acid polar organic phase mode, it was proved that cinchona alkaloid moieties introduced excellent enantiorecognitions for chiral acid compounds; in some separations, the peptoid moiety affected enantioseparations as well. Overall, chiral moieties with specific enantioselectivity were demonstrated to improve the performance of peptoid chiral stationary phase efficiently.     

Study of chiral recognition mechanism of O,O-diethyl (p-methylbenzenesulfonamindo)-aryl(alkyl)-methylphosphonates by HPLC with a series of CSPs

Five chiral stationary phases (CSPs) were used to separate the enantiomers of a series of O,O-diethyl (p-methyl-benzenesulfonamindo)- aryl(alkyl)-methylphosphonates. A chiral recognition mechanism was presented to explain the resolution of these compounds. Results show that CSP with strong π-acceptor 3,5-dinitrobenzoyl group and high steric hindrance has the best resolution ability in chiral separation of O,O-diethyi (p-methyl-benzenesulfonamindo)- aryl(alkyl)-methylphosphonates. When a CSP has just a strong π-acceptor 3,5-dinitrobenzoyl or high steric hindrance it does not have good chiral resolution ability. The chiral recognition is more difficult when the CSP has more than one asymmetric center.     

Effect of the structure of organic phosphonate compounds on chiral separations on derivatized cellulose chiral stationary phase

Summary The enantiomers of eightO,O-dialkyl-2-benzyloxycarbonylaminoarylmethyl phosphonates have been directly separated on a tris(3,5-dimethylphenylcarbamate) cellulose column. The results are very different from those obtained by separation on anN-(3,5-dinitrobenzoyl)leucine (DNBleu) column. The effect of mobile phase composition and column temperature on retention and enantioselectivity were investigated. The effect on chiral separation of the length of, and steric hindrance by, alkoxyl groups of the phosphonate ester and of the nature of the substitutentsp-Cl andp-H on the benzene ring attached to the chiral carbon atom are also discussed.     

Influence of the structure of organic phosphonate compounds on chiral separation on a pirkle type chiral stationary phase

Summary The enantiomers of eightO,O-dialkyl-2-benzyloxycarbonyl-aminoarylmethyl-phosphonates are directly separated on anN-(3,5-dinitrobenzoyl)leucine (DNBleu) column. The influence of the mobile phase composition and the column temperature on the retention and the enantioselectivity are investigated. The influence of the length and steric hindrance of alkoxyl groups of the phosphonate ester and the nature of the substituentp-Cl and pH on the benzene ring which is attached to the chiral carbon atom on chiral separation are discussed also.     

纤维素-[2,3-(4-取代苯基)-6-(3,5-二氯苯基)]氨基甲酸酯的合成及作为HPLC手性固定相的手性识别

合成了3种新的纤维素苯基氨基甲酸酯类衍生物:纤维素-[2,3-二苯基-6(3,5-二氯苯基)]氨基甲酸酯、纤维素-[2,3-二(4-甲基苯基)-6-(3,5-二氯苯基)]氨基甲酸酯及[2,3-二(4-氯苯基)-6-(3,5-二氯苯基)]氨基甲酸酯,并将其涂敷在氨丙基硅胶表面制备 HPLC 手性固定相.利用<'1>H N...     

Comparison of the chiral resolution on cis-trans isomeric chiral stationary phases derived from (S)-1-(1-naphthyl)ethylamine

A pair of cis-trans isomeric chiral stationary phases (CSPs) derived from (S)-1-(1-naphtyl)ethylamine was prepared. The chromatographic behaviours on both CSPs with regard to the resolution of enantiomeric amino acids, amino alcohols, amines, and carboxylic acid were studied. According to separation factors, the trans-CSP showed better chiral recognition ability for the separation of most analytes chosen in this study. Three homologous series of the alkyl esters of racemic amino acids were resolved on both CSPs using n-hexane-2-propanol and n-hexane-dichloromethane as mobile phases. The trans-CSP also showed better enantioselectivity for the resolution of homologues. A reverse of elution order was observed for the resolution of the homologous series of phenylglycine alkyl esters on both CSPs. It was found that the relationship between the separation factor and the alkyl chain length of the ester homologous series depended upon the components of mobile phase. A higher magnitude of difference between the two CSPs in enantioselectivity for the resolution of a given homologue was obtained when n-hexane-dichloromethane was used as a mobile phase. A chiral recognition process, in which steric repulsion, face-to-face π-π interaction, face-to-edge π-π interaction and hydrogen bonding interaction were involved, was also suggested to describe the separation of enantiomeric homologues on both CSPs. This study clearly indicates that the chiral resolution is influenced by the geometry of the double bond in a CSP.     

