- Ligand-Free Copper-Catalyzed Ullmann-Type C?O Bond Formation in Non-Innocent Deep Eutectic Solvents under Aerobic Conditions
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An efficient and novel protocol was developed for a Cu-catalyzed Ullmann-type aryl alkyl ether synthesis by reacting various (hetero)aryl halides (Cl, Br, I) with alcohols as active components of environmentally benign choline chloride-based eutectic mixtures. Under optimized conditions, the reaction proceeded under mild conditions (80 °C) in air, in the absence of additional ligands, with a catalyst [CuI or CuII species] loading up to 5 mol% and K2CO3 as the base, providing the desired aryloxy derivatives in up to 98 % yield. The potential application of the methodology was demonstrated in the valorization of cheap, easily available, and naturally occurring polyols (e. g., glycerol) for the synthesis of some pharmacologically active aryloxypropanediols (Guaiphenesin, Mephenesin, and Chlorphenesin) on a 2 g scale in 70–96 % yield. Catalyst, base, and deep eutectic solvent could easily and successfully be recycled up to seven times with an E-factor as low as 5.76.
- Capriati, Vito,García-álvarez, Joaquín,Marinò, Manuela,Perna, Filippo M.,Quivelli, Andrea Francesca,Vitale, Paola
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- Highly regio- and enantio-selective hydrolysis of two racemic epoxides by GmEH3, a novel epoxide hydrolase from Glycine max
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A novel epoxide hydrolase from Glycine max, designated GmEH3, was excavated based on the computer-aided analysis. Then, gmeh3, a GmEH3-encoding gene, was cloned and successfully expressed in E. coli Rosetta(DE3). Among the ten investigated rac-epoxides, GmEH3 possessed the highest and best complementary regioselectivities (regioselectivity coefficients, αS = 93.7% and βR = 97.2%) in the asymmetric hydrolysis of rac-m-chlorostyrene oxide (5a), and the highest enantioselectivity (enantiomeric ratio, E = 55.6) towards rac-phenyl glycidyl ether (7a). The catalytic efficiency (kcatS/KmS = 2.50 mM?1 s?1) of purified GmEH3 for (S)-5a was slightly higher than that (kcatR/KmR = 1.52 mM?1 s?1) for (R)-5a, whereas the kcat/Km (5.16 mM?1 s?1) for (S)-7a was much higher than that (0.09 mM?1 s?1) for (R)-7a. Using 200 mg/mL wet cells of E. coli/gmeh3 as the biocatalyst, the scale-up enantioconvergent hydrolysis of 150 mM rac-5a at 25 °C for 1.5 h afforded (R)-5b with 90.2% eep and 95.4% yieldp, while the kinetic resolution of 500 mM rac-7a for 2.5 h retained (R)-7a with over 99% ees and 43.2% yields. Furthermore, the sources of high regiocomplementarity of GmEH3 for (S)- and (R)-5a as well as high enantioselectivity towards rac-7a were analyzed via molecular docking (MD) simulation.
- Zhang, Chen,Li, Chuang,Zhu, Xiu-xiu,Liu, You-yi,Zhao, Jun,Wu, Min-chen
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p. 2795 - 2803
(2020/09/01)
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- MnIII Porphyrins: Catalytic Coupling of Epoxides with CO2 under Mild Conditions and Mechanistic Considerations
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A series of 5,10,15,20-tetrakis(2,3-dichlorophenyl)porphyrinate complexes of manganese(III) [MnIII(T2,3DCPP)X] with six different axial ligands (X=NO3 ?, AcO?, IO3 ?, Br?, Cl?, HO?) were investigated as catalysts in the cycloaddition reactions of CO2 and styrene oxide (SO), under mild conditions, i. e., atmospheric pressure and 60 °C. [MnIIIT(2,3DCPP)IO3] showed the best catalytic performance, selectively producing the respective cyclic carbonate from diverse epoxides using tetrabutylammonium bromide as a nucleophile source. Mechanistic considerations were inferred from electronic spectra and spectrophotometric titrations, showing that there are a series of equilibriums involved in the formation of the catalytic active species. Stability constants for the proposed equilibrium models were determined using SQUAD software. A catalytic cycle has been proposed based on those observations.
