- EDTA bis-(ethyl phenylalaninate): A novel transition metal-ion chelating hydroxyl radical scavenger with a potential anti-inflammatory role
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Conjugation of ethylenediaminetetraacetic acid (EDTA) to ethyl phenylalaninate generates a novel radical scavenging metal-ion chelator EDTA bis-(ethyl phenylalaninate) (EBEP). The oxidation products o-, m- and p-tyrosine were isolated from hydrolysed, aqueous and aerated solutions containing EBEP, Fe(II) and H2O2. Data obtained demonstrate the potential of EBEP to act as a radical scavenging, iron-ion chelating antioxidant under physiologically relevant conditions.
- Naughton, Declan P.,Grootveld, Martin
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Read Online
- Inhibition of acetylcholinesterase by coumarin-linked amino acids synthetized via triazole associated with molecule partition coefficient
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A previous study for the identification of acetylcholinesterase (AChE) inhibitors demonstrated that the hybrid between tyrosol, the 1,2,3-triazole nucleus, and the coumarin group, namely 7-({1-[2-(4-hydroxyphenyl)ethyl]-1H-1,2,3-triazol-4-yl}methoxy)-4-methyl-2H-chromen-2-one (10), has a high enzyme inhibitory activity. Here, we synthesized analogues of 10 via triazole with pharmacophoric groups represented by tyrosine, phenylalanine, tryptophan, and glycine in addition to evaluating the impact of coumarin-linked amino acids on AChE inhibition. We obtained eight triazoles, six of which are undescribed. In general, the presence of carboxylic acid decreased the inhibitory activity, while aromatic amino acids increased enzymatic inhibition compared to glycine. The derivative containing tyrosine, structurally most similar to 10, presented the lowest inhibition percentage, indicating that phenolic hydroxyl is not the preponderant factor for inhibition. Molecular docking was not enough to explain in vitro experiments. On the other hand, MlogP (logP calculated by the Moriguchi method) was related positively to enzymatic inhibition. To increase the hydrophobicity of the molecules, we tested the esterified triazole derivatives comparatively with the enzyme. The compound ethyl 2-(4-(((4-methyl-2-oxo-2H-chromen-7-yl)oxy)methyl)- 1H-1,2,3-triazol-1-yl)acetate (6) presented an increment of inhibitory activity of 46.97 ± 1.75% at 100 μmol L-1. We also associated the best activity with the lowest van der Waals volume and molar mass values.
- De Sousa, Bianca L.,Leite, Jo?o P.V.,Mendes, Tiago A.O.,Varej?o, Eduardo V.V.,Chaves, Anna C.S.,da Silva, Júnio G.,Agrizzi, Ana P.,Ferreira, Priscila G.,Pilau, Eduardo J.,Silva, Evandro,dos Santos, Marcelo H.
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p. 652 - 664
(2021/02/16)
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- Rh(iii)-Catalyzed diastereoselective transfer hydrogenation: An efficient entry to key intermediates of HIV protease inhibitors
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A highly efficient diastereoselective transfer hydrogenation of α-aminoalkyl α′-chloromethyl ketones catalyzed by a tethered rhodium complex was developed and successfully utilized in the synthesis of the key intermediates of HIV protease inhibitors. With the current Rh(iii) catalyst system, a series of chiral 3-amino-1-chloro-2-hydroxy-4-phenylbutanes were produced in excellent yields and diastereoselectivities (up to 99% yield, up to 99?:?1 dr). Both diastereomers of the desired products could be efficiently accessed by using the two enantiomers of the Rh(iii) catalyst.
- Chen, Gen-Qiang,Lang, Qi-Wei,Phansavath, Phannarath,Ratovelomanana-Vidal, Virginie,Wang, Fangyuan,Wu, Ting,Yin, Congcong,Zhang, Xumu,Zheng, Long-Sheng
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supporting information
p. 3119 - 3122
(2020/03/23)
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- Stereospecific Synthesis of 3,4-Dihydro-2 H-naphtho-1,4-oxazin-2-ones by Unification of Benzoxepine-4-carboxylates with Chiral Amino Acid Ethyl Esters
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A novel and efficient stereocontrolled method has been developed for the preparation of chiral 3,4-dihydro-2H-naphtho[1,2-b][1,4]oxazin-2-ones by the reaction of benzoxepine-4-carboxylates with chiral amino acid ethyl esters for the first time. The chiral 3,4-dihydro-2H-naphtho-1,4-oxazinones have been achieved in one step by the formation of C-N, C-C, and C-O bonds.
- Bhimapaka, China Raju,Kasagani, Veera Prasad,Kurma, Siva Hariprasad
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supporting information
p. 2976 - 2983
(2020/03/23)
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- Reductive Alkylation of Amines with Carboxylic Ortho Esters
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We have demonstrated for the first time that carboxylic ortho esters could be used as an alkylating agent in the reductive alkylation of amines. A variety of amines, including amino acid esters, were alkylated affording mono-alkylated products with high selectivity in practical to high yields using standard heterogeneous catalysts. By applying acyclic ortho esters alkylation was completed at room temperature. (Figure presented.).
- Kadyrov, Renat,Moebus, Konrad
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supporting information
p. 3352 - 3357
(2020/07/04)
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- OX2R COMPOUNDS
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Methods and compositions for agonizing a type-2 orexin receptor (OX2R) in a cell determined to be in need thereof, including the general method of (a) administering to a subject a cyclic guanidinyl OX2R agonist and (b) detecting a resultant enhanced wakefulness or increased resistance to diet-induced accumulation of body fat, or abbreviated recovery from general anesthesia or jet lag.
