- Deracemizing α-Branched Carboxylic Acids by Catalytic Asymmetric Protonation of Bis-Silyl Ketene Acetals with Water or Methanol
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We report a highly enantioselective catalytic protonation of bis-silyl ketene acetals. Our method delivers α-branched carboxylic acids, including nonsteroidal anti-inflammatory arylpropionic acids such as Ibuprofen, in high enantiomeric purity and high yields. The process can be incorporated in an overall deracemization of α-branched carboxylic acids, involving a double deprotonation and silylation followed by the catalytic asymmetric protonation.
- Mandrelli, Francesca,Blond, Aurélie,James, Thomas,Kim, Hyejin,List, Benjamin
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p. 11479 - 11482
(2019/07/18)
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- HDAC3-SELECTIVE INHIBITORS
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Disclosed herein are selective HDAC inhibitors. In some embodiments, the compounds are selective HDAC3 inhibitors. The compounds are useful to treat a variety of conditions, including cancers, i.e., breast cancer, cachexia, and liver steatosis.
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Page/Page column 29
(2019/01/05)
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- Targeting breast cancer stem cells by novel HDAC3-selective inhibitors
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Although histone deacetylase (HDAC) inhibitors have been known to suppress the cancer stem cell (CSC) population in multiple types of cancer cells, it remains unclear which HDAC isoforms and corresponding mechanisms contribute to this anti-CSC activity. Pursuant to our previous finding that HDAC8 regulates CSCs in triple-negative breast cancer (TNBC) cells by targeting Notch1 stability, we investigated related pathways and found HDAC3 to be mechanistically linked to CSC homeostasis by increasing β-catenin expression through the Akt/GSK3β pathway. Accordingly, we used a pan-HDAC inhibitor, AR-42 (1), as a scaffold to develop HDAC3-selective inhibitors, obtaining the proof-of-concept with 18 and 28. These two derivatives exhibited high potency and isoform selectivity in HDAC3 inhibition. Equally important, they showed in vitro and/or in vivo efficacy in suppressing the CSC subpopulation of TNBC cells via the downregulation of β-catenin.
- Hsieh, Hao-Yu,Chuang, Hsiao-Ching,Shen, Fang-Hsiu,Detroja, Kinjal,Hsin, Ling-Wei,Chen, Ching-Shih
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supporting information
p. 42 - 51
(2017/09/20)
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- Iridium-catalyzed enantioselective hydrogenation of α,β- unsaturated carboxylic acids with tetrasubstituted olefins
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A highly efficient asymmetric hydrogenation of α,β-unsaturated carboxylic acids with tetrasubstituted olefin catalyzed by chiral spiro iridium complexes has been developed for the preparation of chiral α-substituted carboxylic acids in excellent enantioselectivities (up to 99% ee).
- Song, Song,Zhu, Shou-Fei,Li, Yu,Zhou, Qi-Lin
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p. 3722 - 3725
(2013/08/23)
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- Highly enantioselective direct alkylation of arylacetic acids with chiral lithium amides as traceless auxiliaries
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A direct, highly enantioselective alkylation of arylacetic acids via enediolates using a readily available chiral lithium amide as a stereodirecting reagent has been developed. This approach circumvents the traditional attachment and removal of chiral auxiliaries used currently for this type of transformation. The protocol is operationally simple, and the chiral reagent is readily recoverable.
- Stivala, Craig E.,Zakarian, Armen
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supporting information; experimental part
p. 11936 - 11939
(2011/09/19)
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- Efficient parallel resolution of pentafluorophenyl active esters using quasi-enantiomeric combinations of oxazolidin-2-ones
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The parallel resolution of racemic pentafluorophenyl 2-aryl/ phenylpropanoates and butanoates using an equimolar combination of quasi-enantiomeric Evans oxazolidin-2-ones is discussed. The levels of diastereoselectivity were excellent (>90% de) leading to separable quasi-enantiomeric oxazolidin-2-ones in good yield. This methodology was used to resolve a series of structurally related 2-aryl/phenylpropanoic and butanoic acids.