- Milani, Jorge L. S.,Meireles, Alexandre M.,Bezerra, Werberson A.,Martins, Dayse. C. S.,Cangussu, Danielle,das Chagas, Rafael P.
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p. 4393 - 4402
(2019/08/01)
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- Asymmetric hydrolysis of styrene oxide by PvEH2, a novel Phaseolus vulgaris epoxide hydrolase with extremely high enantioselectivity and regioselectivity
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A novel EH from Phaseolus vulgaris, PvEH2, was discovered based on the computer-aided analysis, and its encoding gene was cloned and expressed in E. coli Rossetta (DE3). The substrate spectrum of recombinant (re) PvEH2 was assayed, among which the enantiomeric ratio of rePvEH2 towards racemic styrene oxide (rac-1a) was > 200, while its regioselectivity coefficients, αS and βR, towards (S)- and (R)-1a were 99.1 and 69.8%, respectively. The asymmetric hydrolysis of 20 mM rac-1a by rePvEH2-expressing whole cells was performed at 25 °C, retaining (R)-1a with > 99.5% ees and 49.4% yield and producing (R)-phenyl-1,2-ethanediol (1b) with 96.2% eep and 49.7% yield in 40 min.
- Li, Chuang,Hu, Die,Zong, Xun-Cheng,Deng, Chao,Feng, Lei,Wu, Min-Chen,Li, Jian-Fang
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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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- Stereoselective Hydrolysis of Epoxides by reVrEH3, a Novel Vigna radiata Epoxide Hydrolase with High Enantioselectivity or High and Complementary Regioselectivity
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To provide more options for the stereoselective hydrolysis of epoxides, an epoxide hydrolase (VrEH3) gene from Vigna radiata was cloned and expressed in Escherichia coli. Recombinant VrEH3 displayed the maximum activity at pH 7.0 and 45 °C and high stability at pH 4.5-7.5 and 55 °C. Notably, reVrEH3 exhibited high and complementary regioselectivity toward styrene oxides 1a-3a and high enantioselectivity (E = 48.7) toward o-cresyl glycidyl ether 9a. To elucidate these interesting phenomena, the interactions of the three-dimensional structure between VrEH3 and enantiomers of 1a and 9a were analyzed by molecular docking simulation. Using E. coli/vreh3 whole cells, gram-scale preparations of (R)-1b and (R)-9a were performed by enantioconvergent hydrolysis of 100 mM rac-1a and kinetic resolution of 200 mM rac-9a in the buffer-free water system at 25 °C. These afforded (R)-1b with >99% eep and 78.7% overall yield after recrystallization and (R)-9a with >99% ees, 38.7% overall yield, and 12.7 g/L/h space-time yield.
- Hu, Die,Tang, Cunduo,Li, Chuang,Kan, Tingting,Shi, Xiaoling,Feng, Lei,Wu, Minchen
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p. 9861 - 9870
(2017/11/22)
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- A PROPYL-PHENYL-ETHER DERIVATIVE, AND MELANOGENESIS INHIBITOR, SKIN-LIGHTENING AGENT, ANTIMICROBIAL AGENT AND COSMETIC CONTAINING SAID PROPYL-PHENYL-ETHER DERIVATIVE
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Provided is a compound that exhibits an excellent melanogenesis-inhibiting effect (skin-lightening effect), exhibits an excellent antimicrobial effect, excels in terms of temporal stability and the like, and is suitable for use as an ingredient of a cosmetic. Said compound is a propyl-phenyl-ether derivative compound comprising a propyl group that has a substituent such as a hydroxyl group and is bound to the hydroxyl group of a phenol group that has a substituent such as a tert-butyl group. A melanogenesis inhibitor, skin-lightening agent, and antimicrobial agent containing the aforementioned compound as an active ingredient are also provided, as is a cosmetic characterized by containing said compound.