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Paragraph 0475; 0476; 0516; 0519
(2019/10/19)
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- Synthesis of DiN-substituted glycyl-phenylalanine derivatives by using Ugi four component reaction and their potential as acetylcholinesterase inhibitors
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Ugi four component reaction (Ugi-4CR) isocyanide-based multicomponent reactions were used to synthesize diN-substituted glycyl-phenylalanine (diNsGF) derivatives. All of the synthesized compounds were characterized by spectroscopic and spectrometric techniques. In order to evaluate potential biological applications, the synthesized compounds were tested in computational models that predict the bioactivity of organic molecules by using only bi-dimensional molecular information. The diNsGF derivatives were predicted as cholinesterase inhibitors. Experimentally, all of the synthesized diNsGF derivatives showed moderate inhibitory activities against acetylcholinesterase (AChE) and poor activities against butyrylcholinesterase (BuChE). Compound 7a has significant activity and selectivity against AChE, which reveals that the diNsGF scaffold could be improved to reach novel candidates by combining other chemical components of the Ugi-4CR in a high-throughput combinatorial screening experiment. Molecular docking experiments of diNsGF derivatives inside AChE suggest that these compounds placed the phenylalanine group at the peripheral site of AChE. The orientations and chemical interactions of diNsGF derivatives were analyzed, and the changeable groups were identified for future exploration of novel candidates that could lead to the improvement of diNsGF derivative inhibitory activities.
- Prent-Pe?aloza, Luis,De La Torre, Alexander F.,Velázquez-Libera, José L.,Gutiérrez, Margarita,Caballero, Julio
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- Synthesis, self-assembly, bacterial and fungal toxicity, and preliminary biodegradation studies of a series of l-phenylalanine-derived surface-active ionic liquids
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We report for the first time a comprehensive study on the synthesis (supported by green chemistry metrics), aggregation properties, bacterial/fungal toxicities and preliminary data on biodegradation of a series of 24 l-phenylalanine derived surface-active ionic liquids (SAILs). The various cationic headgroups included pyridinium, imidazolium, and cholinium groups and enabled a comprehensive analysis of the effect of the alkyl ester chain (from C2 to C16) on the synthesis, toxicity, biodegradability, and surfactant properties of the novel SAILs. The evaluation of the SAILs revealed that a wide variety of properties were strictly dependent on the side chain length, including their bacterial and fungal toxicities (from low toxicity to high toxicity), and aggregation properties. Addition of the l-phenylalanine moiety which connects the lipophilic side chain to the cationic head group results in the phenyl group essentially contributing to the self-assembling properties. The interplay of dispersion interactions of the phenyl ring and the side chain hydrophobicity allows us to rank the novel SAILs (thus identifying the remarkable ones) as compared to other surfactants. The CMC values for the SAILs reported in this study are significantly (up to 10 times) lower than those reported for conventional surfactants with the same length of the side chain. Adsorption and micellization are among the factors affecting the toxicity of the studied SAILs. Preliminary biodegradation studies have shown that no clear trend was observed when comparing the closed bottle test results of the SAIL C2 and C10 derivatives. Medium chain length (C6 to C8) pyridinium SAILs have been recommended as the most prospective green alternatives for conventional cationic surfactants. These findings can contribute to designing new efficient amphiphiles with optimized antimicrobial activities and to employ them as potential environmentally benign mineralisable surfactants.
- Kapitanov, Illia V.,Jordan, Andrew,Karpichev, Yevgen,Spulak, Marcel,Perez, Lourdes,Kellett, Andrew,Kümmerer, Klaus,Gathergood, Nicholas
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supporting information
p. 1777 - 1794
(2019/04/08)
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- Ionic liquids with methotrexate moieties as a potential anticancer prodrug: Synthesis, characterization and solubility evaluation
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The technological utility of active pharmaceutical ingredients (APIs) is enormously improved when they are converted into ionic liquids (ILs). API-ILs possess better aqueous solubility and thermal stability than that of solid-state salt or crystalline drugs. However, many such API-ILs are not biocompatible or biodegradable. In the current study, we synthesized a series of IL-APIs using methotrexate (MTX), a potential anticancer prodrug, and biocompatible IL-forming cations (choline and amino acid esters). The MTX-IL moieties were characterized through 1H NMR, FTIR, p-XRD, DSC and thermogravimetric analysis. The solubility of the MTX-ILs was evaluated in simulated body fluids (phosphate-buffered saline, simulated gastric, and simulated intestinal fluids). An assessment of the in vitro antitumor activity of the MTX-ILs in a mammalian cell line (HeLa cells) was used to evaluate their cytotoxicity. The MTX-ILs showed aqueous solubility at least 5000 times higher than that of free MTX and two orders of magnitude higher compared with that of a sodium salt of MTX in both water and simulated body fluids. Importantly, a proline ethyl ester MTX prodrug showed similar solubility as the MTX sodium salt but it provided improved in vitro antitumor activity. These results clearly suggest that the newly synthesized API-ILs represent promising potential drug formulations.
