- Enantioselective acyl-transfer catalysis by fluoride ions
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The asymmetric nucleophilic catalysis by fluoride ions at a carbon-based electrophile has been demonstrated for the first time. Using a library of ad hoc designed bifunctional phase-transfer catalysts in which both the anion and the cation are directly involved in the reaction, the desymmetrisation of meso-succinic and -glutaric anhydrides is possible.19F NMR spectroscopic studies support the intermediacy of an acyl fluoride intermediate.
- Craig, Ryan,Litvajova, Mili,Cronin, Sarah A.,Connon, Stephen J.
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Read Online
- Discovery of 6-Oxo-4-phenyl-hexanoic acid derivatives as RORγt inverse agonists showing favorable ADME profile
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The retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt), which is a promising therapeutic target for immune diseases, is a major transcription factor of genes related to psoriasis pathogenesis, such as interleukin (IL)-17A, IL-22, and IL-23R. Inspired by the co-crystal structure of RORγt, a 6-oxo-4-phenyl-hexanoic acid derivative 6a was designed, synthesized, and identified as a ligand of RORγt. The structure–activity relationship (SAR) studies in 6a, which focus on the improvement of its membrane permeability profile by introducing chlorine atoms, led to finding 12a, which has a potent RORγt inhibitory activity and a favorable pharmacokinetic profile.
- Nakajima, Ryota,Oono, Hiroyuki,Kumazawa, Keiko,Ida, Tomohide,Hirata, Jun,White, Ryan D.,Min, Xiaoshan,Guzman-Perez, Angel,Wang, Zhulun,Symons, Antony,Singh, Sanjay K.,Mothe, Srinivasa Reddy,Belyakov, Sergei,Chakrabarti, Anjan,Shuto, Satoshi
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Read Online
- Organocatalytic kinetic resolution of racemic secondary nitroallylic alcohols combined with simultaneous desymmetrization of prochiral cyclic anhydrides
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This study describes an organocatalytic kinetic resolution of racemic secondary nitroallylic alcohols (2) combined with simultaneous desymmetrization of prochiral cyclic anhydrides (1). The experimental results revealed that enantioselective alcoholysis of 3-substituted glutaric anhydrides afforded hemiesters (3) with high levels of enantioselectivities (up to 99% ee) in the presence of cinchonidine-derived thiourea catalyst (IV). The highly optical enrichment (up to 95% ee) of (S)-nitroallylic alcohols (2) was recovered.
- Roy, Suparna,Chen, Kan-Fu,Gurubrahamam, Ramani,Chen, Kwunmin
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Read Online
- Synthesis of chiral fluorides by sequential organocatalyzed desymmetrization of glutaric anhydrides and photoredox-catalyzed decarboxylic fluorination
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We have developed an efficient method for the preparation of chiral fluorinated compounds by sequential organocatalyzed desymmetrization of 3-substituted glutaric anhydrides and photoredox-catalyzed decarboxylic fluorination. Chiral fluorides can be prepa
- Zhao, Jia-Jia,Yu, Shouyun
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supporting information
p. 391 - 394
(2020/10/06)
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- N-Heterocyclic carbene as a Br?nsted base catalyst for the amination of naphthol derivatives and alcoholysis of glutaric anhydrides
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A non-covalent Br?nsted-basic N-heterocyclic carbene catalyzed (NHC) Friedel-Crafts type amination of naphthol derivatives using dialkyl azodicarboxylates as the aminating source and alcoholysis of various glutaric anhydrides using alcohol as pronucleophile is presented. Both of these reactions are performed in the presence of either commercially available free-carbene catalyst or in situ-generated carbene catalyst. Friedel-Crafts type amination reaction is an example of a hydroxy group facilitated amination reaction. Both reactions proceed via in situ activations of –OH group by the carbene catalyst through hydrogen bonding interaction and furnish the relevant products in moderate to excellent yields.