- Shaye, Najla Al,Chavda, Sameer,Coulbeck, Elliot,Eames, Jason,Yohannes, Yonas
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experimental part
p. 439 - 463
(2011/06/17)
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- Enantiopure tert-butyl(phenyl)phosphine oxide. Chirality-recognition ability and mechanism
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When enantiopure tert-butyl(phenyl)phosphine oxide 1 was used as a resolving agent, it showed an acceptable to good chirality-recognition ability for several kinds of racemic carboxylic acids 2. A study on a chirality-recognition mechanism based on X-ray crystallographic analyses of the diastereomeric complexes of 2 with 1 revealed that the complex crystals consisted of helical columns and that 1 was not responsible for the formation of the helical column and occupied a void between the columns; although 1 interacted with 2 via a hydrogen bond to primarily form a pair with 2, the complex crystals were mainly stabilized by the accumulation of weak interactions, such as CH/π, π/π and CH...O interactions, between 1/1, 1/2 and 2/2.
- Ribeiro, Nigel,Saigo, Kazuhiko
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experimental part
p. 2704 - 2708
(2010/04/29)
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- Introduction of single mutation changes arylmalonate decarboxylase to racemase
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The introduction of only one mutation based on the estimated reaction mechanism endowed arylmalonate decarboxylase with a racemase activity, which catalyses racemisation of α-arylpropionates. The Royal Society of Chemistry 2006.
- Terao, Yosuke,Miyamoto, Kenji,Ohta, Hiromichi
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p. 3600 - 3602
(2008/09/20)
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- QUINOLINE 4-CARBOXAMIDE DERIVATIVES AND THEIR USE AS NEUROKININ 3 (NK-3) RECEPTOR ANTAGONISTS
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The invention relates to novel quinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments particularly in treating disorders of the central nervous system (CNS).
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Page/Page column 20
(2010/02/10)
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- Modular chiral ligands: The profiling of the Mandyphos and Taniaphos ligand families
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A set of 11 ferrocenyl based diphosphine ligands (eight Mandyphos and three Taniaphos) was tested in more than 150 experiments using 20 test reactions. For the assessment of new ligands, a two-pronged strategy was developed consisting of a basic and an extended profiling. The basic profiling showed that the choice of the substituents at the P atoms has a significant effect on the catalyst performance. In the extended profiling it was confirmed that the Mandyphos ligands, in particular M4 with two bis(3,5-dimethyl-4-methoxyphenyl)phosphino groups, and the Taniaphos ligands, especially the all-phenyl derivative T1, showed good to outstanding performances in the hydrogenation of selected α- and β-enamides, acrylic acid derivatives, itaconates, β-ketoesters and 1,3-diketones yielding the corresponding products with up to 99% ee and at substrate/catalyst ratios up to 25,000.
- Spindler, Felix,Malan, Christophe,Lotz, Matthias,Kesselgruber, Martin,Pittelkow, Ulrich,Rivas-Nass, Andreas,Briel, Oliver,Blaser, Hans-Ulrich
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p. 2299 - 2306
(2007/10/03)
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- Rational design of CH/π interaction sites in a basic resolving agent
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A novel synthetic basic resolving agent, cis-1-aminobenz[f]indan-2-ol (ABI), was rationally designed by introducing effective CH/π interaction sites to cis-1-aminoindan-2-ol (AI), whose chiral recognition ability has been reported from our laboratory. ABI was applicable to a wide variety of racemic arylalkanoic acids and showed moderate to excellent chiral recognition ability, which was obviously higher than that of AI. The fundamental and important role of CH/π interactions, such as tunable CH(sp2)/π and CH(sp 3)/π interactions, in the chiral recognition by ABI was revealed by X-ray crystallographic study.
