- Engineering of an epoxide hydrolase for efficient bioresolution of bulky pharmaco substrates
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Optically pure epoxides are essential chiral precursors for the production of (S)-propranolol, (S)-alprenolol, and other β-adrenergic receptor blocking drugs. Although the enzymatic production of these bulky epoxides has proven difficult, here we report a method to effectively improve the activity of BmEH, an epoxide hydrolase from Bacillus megaterium ECU1001 toward α-naphthyl glycidyl ether, the precursor of (S)-propranolol, by eliminating the steric hindrance near the potential product-release site. Using X-ray crystallography, mass spectrum, and molecular dynamics calculations, we have identified an active tunnel for substrate access and product release of this enzyme. The crystal structures revealed that there is an independent product-release site in BmEH that was not included in other reported epoxide hydrolase structures. By alanine scanning, two mutants, F128A and M145A, targeted to expand the potential product-release site displayed 42 and 25 times higher activities toward α-naphthyl glycidyl ether than the wild-type enzyme, respectively. These results show great promise for structure-based rational design in improving the catalytic efficiency of industrial enzymes for bulky substrates. epoxide hydrolase X-ray crystallography protein engineering product release bulky substrate We are grateful for access to beamline BL17U1 at Shanghai Synchrotron Radiation Facility and thank the beamline staff for technical support. We also thank Dr. Peter K. Park and Profs. Zhihong Guo and Ran Hong for helpful discussions. This work was supported by National Program on Key Basic Research of China Grant 2011CB710800 (to J.-H.X. and J.Z.), National Grand Project for Medicine Innovation Grant 2012ZX10002006 (to J.Z.), National Natural Science Foundation of China Grant 21276082 (to J.-H.X.), and a grant from the Open Fund from the State Key Laboratory of Bioreactor Engineering (to J.Z.).
- Kong, Xu-Dong,Yuan, Shuguang,Li, Lin,Chen, She,Xu, Jian-He,Zhou, Jiahai
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- Optical resolution and optimization of (R, S) - Propranolol using dehydroabietic acid via diastereomeric crystallization
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The optical resolution of (R, S)-propranolol by the diastereomeric crystallization method was successfully performed using dehydroabietic acid (DHAA) as the resolving agent in methanol. The three important parameters: DHAA amount, solvent (methanol) amount, and crystallization temperature of diastereomeric salts were optimized employing the response surface methodology (RSM). When maintaining a lower limit of 95% for the purity of (S)-propranolol, the optimal resolution conditions were a DHAA/(R, S)-propranolol molar ratio of 1.1, solvent/(R, S)-propranolol ratio of 16.2 mL.g-1, and crystallization temperature of -5°C. The desired (S)-propranolol was prepared with 94.8% optical purity and 72.2% yield under the optimal conditions.
- Ge, Li,Zhao, Qiongqiong,Yang, Kedi,Liu, Shishi,Xia, Fan
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- Kinetic resolution of propranolol by a lipase-catalyzed N-acetylation
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An enzymatic method for the direct resolution of propranolol is described. Candida cylindracea lipase enantioselectively catalyzed N-acetylation of S-propranolol with isopropenyl acetate in isopropyl ether. The ee values of the two enantiomers of N-acetylpropranolol were determined by an HPLC equipped with a chiral column. The effects of organic solvent nature and substrate concentration on enantioselectivity were also studied.
- Chiou, Tzyy-Wen,Chang, Cheng-Chi,Lai, Chung-Torr,Tai, Dar-Fu
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- THE SYNTHESIS OF E-(2S,3S)-3-TRIMETHYLSILYLGLYCIDOL AND ITS CONVERSION TO (-)-PROPRANOLOL
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(-)-Propranolol was synthesized in a highly enantio- and regioselective manner by using titanium mediated asymmetric epoxidation via the key intermediate, E-(2S,3S)-3-trimethylsilylglycidol.
- Katsuki, Tsutomu
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- Preparation of a novel hydroxypropyl-γ-cyclodextrin functionalized monolith for separation of chiral drugs in capillary electrochromatography
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In this study, a novel hydroxypropyl-γ-cyclodextrin (HP-γ-CD) functionalized monolithic capillary column was prepared by one-pot sequential strategy and used for chiral separation in capillary electrochromatography for the first time. In one pot, GMA-HP-γ-CD as functional monomer was allowed to be formed via the ring opening reaction between HP-γ-CD and glycidyl methacrylate (GMA) catalyzed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and then copolymerized directly with ethylene dimethacrylate (EDMA) and 2-acrylamido-2-methyl propane sulfonic acid (AMPS) in the presence of porogenic solvents via thermally initiated free radical polymerization. The preparation conditions of monoliths were optimized. Enantiomer separations of six chiral drugs including pindolol, clorprenaline, tulobuterol, clenbuterol, propranolol, and tropicamide were achieved on the monolith. Among them, pindolol, clorprenaline, and tropicamide were baseline separated with resolution values of 1.62, 1.73, and 1.55, respectively. The mechanism of enantiomer separation was discussed by comparison of the HP-γ-CD and HP-β-CD functionalized monoliths.
- Deng, Miaoduo,Xue, Mengyao,Liu, Yanru,Zhao, Min
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p. 188 - 195
(2021/02/26)
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- Preparation and evaluation of a triazole-bridged bis(β-cyclodextrin)–bonded chiral stationary phase for HPLC
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A triazole-bridged bis(β-cyclodextrin) was synthesized via a high-yield Click Chemistry reaction between 6-azido-β-cyclodextrin and 6-propynylamino-β-cyclodextrin, and then it was bonded onto ordered silica gel SBA-15 to obtain a novel triazole-bridged bis (β-cyclodextrin)–bonded chiral stationary phase (TBCDP). The structures of the bridged cyclodextrin and TBCDP were characterized by the infrared spectroscopy, mass spectrometry, elemental analysis, and thermogravimetric analysis. The chiral performance of TBCDP was evaluated by using chiral pesticides and drugs as probes including triazoles, flavanones, dansyl amino acids and β-blockers. Some effects of the composition in mobile phase and pH value on the enantioseparations were investigated in different modes. The nine triazoles, eight flavanones, and eight dansyl amino acids were successfully resolved on TBCDP under the reversed phase with the resolutions of hexaconazole, 2′-hydroxyflavanone, and dansyl-DL-tyrosine, which were 2.49, 5.40, and 3.25 within 30 minutes, respectively. The ten β-blockers were also separated under the polar organic mode with the resolution of arotinolol reached 1.71. Some related separation mechanisms were discussed preliminary. Compared with the native cyclodextrin stationary phase (CDSP), TBCDP has higher enantioselectivity to separate more analytes, which benefited from the synergistic inclusion ability of the two adjacent cavities and bridging linker of TBCDP, thereby enabling it a promising prospect in chiral drugs and food analysis.
