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.     

Cellulose Derivatives Used as Chiral Stationary Phases in Capillary Gas Chromatography

Abstract

In this work, we present the first separation of enantiomers in gas chromatography (GC) using a fused‐silica capillary column containing cellulose triacetate, cellulose triphenylcarbamate, or cellulose tris(3,5‐dimethylphenylcarbamate) as the new chiral stationary phase. The separated solutes included alcohols, amine, ketone, ether, ester, and amino acid. Their column efficiency, polarity, and chiral selectivity were studied. The retention mechanism was discussed. The results showed that those derivatives had relatively high chiral recognition abilities and can be used as the chiral stationary phases in GC.     

纤维素苯基氨基甲酸酯的均相合成及其手性拆分性能评价

认识多糖类手性拆分材料的结构性能关系对于构建新型高效手性固定相具有重要指导意义。该文中,以1-烯丙基-3-甲基咪唑氯离子液体为介质,合成了系列不同结构的纤维素苯基氨基甲酸酯,进而考察了取代度、取代基团种类和位置对产物手性拆分性能的影响。结果表明,随着取代度的增加,纤维素苯基氨基甲酸酯对于绝大部分手性分子的拆分效果提高;苯环上取代基团的种类和位置对纤维素苯基氨基甲酸酯手性拆分性能影响显著,弱吸电子基团氯基和给电子基团甲基在合适的位置能显著增强纤维素苯基氨基甲酸酯的手性拆分性能;纤维素3-甲基-4-氯苯基氨基甲酸酯、3,5-二氯苯基氨基甲酸酯和2-甲基-5-氯苯基氨基甲酸酯对一些手性分子的拆分效果优于纤维素3,5-二甲基苯基氨基甲酸酯。     

Phenylcarbamate derivatives of cellulose and amylose immobilized onto silica gel as chiral stationary phases for high-performance liquid chromatography

Three polysaccharide phenylcarbamate derivatives [cellulose 2,3-bis(3,5-dimethylphenylcarbamate)-6-(3,5-dimethylphenylcarbamate)/(2-methacryloyloxyethylcarbamate), cellulose 2,3-bis(3,5-dichlorophenylcarbamate)-6-(3,5-dichlorophenylcarbamate)/(2-methacryloyloxyethylcarbamate), and amylose 2,3-bis(3, 5-dimethylphenylcarbamate)-6-(3,5-dimethylphenylcarbamate)/(2-methacryloyloxyethylcarbamate)] with vinyl groups were prepared and coated onto silica gel to immobilize them via radical copolymerization with 2,3-dimethylbutadiene. The copolymerization efficiently proceeded, and the coated polysaccharide derivatives were mostly immobilized on the surface of the silica gel. The immobilized polysaccharide derivatives showed high chiral recognition abilities similar to those of the corresponding coated polysaccharide derivatives. They could be used with an eluent containing chloroform, which dissolved the polysaccharide derivatives. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 4704–4710, 2004     

Preparation and chiral recognition ability of crosslinked beads of polysaccharide derivatives

The spherical beads consisting of cellulose 3,5-dimethylphenylcarbamate with partial hydroxyl groups were prepared to be used as chiral packing materials (CPMs) for HPLC. The beads were obtained without using macroporous silica gel, which is usually used as the support of the CPMs based on the polysaccharide derivatives. After the crosslinking in the bead with diisocyanates, such as 4,4'-diphenylmethane diisocyanate (MDI), 4,4'-dibenzyl diisocyanate (DBDI), tolylene-2,4-diisocyanate (TDI), and m-xylylene diisocyanate (XDI), the obtained beads were packed into an HPLC column. As the content of the hydroxyl groups of the cellulose derivatives decreased, the obtained CPM exhibited a higher chiral recognition ability. The beads possessed a higher loading capacity than the CPM prepared by coating the cellulose derivative on silica gel. The crosslinked beads could be used with the eluent containing chloroform. The amylose derivative beads were also prepared as a CPM for chiral HPLC.     