- Moshikur, Rahman Md.,Chowdhury, Md. Raihan,Wakabayashi, Rie,Tahara, Yoshiro,Moniruzzaman, Muhammad,Goto, Masahiro
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p. 226 - 233
(2019/01/23)
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- Probe compounds for fluorescence recognition of amino acid enantiomers and synthesis and applications thereof
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The invention provides probe compounds for fluorescence recognition of amino acid enantiomers. Probe compounds (a, b, c) are prepared by following steps: dissolving dimethyl squarate into anhydrous methanol, dropwise adding methanol solutions of phenylalanine ethyl ester, phenylalanine benzyl ester, and phenylalanine tert-butyl ester, after addition, stirring the solution for 20 to 24 hours at a room temperature, filtering the solution, and finally washing the filter residues by ethyl acetate several times. When D-proline is added into ethanol-water solutions of chiral probe compounds (a, c),the fluorescence strength of the solutions is reduced; when L-proline is added into the solutions, the fluorescence strength of the solutions is enhanced obviously; and thus the probe compounds (a,c)have a good recognition effect on two enantiomers of proline. When L-valine is added into ethanol-water solutions of the probe compound (b), the fluorescence strength of the solution is obviously reduced; when D-valine is added into the solution, the fluorescence strength of the solution is not changed; and thus the probe compound (b) has a good recognition effect on two enantiomers of valine.
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Paragraph 0026
(2019/01/05)
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- Characterization and cytotoxicity evaluation of biocompatible amino acid esters used to convert salicylic acid into ionic liquids
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The technological utility of active pharmaceutical ingredients (APIs) is greatly enhanced when they are transformed into ionic liquids (ILs). API-ILs have better solubility, thermal stability, and the efficacy in topical delivery than solid or crystalline drugs. However, toxicological issue of API-ILs is the main challenge for their application in drug delivery. To address this issue, 11 amino acid esters (AAEs) were synthesized and investigated as biocompatible counter cations for the poorly water-soluble drug salicylic acid (Sal) to form Sal-ILs. The AAEs were characterized using 1H and 13C NMR, FTIR, elemental, and thermogravimetric analyses. The cytotoxicities of the AAE cations, Sal-ILs, and free Sal were investigated using mammalian cell lines (L929 and HeLa). The toxicities of the AAE cations greatly increased with inclusion of long alkyl chains, sulfur, and aromatic rings in the side groups of the cations. Ethyl esters of alanine, aspartic acid, and proline were selected as a low cytotoxic AAE. The cytotoxicities of the Sal-ILs drastically increased compared with the AAEs on incorporation of Sal into the cations, and were comparable to that of free Sal. Interestingly, the water miscibilities of the Sal-ILs were higher than that of free Sal, and the Sal-ILs were miscible with water at any ratio. A skin permeation study showed that the Sal-ILs penetrated through skin faster than the Sal sodium salt. These results suggest that AAEs could be used in biomedical applications to eliminate the use of traditional toxic solvents for transdermal delivery of poorly water-soluble drugs.
- Moshikur, Rahman Md.,Chowdhury, Md. Raihan,Wakabayashi, Rie,Tahara, Yoshiro,Moniruzzaman, Muhammad,Goto, Masahiro
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- Synthesis of Nitrogen-Containing Heterocycles and Cyclopentenone Derivatives via Phosphine-Catalyzed Michael Addition/Intramolecular Wittig Reaction
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The phosphine-catalyzed Michael addition/intramolecular Wittig reaction between dialkyl acetylenedicarboxylate and amino-carbaldehyde or amino ester derivatives has been developped. This reaction can be rendered catalytic in phosphine by the in situ chemoselective reduction of the phosphine oxide with silane. This methodology enables rapid access to a variety of nitrogen-containing heterocycles, which are present in numerous natural products and/or bioactive compounds. Either classical heating or microwave conditions give access to the desired products in good yields (15 examples, 60–99% yields). This catalytic methodology is further applicable to the synthesis of enantioenriched 1H-pyrrole derivatives, with the use of chiral phosphines. Finally, we successfully extended the reaction to the synthesis of a polysubstituted cyclopentenone, starting from butane-2,3-dione as substrate. (Figure presented.).
- Saleh, Nidal,Blanchard, Florent,Voituriez, Arnaud
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supporting information
p. 2304 - 2315
(2017/07/07)
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- COMPOUNDS USEFUL AS CSF1 MODULATORS
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This invention relates to novel compounds and to pharmaceutical compositions comprising the novel compounds. More specifically, the invention relates to compounds useful as Colony Stimulating Factor 1 Receptor (cFMS) modulators (e.g. cFMS inhibitors). This invention also relates to processes for preparing the compounds, uses of the compounds in treatment and methods of treatment employing the compounds. Specifically, the invention relates to the use of the compounds for the treatment of cancer and autoimmune diseases.
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Paragraph 00432; 00433
(2016/04/26)
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- Synthesis of a series of amino acid derived ionic liquids and tertiary amines: Green chemistry metrics including microbial toxicity and preliminary biodegradation data analysis
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A series of l-phenylalanine ionic liquids (ILs), l-tyrosine ILs, tertiary amino analogues and proposed transformation products (PTPs) have been synthesised. Antimicrobial toxicity data, as part of the green chemistry metrics evaluation and to supplement preliminary biodegradation studies, was determined for ILs, tertiary amino analogues and PTPs. Good to very good overall yields (76 to 87%) for the synthesis of 6 ILs from l-phenylalanine were achieved. A C2-symmetric IL was prepared from TMS-imidazole in a one-pot two-step method in excellent yield (91%). Synthesis of the l-tyrosine IL derivatives utilised a simple protection group strategy by using an extra equivalent of the bromoacetyl bromide reagent. Improvements in the synthesis of the α-bromoamide alkylating reagent from l-phenylalanine were achieved, directed by green chemistry metric analysis. A solvent switch from dichloromethane to THF is described, however the yield was 15% lower. Antimicrobial activity testing of l-phenylalanine ILs, l-tyrosine ILs, tertiary amino analogues and PTPs, against 8 bacteria and 12 fungi strains, showed that no compound had a high antimicrobial activity, apart from an l-proline analogue. In this exceptional case, the highest toxicity (IC95 = 125 and 250 μM) was observed towards the two Gram positive strains Staphylococcus aureus and Staphylococcus epidermidis respectively. High antimicrobial activity was not found for the other bacteria or fungi strains screened. The limitations of the antimicrobial activity study is discussed in relation to SAR studies. Preliminary analysis of biodegradation data (Closed Bottle Test, OECD 301D) is presented. The pyridinium IL derivative is the preferred green IL of the series based on synthesis, toxicity and biodegradation considerations. This work is a joint study with Kümmerer and co-workers and the PTPs were selected as target compounds based on concurrent biodegradation studies by the Kümmerer group. For the comprehensive biodegradation and transformation product analysis see the accompanying paper.