- -
-
Paragraph 0158-0160
(2016/12/12)
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- Three different types of chirality-driven crystallization within the series of uniformly substituted phenyl glycerol ethers
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Seven chiral arylglycerol ethers 2-R-C6H4-O-CH2CH(OH)CH2OH (R 5 H, Me, Et, Allyl, n-Pr, i-Pr, tert-Bu) were synthesized in racemic and scalemic form. The IR spectra, melting points, and enthalpies of fusion for racemic and scalemic samples of every species were measured, the entropies of enantiomers mixing in the liquid state and Gibbs free energies of a racemic compound formation were derived and binary phase diagrams were reconstructed for the whole family. Solid racemic compounds stabilities were ranked for the four substances. Spontaneous resolution was established for the registered chiral drug mephenesin and its ethyl analogue. Metastable anomalous conglomerate, forming crystals having three independent R and one independent S molecules in the unit cell, is formed during solution crystallization of tert-butyl derivative; metastable phase transforms slowly into traditional racemic conglomerate. Chirality 20:1092-1103, 2008.
- Bredikhin, Alexander A.,Bredikhina, Zemfira A.,Novikova, Victorina G.,Pashagin, Alexander V.,Zakharychev, Dmitry V.,Gubaidullin, Aidar T.
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p. 1092 - 1103
(2015/02/05)
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- Asymmetric hydrolytic kinetic resolution with recyclable polymeric Co(iii)-salen complexes: A practical strategy in the preparation of (S)-metoprolol, (S)-toliprolol and (S)-alprenolol: Computational rationale for enantioselectivity
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A series of chiral polymeric Co(iii)-salen complexes based on a number of achiral and chiral linkers were synthesized and their catalytic performances were assessed in the asymmetric hydrolytic kinetic resolution of terminal epoxides. The effects of the linker were judiciously studied and it was found that in the case of the chiral BINOL-based polymeric salen complex 1, there was an enrichment in catalyst reactivity and enantioselectivity of the unreacted epoxide, particularly in the case of short as well as long chain aliphatic epoxides. Good isolated yields of the unreacted epoxide (up to 46% compared to 50% theoretical yield) along with high enantioselectivity (up to 99%) were obtained in most cases using catalyst 1. Further studies showed that catalyst 1 could retain its catalytic activity for six cycles under the present reaction conditions without any significant loss in activity or enantioselectivity. To show the practical applicability of the above synthesized catalyst we have synthesised some potent chiral β-blockers in moderate yield and high enantioselectivity using complex 1. The DFT (M06-L/6-31+G??//ONIOM(B3LYP/6-31G?:STO-3G)) calculations revealed that the chiral BINOL linker influences the enantioselectivity achieved with Co(iii)-salen complexes. Further, the transition state calculations show that the R-BINOL linker with the (S,S)-Co(iii)-salen complex is energetically preferred over the corresponding S-BINOL linker with the (S,S)-Co(iii)-salen complex for the HKR of 1,2-epoxyhexane. The role of non-covalent C-H?π interactions and steric effects has been discussed to control the HKR reaction of 1,2-epoxyhexane.
- Roy, Tamal,Barik, Sunirmal,Kumar, Manish,Kureshy, Rukhsana I.,Ganguly, Bishwajit,Khan, Noor-Ul H.,Abdi, Sayed H. R.,Bajaj, Hari C.
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p. 3899 - 3908
(2015/02/19)
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- One-pot synthesis of aryloxypropanediols from glycerol: Towards valuable chemicals from renewable sources
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Glycerol offers an easy and green route for the synthesis of aryloxypropanediols of known pharmacological activity. Glycerol is selectively converted to aryloxypropanediols in a one-pot reaction, through in situ formed glycerol carbonate, under benign and solvent-free conditions. Catalyst and unreacted reagent can be recycled.