- Shuang, Yazhou,Liao, Yuqin,Wang, Hui,Wang, Yuanxing,Li, Laisheng
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p. 168 - 184
(2019/11/25)
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- Enantioseparation of mandelic acid on vancomycin column: Experimental and docking study
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So far, no detailed view has been expressed regarding the interactions between vancomycin and racemic compounds including mandelic acid. In the current study, a chiral stationary phase was prepared by using 3-aminopropyltriethoxysilane and succinic anhydride to graft carboxylated silica microspheres and subsequently by activating the carboxylic acid group for vancomycin immobilization. Characterization by elemental analysis, Fourier transform infrared spectroscopy, solid-state nuclear magnetic resonance, and thermogravimetric analysis demonstrated effective functionalization of the silica surface. R and S enantiomers of mandelic acid were separated by the synthetic vancomycin column. Finally, the interaction between vancomycin and R/S mandelic acid enantiomers was simulated by Auto-dock Vina. The binding energies of interactions between R and S enantiomers and vancomycin chiral stationary phase were different. In the most probable interaction, the difference in mandelic acid binding energy was approximately 0.2 kcal/mol. In addition, circular dichroism spectra of vancomycin interacting with R and S enantiomers showed different patterns. Therefore, R and S mandelic acid enantiomers may occupy various binding pockets and interact with different vancomycin functions. These observations emphasized the different retention of R and S mandelic acid enantiomers in vancomycin chiral column.
- Shahnani, Mostafa,Sefidbakht, Yahya,Maghari, Shokoofeh,Mehdi, Ahmad,Rezadoost, Hassan,Ghassempour, Alireza
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supporting information
p. 1289 - 1298
(2020/08/19)
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- Preparation of polar group derivative β-cyclodextrin bonded hydride silica chiral stationary phases and their chromatography separation performances
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Three novel β-cyclodextrin compounds derived with piperidine which is flexible, L-proline containing a chiral center, ionic liquid with 3,5-diamino-1,2,4-triazole as the cation were designed and synthesized as chiral selectors for enantiomer separation, whose name were (mono-6-deoxy-6-(piperidine)-β-cyclodextrin, mono-6-deoxy-6-(L-proline)-β-cyclodextrin, mono-6-deoxy-6-(3,5-diamino-1,2,4-triazole)-β-cyclodextrin, multi-substituted 3,5-diamino-1,2,4- triazole-(p-toluenesulfonic)-β-cyclodextrin), respectively. In addition, to enhance the polarity of chiral stationary phases, hydrosilylation and silylation reactions were implemented to derive ordinary silica, the common used selector carrier, to hydride silica, whose surface is covered with proton. 31 pyrrolidine compounds and some chiral drugs were tested in both polar organic mobile phase mode and normal mobile phase mode. 6-Deoxy-6-L-proline-β-cyclodextrin-CSP showed satisfactory separations in polar organic mobile phase mode and exihibited a strong separation capability in different pH values; multi-substituted 3,5-diamino-1,2,4-triazole-(p-toluenesulfonic)-β-cyclodextrin-CSP can separate pyrrolidine compounds in both mobile phase modes with high resolutions and separation efficiency compared to commercially available CSPs, making it to be the most valuable object to study. The composition of mobile phase, type of stationary phase as well as the peak problem of chromatograms was discussed deeply.
- Zhao, Baojing,Li, Lan,Wang, Yuting,Zhou, Zhiming
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p. 643 - 649
(2018/11/27)
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- Enantioseparation of chiral pharmaceuticals by vancomycin-bonded stationary phase and analysis of chiral recognition mechanism
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The drug chirality is attracting increasing attention because of different biological activities, metabolic pathways, and toxicities of chiral enantiomers. The chiral separation has been a great challenge. Optimized high-performance liquid chromatography (HPLC) methods based on vancomycin chiral stationary phase (CSP) were developed for the enantioseparation of propranolol, atenolol, metoprolol, venlafaxine, fluoxetine, and amlodipine. The retention and enantioseparation properties of these analytes were investigated in the variety of mobile phase additives, flow rate, and column temperature. As a result, the optimal chromatographic condition was achieved using methanol as a main mobile phase with triethylamine (TEA) and glacial acetic acid (HOAc) added as modifiers in a volume ratio of 0.01% at a flow rate of 0.3?mL/minute and at a column temperature of 5°C. The thermodynamic parameters (eg, ΔH, ΔΔH, and ΔΔS) from linear van 't Hoff plots revealed that the retention of investigated pharmaceuticals on vancomycin CSP was an exothermic process. The nonlinear behavior of lnk′ against 1/T for propranolol, atenolol, and metoprolol suggested the presence of multiple binding mechanisms for these analytes on CSP with variation of temperature. The simulated interaction processes between vancomycin and pharmaceutical enantiomers using molecular docking technique and binding energy calculations indicated that the calculated magnitudes of steady combination energy (ΔG) coincided with experimental elution order for most of these enantiomers.
- Li, Jiaxi,Liu, Ruixia,Wang, Liyang,Liu, Xiaoling,Gao, Hongjie
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p. 236 - 247
(2019/02/01)
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- HPLC with cellulose Tris (3,5-DimethylPhenylcarbamate) chiral stationary phase: Influence of coating times and coating amount on chiral discrimination
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Coating cellulose tris (3,5-dimethylphenylcarbamate) (CDMPC) on silica gels with large pores have been demonstrated as an efficient way for the preparation of chiral stationary phase (CSP) for high-performance liquid chromatography (HPLC). During the process, a number of parameters, including the type of coating solvent, amount of coating, and the method for subsequent solvent removing, have been proved to affect the performance of the resultant CSPs. Coating times and the concentration of coating solution, however, also makes a difference to CSPs' performance by changing the arrangement of cellulose derivatives while remaining the coating amount constant, have much less been studied before, and thereby, were systematically investigated in this work. Results showed that CSPs with more coating times exhibited higher chiral recognition and column efficiency, suggesting that resolution was determined by column efficiency herein. Afterwards, we also investigated the effect of coating amount on the performance of CSPs, and it was shown that the ability of enantio-recognition did not increase all the time as the coating amount; and four of seven racemates achieved best resolution when the coating amount reached to 18.37%. At the end, the reproducibility of CDMPC-coated CSPs were further confirmed by two methods, ie, reprepared the CSP-0.15-3 and reevaluated the effect of coating times.
- Wei, Qiuhong,Su, Hongjiu,Gao, Diannan,Wang, Shudong
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p. 164 - 173
(2019/01/18)
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- Effect of vitamin C template on morphology and structure of alumina: emerging application in enantiomer separation
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Mesoporous nano-aluminas were prepared using aluminium isopropoxide, vitamin C (VC as a chiral template and a co-structural directing agent with molar ratios of 50:50 and 90:10) and water. These compositions when dried at 120?°C and calcined at 250, 350 and 500?°C for 8?h under air atmosphere transformed to boehmite and γ-alumina depending on the concentration of VC. The influence of vitamin C and its degradation products on the morphology and texture of alumina was investigated by the means of XRD, FT-IR, SEM, EDX, TEM, TGA, DSC, BET and N2 adsorption–desorption isotherm. Mesoporous aluminas possess excellent characteristics such as large surface area (ca. 394?m2/g), 0.4?cm3/g pore volume and narrow pore size distributions that can be synthesized through a facile and green procedure. In addition, the enantiomers of propranolol hydrochloride were successfully resolved from its racemate using Al50VC50T350 (AlMolar ratio of the Aluminium isopropoxide, VCMolar ratio of the Vitamin C,TTemperature) (Rs = 2.5) as chiral stationary phase. The synthesis of chiral stationary phase was accomplished in a green, facile and inexpensive procedure that is of paramount importance in food and pharmaceutical industries.