- Jordan, Andrew,Hai?, Annette,Spulak, Marcel,Karpichev, Yevgen,Kümmerer, Klaus,Gathergood, Nicholas
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p. 4374 - 4392
(2016/08/19)
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- Pd-catalyzed directed ortho -C-H alkenylation of phenylalanine derivatives
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A practical Pd-catalyzed ortho-olefination of enantioenriched N-(SO2Py)-protected aryl-alanine and norephedrine derivatives with electron-deficient alkenes has been developed using N-fluoro-2,4,6-trimethylpyridinium triflate as the terminal oxidant. The reaction occurs efficiently with excellent monosubstitution selectivity and without loss of enantiopurity. This cross-coupling proved to be broad in scope, tolerating a variety of steric and electronic changes to both coupling partners. Removal of the directing group under mild conditions provides access to optically active tetrahydroisoquinoline-3-carboxylic acid derivatives (Tics) with good diastereocontrol and with very small erosion of enantiomeric purity.
- García-Rubia, Alfonso,Laga, Eduardo,Cativiela, Carlos,Urriolabeitia, Esteban P.,Gómez-Arrayás, Ramón,Carretero, Juan C.
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p. 3321 - 3331
(2015/03/30)
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- Design and synthesis of a s-triazene based asymmetric organocatalyst and its application in enantioselective alkylation
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A very efficient chiral organocatalyst was prepared from the readily available cyanuric chloride. The asymmetric catalyst exhibited a highly enantioselective catalytic performance for the alkylation of a glycinate Schiff base, which provides a useful procedure for the enantioselective synthesis of structurally diverse natural and unnatural α-alkyl-α-amino acids.
- Mangawa, Shrawan K.,Singh, Ashawani K.,Awasthi, Satish K.
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p. 61144 - 61147
(2015/08/03)
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- Continuous flow chemistry: A discovery tool for new chemical reactivity patterns
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Continuous flow chemistry as a process intensification tool is well known. However, its ability to enable chemists to perform reactions which are not possible in batch is less well studied or understood. Here we present an example, where a new reactivity pattern and extended reaction scope has been achieved by transferring a reaction from batch mode to flow. This new reactivity can be explained by suppressing back mixing and precise control of temperature in a flow reactor set up. This journal is the Partner Organisations 2014.
- Hartwig, Jan,Metternich, Jan B.,Nikbin, Nikzad,Kirschning, Andreas,Ley, Steven V.
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supporting information
p. 3611 - 3615
(2014/06/09)
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- Friedel-Crafts alkylation of natural amino acid-derived pyrroles with CF3-substituted cyclic imines
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Natural amino acid-derived ethyl 2-(1-pyrrolyl)alkanoates react with 2-trifluoromethyl-1-azacycloalkenes selectivity at the β-position of the pyrrole moiety to afford ethyl 2-[3-(1-trifluoromethyl-2-azacycloalkyl)pyrrol-1- yl]alkanoates.
- Shmatova, Olga I.,Shevchenko, Nikolay E.,Balenkova, Elizabeth S.,R?schenthaler, Gerd-Volker,Nenajdenko, Valentine G.
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- Synthesis of helical poly(phenylacetylene)s with amide linkage bearing l -phenylalanine and l -phenylglycine ethyl ester pendants and their applications as chiral stationary phases for HPLC
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Novel stereoregular helical poly(phenylacetylene) derivatives (PPA-Phe and PPA-Phg) with an amide linkage bearing l-phenylalanine and l-phenylglycine ethyl ester pendants were synthesized for use as chiral stationary phases (CSPs) in HPLC. The polymers showed different chiral recognition abilities depending on the coating solvents. Both PPA-Phe and PPA-Phg exhibited higher chiral recognitions when coated with CHCl3 by having preferable conformations. Their chiral recognition abilities depended on their molecular weight and optical rotations which were influenced by the polymerization solvents and monomer concentration. PPA-Phe and PPA-Phg showed rather different chiral recognitions, indicating that the benzyl group of the former and the phenyl group of the latter also play important roles in the chiral recognition. A few racemates were completely separated on PPA-Phe or PPA-Phg with separation factors comparable or higher than those obtained on the popular polysaccharide-based CSPs.
- Zhang, Chunhong,Wang, Hailun,Geng, Qianqian,Yang, Taotao,Liu, Lijia,Sakai, Ryosuke,Satoh, Toshifumi,Kakuchi, Toyoji,Okamoto, Yoshio
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p. 8406 - 8415
(2013/12/04)
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- Stereoselective catalytic hydrogenation and conjugate reduction of 4-methyl itaconate derivatives bearing a chiral auxiliary
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The catalytic hydrogenation of 4-methyl itaconate derivatives bearing a chiral auxiliary and their conjugate reduction with n-Bu3SnH in the presence of Lewis acid were examined to reveal their diastereoselectivity. The homogeneous catalytic hydrogenation of 4-methyl itaconyl (1S)-(-)-2,10- camphorsultam with the Crabtree's catalyst [Ir(COD)(PCy3)(py)]PF 6 in CH2Cl2-MeOH (2:1 v/v) gave less polar (1S,2′S)-diastereomer in 84% yield, while the conjugate reduction of the α-methylene amide with n-Bu3SnH (2 equiv) using MgI2 (7 equiv) as an additive in CH2Cl2 gave more polar (1S,2′R)-diastereomer in 70% yield.