- Truscello, Ada M.,Gambarotti, Cristian,Lauria, Mirvana,Auricchio, Sergio,Leonardi, Gabriella,Shisodia, Suresh U.,Citterio, Attilio
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supporting information
p. 625 - 628
(2013/03/29)
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- Guaifenesin derivatives promote neurite outgrowth and protect diabetic mice from neuropathy
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In diabetic patients, an early index of peripheral neuropathy is the slowing of conduction velocity in large myelinated neurons and a lack of understanding of the basic pathogenic mechanisms hindered therapeutics development. Racemic (R/S)-guaifenesin (1) was identified as a potent enhancer of neurite outgrowth using an in vitro screen. Its R-enantiomer (R)-1 carried the most biological activity, whereas the S-enantiomer (S)-1 was inactive. Focused structural variations to (R/S)-1 was conducted to identify potentially essential groups for the neurite outgrowth activity. In vivo therapeutic studies indicated that both (R/S)-1 and (R)-1 partially prevented motor nerve conduction velocity slowing in a mouse model of type 1 diabetes. In vitro microsomal assays suggested that compounds (R)-1 and (S)-1 are not metabolized rapidly, and PAMPA assay indicated moderate permeability through the membrane. Findings revealed here could lead to the development of novel drugs for diabetic neuropathy.
- Hadimani, Mallinath B.,Purohit, Meena K.,Vanampally, Chandrashaker,Van Der Ploeg, Randy,Arballo, Victor,Morrow, Dwane,Frizzi, Katie E.,Calcutt, Nigel A.,Fernyhough, Paul,Kotra, Lakshmi P.
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p. 5071 - 5078
(2013/07/26)
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- Synergistic dual activation catalysis by palladium nanoparticles for epoxide ring opening with phenols
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Synergistic dual activation catalysis has been devised for epoxide phenolysis wherein palladium nanoparticles induce electrophilic activation via coordination with the epoxide oxygen followed by nucleophilic activation through anion-π interaction with the aromatic ring of the phenol, and water (reaction medium) also renders assistance through 'epoxide-phenol' dual activation.
- Seth, Kapileswar,Roy, Sudipta Raha,Pipaliya, Bhavin V.,Chakraborti, Asit K.
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supporting information
p. 5886 - 5888
(2013/07/25)
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- Chiral nanoporous metal-metallosalen frameworks for hydrolytic kinetic resolution of epoxides
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Chiral nanoporous metal-organic frameworks are constructed by using dicarboxyl-functionalized chiral Ni(salen) and Co(salen) ligands. The Co(salen)-based framework is shown to be an efficient and recyclable heterogeneous catalyst for hydrolytic kinetic resolution (HKR) of racemic epoxides with up to 99.5% ee. The MOF structure brings Co(salen) units into a highly dense arrangement and close proximity that enhances bimetallic cooperative interactions, leading to improved catalytic activity and enantioselectivity in HKR compared with its homogeneous analogues, especially at low catalyst/substrate ratios.
- Zhu, Chengfeng,Yuan, Guozan,Chen, Xu,Yang, Zhiwei,Cui, Yong
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supporting information; experimental part
p. 8058 - 8061
(2012/07/14)
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- An unusual (R)-selective epoxide hydrolase with high activity for facile preparation of enantiopure glycidyl ethers
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A novel epoxide hydrolase (BMEH) with unusual (R)-enantioselectivity and very high activity was cloned from Bacillus megaterium ECU1001. Highest enantioselectivities (E>200) were achieved in the bioresolution of ortho-substituted phenyl glycidyl ethers and para-nitrostyrene oxide. Worthy of note is that the substrate structure remarkably affected the enantioselectivities of the enzyme, as a reversed (S)-enantiopreference was unexpectedly observed for the ortho-nitrophenyl glycidyl ether. As a proof-of-concept, five enantiopure epoxides (>99% ee) were obtained in high yields, and a gram-scale preparation of (S)-ortho-methylphenyl glycidyl ether was then successfully performed within a few hours, indicating that BMEH is an attractive biocatalyst for the efficient preparation of optically active epoxides. Copyright
- Zhao, Jing,Chu, Yan-Yan,Li, Ai-Tao,Ju, Xin,Kong, Xu-Dong,Pan, Jiang,Tang, Yun,Xu, Jian-He
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experimental part
p. 1510 - 1518
(2011/08/03)
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- Bacillus alcalophilus MTCC10234 catalyzed enantioselective kinetic resolution of aryl glycidyl ethers
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The phenyl glycidyl ether derivatives have been kinetically resolved with the growing cells of Bacillus alcalophilus MTCC10234 yielding (S)-epoxides with up to >99% ee and (R)-diols with up to 89% ee. The enantiomeric ratio (E) of up to 67 has been obtained for biohydrolysis process. The effect of different substituents of phenyl glycidyl ether on the biocatalytic efficiency of B. alcalophilus MTCC10234 showed preference for methyl- and chloro-substituted aryl glycidyl ether derivatives whereas nitro-derivatives were transformed at a slower rate. 2,6-Dimethylphenyl glycidyl ether which contains a bulky aryl group having methyl group on both the ortho positions was resolved with an E=39.