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.     

正相条件下温度和流速对衍生化环糊精键合手性高效液相色谱固定相立体异构体选择性的影响

合成了苯基氨基甲酸酯衍生化的β-环糊精键合固定相,9个α-氨基膦酸酯类化合物首次在环糊精类固定相上进行了有效拆分,研究了温度和流速对异构体选择性的影响,讨论了可能的手性识别机理.     

Improved preparation of chiral stationary phases via immobilization of polysaccharide derivative‐based selectors using diisocyanates

The classical method for the preparation of immobilized polysaccharide‐based chiral stationary phases (CSPs) with a diisocyanate was improved. Cellulose or amylose was directly coated onto 3‐aminopropyl silica gel after it was dissolved in a mixture of N,N‐dimethylacetamide, LiCl, and pyridine, then immobilized onto silica gel with a diisocyanate, and finally allowed to react with an excess of corresponding isocyanate. Four polysaccharide derivatives, 3,5‐dimethylphenylcarbamate and 3,5‐dichlorophenylcarbamate of cellulose, and 3,5‐dimethylphenylcarbamate and 5‐chloro‐2‐methylphenylcarbamate of amylose, were immobilized onto silica gel utilizing this method. Compared with the classical diisocyanate method, the improved procedure avoided the derivatization and regeneration of 6‐hydroxyl groups of cellulose and amylose, and thus showed an advantage for simple and economical preparation. The relationships among the amount of diisocyanate used, immobilization efficiency, and enantioseparation on the cellulose‐based CSPs were investigated. Also, the solvent durability of the obtained CSPs was examined with eluents containing chloroform or THF. By utilizing these eluents, the chiral recognition abilities of the obtained CSPs for some of the tested racemates were improved.     

复合型多糖类手性固定相的制备及其手性识别能力

将纤维素三(3,5-二甲基苯基氨基甲酸酯)(cellulose tris(3,5-dimethyIphenylcarbamate),CDMPC)和淀粉三(3,5-二甲基苯基氨基甲酸酯)(Amylose tris(3,5-dimethylphenylcarbamate),ADMPC)分别涂敷于氨丙基硅胶上然后混合,或者将...     

Novel cinchona alkaloid O9-hydrazide derivatives as chiral anion-exchange-type selectors: Synthesis and chromatographic evaluation

Summary Six new quinine (QN) O₉-hydrazide derivatives with different substituents have been synthesized and immobilized on porous silica gel for HPLC. The chiral resolving power of these anion-exchange-type chiral stationary phases (CSPs) has been investigated and compared with that of four carbamate QN derivatives with analogous substitution. The unsubstituted QN-hydrazide derivative was usually the best chiral selector of the hydrazide series. Among the substituted hydrazide derivatives the introduction of a tritylcarbonyl or atert-butylcarbonyl group at the β position of the hydrazide function improved chiral recognition by the resulting CSPs. Although carbamate functionality seemed to favour the resolution of the enantiomers of many of the racemic compounds tested, the hydrazide series resulted in better separations of the enantiomers of the DNP derivatives of amino acids and of certain acidic drugs of therapeutic interest, such as the profens. The selectivity factors of these types of compounds on these QN-hydrazide derivatives are the best yet obtained on QN-derived chiral selectors.     

Stationary phase-related investigations of quinine-based zwitterionic chiral stationary phases operated in anion-, cation-, and zwitterion-exchange modes

The concept of recently introduced Cinchona alkaloid-type zwitterionic chiral stationary phases (CSPs) is based on fusing key cation- and anion-exchange (CX, AX) moieties in one single low-molecular mass chiral selector (SO) with the resulting CSPs allowing enantiomer separations of a wide range of chiral ionizable analytes comprising acids, bases, and zwitterionic compounds. Herein, we report principal, systematic investigations of the ion-exchange-type retention mechanisms available with the novel zwitterionic CSPs in nonaqueous polar organic mode. Typical CX and AX processes, corresponding to the parent single ion exchangers, are confirmed also for zwitterionic CSPs. Also the mechanism leading to recognition and retention of zwitterions was found to be ion exchange mediated in a zwitterion-exchange (ZX) mode. In both AX and CX modes the additional ionizable group within the SO besides the site responsible for the respective ion-exchange process could be characterized as an intramolecular counterion (IMCI) that effectively participates in the ion-exchange equilibria and thus, contributes to solute elution. In the ZX mode both oppositely charged groups of the zwitterionic SO were found not only to be the sites for simultaneous ion pairing with the analyte but also functioned as IMCIs at the same time. The main practical consequences of the IMCI feature were significant reduction of the amounts and even elimination of acidic and basic additives required in the eluent systems to afford analyte elution while still providing faster analysis than the parent single ion-exchanger-type CSPs. The set of ten structurally different zwitterionic CSPs employed in this study facilitated the establishment of correlations between chromatographic behavior of the CSPs with particular SO elements, thereby supporting the understanding of the working principles of these novel packing materials on a molecular level.     