- Kumazaki, Eri,Nagano, Hajime
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p. 3486 - 3494
(2013/05/08)
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- HMDO-promoted peptide and protein synthesis in ionic liquids
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Hexamethyldisiloxane (HMDO) has been developed to efficiently promote the metal-free direct coupling of an amino function of one cysteine-free peptide or protein and a C-terminal thioester of the second peptide in ionic liquids. The amide-coupling reaction proceeds smoothly under mild conditions to afford the corresponding products in good to excellent yields (63-94%). Peptide couplings were also achieved using in-situ-generated thioesters by the thioesterification of oxo esters.
- Duan, Jianli,Sun, Yao,Chen, Hao,Qiu, Guofu,Zhou, Haibing,Tang, Ting,Deng, Zixin,Hong, Xuechuan
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p. 7013 - 7022
(2013/08/23)
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- Double stereodifferentiation in the catalytic asymmetric aziridination of imines prepared from α-chiral amines
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The catalytic asymmetric aziridination of imines and diazo compounds (AZ reaction) mediated by boroxinate catalysts derived from the VANOL and VAPOL ligands was investigated with chiral imines derived from five different chiral, disubstituted, methyl amines. The strongest matched and mismatched reactions with the two enantiomers of the catalyst were noted with disubstituted methyl amines that had one aromatic and one aliphatic substituent. The synthetic scope for the AZ reaction was examined in detail for α-methylbenzyl amine for cis-aziridines from α-diazo esters and for trans-aziridines from α-diazo acetamides. Optically pure aziridines could be routinely obtained in good yields and with high diastereoselectivity and the minor diastereomer (if any) could be easily separated. The matched case for cis-aziridines involved the (R)-amine with the (S)-ligand, but curiously, for trans-aziridines the matched case involved the (R)-amine with the (R)-ligand for imines derived from benzaldehyde and n-butanal, and the (R)-amine with the (S)-ligand for imines derived from the bulkier aliphatic aldehydes pivaldehyde and cyclohexane carboxaldehyde.
- Huang, Li,Zhang, Yu,Staples, Richard J.,Huang, Rui H.,Wulff, William D.
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supporting information; experimental part
p. 5302 - 5313
(2012/05/20)
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- Enantioselective and regioselective Friedel-Crafts alkylation of pyrroles with nitroalkenes catalyzed by a tridentate Schiff base-copper complex
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On a (pyr)role: A mild and highly efficient catalytic system has been developed for the asymmetric Friedel-Crafts alkylation of pyrroles with nitroalkenes (see scheme). High yields, and excellent enantioselectivities and regioselectivities were obtained for a broad range of substrates. The synthetic utility of this methodology and mechanistic studies involving a novel, negative, nonlinear effect are also presented. Copyright
- Guo, Fengfeng,Chang, Dalu,Lai, Guoyin,Zhu, Tao,Xiong, Shunshun,Wang, Sujing,Wang, Zhiyong
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supporting information; experimental part
p. 11127 - 11130
(2011/12/02)
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- A highly efficient flow reactor process for the synthesis of N-Boc-3,4-dehydro-l-proline methyl ester
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The multi-step preparation of N-Boc-3,4-dehydro-l-proline methyl ester using a modular flow reactor is reported. The use of immobilised reagents and scavengers in pre-packed glass tubes allows us to obtain the pure product in 87% overall yield, 97% purity, and >98% enantiomeric excess without any additional purification step. Our flow-based protocol enables the rapid multi-gram synthesis (about 9 g/12 h) of the desired product.
- Tamborini, Lucia,Conti, Paola,Pinto, Andrea,Micheli, Carlo De
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experimental part
p. 222 - 225
(2010/05/02)
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- Synthesis and cytotoxic evaluation of N2-benzylated quaternary β-carboline amino acid ester conjugates
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The β-carboline alkaloids have been characterized as a class of potential antitumor agents. To further enhance the cytotoxic potency and improve water solubility of β-carboline, a series of new β-carboline amino acid ester, β-carboline amino acid and N2-benzylated quaternary β-carboline amino acid ester conjugates were designed and synthesized, and the cytotoxic activities of these compounds were evaluated using a panel of human tumor cell lines. The N2-benzylated quaternary β-carboline amino acid ester conjugates represented the most interesting cytotoxic activities. Particularly, compounds 8b and 8g were found to be the most potent compounds with IC50 values lower than 20?μM against all human tumor cell lines investigated. These results confirmed that the N2-benzyl substituent on the β-carboline ring played an important role in the modulation of the cytotoxic potencies.