Enantioseparation using alkoxyphenylcarbamates of cellulose and amylose as chiral stationary phase for high-performance liquid chromatography

Cellulose and amylose phenylcarbamates having one or two alkoxy groups on a phenyl ring were synthesized, and their chiral recognition abilities as chiral stationary phases for HPLC were evaluated. Compared to the 4-methoxyphenylcarbamates of cellulose and amylose, which are known to show a poor chiral recognition, the 3-methoxyphenylcarbamates exhibited much higher chiral recognitions. For cellulose derivatives, as the bulkiness of the 3-alkoxy group increased, the chiral recognition ability increased. On the other hand, for the amylose derivatives, a clear relation between the chiral recognition and the bulkiness of the alkoxy group was not observed, and the 3-methoxy, ethoxy, and isopropoxyphenylcarbamates showed relatively high chiral recognitions. The introduction of two methoxy groups to the meta-positions decreased the chiral recognition ability. In order to discuss the relationship between the structure and chiral recognition ability of the alkoxyphenylcarbamates, their molecular models were constructed.     

Enantioseparation of selected chiral sulfoxides using polysaccharide-type chiral stationary phases and polar organic, polar aqueous-organic and normal-phase eluents

HPLC enantioseparation of selected chiral sulfoxides was studied using cellulose and amylose phenylcarbamate derivatives as chiral stationary phases (CSPs). The contributions of various functional groups of a chiral analyte as well as the polysaccharide derivatives in the analyte retention and chiral recognition were evaluated. A very high enantioseparation factor exceeding 110 was observed in the enantioseparation of 2-(benzylsulfinyl)benzamide (BSBA) on cellulose tris(3,5-dichlorophenylcarbamate) (CDCPC) CSP by using 2-propanol as a mobile phase. The enantiomer elution order was opposite on cellulose and amylose phenylcarbamates. For the polysaccharide-type CSPs, pure alcohols such as methanol, ethanol and 2-propanol represent a valuable alternative to more common alcohol-hydrocarbon and reversed-phase eluents.     

Preparation and HPLC application of chiral stationary phase from 4‐tert‐butylphenylcarbamates of cellulose and amylose immobilized onto silica gel

The 4‐tert‐butylphenylcarbamates of cellulose and amylose bearing a small amount of 3‐(triethoxysilyl)propyl residues were synthesized by a one‐pot process and efficiently immobilized onto a silica gel through intermolecular polycondensation of the triethoxysilyl groups. The obtained chiral packing materials (CPMs) were evaluated by HPLC. The polysaccharide derivatives containing about 1–2% of the 3‐(triethoxysilyl)propyl residue were efficiently immobilized with a high chiral recognition ability. The immobilized CPMs could be used with the eluents containing chloroform and tetrahydrofuran (THF), which cannot be used with the conventional coated‐type CPMs. By using these eluents, the chiral recognition for many racemates was improved.     

Preparation and chiral recognition in HPLC of cellulose 3,5-dichlorophenylcarbamates immobilized onto silica gel

The 3,5-dichlorophenylcarbamates (2) of cellulose bearing a small amount of 3-(triethoxysilyl)propyl residues were synthesized by a one-pot process and immobilized onto a silica gel through intermolecular polycondensation of the triethoxysilyl groups. The obtained cellulose derivatives were characterized by (1) H NMR and elemental analysis (EA), and their recognition abilities were evaluated by high-performance liquid chromatography (HPLC). The cellulose derivatives containing about 1-5% of the 3-(triethoxysilyl)propyl residue were efficiently immobilized with a high chiral recognition ability. The immobilized chiral packing materials (CPMs) could be used with the eluents containing chloroform and tetrahydrofuran (THF), which cannot be used with the conventional coated-type chiral packing materials. By using these eluents, the chiral recognition for many racemates was improved.     