- Jayakrishnan,Tamilarasu,Jincy,Kaliyamoorthy, Alagiri
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supporting information
(2019/09/30)
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- Increased selectivity of novozym 435 in the asymmetric hydrolysis of a substrate with high hydrophobicity through the use of deep eutectic solvents and high substrate concentrations
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The effects of the reaction medium and substrate concentration were studied on the selectivity of Novozym 435 using the asymmetric hydrolysis of dimethyl-3-phenylglutarate as a model reaction. Results show that the use of choline chloride ChCl:urea/phosph
- Fredes, Yerko,Chamorro, Lesly,Cabrera, Zaida
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- Effect of Site-Specific Peptide-Tag Labeling on the Biocatalytic Properties of Thermoalkalophilic Lipase from Geobacillus thermocatenulatus
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Tailor-made peptides were investigated for site-specific tag labeling of Geobacillus thermocatenulatus lipase (GTL). GTL was first genetically modified by introducing a unique cysteine on the lid site of the enzyme to produce two variants (GTLσ-A193C and GTLσ-S196C). Chemical modification was performed by using a small library of cysteine-containing peptides. The synthesized peptide–lipase biocatalysts were highly stable, more active, more specific, and more selective toward different substrates than unmodified GTL. Very high enzyme thermostability of GTLσ-A193C modified with peptides Ac-Cys-Phe-Gly-Phe-Gly-Phe-CONH2 (1) and Ac-Cys-Phe-Phe-CONH2 (2) (>95 % activity after 24 h at 60 °C) was observed. The incorporation of 1 and 2 in GTLσ-S196C improved its catalytic activity in the hydrolysis of p-nitrophenyl butyrate by factors of three and greater than five, respectively. The specificity for short-chain versus long-chain esters was also strongly improved. The diacylglycerol activity of GTLσ-S196C was enhanced more than tenfold by the incorporation of 1 and more than threefold by modification of this variant with Ac-Cys-(Arg)7-CONH2 (6) in the hydrolysis of 1-stearoyl-2-arachidonoyl-sn-glycerol. The enantioselectivity of GTLσ-S196C increased for all formed bioconjugates, and the GTLσ-S196C–1 conjugate was the most active and selective in the hydrolysis of dimethylphenyl glutarate at pH 7 (72 % ee), also showing an inversion in the enzyme enantiopreference.
- Romero, Oscar,de las Rivas, Blanca,Lopez-Tejedor, David,Palomo, Jose M.
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p. 369 - 378
(2018/01/11)
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- Novel amide-functionalized chloramphenicol base bifunctional organocatalysts for enantioselective alcoholysis of meso-cyclic anhydrides
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A family of novel chloramphenicol base-amide organocatalysts possessing a NH functionality at C-1 position as monodentate hydrogen bond donor were developed and evaluated for enantioselective organocatalytic alcoholysis of meso-cyclic anhydrides. These structural diversified organocatalysts were found to induce high enantioselectivity in alcoholysis of anhydrides and was successfully applied to the asymmetric synthesis of (S)-GABOB.
- Xu, Lingjun,Han, Shuwen,Yan, Linjie,Wang, Haifeng,Peng, Haihui,Chen, Fener
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supporting information
p. 309 - 317
(2018/02/19)
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- Development of Bifunctional Thiourea Organocatalysts Derived from a Chloramphenicol Base Scaffold and their Use in the Enantioselective Alcoholysis of meso Cyclic Anhydrides
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The synthesis of new chloramphenicol-base-derived thiourea organocatalysts, (1S,2R)-12 a–f and (1R,2R)-15 a–c, and their use in the enantioselective alcoholysis of meso-anhydrides are described. In particular, hemiesters afforded excellent enantioselectivities if low loadings of (1S,2R)-12 a–f were used. Almost no enantioselectivities were achieved with the use of (1R,2R)-15 a–c. This technique was used to synthesize (R)-(?)-baclofen.