- Bala, Neeraj,Chimni, Swapandeep Singh,Saini, Harvinder Singh,Chadha, Bhupinder Singh
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experimental part
p. 128 - 134
(2010/10/04)
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- Directed evolution of an enantioselective epoxide hydrolase: Uncovering the source of enantioselectivity at each evolutionary stage
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Directed evolution of enzymes as enantioselective catalysts in organic chemistry is an alternative to traditional asymmetric catalysis using chiral transition-metal complexes or organocatalysts, the different approaches often being complementary. Moreover, directed evolution studies allow us to learn more about how enzymes perform mechanistically. The present study concerns a previously evolved highly enantioselective mutant of the epoxide hydrolase from Aspergillus niger in the hydrolytic kinetic resolution of racemic glycidyl phenyl ether. Kinetic data, molecular dynamics calculations, molecular modeling, inhibition experiments, and X-raystructural work for the wild-type (WT) enzyme and the best mutant revea l the basis of the large increase in enantioselectivity (E = 4.6 versus E = 115). The overall structures of the WT and the mutant are essentially identical, but dramatic differences are observed in the active site asrevealed by the X-ray structures. All of the experimental and computati onal results support a model in which productive positioning of the preferred (S)-glycidyl phenyl ether, but not the (R)-enantiomer, forms the basis of enhanced enantioselectivity. Predictions regarding substrate scope and enantioselectivity of the best mutant are shown to be possible.
- Reetz, Manfred T.,Bocola, Marco,Wang, Li-Wen,Sanchis, Joaquin,Cronin, Annette,et al.
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supporting information; experimental part
p. 7334 - 7343
(2009/10/17)
-
- Jacobsen-type enantioselective hydrolysis of aryl glycidyl ethers. 31P NMR analysis of the enantiomeric composition of oxiranes
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The enantioselective partial hydrolysis of a number of racemic aryl glycidyl ethers in the presence of chiral Co(salen)-catalyst was studied. The enantiomeric composition of the isolated (R)-aryl glycidyl ethers was analyzed by 31P NMR using optically active substituted 2-chloro-1,3,2- dioxaphospholanes. A synthesis of β-adrenoblocking agents (S)-toliprolol and (S)-moprolol based on the simultaneously obtained (S)-3-aryloxypropane-1,2- diols was proposed.
- Bredikhin,Strunskaya,Novikova,Azancheev,Sharafutdinova,Bredikhina
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p. 213 - 218
(2007/10/03)
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- Cardiovascular hybrid drugs: New benzazepinone derivatives as bradycardic agents endowed with selective β1-Non-competitive antagonism
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The synthesis and pharmacological profile of some hybrid compounds bearing both the benzazepinone moiety present in Zatebradine and typical β-blocker aryloxypropanolamine groups are described. The new compounds proved to be endowed with negative chronotropic and inotropic activity and are weak vasorelaxant agents. The cardiodepressant action is probably due to selective β1-noncompetitive reversible antagonism. Both enantiomers of the most active compound 5c were synthesized and they showed a different cardiovascular profile, that is (+)-(R)-enantiomer displays affinity for cardiac β1-adrenoceptors, while (-)-(S)-enantiomer shows specificity for vessel smooth muscle.