Separation and Recognition of the Enantiomers of trans Arylcyclopropanecarboxylic Acids and their Amide and Nitrile Derivatives on Polysaccharide Stationary Phases

Separation of the enantiomers of several trans arylcyclopropanecarboxylic acids and their amide and nitrile derivatives has been systematically studied on three polysaccharide HPLC stationary phases, amylose tris-(3,5-dimethylphenylcarbamate), cellulose tris-(3,5-dimethylphenylcarbamate), and cellulose tris-(4-methylbenzoate). Enantiomer recognition by the chiral stationary phases is discussed in terms of the type of functional group, electronic and steric effects of substituents on the analytes, the structure of the chiral stationary phase, and mobile phase composition.     

外消旋萘普生酯类在四种纤维素衍生物手性柱上分离及手性 识别机理研究

在纯聚合物型的纤维素三醋酸酯(CTA)、纤维素三苯甲酸酯(CTB)与涂敷型的CTB、纤维素三(4-甲基苯甲酸酯)(CTMB)四种纤维素衍生手性柱上成功地分离了几种外消旋萘普生酯,研究了流动相组成以及溶质的结构对手性分离的影响,探讨了纤维素衍生物手性固定相对外消旋萘普生酯手性识别的机理,得出溶质在固定相手性空腔中体积大小的适应性,尤其是立体结构上的空间适应性是手性识别的关键,不同的固定相这种适应性有所不同,     

Synthesis of 4-aryl-2-pyrrolidones and beta-aryl-gamma-amino-butyric acid (GABA) analogues by Heck arylation of 3-pyrrolines with arenediazonium tetrafluoroborates. Synthesis of (+/-)-rolipram on a multigram scale and chromatographic resolution by semipreparative chiral simulated moving bed chromatography

We report herein a new, practical, and economic synthesis of the phosphodiesterase inhibitor Rolipram on a multigram scale as well as the synthesis of new 4-aryl pyrrolidones and beta-aryl-gamma-amino butyric acids (GABA derivatives) employing an efficient Heck-Matsuda arylation of 3-pyrroline with aryldiazonium tetrafluoroborates. Racemic Rolipram was resolved into its enantiomers using chiral simulated moving bed chromatography having the low-cost microcrystalline cellulose triacetate as a chiral stationary phase.     

Chloromethylphenylcarbamate derivatives of cellulose as chiral stationary phases for high-performance liquid chromatography

A new class of eight chloromethylphenylcarbamate derivatives of cellulose was prepared by introducing both an electron-donating methyl group and an electron-withdrawing chloro group on to the phenyl moieties and their chiral recognition abilities were evaluated as chiral stationary phases (CSPs) for high-performance liquid chromatography. The superiority of these derivatives over dichloro- and dimethylphenylcarbamates of cellulose as CSPs was demonstrated for some racemic compounds. The elution order and enantioselectivity were greatly dependent on the positions of the substituents. Meta- and para-disubstituted derivatives showed higher chiral recognition than ortho- and meta- or para- disubstituted derivatives. The correlation between the chemical shifts of the N---H protons of the carbamate moieties and the enantiomer-resolving abilities of the derivatives is discussed. Some of the derivatives were effective CSPs in both normal- and reversed- phase conditions and could efficiently separate some chiral drug enantiomers.     

Preparation of HPLC chiral packing materials using cellulose tris(4-methylbenzoate) for the separation of chrysanthemate isomers

We investigated the separation of chrysanthemate isomers ( 1 ), particularly the (1R)-trans form, by high-performance liquid chromatography (HPLC) using polysaccharide derivatives, such as the phenylcarbamates and benzoates of cellulose and amylose, as the chiral stationary phases (CSPs). The chiral packing materials (CPMs) having a high chiral recognition for the chrysanthemic acid ethyl ester ( 1a ) were prepared by coating cellulose tris(4-methylbenzoate) ( 2a ) dissolved in solvents containing methyl benzoate or acetophenone as an additive on silica gel. The separation factor for 1a significantly depended on the preparation conditions of CPM 2a , such as the coating amount of 2a and the type and amount of additives. The chiral recognition ability created by imprinting the additives was lost when the CPM was heated at a high temperature, and was recovered by contacting it with the additive in a packed column. The structural change in 2a during these treatments was not clearly detected by spectroscopic methods. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 5087–5097, 2006     