- Yan, Lin-Jie,Wang, Hai-Feng,Chen, Wen-Xue,Tao, Yuan,Jin, Kai-Jun,Chen, Fen-Er
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p. 2249 - 2253
(2016/07/19)
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- Asymmetric hydrolysis of dimethyl-3-phenylglutarate in sequential batch reactor operation catalyzed by immobilized Geobacillus thermocatenulatus lipase
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Abstract The main goal of this work was to study the stereoselective behavior of immobilized Geobacillus thermocatenulatus lipase (BTL2) in a sequential batch reactor using the partial and asymmetric hydrolysis of dimethyl-3 phenylglutarate (DMFG) as a mo
- Guajardo, Nadia,Bernal, Claudia,Wilson, Lorena,Cabrera, Zaida
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- A family of novel bifunctional organocatalysts: Highly enantioselective alcoholysis of meso cyclic anhydrides and its application for synthesis of the key intermediate of P2X7 receptor antagonists
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A family of novel squaramides/sulfamides based on 1,2-alkamine was developed as chiral bifunctional catalysts to promote the asymmetric alcoholysis of meso cyclic anhydrides. The hemiesters were obtained in high yield with up to 93% ee. The usefulness of this methodology was demonstrated in the asymmetric synthesis of the key intermediate of P2X7 receptor antagonists.
- Yang, Hong-Jun,Xiong, Fang-Jun,Li, Jie,Chen, Fen-Er
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p. 553 - 558
(2013/07/27)
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- Catalytic enantioselective desymmetrization of meso-glutaric anhydrides using a stable Ni2-schiff base catalyst
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We describe the desymmetrization of meso-glutaric anhydrides to chiral hemiesters using a bench-stable homodinuclear Ni2-(Schiff base) complex as the catalyst in good to excellent yield (up to 99%) and enantioselectivity (up to 94%). Using the opposite enantiomer of the catalyst, we obtained the same yield and enantioselectivity with the opposite configuration, thereby gaining access to both hemiester enantiomers.
- Gopinath, Purushothaman,Watanabe, Takumi,Shibasaki, Masakatsu
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supporting information; experimental part
p. 1358 - 1361
(2012/04/23)
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- Enantioselective desymmetrization of prochiral diesters catalyzed by immobilized Rhizopus oryzae lipase
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The asymmetric hydrolysis of dimethyl 3-phenylglutarate 1 catalyzed by different immobilized preparations of Rhizopus oryzae lipase (ROL) has been studied. The Lewatit CNP 105 commercial support was activated to aldehyde groups (Lewatit-aldehyde) and used
- Cabrera, Zaida,Palomo, Jose M.
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experimental part
p. 2080 - 2084
(2012/03/26)
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- CINCHONA-BASED BIFUNCTIONAL ORGANOCATALYSTS AND METHOD FOR PREPARING CHIRAL HEMIESTERS USING THE SAME
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The present invention relates to cinchona-based bifunctional organocatalysts and methods for preparing chiral hemiesters using the same. More specifically, the present invention relates to methods for preparing chiral hemiesters from prochiral or meso cyclic acid anhydrides via desymmetrization, using bifunctional cinchona alkaloid catalysts comprising sulfonamide functional groups.
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Page/Page column 18
(2011/09/20)
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- CINCHONA-BASED BIFUCNTIONAL ORGANOCATALYSTS AND METHOD FOR PREPARING CHIRAL HEMIESTERS USING THE SAME
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The present invention relates to cinchona-based bifunctional organocatalysts and methods for preparing chiral hemiesters using the same. More specifically, the present invention relates to methods for preparing chiral hemiesters from prochiral or meso cyclic acid anhydrides via desymmetrization, using birunctional cinchona alkaloid catalysts comprising sulfonamide functional groups.