- Ma, Chunming,Cao, Rihui,Shi, Buxi,Li, Shaoxue,Chen, Zhiyong,Yi, Wei,Peng, Wenlie,Ren, Zhenhua,Song, Huacan
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experimental part
p. 1515 - 1523
(2010/06/16)
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- Controlled diastereo-and enantioselection in a catalytic asymmetric aziridination
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Chiral polyborate based Bronsted acids prepared from the VANOL and VAPOL ligands are known to catalyze the reaction of diarylmethyl imines with diazoesters to give cis-aziridines. In the present work, this same catalyst is shown to catalyze the reaction of the same imines with diazoacetamides to give trans-aziridines with the same high asymmetric inductions as seen with cis-aziridines, enabling the development of an unprecedented universal catalytic asymmetric aziridination protocol. The substrate scope is broad and includes imines prepared from both electron-rich and electron-poor aromatic aldehydes and also from 1°, 2°, and 3° aliphatic aldehydes. The face selectivity of the addition to the imine was found to be independent of the diazo compounds. The (S)-VANOL or (S)-VAPOL derived catalyst will cause both diazoesters and diazoacetamides to add to the Si-face of the imine when cis-aziridines are formed and both to add to the Re-face of the imine when trans-aziridines are formed.
- Desai, Aman A.,Wulff, William D.
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supporting information; experimental part
p. 13100 - 13103
(2010/12/19)
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- Resolution of N-protected amino acid esters using whole cells of Candida parapsilosis ATCC 7330
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Whole cells of Candida parapsilosis ATCC 7330 were used for the resolution of N-acetyl amino acid esters. Excellent enantioselectivities (E = 40 to >500) were achieved for the resolution of N-protected protein and non-protein amino acid esters giving good yields (28-50%) and high enantiomeric excesses (up to >99%) for both enantiomers.
- Stella, Selvaraj,Chadha, Anju
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experimental part
p. 457 - 460
(2010/06/21)
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- Applications of the N-tert-butylsulfonyl (Bus) protecting group in amino acid and peptide chemistry
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The utility of the tert-butylsulfonyl group (Bus) for the temporary protection of amino acids and peptides is reported. Compatibility and orthogonality in the presence of other N- and O-protecting groups were studied.
- Hanessian, Stephen,Wang, Xiaotian
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experimental part
p. 2803 - 2808
(2010/03/03)
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- Asymmetric Henry reaction catalyzed by a copper tridentate chiral schiff-base complex
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A series of copper-tridentate chiral Schiff-base complexes were prepared and employed in an asymmetric Henry reaction, affording the corresponding adducts in good yields and with high enantioselectivities (up to 96% ee).
- Lai, Guoyin,Wang, Sujing,Wang, Zhiyong
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p. 1813 - 1819
(2008/12/22)
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- Induced-fit in the gas phase: Conformational effects on the enantioselectivity of chiral tetra-amide macrocycles
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The structure, stability, and reactivity of proton-bound diastereomeric [M?H?A]+ complexes between some amino acid derivatives (A) and several chiral tetra-amide macrocycles (M) have been investigated in the gas phase by ESI-FT-ICR and ESI-ITMS-CID mass spectrometry. The displacement of the A guest from the diastereomeric [M?H?A]+ complexes by reaction with the 2-aminobutane enantiomers (B) exhibits a distinct enantioselectivity with regards to the leaving amino acid A and, to a minor extent, to the amine reactant B. The emerging selectivity picture, discussed in the light of molecular mechanics calculations, provides compelling evidence that the most stable conformers of the selected chiral tetraamide macrocycles M may acquire in the gas phase a different conformation by induced fit on complexation with some representative amino acid derivatives A. This leads to the coexistence in the gas phase of stable diastereomeric [M?H?A] + eq-eq and ax-ax structures, in proportions depending on the configuration of A and M and characterized by different stability and reactivity toward the 2-aminobutane enantiomers. The enantioselectivity of the gas-phase A-to-B displacement in the diastereomeric [M?H?A]+ complexes essentially reflects the free energy gap between the homo- and heterochiral [M?H?A]+ complexes, except when the tetra-amidic host presents an additional macrocycle generated by a decamethylene chain. In this case, the measured enantioselectivity mostly reflects the stability difference between the relevant diastereomeric transition structures.
- Gasparrini, Francesco,Pierini, Marco,Villani, Claudio,Filippi, Antonello,Speranza, Maurizio
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p. 522 - 534
(2008/10/09)
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- Structure-activity study of endomorphin-2 analogs with C-terminal modifications by NMR spectroscopy and molecular modeling
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Endomorphin-2 (EM-2) is a putative endogenous μ-opioid receptor ligand. To get insight into the important role of C-terminal amide group of EM-2, we investigated herein a series of EM-2 analogs by substitution of the C-terminal amide group with -NHNH2, -NHCH3, -N(CH3)2, -OCH3, -OCH2CH3, -OC(CH3)3, and -CH2-OH. Their binding affinity and bioactivity were determined and compared. Despite similar (analogs 1, 4, and 7) or decreased (analogs 2, 3,5, and 6) μ affinity in binding assays, all analogs showed low guinea pig ileum (GPI) and mouse vas deferens (MVD) potencies compared to their parent peptide. Interestingly, as for analogs 2 and 3 (a single and double N-methylation of C-terminal amide), the potency order with the Ki (μ) values was 2 > 3; for the C-terminal esterified analogs 4-6, the potency order with the Ki (μ) values was 4 > 5 > 6. Thus, we concluded that the steric hindrance of C-terminus might play an important role in opioid receptor affinity. We further investigated the conformational properties of these analogs by 1D and 2D 1H NMR spectroscopy and molecular modeling. Evaluating the ratios of cis- and trans-isomers, aromatic interactions, dihedral angles, and stereoscopic views of the most convergent conformers, we found that modifications at the C-terminal amide group of EM-2 affected these analog conformations markedly, therefore changed the opioid receptor affinity and in vitro bioactivity.