Chiral polymers for resolution of enantiomers

In 1979, the formation of one‐handed helical poly(triphenylmethyl methacrylate) (PTrMA) was found through the helix‐sense‐selective polymerization of methacrylate using chiral anionic initiators, and the existence of a stable helical polymer without chiral side chains was proved. The chiral polymer exhibited unexpected high chiral recognition of various racemic compounds when used as the chiral packing material (CPM) for HPLC, which was commercialized in 1982 as the first chiral column based on an optically active polymer. This success encouraged us to develop further useful commercial chiral packing materials (CPMs) based on polysaccharides, cellulose, and amylose. By using these polysaccharide‐based CPMs, particularly phenylcarbamate derivatives, nearly 90% of chiral compounds can be resolved not only analytically but also preparatively, and several chiral drugs have been produced using the CPMs. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 1731–1739, 2009     

Immobilization of polysaccharide derivatives onto silica gel Facile synthesis of chiral packing materials by means of intermolecular polycondensation of triethoxysilyl groups

The 3,5-dimethylphenylcarbamates of cellulose and amylose bearing a small amount of 3-(triethoxysilyl)propyl residues were synthesized by a simple process and efficiently immobilized onto a silica gel support by intermolecular polycondensation of the triethoxysilyl groups. The obtained chiral packing materials (CPMs) were evaluated by high-performance liquid chromatography. The polysaccharide derivatives containing about 1-2% of the 3-(triethoxysilyl)propyl residue were efficiently immobilized with a high chiral recognition. The immobilized CPMs could be used with the eluents containing chloroform and tetrahydrofuran, which cannot be used with the conventional coated-type CPMs. By using these eluents, the chiral recognitions for many racemates could be improved.     

Preparation and chromatographic evaluation of β-cyclodextrin derivative CSPs bearing substituted phenylcarbamate groups for HPLC

Five β-cyclodextrin (β-CD) derivatives bearing substituted phenylcarbamate/3-(triethoxysilyl)propylcarbamate groups at the 2-, 3-, and 6-positions of glucose unit and another five derivatives containing benzoate at the 2-position and substituted phenylcarbamate/3-(triethoxysilyl)propylcarbamate groups at the 3- and 6-positions were synthesized using the regioselective esterification method. The obtained β-CD derivatives were efficiently immobilized onto the silica gel through the intermolecular polycondensation of a small amount of the triethoxysilyl groups, which were used as the chiral stationary phases (CSPs) for high-performance liquid chromatography (HPLC). The chiral separation properties of these CSPs were evaluated under the normal-phase HPLC. The effects of solvent polarity and the side chain structures of β-CD derivatives on the chiral recognition ability of the immobilized CSPs were investigated. Among these β-CD derivative CSPs, 2,3,6-tris(3,5-dichlorophenylcarbamate)-β-CD CSP showed a relatively high chiral recognition ability for the studied racemates. The regioselective esterification at the 2-position of glucose unit in the β-CD decreased the chiral recognition ability at the same conditions. For some racemates, the β-CD derivative CSPs showed chiral recognition abilities comparable or better to some chemical bonded β-CD derivative CSPs and 3,5-dichloro- and 3,5-dimethylphenylcarbamates of cellulose and amylose CSPs.     

外消旋硫代缩水甘油醚在多糖基质手性柱上的手性拆分

在自行合成的3种多糖基质的手性固定相上直接拆分了7种外消旋硫代缩水甘油醚，初步探讨了手性化合物结构在手性识别过程中对手性拆分的影响，并对手性固定相的手性识别能力进行了评价。     

纤维素类手性固定相及高效液相色谱-旋光仪联用技术的研究

合成了3种纤维素衍生物并分别填充分析型色谱柱,研究了不同的涂敷条件对柱效的影响以及色谱柱的稳定性,对外消旋化合物进行了手性拆分。实现了高效液相色谱－旋光仪的联用,获得了在线旋光曲线。     

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.