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Page/Page column 43; 46
(2010/04/03)
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- Enantioselective alcoholysis of meso-glutaric anhydrides catalyzed by Cinchona-based sulfonamide catalysts
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The bifunctional Cinchona-based sulfonamide catalysts showed the highest levels of enantioselectivity reported to date in the alcoholytic desymmetrization of meioglutaric anhydrides. Density functional theory (DFT) computational studies provide detailed insight into the observed sense of enantioselectivity. Moreover, detailed experimental studies and single crystal X-ray analysis confirmed that these bifunctional organocatalysts 3 do not form Hbonded self-aggregates in both solution and solid state. The synthetic utility of this methodology was also demonstrated in the synthesis of pharmaceutically important γ-amino acids, such as (S)-pregabalin. Of the many asymmetric syntheses of enantiomerically pure (S)-pregabalin reported to date, our synthesis requires the least number of and the simplest steps.
- Park, Sang Eun,Nam, Eun Hye,Jang, Hyeong Bin,Oh, Joong Suk,Some, Surajit,Lee, Yong Seop,Song, Choong Eui
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supporting information; experimental part
p. 2211 - 2217
(2010/11/19)
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- Highly enantioselective desymmetrizations of meso-anhydrides
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Readily available, low molecular cyclohexane-based organocatalysts promote highly enantioselective desymmetrizations of cyclic meso-anhydrides applying alcohols and benzyl mercaptan as nucleophiles. Both succinic and glutaric anhydrides furnished the corresponding products with up to 96% ee in mostly quantitative yields.
- Schmitt, Ellen,Schiffers, Ingo,Bolm, Carsten
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experimental part
p. 6349 - 6357
(2010/10/03)
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- A chiral bifunctional sulfonamide as an organocatalyst: Alcoholysis of σ-symmetric cyclic dicarboxylic anhydrides
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Enantioselective alcoholysis of σ-symmetric cyclic dicarboxylic anhydrides with benzyl alcohol catalyzed by a chiral bifunctional sulfonamide was achieved in up to 98% ee at 5 mol% loading. Georg Thieme Verlag Stuttgart - New York.
- Honjo, Takashi,Tsumura, Takeshi,Sano, Shigeki,Nagao, Yoshimitsu,Yamaguchi, Kentaro,Sei, Yoshihisa
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experimental part
p. 3279 - 3282
(2010/03/05)
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- A novel cost-effective thiourea bifunctional organocatalyst for highly enantioselective alcoholysis of meso-cyclic anhydrides: Enhanced enantioselectivity by configuration inversion
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A novel inexpensive thiourea bifunctional organocatalyst which can promote the highly enantioselective (up to 95% ee) alcoholysis of mesocyclic anhydrides has been developed. Computational studies on the catalytic process as well as a synthetic application of this new catalyst are also presented.
- Wang, Su-Xi,Chen, Fen-Er
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supporting information; scheme or table
p. 547 - 552
(2009/10/25)
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- A polymer-supported Cinchona-based bifunctional sulfonamide catalyst: A highly enantioselective, recyclable heterogeneous organocatalyst
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The design, synthesis, and catalytic application of a highly enantioselective and indefinitely stable polymer-supported Cinchona-based bifunctional sulfonamide is reported.
- Youk, Sung Hun,Oh, Sang Ho,Rho, Ho Sik,Lee, Je Eun,Lee, Ji Woong,Song, Choong Eui
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supporting information; scheme or table
p. 2220 - 2222
(2009/09/06)
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- Highly enantioselective desymmetrization of meso anhydrides by a bifunctional thiourea-based organocatalyst at low catalyst loadings and room temperature
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(Chemical Equation Presented) Bifunctional (thio)urea-based cinchona alkaloid derivatives have been shown to promote highly efficient enantioselective desymmetrization reactions of meso anhydrides. The most selective of these catalysts is capable of the enantioselective methanolysis of succinic and glutaric anhydride derivatives to form hemiester products with >90% yield and enantiomeric excess at 1 mol % loading and ambient temperature.
- Peschiulli, Aldo,Gun'ko, Yurii,Connon, Stephen J.