- Kobayashi, Yuka,Kurasawa, Toshie,Kinbara, Kazushi,Saigo, Kazuhiko
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p. 7436 - 7441
(2007/10/03)
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- The crystallographic structure of a Lewis acid-assisted chiral Bronsted acid as an enantioselective protonation reagent for silyl enol ethers
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It is difficult to control the enantioselectivity in the protonation of silyl enol ethers with simple chiral Bronsted acids, mainly due to bond flexibility between the proton and its chiral counterion, the orientational flexibility of the proton, and the fact that the proton sources available are limited to acidic compounds such as chiral carboxylic acids. To overcome these difficulties, we have developed a Lewis acid-assisted chiral Bronsted acid (LBA) system. The coordination of Lewis acids with Bronsted acids restricts the orientation of protons and increases their acidity. Optically active binaphthol (BINOL) derivative·SnCl4 complexes are very effective as enantioselective protonation reagents for silyl enol ethers. However, their exact structures have not yet been determined. We describe here optically active 1,2-diarylethane-1,2-diol derivative·SnCl4 as a new type of LBA for the enantioselective protonation as well as its crystallographic structure. A variety of optically active 1,2-diarylethane-1,2-diols could be readily prepared by asymmetric syn-dihydroxylation. This is a great advantage over BINOL for the flexible design of a new LBA. The most significant finding is that we were able to specify the conformational direction of the H-O bond of LBA, which has some asymmetric inductivity, by X-ray diffraction analysis. The stereochemical course in the enantioselective protonation of silyl enol ethers using LBA would be controlled by a linear OH/π interaction with an initial step. The absolute stereopreference in enantioselective reactions using BINOL·SnCl4 can also be explained in terms of this uniformly mechanistic interpretation. Copyright
- Ishihara, Kazuaki,Nakashima, Daisuke,Hiraiwa, Yukihiro,Yamamoto, Hisashi
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- Enantioselective biotransformations of racemic α-substituted phenylacetonitriles and phenylacetamides using Rhodococcus sp. AJ270
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Rhodococcus sp. AJ270 is an efficient whole-cell system able to catalyze the stereoselective conversions of racemic α-substituted phenylacetonitriles and amides under very mild conditions into enantiopure carboxylic acids and derivatives. The nitrile hydratase involved generally has a broad substrate spectrum against phenylacetonitriles irrespective of the electronic nature of the α-substituent while the amidase is very sensitive to both the electronic and steric factors of the substituent of amides. The overall enantioselectivity of nitrile hydrolysis is mainly determined by the combination of selectivities of nitrile hydratase and of amidase, with the latter being a major contributor. The amidase has high S-enantiocontrol against amides while the nitrile hydratase exhibits low R-selectivity against nitriles. The scope and limitations of this enantioselective biotransformation process are discussed. Copyright (C) 2000 Elsevier Science Ltd.
- Wang, Mei-Xiang,Lu, Gang,Ji, Gai-Jiao,Huang, Zhi-Tang,Meth-Cohn, Otto,Colby, John
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p. 1123 - 1135
(2007/10/03)
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- Chiral α-substituted carbonyls and alcohols from the S(N)2' displacement of cuprates on chiral carbonates: An alternative to the alkylation of chiral enolates
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A highly stereoselective sequence of reactions, based on the anti-selective S(N)2' addition of cuprates to allylic carbonates, transforms alkynes or alkenyl halides into carbonyls having α-chiral centers. The method, which uses menthone as a chiral auxiliary, is a useful alternative to the alkylation of chiral enolates with the added advantage of allowing for the 'alkylation' of sec- and tert-alkyl and aryl groups.
- Spino,Beaulieu,Lafreniere
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p. 7091 - 7097
(2007/10/03)
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- Efficient syntheses of optically active 2-arylalkanoic acids
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A highly enantioselective synthesis of 2-axylpropanoic acid was achieved, using a new developed methodology of cuprate addition to chiral carbonates derived from menthone.