- Dabbagh, Hossein A.,Mozaffari Majd, Mahdieh,Bahrami, Fahimeh,Gholami, Ali
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p. 1931 - 1943
(2019/09/03)
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- Enantiomeric separation of β-blockers and tryptophan using heparin as stationary and pseudostationary phases in capillary electrophoresis
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The separation methods of the enantiomers of two β-blockers and tryptophan were studied using capillary electrochromatography with heparin covalently as well as non-covalently, bonded onto the capillary inner wall as stationary phase and electrokinetic chromatography with heparin as pseudostationary phase. In the case of heparin, used as a stationary phase, the method was unable to resolve enantiomers in both cases β-blockers and tryptophan. On the other hand, when heparin was used as a pseudostationary phase, the resolution of the enantiomers was obtained only with 3-aminopropyltriethoxysilane which were immobilised onto the inner phase of the capillary. The results of this study let us infer that the electrostatic, hydrophobic, and steric interactions were involved in the separation mechanisms. The separation was achieved in less than 10?minutes under the optimized conditions: 30?mM phosphate buffer (pH?2.5) with the adding of 15?mg/mL of heparin at 15°C and 10?kV. The usefulness of heparin as a chiral selector both in electrokinetic chromatography using 3-aminopropyltriethoxysilane attached to the capillary was demonstrated for the first time. The developed method was powerful, sensitive, and fast, and it could be considered an important alternative to conventional methods used for chiral separation.
- Liu, Yi,Sombra, Lorena L.,Stege, Patricia W.
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p. 988 - 995
(2018/07/29)
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- Cellulose type chiral stationary phase based on reduced graphene oxide@silica gel for the enantiomer separation of chiral compounds
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The graphene oxide (GO) was covalently coupled to the surfaces of silica gel (SiO2) microspheres by amide bond to get the graphene oxide@silica gel (GO@SiO2). Then, the GO@SiO2 was reduced with hydrazine to the reduced graphene oxide@silica gel (rGO@SiO2), and the cellulose derivatives were physically coated on the surfaces of rGO@SiO2 to prepare a chiral stationary phase (CSP) for high performance liquid chromatography. Under the optimum experimental conditions, eight benzene-enriched enantiomers were separated completely, and the resolution of trans-stilbene oxide perfectly reached 4.83. Compared with the blank column of non-bonded rGO, the separation performance is better on the new CSP, which is due to the existence of rGO to produce special retention interaction with analytes, such as π-π stacking, hydrophobic effect, π-π electron-donor–acceptor interaction, and hydrogen bonding. Therefore, the obtained CSP shows special selectivity for benzene-enriched enantiomers, improves separation selectivity and efficiency, and rGO plays a synergistic effect with cellulose derivatives on enantioseparation.
- Li, Yuanyuan,Li, Qiang,Zhu, Nan,Gao, Zhuxian,Ma, Yulong
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p. 996 - 1004
(2018/07/29)
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- Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase
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A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.
- Hellinghausen, Garrett,Lopez, Diego A.,Lee, Jauh T.,Wang, Yadi,Weatherly, Choyce A.,Portillo, Abiud E.,Berthod, Alain,Armstrong, Daniel W.
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p. 1067 - 1078
(2018/08/01)
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- Ultrafast chiral separations for high throughput enantiopurity analysis
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Recent developments in fast chromatographic enantioseparations now make high throughput analysis of enantiopurity on the order of a few seconds achievable. Nevertheless, routine chromatographic determinations of enantiopurity to support stereochemical investigations in pharmaceutical research and development, synthetic chemistry and bioanalysis are still typically performed on the 5-20 min timescale, with many practitioners believing that sub-minute enantioseparations are not representative of the molecules encountered in day to day research. In this study we develop ultrafast chromatographic enantioseparations for a variety of pharmaceutically-related drugs and intermediates, showing that sub-minute resolutions are now possible in the vast majority of cases by both supercritical fluid chromatography (SFC) and reversed phase liquid chromatography (RP-LC). Examples are provided illustrating how such methods can be routinely developed and used for ultrafast high throughput analysis to support enantioselective synthesis investigations.
- Barhate, Chandan L.,Joyce, Leo A.,Makarov, Alexey A.,Zawatzky, Kerstin,Bernardoni, Frank,Schafer, Wes A.,Armstrong, Daniel W.,Welch, Christopher J.,Regalado, Erik L.
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supporting information
p. 509 - 512
(2017/01/13)
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- Enantioselective potential of polysaccharide-based chiral stationary phases in supercritical fluid chromatography
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The enantioselective potential of two polysaccharide-based chiral stationary phases for analysis of chiral structurally diverse biologically active compounds was evaluated in supercritical fluid chromatography using a set of 52 analytes. The chiral selectors immobilized on 2.5?μm silica particles were tris-(3,5-dimethylphenylcarmabate) derivatives of cellulose or amylose. The influence of the polysaccharide backbone, different organic modifiers, and different mobile phase additives on retention and enantioseparation was monitored. Conditions for fast baseline enantioseparation were found for the majority of the compounds. The success rate of baseline and partial enantioseparation with cellulose-based chiral stationary phase was 51.9% and 15.4%, respectively. Using amylose-based chiral stationary phase we obtained 76.9% of baseline enantioseparations and 9.6% of partial enantioseparations of the tested compounds. The best results on cellulose-based chiral stationary phase were achieved particularly with propane-2-ol and a mixture of isopropylamine and trifluoroacetic acid as organic modifier and additive to CO2, respectively. Methanol and basic additive isopropylamine were preferred on amylose-based chiral stationary phase. The complementary enantioselectivity of the cellulose- and amylose-based chiral stationary phases allows separation of the majority of the tested structurally different compounds. Separation systems were found to be directly applicable for analyses of biologically active compounds of interest.
- Kucerova, Gabriela,Kalikova, Kveta,Tesarova, Eva
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supporting information
p. 239 - 246
(2017/05/29)
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- Comparison of three S-β-CDs with different degrees of substitution for the chiral separation of 12 drugs in capillary electrophoresis
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Three kinds of sulfated β-cyclodextrin (S-β-CD), including a single isomer, heptakis-6-sulfato-β-cyclodextrin (HS-β-CD), degree of substitution (DS) of 7, which was synthesized in our laboratory and another two commercialized randomly substituted mixtures, a sulfated β-cyclodextrin with DS of 7 to 11, as well as a highly sulfated-β-cyclodextrin with DS of 12 to 15, were used for the enantioresolution of 12 drugs (the β-blockers, phenethylamines, and anticholinergic agents) in capillary electrophoresis. The enantioseparation under varying concentrations of S-β-CD and background electrolyte pH were systematically investigated and compared. Based on the experimental results, the effect of the nature of S-β-CD and analyte structure on the enantioseparation is discussed.
- Wang, Zhaokun,Zhang, Qiongwen,Luo, Linda,Sun, Tiemin,Guo, Xingjie
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p. 558 - 565
(2017/08/26)
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- Optimization of throughput in semipreparative chiral liquid chromatography using stacked injection
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An interesting mode of chromatography for preparation of pure enantiomers from pure samples is the method of stacked injection as a pseudocontinuous procedure. Maximum throughput and minimal production costs can be achieved by the use of total chiral column length in this mode of chromatography. To maximize sample loading, often touching bands of the two enantiomers is automatically achieved. Conventional equations show direct correlation between touching-band loadability and the selectivity factor of two enantiomers. The important question for one who wants to obtain the highest throughput is “How to optimize different factors including selectivity, resolution, run time, and loading of the sample in order to save time without missing the touching-band resolution?” To answer this question, tramadol and propranolol were separated on cellulose 3,5-dimethyl phenyl carbamate, as two pure racemic mixtures with low and high solubilities in mobile phase, respectively. The mobile phase composition consisted of n-hexane solvent with alcohol modifier and diethylamine as the additive. A response surface methodology based on central composite design was used to optimize separation factors against the main responses. According to the stacked injection properties, two processes were investigated for maximizing throughput: one with a poorly soluble and another with a highly soluble racemic mixture. For each case, different optimization possibilities were inspected. It was revealed that resolution is a crucial response for separations of this kind. Peak area and run time are two critical parameters in optimization of stacked injection for binary mixtures which have low solubility in the mobile phase.
