- NiH-Catalyzed Remote Asymmetric Hydroalkylation of Alkenes with Racemic α-Bromo Amides
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Reported here is a terminal-selective, remote asymmetric hydroalkylation of olefins with racemic α-bromo amides. The reaction proceeds by NiH-catalyzed alkene isomerization and subsequent alkylation reaction, and can enantioconvergently introduce an unsymmetrical secondary alkyl group from a racemic α-bromo amide onto a terminal C(sp3)?H position along the hydrocarbon chain of the alkene. This mild process affords a range of structurally diverse chiral α-alkylalkanoic amides in excellent yields, and high regio- and enantioselectivities. In addition, the synthetic utility of this protocol is further highlighted by the regioconvergent conversion of industrial raw materials of isomeric olefin mixtures into enantioriched α-alkylalkanoic amides on large scale.
- Zhou, Fang,Zhang, Yao,Xu, Xianfeng,Zhu, Shaolin
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supporting information
p. 1754 - 1758
(2019/01/19)
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- Benzoxazinone-containing 3,5-dimethylisoxazole derivatives as BET bromodomain inhibitors for treatment of castration-resistant prostate cancer
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The bromodomain and extra-terminal proteins (BET) have emerged as promising therapeutic targets for the treatment of castration-resistant prostate cancer (CRPC). We report the design, synthesis and evaluation of a new series of benzoxazinone-containing 3,5-dimethylisoxazole derivatives as selective BET inhibitors. One of the new compounds, (R)-12 (Y02234), binds to BRD4(1) with a Kd value of 110 nM and blocks bromodomain and acetyl lysine interactions with an IC50 value of 100 nM. It also exhibits selectivity for BET over non-BET bromodomain proteins and demonstrates reasonable anti-proliferation and colony formation inhibition effect in prostate cancer cell lines such as 22Rv1 and C4-2B. The BRD4 inhibitor (R)-12 also significantly suppresses the expression of ERG, Myc and AR target gene PSA at the mRNA level in prostate cancer cells. Treatment with (R)-12 significantly suppresses the tumor growth of prostate cancer (TGI = 70%) in a 22Rv1-derived xenograft model. These data suggest that compound (R)-12 is a promising lead compound for the development of a new class of therapeutics for the treatment of CRPC.
- Xue, Xiaoqian,Zhang, Yan,Wang, Chao,Zhang, Maofeng,Xiang, Qiuping,Wang, Junjian,Wang, Anhui,Li, Chenchang,Zhang, Cheng,Zou, Lingjiao,Wang, Rui,Wu, Shuang,Lu, Yongzhi,Chen, Hongwu,Ding, Ke,Li, Guohui,Xu, Yong
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p. 542 - 559
(2018/05/24)
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- Enantioselective construction of tetrasubstituted stereogenic carbons through bronsted base catalyzed michael reactions: α′-hydroxy enones as key enoate equivalent
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Catalytic and asymmetric Michael reactions constitute very powerful tools for the construction of new C-C bonds in synthesis, but most of the reports claiming high selectivity are limited to some specific combinations of nucleophile/electrophile compound types, and only few successful methods deal with the generation of all-carbon quaternary stereocenters. A contribution to solve this gap is presented here based on chiral bifunctional Bronsted base (BB) catalysis and the use of α′-oxy enones as enabling Michael acceptors with ambivalent H-bond acceptor/donor character, a yet unreported design element for bidentate enoate equivalents. It is found that the Michael addition of a range of enolizable carbonyl compounds that have previously demonstrated challenging (i.e., α-substituted 2-oxindoles, cyanoesters, oxazolones, thiazolones, and azlactones) to α′-oxy enones can afford the corresponding tetrasubstituted carbon stereocenters in high diastereo- and enantioselectivity in the presence of standard BB catalysts. Experiments show that the α′-oxy ketone moiety plays a key role in the above realizations, as parallel reactions under identical conditions but using the parent α,β-unsaturated ketones or esters instead proceed sluggish and/or with poor stereoselectivity. A series of trivial chemical manipulations of the ketol moiety in adducts can produce the corresponding carboxy, aldehyde, and ketone compounds under very mild conditions, giving access to a variety of enantioenriched densely functionalized building blocks containing a fully substituted carbon stereocenter. A computational investigation to rationalize the mode of substrate activation and the reaction stereochemistry is also provided, and the proposed models are compared with related systems in the literature.