- Bisi, Alessandra,Rampa, Angela,Budriesi, Roberta,Gobbi, Silvia,Belluti, Federica,Ioan, Pierfranco,Valoti, Ermanno,Chiarini, Alberto,Valenti, Piero
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p. 1353 - 1361
(2007/10/03)
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- Systematic search for conglomerates among glycerol aromatic monoethers: Guaifenesin and mephenesin are the cases
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Within the family of biologically active 3-aryloxy-1,2-propanediols, three new conglomerate-forming compounds have been found and resolved into enantiomers using the entrainment procedure.
- Bredikhin, Alexander A.,Bredikhina, Zemfira A.,Lazarev, Sergey N.,Savel'ev, Dmitry V.
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p. 104 - 105
(2007/10/03)
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- Synthesis of [14C]-Labelled glycidyl and glycerol ethers of aliphatic and aromatic alcohols.
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The synthesis of [14C]-labelled glycidyl ethers and the corresponding glycerol ethers is described for the monofunctional compounds 1-dodecanol and ortho-cresol and the bifunctional compounds 4,4'-dihydroxy-3,3',5,5'-tetramethyl biphenyl and 1,6-hexanediol. The synthesis is based on reaction between the alcohol and [U-14C]-epichlorohydrin. The aromatic compounds have been converted to the corresponding glycidyl ethers by using sodium hydroxide and the aliphatic compounds by using tin(IV) chloride as a catalyst. Thus radio-labelled glycidyl ethers were obtained in yields between 50-80, with a chemical purity of > 92 and a radiochemical purity of > 95 by HPLC. The specific activities of the glycidyl ethers were approximately 0.2 mCi/mmol for the monofunctional compounds and approximately 0.4 mCi/mmol for the bifunctional compounds.
- Van Elburg,Ormskerk,De Kloe,Boogaard
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p. 147 - 167
(2007/10/03)
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- Dermal penetration and metabolism of five glycidyl ethers in human, rat and mouse skin
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1. Glycidyl ethers (GE), an important class of industrial chemicals, are considered to be potentially mutagenic in vivo because some GE have been shown to be direct mutagens in short-term in vitro tests. 2. The percutaneous penetration and metabolism of representatives of different classes of GE was studied in the fresh, full-thickness C3H mouse, and dermatomed human and Fisher 344 rat skin to determine th apparent permeability constants, lag times and metabolic profiles. 3. Five different GE, the diglycidyl ethers of bisphenol A (BADGE), 4,4'-dihydroxy-3,3',5,5'-tetramethylbiphenyl (Epikote YX4000) and 1,6-hexanediol (HDDGE) and the GE of 1-dodecanol (C12GE) and o-cresol (o-CGE), were synthesized by reaction of their alcohols with epichlorohydrin. Their radiolabelled analogues were synthesized with a 14C-label using [U-14C]-epichlorohydrin. 4. There was a large variation (four orders of magnitude) in percutaneous penetration between the five GE. In general, penetration through full-thickness mouse skin was higher than through dermatomed rat skin, whereas dermatomed human skin was the least permeable. The permeability increased in the order YX4000 12GE 12GE and o-CGE penetrated the skin unchanged. For o-CGE, but none of the other GE, the percentage of the applied dose that penetrated the skin unchanged increased over time. 7. The large variation in response observed with the five selected GE indicates that GE should not be considered as a single class of compounds but rather on the basis of their individual properties.