- Taheri, Mohammadreza,Fotovati, Mohsen,Hosseini, Seyed-Kiumars,Ghassempour, Alireza
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p. 579 - 588
(2017/09/29)
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- Multifunctional cinnamic acid derivatives
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Our research to discover potential new multitarget agents led to the synthesis of 10 novel derivatives of cinnamic acids and propranolol, atenolol, 1-adamantanol, naphth-1-ol, and (benzylamino) ethan-1-ol. The synthesized molecules were evaluated as trypsin, lipoxygenase and lipid peroxidation inhibitors and for their cytotoxicity. Compound 2b derived from phenoxyphenyl cinnamic acid and propranolol showed the highest lipoxygenase (LOX) inhibition (IC50 = 6 uM) and antiproteolytic activity (IC50 = 0.425 uM). The conjugate 1a of simple cinnamic acid with propranolol showed the higher antiproteolytic activity (IC50 = 0.315 uM) and good LOX inhibitory activity (IC50 = 66 uM). Compounds 3a and 3b, derived from methoxylated caffeic acid present a promising combination of in vitro inhibitory and antioxidative activities. The S isomer of 2b also presented an interesting multitarget biological profile in vitro. Molecular docking studies point to the fact that the theoretical results for LOX-inhibitor binding are identical to those from preliminary in vitro study.
- Peperidou, Aikaterini,Pontiki, Eleni,Hadjipavlou-Litina, Dimitra,Voulgari, Efstathia,Avgoustakis, Konstantinos
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- Asymmetric Hydrolytic and Aminolytic Kinetic Resolution of Racemic Epoxides using Recyclable Macrocyclic Chiral Cobalt(III) Salen Complexes
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New chiral macrocyclic cobalt(III) salen complexes were synthesized and used as catalyst for the asymmetric kinetic resolution (AKR) of terminal epoxides and glycidyl ethers with aromatic/aliphatic amines and water as nucleophiles. This is the first occasion where a Co(III) salen complex demonstrated its ability to catalyze AKR as well as hydrolytic kinetic resolution (HKR) reactions. Excellent enantiomeric excesses of the epoxides, the corresponding amino alcohols and diols (upto 99%) with quantitative yields were achieved by using the chiral Co(III) salen complexes in dichloromethane at room temperature. This protocol was further extended for the synthesis of two important drug molecules, i.e., (S)-propranolol and (R)-naftopidil. The catalytic system was also explored for the synthesis of chirally pure diols and chiral cyclic carbonates using carbon dioxide as a greener renewable C1 source. The catalyst was recycled for upto 5 catalytic cycles with retention of enantioselectivity. (Figure presented.).
- Tak, Rajkumar,Kumar, Manish,Menapara, Tusharkumar,Gupta, Naveen,Kureshy, Rukhsana I.,Khan, Noor-ul H.,Suresh
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supporting information
p. 3990 - 4001
(2017/11/22)
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- Enantiomer separation of propranolol and tryptophan using bovine serum albumin functionalized silica nanoparticles as adsorbents
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The immobilization of popular chiral selectors on the surface of nanomaterials to prepare new chiral adsorbents for preparative chiral separation is a research hotspot in separation science nowadays. In this study, bovine serum albumin (BSA) modified silica nanoparticles were prepared by using polydopamine (PDA) as a versatile multifunctional secondary reaction platform. The preparation method was facile, cost-effective and environmentally friendly. The new chiral adsorbents were then investigated for the separation of representative chiral drug enantiomers. For propranolol and tryptophan, the multi-step adsorption enhanced the chiral performance to a great degree. On increasing the starting percent enantiomeric excess (%, e.e.) of the enantiomeric mixtures, the %, e.e. value of the resulting solution increased to almost 100% under the same operating conditions. For simplicity and rapidness, the results of adsorption were measured by capillary electrophoresis (CE) using carboxymethyl-β-cyclodextrin (CM-β-CD) or α-cyclodextrin (α-CD) as additives into the background electrolyte solution. The experimental results also showed that the thus-prepared nanomaterials could be readily recycled at least three times, demonstrating their great stability and possibility in practical use.
- Li, Wei,Ding, Guo-Sheng,Tang, An-Na
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p. 93850 - 93857
(2015/11/17)
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- Synthesis of (S)-(-)-propranolol by using Cs2.5H0.5PW12O40 nanocatalyst as green, eco-friendly, reusable, and recyclable catalyst
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The Cs2.5H0.5PW12O40 nanoparticle catalyst appear to be a new and efficient solid acid catalyst for an economical, environmentally benign synthesis of (S)-(-)-propranolol. Cs2.5H0.5PW12O40 nanocatalyst are used as a new, recyclable and reusable. Synthesis of (S)-(-)-propranolol is carried out in two steps with usual reagents: heteropolyacid, (+)-tartaric acid catalyzed enantioselective synthesis of (S)-(-)-propranolol via kinetic resolution of key intermediate α-naphthyl glycidyl ether with high optical and chemical yield. With this synthesis, we have two products in the first reaction and it is not necessary to purify the crude oil. This by-product is removed in the second step by extraction and yield is satisfactory. The nanocatalyst of Cs2.5H0.5PW12O40 catalyzed the synthesis of propranolol in high yields and good selectivity.
- Gharib, Ali,Jahangir, Manouchehr,Roshani, Mina,Pesyan, Nader Noroozi,Scheeren,Mohadesazadeh, Sara,Lagzian, Shirin
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p. 350 - 355
(2015/02/02)
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- Chemoenzymatic synthesis of (R)- and (S)-propranolol using an engineered epoxide hydrolase with a high turnover number
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Simultaneous synthesis of the R- and S-enantiomers of biologically active propranolol, a typical β-blocker, was achieved in high optical purity via an epoxide hydrolase-catalyzed resolution of racemic α-naphthyl glycidyl ether (rac-1). A preparative resolution of 100 g/L rac-1 was accomplished with high enantioselectivity (E = 92) using a variant of Bacillus megaterium epoxide hydrolase (BmEHF128T). A biphasic system (isopropyl ether/isooctane/aqueous) was used, in which the product 3-(1′-naphthyloxy)-propane-1,2-diol (2) precipitated instantly, facilitating its separation and increasing the enantiopurity of (R)-2 (>99.5% ee). This enzymatic resolution had a total turnover number of 70,000, affording enantiopure epoxide (S)-1 (>99% ee) and 1,2-diol (R)-2 (>99% ee) in 45.3% and 42.4% yields, respectively. (R)-2 and (S)-1 were subsequently converted to (R)- and (S)-propranolol (3) (>99% ee) in overall yields of 31.4% and 44.8%. To the best of our knowledge, this is the best case for enzymatic resolution of rac-1 using an epoxide hydrolase, giving high space-time yields [136 g L-1 days-1 for (S)-1 and 139 g L-1 days-1 for (R)-2] under mild reaction conditions. It provides a new and eco-friendly route that complements other methods using organometallic catalysts.