- Badiola, Eider,Fiser, Bla,Gmez-Bengoa, Enrique,Mielgo, Antonia,Olaizola, Iurre,Urruzuno, Iaki,Garca, Jess M.,Odriozola, Jos M.,Razkin, Jess,Oiarbide, Mikel,Palomo, Claudio
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supporting information
p. 17869 - 17881
(2015/02/19)
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- Synthesis of enantiomerically enriched-bromonitriles from amino acids
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Two methods were investigated for the preparation of six chiral-bromonitriles with different optic purities. The nitrous deamination of amino acids gives-bromoacids, which react with chlorosulfonyl isocyanate followed by triethylamine to afford-bromonitriles with moderate enantiomeric excess. However, the dehydration of corresponding-bromoamids using thionyl chloride gives-bromonitriles with good enantiomeric excess up to 94%. The use of phosphoryl chloride instead of thionyl chloride results in more than 30% racemization as determined by high-performance liquid chromatograpic analysis.
- Tka, Najeh,Kraem, Jamil,Hassine, Bechir Ben
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p. 735 - 743
(2013/01/15)
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- Highly stereoselective synthesis of α-alkyl-α-hydroxycarboxylic acid derivatives catalyzed by a dinuclear zinc complex
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A dinuclear zinc-ProPhenol catalyst enables highly enantioselective nitro-Michael reactions with oxazol-4(5H)-ones as nucleophilic substrates (see scheme, Nap=2-naphthyl). This work highlights the utility of the ProPhenol family of ligands. The modular nature of these ligands proved crucial in the optimization of reaction conditions to achieve excellent stereoselectivities. Copyright
- Trost, Barry M.,Hirano, Keiichi
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supporting information; experimental part
p. 6480 - 6483
(2012/07/30)
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- Investigation of the synthetic and mechanistic aspects of the highly stereoselective transformation of α-thioamides to α-thio-β- chloroacrylamides
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Treatment of a series of α-thioamides with N-chlorosuccinimide results in efficient transformation to the analogous α-thio-β- chloroacrylamides. The mechanistic pathway has been established through isolation and characterisation of intermediate compounds. The scope of the transformation has been explored - aryl and alkylthio substituents, primary, secondary and tertiary amides can be employed. In most instances, the chloroacrylamides are formed exclusively as the Z-stereoisomer; however, with tertiary propanamides or with amides derived from butanoic or pentanoic acid a mixture of E- and Z-stereoisomers is formed. The Royal Society of Chemistry.
- Murphy, Maureen,Lynch, Denis,Schaeffer, Marcel,Kissane, Marie,Chopra, Jay,O'Brien, Elisabeth,Ford, Alan,Ferguson, George,Maguire, Anita R.
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p. 1228 - 1241
(2008/02/03)
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- Carboxylic Acid Compounds and Use Thereof
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Provision of a superior URAT1 activity inhibitor effective for the treatment and the like of a pathology involving uric acid, such as hyperuricemia, gouty tophus, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urinary lithiasis, renal dysfunction, coronary heart disease, ischemic cardiac diseases and the like. A URAT1 activity inhibitor containing a compound represented by the following formula [1] or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient: [image] wherein each symbol is as defined in the specification.
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Page/Page column 84
(2010/11/28)
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- Privileged structure based ligands for melanocortin receptors - Substituted benzylic piperazine derivatives
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Replacement of the aryl piperazine moiety in compound 1 with a variety of substituted benzylic piperazines (6) yields compounds that afford melanocortin receptor 4 (MCR4) activity. Analogs with ortho substitution on the aromatic ring afforded the highest
- Fisher, Matthew J.,Backer, Ryan T.,Collado, Ivan,De Frutos, Oscar,Husain, Saba,Hsiung, Hansen M.,Kuklish, Steve L.,Mateo, Ana I.,Mullaney, Jeffrey T.,Ornstein, Paul L.,Paredes, Cristina Garcia,O'Brian, Thomas P.,Richardson, Timothy I.,Shah, Jikesh,Zgombick, John M.,Briner, Karin
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p. 4973 - 4978
(2007/10/03)
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- N-(mercaptoacyl)aminoacids
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Compounds useful for prophylaxis and therapy in treating a metabolic disorder, such as nosotoxicosis due to a heavy metal radiation disorder, diabetes or hepatitis. EQU1 and intermediates therefor are disclosed.
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