- Boogaard,Denneman,Van Sittert
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p. 469 - 483
(2007/10/03)
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- Metabolic inactivation of five glycidyl ethers in lung and liver of humans, rats and mice in vitro
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1. Some glycidyl ethers (GE) have been shown to be direct mutagens in short-term in vitro tests and consequently GE are considered to be potentially mutagenic in vivo. However, GE may be metabolically inactivated in the body by two different enzymatic routes: conjugation of the epoxide moiety with the endogenous tripeptide glutathione (GSH) catalysed by glutathione S-transferase (GST) or hydrolysis of the epoxide moiety catalysed by epoxide hydrolase (EH). 2. The metabolic inactivation of five different GE, the diglycidyl ethers of bisphenol A (BADGE), 4,4'-dihydroxy-3,3',5,5'-tetramethylbiphenyl (Epikote YX4000) and 1,6-hexanediol (HDDGE) and the GE of 1-dodecanol (C12GE) and o-cresol (o-CGE), has been studied in subcellular fractions of human, C3H mouse and F344 rat liver and lung. 3. All GE were chemically very stable and resistant to aqueous hydrolysis, but were rapidly hydrolysed by EH in cytosolic and microsomal fractions of liver and lung. The aromatic GE were very good substrates for EH. In general, microsomal EH is more efficient than cytosolic EH in hydrolysis of GE, and human microsomes are more efficient than rodent microsomes. 4. The more water-soluble GE, o-CGE and HDDGE, were good substrates for GST whereas the more lipophilic GE, YX4000 and C12GE, were poor substrates for GST. In general, rodents are more efficient in GSH conjugation of GE than humans. 5. In general, the epoxide groups of YX4000 are the most and those of HDDGE the least efficiently inactivated of the five GE under study. For the other three GE no general trend was observed: the relative efficiency of inactivation varied with organ and species. 6. The large variation in metabolism observed with five representative GE indicate that GE have variable individual properties and should not be considered as a single, homogenous class of compounds.
- Boogaard,De Kloe,Bierau,Kuiken,Borkulo,VanSittert
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p. 485 - 502
(2007/10/03)
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- CsF in organic synthesis. Regioselective nucleophilic reactions of phenols with oxiranes leading to enantiopure β-blockers
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The two modes of the paths in the reaction of oxiranes with phenols are completely controlled by CsF. Glycidyl nosylate undergoes exclusive substitution at the C1 position whereas the ring-opening (C-3 attack) occurs with epichlorohydrin, glycidol, and 1,2-epoxyalkanes. These reactions provide convenient access to enantiopure β-blockers.
- Kitaori, Kazuhiro,Furukawa, Yoshiro,Yoshimoto, Hiroshi,Otera, Junzo
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p. 14381 - 14390
(2007/10/03)
-
- Baker's yeast mediated stereoselective biotransformation of 1-acetoxy-3-aryloxypropan-2-ones
-
A series of 1-acetoxy-3-aryloxypropan-2-ones 1a-m were synthesized and subjected to biotransformation by baker's yeast yielding optically active monoacetates 5 or ent-5 and/or diols 4 of moderate to excellent enantiomeric purity. The dependence of the reduction/hydrolysis ratio and stereoselectivity on the size and substitution pattern of the aromatic moiety in the substrate is also discussed.
- Egri, Gabriella,Kolbert, Attila,Balint, Jozsef,Fogassy, Elemer,Novak, Lajos,Poppe, Laszlo
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p. 271 - 283
(2007/10/03)
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- N-Acyl-2-substituted-1,3-thiazolidines, a New Class of Non-narcotic Antitussive Agents: Studies Leading to the Discovery of Ethyl 2--β-oxothiazolidine-3-propanoate
-
The synthesis of a novel class of antitussive agents is described.The compounds were examined for antitussive activity in guinea pig after cough induction by electrical or chemical stimulation.Ethyl 2--β-oxothiazolidine-3-propanoate (BBR 2173, moguisteine, 7) and other structurally related compounds showed a significant level of activity, comparable to that of codeine and dextromethorphan.The compounds presented in this paper are characterized by the N-acyl-2-substituted-1,3-thiazolidine moiety, which is a novel entry in the field of antitussive agents.The serendipitous discovery of the role played by the thiazolidine moiety in the determining the antitussive effect promoted extensive investigations on these structures.This optimization process on N-acyl-2-substituted-1,3-thiazolidines led to the initial identification of 2--3--1,3-thiazolidine (18a) as an interesting lead compound.The careful study of the rapid and very complicated metabolism of 18a provided further insights for the design of newer related derivatives.The observation that the metabolic oxidation on the lateral chain's sulfur of 18a to sulfoxide maintained the antitussive properties suggested the introduction of isosteric functional groups with respect to the sulfoxide moiety.Subsequent structural modifications showed that hydrolyzable malonic residues in the 3-position of the thiazolidine ring were able to assure high antitussive activity.This optimization ultimately led to the selection of moguisteine (7) as the most effective and safest representative of the series.Moguisteine is completely devoid of unwanted side effects (such as sedation and addiction), and its activity was demonstrated also in clinical studies.