- Kong, Xu-Dong,Yu, Hui-Lei,Yang, Sheng,Zhou, Jiahai,Zeng, Bu-Bing,Xu, Jian-He
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p. 275 - 281
(2015/11/02)
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- Continuous and convergent access to vicinyl amino alcohols
-
Five active pharmaceutical ingredients (APIs) containing the vicinyl amino alcohol moiety were synthesized using a convergent chemical assembly system. The continuous system is composed of four flow reaction modules: biphasic oxidation, Corey-Chaykovsky epoxidation, phenol alkylation, and epoxide aminolysis. Judicious choice of reagents and module order allowed for two classes of β-amino alcohols, aryl and aryloxy, to be synthesized in good (27-69%) overall yields.
- Nobuta, Tomoya,Xiao, Guozhi,Ghislieri, Diego,Gilmore, Kerry,Seeberger, Peter H.
-
supporting information
p. 15133 - 15136
(2015/10/12)
-
- HPLC-fluorescence method for the enantioselective analysis of propranolol in rat serum using immobilized polysaccharide-based chiral stationary phase
-
A stereoselective high-performance liquid chromatographic (HPLC) method was developed and validated to determine S-(-)- and R-(+)-propranolol in rat serum. Enantiomeric resolution was achieved on cellulose tris(3,5- dimethylphenylcarbamate) immobilized onto spherical porous silica chiral stationary phase (CSP) known as Chiralpak IB. A simple analytical method was validated using a mobile phase consisted of n-hexane-ethanol-triethylamine (95:5:0.4%, v/v/v) at a flow rate of 0.6 mL min-1 and fluorescence detection set at excitation/emission wavelengths 290/375 nm. The calibration curves were linear over the range of 10-400 ng mL-1 (R = 0.999) for each enantiomer with a detection limit of 3 ng mL-1. The proposed method was validated in compliance with ICH guidelines in terms of linearity, accuracy, precision, limits of detection and quantitation, and other aspects of analytical validation. Actual quantification could be made for propranolol isomers in serum obtained from rats that had been intraperitoneally (i.p.) administered a single dose of the drug. The proposed method established in this study is simple and sensitive enough to be adopted in the fields of clinical and forensic toxicology. Molecular modeling studies including energy minimization and docking studies were first performed to illustrate the mechanism by which the active enantiomer binds to the β-adrenergic receptor and second to find a suitable interpretation of how both enantiomers are interacting with cellulose tris(3,5-dimethylphenylcarbamate) CSP during the process of resolution. The latter interaction was demonstrated by calculating the binding affinities and interaction distances between propranolol enantiomers and chiral selector. Chirality 26:194-199, 2014. 2014 Wiley Periodicals, Inc. Copyright
- Alanazi, Amer M.,Hefnawy, Mohamed M.,Al-Majed, Abdulrahman A.,Al- Suwailem, Aymen K.,Kassem, Mohamed G.,Mostafa, Gamal A.,Attia, Sabry M.,Khedr, Mohammed M.
-
p. 194 - 199
(2014/04/17)
-
- Electrically assisted liquid-phase microextraction combined with capillary electrophoresis for quantification of propranolol enantiomers in human body fluids
-
In this study, electromembrane extraction (EME) combined with cyclodextrin (CD)-modified capillary electrophoresis (CE) was applied for the extraction, separation, and quantification of propranolol (PRO) enantiomers from biological samples. The PRO enantiomers were extracted from aqueous donor solutions, through a supported liquid membrane (SLM) consisting of 2-nitrophenyl octyl ether (NPOE) impregnated on the wall of the hollow fiber, and into a 20-μL acidic aqueous acceptor solution into the lumen of hollow fiber. Important parameters affecting EME efficiency such as extraction voltage, extraction time, pH of the donor and acceptor solutions were optimized using a Box-Behnken design (BBD). Then, under these optimized conditions, the acceptor solution was analyzed using an optimized CD-modified CE. Several types of CD were evaluated and best results were obtained using a fused-silica capillary with ammonium acetate (80 mM, pH 2.5) containing 8 mM hydroxypropyl-β-CD as a chiral selector, applied voltage of 18 kV, and temperature of 20C. The relative recoveries were obtained in the range of 78-95%. Finally, the performance of the present method was evaluated for the extraction and determination of PRO enantiomers in real biological samples. Chirality 26:260-267, 2014. 2014 Wiley Periodicals, Inc.
- Tabani, Hadi,Fakhari, Ali Reza,Shahsavani, Abolfath,Gharari Alibabaou, Hossein
-
p. 260 - 267
(2014/05/06)
-
- Minor enantiomer recycling: Application to enantioselective syntheses of beta blockers
-
Continuous recycling of the minor product enantiomer obtained from the acetylcyanation of prochiral aldehydes provided access to highly enantiomerically enriched products. Cyanohydrin derivatives, which under normal conditions are obtained with modest or poor enantiomeric ratios, were formed with high enantiomeric purity by using a reinforcing combination of a chiral Lewis acid catalyst and a biocatalyst. The primarily obtained products were transformed into β-adrenergic antagonists (S)-propanolol, (R)-dichloroisoproterenol, and (R)-pronethalol by means of a two-step procedure.
- Wen, Ye-Qian,Hertzberg, Robin,Gonzalez, Inanllely,Moberg, Christina
-
p. 3806 - 3812
(2014/04/03)
-
- Silver nanoparticle-catalysed phenolysis of epoxides under neutral conditions: Scope and limitations of metal nanoparticles and applications towards drug synthesis
-
Chemo- and regio-selective epoxide phenolysis is reported for the first time under neutral condition catalysed by silver nanoparticles. Other metal nanoparticles (e.g., Au, Pd, Cu, In, and Ru) are less effective. The choice of solvent is critical with 2-propanol being the best followed by DEF. Amongst various stabilisers used (surfactants, PEGs, tetra-alkylammonium halides) the tetra-alkylammonium halides are found to be the most effective (TBAF > TBAB > TBACl > TBAI). The role of the silver nanoparticles is envisaged as synchronous mode epoxide-phenol dual activation via a cooperative network of coordination, anion-π interaction, and hydrogen bond. The silver nanoparticles are recovered and reused for five consecutive times. The reaction has been used for the synthesis of propranolol and naftopidil as a few representative cardiovascular drugs.
- Seth, Kapileswar,Roy, Sudipta Raha,Kommi, Damodara N.,Pipaliya, Bhavin V.,Chakraborti, Asit K.
-
p. 164 - 172
(2014/06/23)
-
- Predictability of enantiomeric chromatographic behavior on various chiral stationary phases using typical reversed phase modeling software
-
Pharmaceutical companies worldwide tend to apply chiral chromatographic separation techniques in their mass production strategy rather than asymmetric synthesis. The present work aims to investigate the predictability of chromatographic behavior of enantiomers using DryLab HPLC method development software, which is typically used to predict the effect of changing various chromatographic parameters on resolution in the reversed phase mode. Three different types of chiral stationary phases were tested for predictability: macrocyclic antibiotics-based columns (Chirobiotic V and T), polysaccharide-based chiral column (Chiralpak AD-RH), and protein-based chiral column (Ultron ES-OVM). Preliminary basic runs were implemented, then exported to DryLab after peak tracking was accomplished. Prediction of the effect of % organic mobile phase on separation was possible for separations on Chirobiotic V for several probes: racemic propranolol with 97.80% accuracy; mixture of racemates of propranolol and terbutaline sulphate, as well as, racemates of propranolol and salbutamol sulphate with average 90.46% accuracy for the effect of percent organic mobile phase and average 98.39% for the effect of pH; and racemic warfarin with 93.45% accuracy for the effect of percent organic mobile phase and average 99.64% for the effect of pH. It can be concluded that Chirobiotic V reversed phase retention mechanism follows the solvophobic theory. 2013 Wiley Periodicals, Inc.