负载型手性钯催化剂的制备和在苯乙酮不对称加氢反应中的应用

在硅烷化硅胶上涂敷手性高分子配位体三苯基氨基甲酸纤维素酯和三（３,５－二甲基苯基氨基甲酸）纤维素酯,然后与ＰｄＣｌ３配位,制备一种新型的负载型不对称加氢催化剂,该催化剂用于苯乙酮的加氢反应,醇收率最高达１００％,但产物的对遇选择性较低的原因。     

Enantioseparation of racemic N-acylarylalkylamines on various amino alcohol derived tau-acidic chiral stationary phases

Five tau-acidic chiral stationary phases (CSPs), CSP 4, CSP 5, CSP 6, CSP 7 and CSP 8, were prepared by connecting the N-(3,5-dimethylbenzoyl) derivative of (R)-alaninol, (S)-leucinol, (1S,2R)-ephedrine and (S)-tert-leucinol and the O-(3,5-dinitrobenzoyl) derivative of (R)-phenylglycinol to silica gel through a carbamate or urea linkage. The CSPs were applied to the resolution of various racemic N-acyl-1-naphthylaminoalkanes by chiral HPLC, and the chromatographic resolution results were compared with those of previously reported CSPs (CSP 2, CSP 3), which are derived from N-(3,5-dinitrobenzoyl)-(1S,2R)-norephedrine and N-(3,5-dinitrobenzoyl-(R)-phenylglycinol. Based on a comparison of the resolution results for each CSP, the role of each functional group on the five chiral selectors is explained.     

Transition from enantioselective high performance to ultra-high performance liquid chromatography: A case study of a brush-type chiral stationary phase based on sub-5-micron to sub-2-micron silica particles

Three brush-type chiral stationary phases (CSPs) differing in the particle size of the starting silica particles have been prepared by covalent grafting of the π-acidic bis-(3,5-dinitrobenzoyl)-derivative of trans-1,2-diaminocyclohexane (DACH-DNB). Starting silica particles of 4.3, 2.6 and 1.9 micron were used to generate the final CSPs using an improved, highly reproducible synthetic methodology, that allowed to assemble and surface-graft the whole chiral selector in only two steps. The different CSPs have been packed in columns of various length and diameters, and fully characterized in terms of flow permeability, kinetic performances and enantioselectivity using a set of test solutes. Very high speed and high resolution applications together with stereodynamic HPLC examples are demonstrated on the columns with reduced particle diameters, on which separations of several enantiomeric pairs are routinely obtained with analysis times in the 15–40 s range.     

Exhaustively substituted bile acids as chiral selectors for enantioselective chromatography. Aim, use and perspectives

The use of chiral stationary phases (CSPs) obtained from cholic and deoxycholic acid derivatives in the HPLC resolution of racemic compounds is presented. The CSPs containing arylcarbamoyl derivatives of bile acids show enantiodiscriminating capabilities depending on the electronic character of the aryl substituents: the CSPs obtained starting from heteroderivatized selectors, i.e. bile acid derivatives containing both pi-acidic and pi-basic arylcarbamoyl moieties, show enantiodiscriminating capabilities strongly dependent on the arrangement of the electronically different arylcarbamates on the cholestanic backbone. The CSPs obtained starting from deoxycholic acid derivatives possessing both arylamido and arycarbamoyl substituents show enantiodiscriminating capabilities restricted to the resolution of benzodiazepine derivatives. Again, the enantioresolution properties depend not only on the electronic nature of the aromatic substituents but also on their arrangement on the cholestanic backbone. The comparison among the different families of bile acid based CSPs allows us to find likeness and differences in the enantiorecognition mechanism exhibited by the different chiral selectors.