- Gandolfi, Carmelo A.,Domenico, Roberto Di,Spinelli, Silvano,Gallico, Licia,Fiocchi, Luigi,et al.
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p. 508 - 525
(2007/10/02)
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- A Practical Synthetic Route to Enantiopure 3-Aryloxy-1,2-propanediols from Chiral Glycidol
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Chiral 3-aryloxy-1,2-propanediols of >98percent ee can be obtained in high yield by the nucleophilic addition of substituted phenols to chiral glycidol in the presence of triethylamine catalyst followed by recrystallization in absolute ethanol.Several enantiopure compounds of pharmaceutical significance are presented as examples.
- Chen, Jian,Shum, Wilfred
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p. 2379 - 2380
(2007/10/02)
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- Kinetic resolution of acyclic 1,2-diols using a sequential lipase- catalyzed transesterification in organic solvents
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A method for the kinetic resolution of 3-(aryloxy)-1,2-propanediols rac- 1a-n without additional protection-deprotection steps using a lipase- catalyzed sequential transesterification with lipase amano PS has been developed. In the first step of this one-pot procedure the racemic 1,2-diols are acylated regioselectively at the primary hydroxy group without enantioselection. The subsequent acylation at the secondary hydroxy group of the formed primary monoacetate is responsible for high enantioselection. The enantioselectivity of this transformation depends significantly on the substitution pattern of the aryl ring and the organic solvent used. 3- (Aryloxy)-1,2-propanediols with substituents in the para-position show a much higher enantioselectivity than the corresponding derivatives with ortho- substituents. Among other substrates, the pharmaceuticals Mephenesin, Guaifenesin, and Chlorphenesin have been resolved. The replacement of the aryloxy by an alkyl substituent causes a dramatic decrease of enantioselectivity.
- Theil,Weidner,Ballschuh,Kunath,Schick
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p. 388 - 393
(2007/10/02)
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- Kinetic Resolution of rac-3-(2-Methylphenoxy)propane-1,2-diol (Mephenesin) by Sequential Lipase-Catalyzed Transesterification
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The kinetic resolution of rac-3-(2-methylphenoxy)propane-1,2-diol (rac-1, Mephenesin) by sequential lipase-catalyzed transesterification with vinyl acetate in tetrahydrofuran/triethylamine in the presence of lipase Amano PS is described.
- Theil, Fritz,Ballschuh, Sibylle,Kunath, Annamarie,Schick, Hans
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p. 1031 - 1034
(2007/10/02)
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- Formation of Optically Active Aryloxyacetaldehyde Cyanohydrin Acetates with the Aid of a Microorganism
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Microorganisms that hydrolyze the one enantiomer of dl-phenoxyacetaldehyde cyanohydrin acetate were screened, and Bacillus coagulans isolated from soil was found to be the best.This bacterium was applied to the asymmetric hydrolysis of other aryloxyacetaldehyde derivatives to give satisfactory results.The effect of adding dimethyl sulfoxide to the medium is also described.
- Ohta, Hiromichi,Miyamae, Yoshitaka,Tsuchihashi, Gen-ichi
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p. 215 - 222
(2007/10/02)
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