- Wagdy, Hebatallah A.,Hanafi, Rasha S.,El-Nashar, Rasha M.,Aboul-Enein, Hassan Y.
-
p. 506 - 513
(2013/09/12)
-
- Chiral separation of basic compounds on sulfated β-cyclodextrin-coated zirconia monolith by capillary electrochromatography
-
Sulfated β-cyclodextrin (SCD)-coated zirconia monolith was used as the chiral stationary phase in capillary electrochromatography for enantiomeric separation of basic chiral compounds. SCD adsorbed on the zirconia surface provided a stable chiral stationary phase in reversed-phase eluents. Retention, chiral selectivity and resolution of a set of six basic chiral compounds were measured in eluents of varying pH, composition of methanol and buffer. Optimum mobile phase condition for the separation of the compounds was found to be methanol content of 30%, buffer concentration of 30 mM and pH of 4.0.
- Hong, Jong-Seong,Park, Jung Hag
-
p. 1809 - 1813
(2013/07/26)
-
- Asymmetric synthesis of propranolol, naftopidil and (R)-monobutyrin using a glycerol desymmetrization strategy
-
Herein, an approach for desymmetrization of glycerol by using a readily available camphorsulfonamide as a starting material is described. The strategy for asymmetric synthesis of (R)/(S)-propranolol, (R)/(S)-naftopidil and (R)-monobutyrin with spiroketal formation by desymmetrization was employed and Mitsunobu reaction was used for epoxide and ether formation. Steglich esterification and CAN (cerium ammonium nitrate) mediated ketal deprotection, were key steps in the synthesis. Regioselective ring opening of epoxide gave desired molecule with good overall yield and optical purity.
- Lokhande, Mahendra N.,Chopade, Manojkumar U.,Bhangare, Dattatrya N.,Nikalje, Milind D.
-
p. 406 - 409
(2013/08/25)
-
- Acetylation of (R,S)-propranolol catalyzed by Candida antarctica lipase B: An experimental and computational study
-
The chemo- and enantioselectivity of the Candida antarctica lipase B (CalB)-catalyzed acetylation reaction of (R,S)-propranolol using vinyl acetate as acyl donor and toluene as organic solvent was studied. Because of the poor solubility of propranolol in toluene small quantities of methanol were added as cosolvent. The effects of the propranolol/vinyl acetate ratio, the enzyme purification procedure and the methanol concentration on the reaction were investigated. The reactions occurring in the system were quantitatively investigated using 1H and 13C NMR spectroscopy. The major reactions were the hydrolysis and alcoholysis of vinyl acetate, as a consequence of the presence of residual water and methanol in the reaction medium. Furthermore, the NMR analysis confirmed that O-acetyl-propranolol was formed exclusively. The reaction was also found to be enantioselective favoring the faster transformation of the R-propranolol. In addition to the experiments, molecular modeling was used to study the formation of the reactive Michaelis complexes between propranolol and acetylated CalB, using a combined molecular docking and molecular dynamics (MD) procedure. Only for the O-acetylation we found binding modes of the substrate leading to formation of the product, which explains the experimentally observed chemoselectivity of CalB.
- Escorcia, Andres M.,Molina, Daniel,Daza, Martha C.,Doerr, Markus
-
-
- Asymmetric aminolytic kinetic resolution of racemic epoxides using recyclable chiral polymeric Co(III)-salen complexes: A protocol for total utilization of racemic epoxide in the synthesis of (R)-naftopidil and (S)-propranolol
-
Chiral polymeric Co(III) salen complexes with chiral ((R)/(S)-BINOL, diethyl tartrate) and achiral (piperazine and trigol) linkers with varying stereogenic centers were synthesized for the first time and used as catalysts for aminolytic kinetic resolution (AKR) of a variety of terminal epoxides and glycidyl ethers to get enantio-pure epoxides (ee, 99%) and N-protected β-amino alcohols (ee, 99%) with quantitative yield in 16 h at RT under optimized reaction conditions. This protocol was also used for the synthesis of two enantiomerically pure drug molecules (R)-Naftopidil (α1- blocker) and (S)-Propranolol (β-blocker) as a key step via AKR of single racemic naphthylglycidyl ether with Boc-protected isoproylamine with 100% epoxide utilization at 1 g level. The catalyst 1 was successfully recycled for a number of times.
- Kumar, Manish,Kureshy, Rukhsana I.,Shah, Arpan K.,Das, Anjan,Khan, Noor-Ul H.,Abdi, Sayed H. R.,Bajaj, Hari C.
-
p. 9076 - 9084
(2013/10/08)
-
- A new catalyst for the asymmetric Henry reaction: Synthesis of β-nitroethanols in high enantiomeric excess
-
A new chiral tetrahydrosalen ligand has been designed and synthesized from cis-2,5-diaminobicyclo[2.2.2]octane. The complex generated in situ by the interaction of the ligand with (CuOTf)2·C6H 5CH3 was an efficient catalyst for the asymmetric Henry reaction, producing nitroaldol products in high yield and good stereoselectivity. Henry reactions catalyzed by this tetrahydrosalen-Cu(I) complex led to syntheses of β-adrenergic blocking agents (S)-toliprolol, (S)-moprolol, and (S)-propanolol.
- White, James D.,Shaw, Subrata
-
p. 6270 - 6273
(2013/02/23)
-
- Asymmetric hydrolytic kinetic resolution with recyclable macrocyclic CoIII-salen complexes: A practical strategy in the preparation of (R)-mexiletine and (S)-propranolol
-
A chiral cobalt(III) complex (1 e) was synthesized by the interaction of cobalt(II) acetate and ferrocenium hexafluorophosphate with a chiral dinuclear macrocyclic salen ligand that was derived from 1R,2R-(-)-1,2-diaminocyclohexane with trigol bis-aldehyde. A variety of epoxides and glycidyl ethers were suitable substrates for the reaction with water in the presence of chiral macrocyclic salen complex 1 e at room temperature to afford chiral epoxides and diols by hydrolytic kinetic resolution (HKR). Excellent yields (47 % with respect to the epoxides, 53 % with respect to the diols) and high enantioselectivity (ee>99 % for the epoxides, up to 96 % for the diols) were achieved in 2.5-16 h. The CoIII macrocyclic salen complex (1 e) maintained its performance on a multigram scale and was expediently recycled a number of times. We further extended our study of chiral epoxides that were synthesized by using HKR to the synthesis of chiral drug molecules (R)-mexiletine and (S)-propranolol.
- Sadhukhan, Arghya,Khan, Noor-Ul H.,Roy, Tamal,Kureshy, Rukhsana I.,Abdi, Sayed H. R.,Bajaj, Hari C.