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p. 2454 - 2457
(2008/09/19)
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- An efficient asymmetric desymmetrization of prochiral glutaric anhydrides with SuperQuat chiral oxazolidin-2-ones
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The asymmetric desymmetrization of 3-substituted glutaric anhydrides 1 bearing silyl, aryl and alkyl groups with the lithium salt of chiral oxazolidin-2-ones has been studied. The effects of the substituents at the 4- and 5-positions of the oxazolidin-2-ones on the diastereoselectivity of the anhydride opening were studied in detail. A SuperQuat chiral oxazolidin-2-one 2e with 5,5-diaryl substituents showed optimum selectivity.
- Chaubey, Narendra,Date, Sonali M.,Ghosh, Sunil K.
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experimental part
p. 2721 - 2730
(2009/04/07)
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- A highly reactive and enantioselective bifunctional organocatalyst for the methanolytic desymmetrization of cyclic anhydrides: Prevention of catalyst aggregation
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(Chemical Equation Presented) Unprecedented reactivity and high stereoselectivity were observed in the ring opening of meso anhydrides under mild conditions with a cinchona-alkaloid-based sulfonamide catalyst (see scheme). Computation of the catalyst-transition-state analogue (right; gray C, white H, green F, blue N, red O, yellow S) provided insight into the origin of the stereoselectivity.
- Oh, Sang Ho,Rho, Ho Sik,Lee, Ji Woong,Lee, Je Eun,Youk, Sung Hoon,Chin, Jik,Song, Choong Eui
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supporting information; experimental part
p. 7872 - 7875
(2009/04/10)
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- Strategies toward improving the brain penetration of macrocyclic tertiary carbinamine BACE-1 inhibitors
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This letter describes replacements for the P3 amide moiety present in previously reported tertiary carbinamine macrolactones. Although P-gp efflux issues associated with these amide-macrolactones were solved and full brain penetration was measured in one
- Moore, Keith P.,Zhu, Hong,Rajapakse, Hemaka A.,McGaughey, Georgia B.,Colussi, Dennis,Price, Eric A.,Sankaranarayanan, Sethu,Simon, Adam J.,Pudvah, Nicole T.,Hochman, Jerome H.,Allison, Timothy,Munshi, Sanjeev K.,Graham, Samuel L.,Vacca, Joseph P.,Nantermet, Philippe G.
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p. 5831 - 5835
(2008/09/19)
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- MACROCYCLIC AMINOPYRIDYL BETA-SECRETASE INHIBITORS FOR THE TREATMENT OF ALZHEIMER'S DISEASE
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The present invention is directed to macrocyclic aminopyridyl compounds represented by general formula (I), which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved,
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Page/Page column 45
(2010/11/08)
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- Enzymatic desymmetrization of 3-arylglutaric acid anhydrides
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Optically active (R)- and (S)-3-arylglutaric acid monoesters 3 were synthesized in quantitative yields and good stereoselectivities by lipase-catalyzed desymmetrization of the corresponding 3-arylglutaric anhydrides 2 with alcohols. It was observed that the stereochemical outcome of the reaction was influenced by the substituents present on the aromatic ring. The influence of the enzyme, alcohol, and solvent was systematically examined. Absolute configurations of the monoesters 3 were assigned by chemical correlation to corresponding lactones 4.
- Fryszkowska, Anna,Komar, Marta,Koszelewski, Dominik,Ostaszewski, Ryszard
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p. 2475 - 2485
(2007/10/03)
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- Cinchona-alkaloid-based catalysts, and asymmetric alcoholysis of cyclic anhydrides using them
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One aspect of the present invention relates to cinchona-alkaloid-based catalysts. A second aspect of the invention relates to a method of preparing a derivatized cinchona alkaloid catalyst by reacting a cinchona-alkaloid with base and a compound that has a suitable leaving group. Another aspect of the present invention relates to a method of preparing a chiral, non-racemic compound from a prochiral cyclic anhydride or a meso cyclic anhydride, comprising the step of: reacting a prochiral cyclic anhydride or a meso cyclic anhydride with a nucleophile in the presence of a catalyst; wherein said prochiral cyclic anhydride or meso cyclic anhydride comprises an internal plane of symmetry or point of symmetry or both; thereby producing a chiral, non-racemic compound; wherein said catalyst is a derivatized cinchona-alkaloid. Yet another aspect of the present invention relates to a method of kinetic resolution, comprising the step of: reacting a racemic cyclic anhydride with an alcohol in the presence of a derivatized cinchona-alkaloid catalyst.