- Wang, Chang-lin,Yao, Jin-long,Yu, Ye,Shao, Xuan,Cui, Yun,Liu, Hong-mei,Lai, Lu-hao,Wang, Rui
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p. 6415 - 6422
(2008/12/21)
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- PROCESS FOR PRODUCTION OF MONO-SUBSTITUTED ALKYLATED COMPOUND USING ALDIMINE OR DERIVATIVE THEREOF
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Disclosed is a process for producing an asymmetric mono-substituted alkylated compound of an α-amino acid which is represented by a specific formula by using an aldimine-type Schiff base. In the process, the alkylation of an aldimine-type Schiff base in a medium in the presence of an optically active quaternary ammonium salt phase transfer catalyst and an inorganic base is started, and subsequently the reaction is quenched at any time preceding the completion of the stoichimetrical reaction, thereby yielding a mono-substituted alkylated product having a high optical purity.
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Page/Page column 97-98
(2008/06/13)
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- Direct access to N-H-aziridines from asymmetric catalytic aziridination with borate catalysts derived from vaulted binaphthol and vaulted biphenanthrol ligands
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The asymmetric catalytic aziridination reaction (AZ reaction) of N-dianisylmethylimines (N-DAM-imines) with ethyl diazoacetate is developed with chiral catalysts prepared from triphenylborate and both the vaulted binaphthol (VANOL) and vaulted biphenanthrol (VAPOL) ligands. Catalysts derived from both ligands were equally effective in terms of asymmetric induction, but the VANOL catalyst was slightly faster. Up to 400 turnovers could be achieved with the VANOL catalyst while still maintaining ≥90% ee in the aziridine product. The ligand could be recovered in 95% yield with no loss in optical purity. Excellent asymmetric inductions were observed with arylimines, and although slightly lower inductions were observed for alkyl-substituted imines, the optical purity of the aziridines from all of the imine substrates could be enhanced to ≥ 99% ee with a single crystallization. Methods were developed for deprotection of the N-DAM-aziridines under acidic conditions without causing an acid-promoted opening of the ring. Excellent yields of the N-H-aziridines could be obtained with both alkyl- and aryl-substituted aziridines. Finally, activation of the N-H-aziridines was achieved with Boc, tosyl, and Fmoc groups. The activated aziridines can be converted to β3-amino esters, and unexpectedly, the N-Boc-protected aziridine-2-carboxylate 16b with a phenyl substituent in the 3-position cis to the ester group was found to undergo ring expansion to a mixture of cis- and trans-oxazolidinones.
- Lu, Zhenjie,Zhang, Yu,Wulff, William D.
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p. 7185 - 7194
(2008/02/05)
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- Enantioselective benzoylation of α-amino esters using (S)-1-benzoyl-2-(α-acetoxyethyl)benzimidazole, a chiral benzimidazolide
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(Chemical Equation Presented) A new chiral benzimidazolide is developed as a nonenzymatic acylating agent for enantioselective benzoylation of racemic α-amino esters. The process is highly efficient, which exhibits uniformly high enantioselectivity for α-amino esters with or without aryl substituents under mild reaction conditions. The chiral benzimidazolide is inexpensive and is easily accessible.
- Karnik, Anil V.,Kamath, Suchitra S.
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p. 7435 - 7438
(2008/02/11)
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- OPTICALLY ACTIVE QUATERNARY AMMONIUM SALT HAVING AXIAL ASYMMETRY AND PROCESS FOR PRODUCING -AMINO ACID AND DERIVATIVE THEREOF WITH THE SAME
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The present invention provides a chiral phase-transfer catalyst of the following formula (I): The compound (I) can be produced by reacting a 2,2'-dimethylene bromide-1,1'-biphenyl derivative, which can be produced through comparatively small number of steps, with an easily available secondary amine.
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Page/Page column 116-117
(2008/06/13)
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- Novel ozone-mediated cleavage of the benzhydryl protecting group from aziridinyl esters
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(Chemical Equation Presented) N-Benzhydryl aziridines-2-carboxylates can be readily obtained from the catalytic asymmetric aziridination reaction from N-benzhydrylimines and ethyl diazoacetate. Cleavage of the benzhydryl group by hydrogenolysis leads to ring opening when R = aryl. Surprisingly, ozone will selectively oxidize the benhydryl group in these aziridines even when R is an aryl group. This allows for a new deprotection strategy for these aziridines whose generality is explored.
- Patwardhan, Aniruddha P.,Lu, Zhenjie,Pulgam, V. Reddy,Wulff, William D.
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p. 2201 - 2204
(2007/10/03)
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- Orthogonality and compatibility between Tsc and Fmoc amino-protecting groups
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New deprotection conditions that provide a complete orthogonality between Tsc and Fmoc amino-protecting groups are described. The potential of these orthogonal deprotection conditions was then demonstrated by the efficient solid-phase synthesis of branched peptides 20 and 21 using doubly protected amino acids such as Tsc-Lys(Fmoc)-OH 4c and Fmoc-Lys(Tsc)-OH 4d.
- Choi, Jin Seok,Kang, Hunhui,Jeong, Nakcheol,Han, Hogyu
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p. 2493 - 2503
(2007/10/03)
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- Compositions and methods for separating amines and amino acids from their counter-enantiomers
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Diketo- and pyridine-containing chiral crown ligands having at least two chiral bulky groups attached to two different chiral carbon atoms of the crown that are covalently bonded to or coated on suitable solid supports, and further coated by hydrophobic organic solvents are disclosed. These compositions and associated methods are characterized by selectivity of several target amine or amino acid enantiomers over their counter-enantiomers and derivatives. The composition preferably has an α-value greater than or equal to 4. This allows for the separation of such enantiomers with non-chromatographic resin bed separations of three separation stages or less.