-
supporting information; experimental part
p. 5256 - 5260
(2012/06/01)
-
- Synthesis of dendrimer-type chiral stationary phases based on the selector of (1S,2R)-(+)-2-amino-1,2-diphenylethanol derivate and their enantioseparation evaluation by HPLC
-
In our recent work, a series of dendritic chiral stationary phases (CSPs) were synthesized, in which the chiral selector was L-2-(p-toluenesulfonamido)-3- phenylpropionyl chloride (selector I), and the CSP derived from three-generation dendrimer showed the best separation ability. To further investigate the influence of the structures of dendrimer and chiral selector on enantioseparation ability, in this work, another series CSPs (CSPs 1-4) were prepared by immobilizing (1S,2R)-1,2-diphenyl-2-(3-phenylureido)ethyl 4-isocyanatophenylcarbamate (selector II) on one- to four-generation dendrimers that were prepared in previous work. CSPs 1 and 4 demonstrated the equivalent enantioseparation ability. CSPs 2 and 3 showed the best and poorest enantioseparation ability respectively. Basically, these two series of CSPs exhibited the equivalent enantioseparation ability although the chiral selectors were different. Considering the enantioseparation ability of the CSP derived from aminated silica gel and selector II is much better than that of the one derived from aminated silica gel and selector I, it is believed that the dendrimer conformation essentially impacts enantioseparation.
- He, Bao-Jiang,Yin, Chuan-Qi,Li, Shi-Rong,Bai, Zheng-Wu
-
experimental part
p. 69 - 76
(2010/09/09)
-
- Chiral separations of some β-adrenergic agonists and antagonists on AmyCoat column by HPLC
-
Sixteen β-adrenergic antagonists namely acebutalol, alprenolol, atenolol, bisoprolol, bopindolol, bufurolol, carazolol, celiprolol, indenolol, metaprolol, nebivolol, oxprenolol, practolol, propranolol, tertalol, and timolol, and two β-adrenergic agonists namely cimeterol and clenbuterol were resolved on AmyCoat (150 x 46 mm, 3 μm size of silica particle) by using (85:15:0.1, v/v/v), (90:10:0.1, v/v/v), and (95:05:0.1, v/v/v) combinations of η-heptane, ethanol, and diethylamine solvents, respectively. The flow rates used were 0.5, 1.0, 2.0, and 3.0 ml/min with detection at 225 nm. The values of capacity, separation, and resolution factors ranged from 0.38 to 19.70, 1.08-2.33, and 1.0 and 4.50, respectively. The maximum and minimum resolutions were achieved for celiprolol and bufurolol, respectively. The chiral recognition mechanisms were also discussed. The values of validation parameters were calculated.
- Ali, Imran,Saleem, Kishwar,Gaitonde, Vinay D.,Aboul-Enein, Hassan Y.,Hussain, Iqbal
-
experimental part
p. 24 - 28
(2010/09/14)
-
- Rearrangement of N-alkyl 1,2-amino alcohols. Synthesis of (S)-toliprolol and (S)-propanolol
-
N-alkyl 1,2-amino alcohols were rearranged stereospecifically by using TFAA/Et3N. This rearrangement has been used to synthesize N-isopropyl-3-(aryloxy)-2-hydroxypropylamines, β-adrenergic blocking agents such as (S)-toliprolol and (S)-propanolol.
- Duthion, Béranger,Métro, Thomas-Xavier,Gomez Pardo, Domingo,Cossy, Janine
-
experimental part
p. 6696 - 6706
(2011/02/26)
-
- Organocatalytic enantioselective synthesis of β-blockers: (S)-propranolol and (S)-naftopidil
-
An efficient enantioselective synthesis of β-adrenergic blockers (S)-propranolol and (S)-naftopidil with >98% ee using an l-proline-catalyzed α-aminoxylation of an aldehyde as a key step is described.
- Panchgalle, Sharad P.,Gore, Rohitkumar G.,Chavan, Subhash P.,Kalkote, Uttam R.
-
experimental part
p. 1767 - 1770
(2009/12/28)
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- Enantioselective synthesis of β-blockers via hydrolytic kinetic resolution of terminal oxiranes by using bimetallic chiral {{2,2′- [cyclohexane-1,2-diylbis(nitrilomethylidyne)]bis[phenolato]}(2-)}cobalt ([Co(salen)])-type complexes
-
The synthesis of chirally pure β-blockers was successfully achieved via hydrolytic kinetic resolution of butyl (±)-4-(oxiran-2-ylmethoxy) benzeneacetate ((±)-1) and (±)-4-(oxiran-2-ylmethoxy) benzeneacetonitrile ((±)-2) in the presence of bimetallic chiral [Co(salen)]-type complexes. The newly synthesized bimetallic chiral [Co(salen)]-type complexes exhibited excellent enantioselectivities of up to >98% ee in good yields (Tables 1-3).
- Kawthekar, Rahul B.,Kim, Geon-Joong
-
scheme or table
p. 317 - 332
(2009/02/07)
-
- Zinc(II) perchlorate hexahydrate catalyzed opening of epoxide ring by amines: Applications to synthesis of (RS)/(R)-propranolols and (RS)/(R)/(S)-naftopidils
-
(Figure Presented) Commercially available zinc(II) Perchlorate hexahydrate [Zn(ClO4)2·6H2O] was found to be a new and highly efficient catalyst for opening of epoxide rings by amines affording 2-amino alcohols in high yields under solvent-free conditions and with excellent chemo-, regio-, and stereoselectivities. For unsymmetrical epoxides, the regioselectivity was influenced by the electronic and steric factors associated with the epoxides and the amines. A complementarity in the regioselectivity was observed during the reaction of styrene oxide with aromatic and aliphatic amines: aromatic amines provided amino alcohols from nucleophilic attack at the benzylic carbon as major products whereas aliphatic amines resulted in formation of the amino alcohols through reaction at the terminal carbon atom of the epoxide ring as the major/sole products. Reaction of aniline with various glycidic ethers gave the amino alcohols by regioselective nucleophilic attack at the terminal carbon atom of the epoxide ring as the only/major product. Zinc(II) Perchlorate hexahydrate was found to be the best catalyst compared to other metal Perchlorates. The counteranion modulated the catalytic property of the various Zn(II) compounds that followed the order Zn(ClO4) 2·6H2O Zn(BF4)2 ~ Zn(OTf)2 ZnI2 > ZnBr2 > ZnCl2 > Zn(OAc)2 > Zn(CO3)2 in parallelism with the acidic strength of the corresponding protic acids (except for TfOH). The applicability of the methodology was demonstrated by the synthesis of cardiovascular drugs propranolol and naftopidil as racemates and optically active enantiomers.
- Shivani,Pujala, Brahmam,Chakraborti, Asit K.
-
p. 3713 - 3722
(2008/02/05)
-
- New propranolol analogues: Binding and chiral discrimination by cellobiohydrolase Cel7A
-
Novel propranolol analogues have been designed and synthesised and their enantioselective binding to the cellulose degrading enzyme, Cel7A, has been evaluated. Affinity and enantioselectivity have been determined by capillary electrophoresis experiments. Ligands with significantly improved affinity and selectivity have been obtained and an analysis of the results has led to insights concerning the relation between the changes in ligand structure and selectivity as well as affinity to the protein. The Royal Society of Chemistry 2006.