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Page/Page column 26
(2008/06/13)
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- l-Menthyl (2S)-2-phenyl-3-(p-anisyl)-(5Z)-benzylidene-4,6-dioxo-1,3-oxazine-2-ca rboxylate: A new chiral heterodiene and Michael acceptor
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The title homochiral oxazinedione has been synthesized from l-menthyl phenylglyoxylate in three steps and found to exhibit high diastereofacial selectivity (≥99%) when used as heterodiene and Michael acceptor.
- Sato,Nagashima,Furuya,Kaneko
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p. 1972 - 1974
(2007/10/02)
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- β-substituted β-phenylpropionyl chymotrypsins. Structural and stereochemical features in stable acyl enzymes
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In order to develop effective alternate substrate inhibitors for serine proteases, we have prepared a series of β-substituted β-phenylpropionic acid esters related to some systems known to form stable acyl enzymes with α-chymotrypsin. Some of these compounds were prepared in enantiomerically pure form by asymmetric synthesis. Acyl enzyme species were generated from chymotrypsin by reaction with the active esters, and the progress of deacylation was monitored by the proflavin displacement assay. In some cases, it was possible to distinguish two different deacylation rates that correspond to the two enantiomers. β-Phenylpropionic acyl enzymes with β-substituents that are nonpolar were not especially stable, but a number of the polar derivatives and particularly the acylamino derivatives showed slow rates of deacylation (k(d) less than 0.005 min-1), with three systems showing deacylation enantioselectivities in the range of 500-1500. These results are consistent with a model in which additional stabilization of the acyl enzyme and enantioselectivity in the deacylation process derives from an additional hydrogen bond between the acyl enzyme species (as an acceptor) and the enzyme (as a donor). A number of active site residues that might be involved in this hydrogen bond are discussed.
- Reed,Katzenellenbogen
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p. 1162 - 1176
(2007/10/02)
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- Enantiotopic-group Differentation. Catalytic Asymmetric Ring-opening of Prochiral Cyclic Acid Anhydrides with Methanol, using Cinchona Alkaloids
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Asymmetric ring-opening of prochiral acid anhydrides (1) with methanol has been achieved by a catalytic quantity of cinchona alkaloids (2).The product, the optically active half-ester (3), has been subjected to functional-group-selective reduction to give the optically active lactones (5).The reaction rate of the ring-opening and the extent of selectivity are dependent on the nature of the reaction medium, the polarity of solvent, and substrate concentration.By selecting the reaction conditions, an enantiometric excess of up to 70percent has been obtained.The kinetic isotope effect and other mechanistic investigations suggest that the reaction proceeds via general-base catalysis by the quinuclidine moiety of the base (2), and that the relative configuration of the C-9 hydroxy group with respect to the C-8 quinuclidine amino function determines the selectivity of the reaction.
- Hiratake, Jun,Inagaki, Minoru,Yamamoto, Yukio,Oda, Jun'ichi
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p. 1053 - 1058
(2007/10/02)
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- Preparations of Chiral δ-Lactones via Enantiotopically Specific Pig Liver Esterase-catalysed Hydrolyses of 3-Substituted Glutaric Acid Diesters
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Pig liver esterase-catalysed hydrolyses of 3-monosubstituted glutaric acid diesters are pro-S enantiotopically specific for a broad range of C-3 substituents and permit either enantiomer of the corresponding 3-substituted valerolactones of 100percent e.e.
- Francis, Christopher J.,Jones, J. Bryan
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p. 579 - 580
(2007/10/02)
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