- Beaulieu, Christian,Spino, Claude
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p. 1637 - 1640
(2007/10/03)
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- 1,1′-binaphthalene-2,2′-diol as a chiral auxiliary. Diastereoselective alkylation of binaphthyl esters, complex-induced proximity effects in enolate formation, and one-step synthesis of an optically active β-substituted ketone
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Diastereoselective alkylation of enolates derived from (S)-naphthyl phenylacetate 1 with LDA in THF gave the S,S-isomer as a major product. The diastereoselectivity increased as the bulkiness of the alkylating agent was increased. The low diastereomeric excess (~70%) of methylation was markedly raised to 92% by the use of n-BuLi as a base due to the complex-induced proximity effect (CIPE) in enolate formation. This highly diastereoselective methylation was used to synthesize the clinically important anti-inflammatory drugs (S)-naproxen (60) and (S)-suprofen (68). The stereochemistry of ketene trimethylsilyl acetals generated from several phenylacetates was investigated to understand the origin of the diastereoselectivity in this alkylation. Methyl phenylacetate (46) predominantly gave a (Z)-enolate by kinetic deprotonation, while the (E)-enolate was predominantly obtained from phenyl phenylacetate (47). An optically active ketone (88) was synthesized from binaphthyl ester 84 by a one-pot procedure involving the 1,4-addition, followed by the 1,2-addition, of organometallics. The CIPE again played a crucial role in the high enantiomeric excess in this case.
- Tanaka, Fujie,Node, Manabu,Tanaka, Kiyoshi,Mizuchi, Maki,Hosoi, Shinzo,Nakayama, Masayo,Taga, Tooru,Fuji, Kaoru
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p. 12159 - 12171
(2007/10/03)
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- Synthesis of Optically Active α-Isopropyl-4-substituted Phenylacetic Acids by Asymmetric Hydrogenation
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Homogeneous hydrogenation of 2-phenyl-3-methyl-2-butenoic acid derivatives in the presence of a catalytic amount of such chiral phosphine-rhodium complexes as Rh/(R)-BINAP, Rh/(R)-, or (S)-Cy-BINAP, Rh/(R)-p-tolyl-BINAP, and Rh/(R)-p-methoxyphenyl-BINAP afforded the corresponding phenylacetic acid derivatives in high enantiomeric excesses and in quantitative chemical yields.The optically activa phenylacetic acid derivatives are useful intermediates of agrochemicals and pharmaceuticals.
- Takemoto, Ichiki,Kawamura, Norio,Kaminaka, Hiroshi
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p. 2071 - 2072
(2007/10/02)
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- RENIN INHIBITING COMPOUNDS
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Compounds which are amino acid derivatives and have the formula STR1 in which R 1 is hydrogen or methyl, R 2 is ethyl, propyl or imidazol-4-yl, R 3 is isobutyl, cyclohexylmethyl or benzyl, and A is defined as herein are useful as renin inhibitors.
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- CHIRAL ORGANOSILICON COMPOUNDS IN SYNTHESIS: REGIO AND STEREOSELECTIVE ALKYLATION OF A CHIRAL α-SILYLCINNAMYL CARBANION
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Good regio- and stereoselectivity can be obtained in the alkylation of chiral α-silylcinnamyl carbanion 8 in toluene.
- Lamothe, S.,Chan, T. H.
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p. 1847 - 1850
(2007/10/02)
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- ENZYMATIC RESOLUTION OF METHYL 2-ALKYL-2-ARYLACETATES
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Horse liver esterase, used as its inexpensive commercial acetone powder, catalyzes the selective hydrolysis of methy 2-alkyl-2-arylacetates to afford R(-)-2-alkyl-2-arylacetic acids and S(+)-methyl 2-alkyl-2-arylacetates.
- Ahmar, M.,Girard, C.,Bloch, R.
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p. 7053 - 7056
(2007/10/02)
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