- Fagerstroem, Alexandra,Nilsson, Mikael,Berg, Ulf,Isaksson, Roland
-
p. 3067 - 3076
(2008/02/12)
-
- Asymmetric synthesis of aryloxypropanolamines via OsO4-catalyzed asymmetric dihydroxylation
-
A simple and effective procedure for the enantioselective synthesis of several β-adrenergic blocking agents incorporating the first asymmetric synthesis of celiprolol, is described. The key steps are (i) sharpless asymmetric dihydroxylation of aryl allyl ethers to introduce chirality into the molecules and (ii) conversion of cyclic sulfates into the corresponding epoxides using a three-step procedure.
- Sayyed, Iliyas A.,Thakur, Vinay V.,Nikalje, Milind D.,Dewkar, Gajanan K.,Kotkar,Sudalai
-
p. 2831 - 2838
(2007/10/03)
-
- New chemoenzymatic pathway for β-adrenergic blocking agents
-
The lipase mediated kinetic resolution of pharmaceutically important β-hydroxy nitriles is described in high enantiomeric excesses and good yields. Some of the chiral β-hydroxy nitriles have been employed in the synthesis of β-adrenergic blocking agents such as propranolol, alprenolol and moprolol. This protocol has also been extended for the enantiopure preparation of 5-(4-tosyloxymethyl)-1,3-oxazolidine-2-one and 3-hydroxy-4-tosyloxybutanenitrile, chiral intermediates of high synthetic value.
- Kamal, Ahmed,Khanna, G.B. Ramesh,Krishnaji,Tekumalla, Venkatesh,Ramu
-
p. 1485 - 1494
(2007/10/03)
-
- Hydrolytic kinetic resolution of α-naphthyl glycidyl ether: A practical access to highly enantioselective β-adrenergic blocking agents
-
Kinetic resolution of (±)-naphthyl glycidyl ether using 0.5 mol% (R,R)-salen Co(III)OAc and water (0.55 equiv) provided enantiomerically pure naphthyl glycidyl ether and 1-naphthylglycerol derivatives with high enantiomeric excess. Application of this approach to highly enantioenriched (S)-naftopidil and (S)-propranolol is described. Georg Thieme Verlag Stuttgart.
- Subhas Bose,Narsimha Reddy,Chavhan, Sanjay W.
-
p. 2345 - 2348
(2007/10/03)
-
- Chemoenzymatic synthesis of (S) and (R)-propranolol and sotalol employing one-pot lipase resolution protocol
-
Synthesis of both enantiomers of biologically active propranolol and sotalol has been achieved in high optical purity by one-pot reduction of 3 and 7 followed by in situ lipase resolution of the respective chlorohydrins. Pseudomonas cepacia lipase immobilized on ceramic particles (PS-C) provided the chlorohydrin and acetate, which on nucleophilic substitution with isopropyl amine afforded the target amino alcohols in high enantioselectivity under mild reaction conditions.
- Kamal, Ahmed,Sandbhor, Mahendra,Ali Shaik, Ahmad
-
p. 4581 - 4583
(2007/10/03)
-
- Asymmetric catalytic synthesis of enantiopure N-protected 1,2-amino alcohols
-
(Chemical Equation Presented) The asymmetric aminolytic kinetic resolution (AKR) of racemic terminal epoxides using carbamates as the nucleophile catalyzed by (salen)CoIII complex provides a practical and straightforward method for the synthesis of both aliphatic and aromatic N-Boc- or N-Cbz-protected 1,2-amino alcohols in almost enantiomerically pure form (ee ≥ 99%). The AKR uses an easily accessible catalyst and inexpensive starting materials, and the reactions are conveniently carried out at room temperature under an air atmosphere.
- Bartoli, Giuseppe,Bosco, Marcella,Carlone, Armando,Locatelli, Manuela,Melchiorre, Paolo,Sambri, Letizia
-
p. 3973 - 3975
(2007/10/03)
-
- Application of cyclam-capped β-cyclodextrin-bonded silica particles as a chiral stationary phase in capillary electrochromatography for enantiomeric separations
-
Two novel types of substituted cyclam-capped β-cyclodextrin (β-CD)-bonded silica particles have been prepared and used as chiral stationary phases in capillary electrochromatography (CEC). The two stationary phases have a chiral selector with three recognition sites: β-CD, cyclam, and the latter's sidearm. They exhibit excellent enantioselectivities in CEC for a wide range of compounds as a result of the cooperative functioning of the anchored β-CD and cyclam. After inclusion of the metal ion (Ni2+) from the running buffer into the substituted cyclams and their sidearm ligands, the bonded stationary phases become positively charged and can provide extra electrostatic interactions with ionizable solutes and enhance the dipolar interactions with some polar neutral solutes. This enhances the host-guest interaction with some solutes and improves chiral recognition and enantioselectivity. These new types of stationary phases exhibit great potential for fast chiral separations in CEC.
- Gong, Yinhan,Lee, Hian Kee
-
p. 1348 - 1354
(2007/10/03)
-
- Nucleophilic reaction of glycidol tosylate and the corresponding cyclic sulfate with various nucleophiles: A comparative study
-
The nucleophilic reaction of glycidol tosylate and the corresponding cyclic sulfate tosylate have been carried out with a number of nucleophiles to study the possible attack of nucleophiles at C1, C2 or C3 positions. The regioselectivity and reactivity of both the substrates i.e. epoxide tosylate 1 and the corresponding cyclic sulfate 2 have been compared and established that under similar conditions cyclic sulfate counterpart shows better regioselectivity and better reactivity than the corresponding epoxide.
- Lohray,Rajesh,Bhushan
-
p. 586 - 592
(2007/10/03)
-
- Dynamic kinetic resolution of β-azido alcohols. An efficient route to chiral aziridines and β-amino alcohols
-
Enzymatic resolution of β-azido alcohols in combination with ruthenium-catalyzed alcohol isomerization led to a successful dynamic kinetic resolution. A variety of racemic β-azido alcohols were efficiently transformed to the corresponding enantiomerically pure acetates (ee up to 99% and conversion up to 98%). The synthetic utility of this procedure has been illustrated by the practical synthesis of (S)-propanolol I and (R)-β-azido-α-(4-methoxyphenyl)ethanol ((R)-1c), a direct precursor of denopamine II.
- Pamies,Baeckvall
-
p. 4022 - 4025
(2007/10/03)
-
- Enantioselective synthesis of β-hydroxy amines and aziridines using asymmetric transfer hydrogenation of α-amino ketones
-
Enantioselective transfer hydrogenation of α-amino ketones is an effective method for the asymmetric synthesis of β-hydroxy amines and aziridines.
- Kawamoto,Wills
-
p. 1916 - 1928
(2007/10/03)
-
- Biotransformations with Rhizopus arrhizus and Geotrichum candidum for the preparation of (S)-atenolol and (S)-propranolol
-
(±)-Atenolol/(±)-propranolol and their acetates were incubated with the fungus Rhizopus arrhizus and Geotrichum candidum separately for different time intervals to afford (S)-atenolol/(S)-propranolol in good optical yield. The time and pH for this biotransformation was optimised. The present biodegradations using Rhizopus arrhizus and Geotrichum candidum provides a simple and useful method to obtain (S)-atenolol and (S)-propranolol which are active enantiomers of the β-adrenergic blockers. Copyright (C) 2000 Elsevier Science Ltd.
- Damle, Subhash V.,Patil, Prashant N.,Salunkhe, Manikrao M.
-
p. 2067 - 2070
(2007/10/03)
-