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- Melphalan derivatives and their use as cancer chemotherapeutic drugs
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The invention refers to new alkylating di- and tripeptides based on a melphalan unit, and one or two additional amino acids or amino acid derivatives, which can be used in the treatment of carcinogenic diseases. Further, the invention refers to a a pharmaceutical composition comprising the alkylating peptides of the invention.
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- An efficient strategy for the synthesis of chiral liquid crystals using Evans' methodology
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The synthesis of liquid crystal compound 2 was achieved using Evans' methodology. The strategy was based on three key synthetic reactions: alkylation of chiral amide enolates, Mitsunobu and, finally, esterification. The final compound presents a stable smectic A phase.
- Merlo, Aloir A.,Fernandes, Mirele S.
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p. 1167 - 1178
(2007/10/03)
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- The enzyme-catalysed stereoselective transesterification of phenylalanine derivatives in supercritical carbon dioxide
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The subtilisin Carlsberg catalysed transesterification of N-acetyl phenylalanine methyl ester (1), N-acetyl phenylalanine ethyl ester (2), N-trifluoroacetyl phenylalanine methyl ester (3) and N-trifluoroacetyl phenylalanine ethyl ester (4) was studied in supercritical carbon dioxide. The water content of the reaction affects the reactivity of the system; for the transesterification of the methyl esters with ethanol the optimum concentration of water was determined to be about 0.74 M, while for the transesterification of the ethyl esters with methanol the optimum concentration of water was about 1.3 M. The conversion is also dependent upon the concentration of alcohol; for ethanol, 2% v/v gives the maximum conversion, whilst for methanol, only 0.8-1. 2% v/v is required. This is probably due to a difference in the solubility of the substrates in the two alcohol/supercritical carbon dioxide mixtures. The reaction is highly stereoselective, in all cases no evidence for reaction of the D-isomer could be detected by chiral gas chromatography.
- Smallridge, Andrew J.,Trewhella, Maurie A.,Wang
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p. 259 - 262
(2007/10/03)
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- Esterification of amino acids and mono acids using triphosgene
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Alkyl esters of several amino acids and acids were prepared using triphosgene [trichloromethyl carbonate, TPA (2)].
- Rivero,Heredia,Ochoa
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p. 2169 - 2175
(2007/10/03)
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- Synthesis and anticholinesterase activity of some benzo-1,3,2-dioxaphospholene, oxazaphospholine and diazaphospholine 2-ones containing 2-amino acid substitution
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Synthesis of the titled compounds has been described. 1H NMR, IR band frequencies and MS fragmentation and rearrangement peaks were analyzed and discussed in detail. Studying the inhibitory effect of these compounds on acetylcholinesterase (AChE) showed that dioxaphospholenes were stronger inhibitors than oxazaphospholines and diazaphospholines. This was explained by increasing the number of nitrogen atoms around the phosphorus atom in the later two series, which reduces the electrophilic character of the phosphorus atom by the overlapping between the dπ - pπ orbitals of the phosphorus and the neighboring nitrogen atoms, and hence reducing the electrophilic attack of the phosphorus atom on a nucleophilic center at the esteratic site of the enzyme. Steric factor of the amino acid moiety showed stronger effect than the electronic factor on the inhibition activity, the observed order was glycine > glutamic > methaionine > phenylalanine > alanine.
- Ali, Hussein M.
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p. 157 - 166
(2007/10/03)
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- Chemo-Enzymic Synthesis of Optically Active α,α-Disubstituted α-Amino Acids
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A series of α,α-disubstituted α-amino esters was chemically synthesized and then resolved through enantioselective hydrolysis catalysed by a new enzyme isolated from crude Humicola langinosa lipase.This enzyme only accepts free amino esters as substrates with neither lipase activity toward olive oil nor esterase activity toward o-nitrophenyl butyrate.It is unique in that it successfully catalyses the resolution of amino esters with two large α-alkyl groups including aliphatic, aromatic and cyclic amino esters.Examples of resolutions where the alkyl groups differ in size by as little as a single carbon atom have been demonstrated.For determination of absolute configuration, some of the optically active α,α-disubstituted amino acids were also prepared through Schoellkopf's asymmetric synthesis and the structures were verified by X-ray crystallography.A model depicting the substrate binding site of the enzyme is proposed.
- Liu, Weiguo,Ray, Paul,Benezra, Steven A.
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p. 553 - 560
(2007/10/02)
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- Method for preparing amino acid esters
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A method for preparing an amino acid ester with sulfuric acid as the catalyst in high yield, in which a mixture of amino acid, sulfuric acid and an alcohol is heated while adding the alcohol as a liquid or gas to the reaction mixture and alcohol from the reaction mixture is distilled off.
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- Selective deprotection of allyl amines using palladium
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Mono and diallylamines can be cleaved using Pdf(0) catalyst and 2-mercaptobenzoic acid as nucleophile. This methodology has been successfully used for the sequential deprotection of diallylamines. The yields of desallylation are good to quantitative.
- Lemaire-Audoire,Lemaire-Audoire, Sandrine,Savignac,Savignac, Monique,Genet,Genet, Jean Pierre,Bernard,Bernard, Jean-Marie
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p. 1267 - 1270
(2007/10/02)
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- Water soluble 3,5-diacetamido-2,4,6-triiodobenzoic acid derivatives
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The invention relates to novel water soluble 3,5-diacetamido-2,4,6-triiodobenzoic acid derivatives, the method for making the same and their use as X-ray contrast agents for vasography, urography, myelography, artrography, fistulography and salpingography.
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