- Synthesis of α-Keto Acids via Oxidation of Alkenes Catalyzed by a Bifunctional Iron Nanocomposite
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An efficient methodology for synthesis of α-keto acids via oxidation of alkenes using TBHP as oxidant catalyzed by a bifunctional iron nanocomposite has been established. A variety of alkenes with different functional groups were smoothly oxidized into their corresponding α-keto acids in up to 80% yield. Moreover, the bifunctional iron nanocomposite catalyst showed outstanding catalytic stability for successive recycles without appreciable loss of activity.
- Song, Tao,Ma, Zhiming,Wang, Xiaoxue,Yang, Yong
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supporting information
p. 5917 - 5921
(2021/07/31)
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- A Bifunctional Iron Nanocomposite Catalyst for Efficient Oxidation of Alkenes to Ketones and 1,2-Diketones
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We herein report the fabrication of a bifunctional iron nanocomposite catalyst, in which two catalytically active sites of Fe-Nx and Fe phosphate, as oxidation and Lewis acid sites, were simultaneously integrated into a hierarchical N,P-dual doped porous carbon. As a bifunctional catalyst, it exhibited high efficiency for direct oxidative cleavage of alkenes into ketones or their oxidation into 1,2-diketones with a broad substrate scope and high functional group tolerance using TBHP as the oxidant in water under mild reaction conditions. Furthermore, it could be easily recovered for successive recycling without appreciable loss of activity. Mechanistic studies disclose that the direct oxidation of alkenes proceeds via the formation of an epoxide as intermediate followed by either acid-catalyzed Meinwald rearrangement to give ketones with one carbon shorter or nucleophilic ring-opening to generate 1,2-diketones in a cascade manner. This study not only opens up a fancy pathway in the rational design of Fe-N-C catalysts but also offers a simple and efficient method for accessing industrially important ketones and 1,2-diketones from alkenes in a cost-effective and environmentally benign fashion.
- Ma, Zhiming,Ren, Peng,Song, Tao,Xiao, Jianliang,Yang, Yong,Yuan, Youzhu
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p. 4617 - 4629
(2020/05/19)
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- Biocatalytic Construction of Quaternary Centers by Aldol Addition of 3,3-Disubstituted 2-Oxoacid Derivatives to Aldehydes
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The congested nature of quaternary carbons hinders their preparation, most notably when stereocontrol is required. Here we report a biocatalytic method for the creation of quaternary carbon centers with broad substrate scope, leading to different compound classes bearing this structural feature. The key step comprises the aldol addition of 3,3-disubstituted 2-oxoacids to aldehydes catalyzed by metal dependent 3-methyl-2-oxobutanoate hydroxymethyltransferase from E. coli (KPHMT) and variants thereof. The 3,3,3-trisubstituted 2-oxoacids thus produced were converted into 2-oxolactones and 3-hydroxy acids and directly to ulosonic acid derivatives, all bearing gem-dialkyl, gem-cycloalkyl, and spirocyclic quaternary centers. In addition, some of these reactions use a single enantiomer from racemic nucleophiles to afford stereopure quaternary carbons. The notable substrate tolerance and stereocontrol of these enzymes are indicative of their potential for the synthesis of structurally intricate molecules.
- Marín-Valls, Roser,Hernández, Karel,Bolte, Michael,Parella, Teodor,Joglar, Jesús,Bujons, Jordi,Clapés, Pere
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p. 19754 - 19762
(2020/12/01)
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- Synthesis of Unnatural α-Amino Acid Derivatives via Light-Mediated Radical Decarboxylative Processes
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Unnatural amino acids (UAAs) are key building blocks with widespread application across several scientific fields. Therefore, it is highly attractive to develop straightforward and simple methodologies capable of granting quick access to these species. Herein we report a light-mediated protocol for the synthesis of UAA via radical decarboxylative processes. This methodology, which employs readily available and abundant starting materials – such as carboxylic and α-keto acids – proceeds under very mild reaction conditions and shows a high functional group tolerance. In addition, the products of the radical reaction can be readily derivatized to grant rapid access to complex UAAs. (Figure presented.).
- Merkens, Kay,Aguilar Troyano, Francisco José,Djossou, Jonas,Gómez-Suárez, Adrián
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supporting information
p. 2354 - 2359
(2020/05/06)
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- Domino Synthesis of α,β-Unsaturated γ-Lactams by Stereoselective Amination of α-Tertiary Allylic Alcohols
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Tertiary allylic alcohols equipped with a carboxyl group can be smoothly aminated under ambient conditions by a conceptually new and stereoselective protocol under palladium catalysis. The in situ formed Z-configured γ-amino acid cyclizes to afford an α,β-unsaturated γ-lactam, releasing water as the only byproduct. This practical catalytic transformation highlights the use of a carboxyl group acting as an activating and stereodirecting functional group to provide a wide series of pharma-relevant building blocks. Various control reactions support the crucial role of the carboxyl group in the substrate to mediate these transformations.
- Xie, Jianing,Xue, Sijing,Escudero-Adán, Eduardo C.,Kleij, Arjan W.
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p. 16727 - 16731
(2018/11/23)
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- Room-Temperature Decarboxylative Couplings of α-Oxocarboxylates with Aryl Halides by Merging Photoredox with Palladium Catalysis
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Enabled by merging iridium photoredox catalysis and palladium catalysis, α-oxocarboxylate salts can be decarboxylatively coupled with aryl halides to generate aromatic ketones and amides at room temperature. DFT calculations suggest that this reaction proceeds through a Pd0-PdII-PdIII pathway, in which the PdIII intermediate is responsible for reoxidizing IrII to complete the IrIII-IrIII-IrII photoredox cycle. Like a mergin': Enabled by merging iridium photoredox catalysis and palladium catalysis, palladium-catalyzed decarboxylative coupling of α-oxocarboxylates with aryl halides can proceed at room temperature. DFT calculations suggest that a Pd0-PdII-PdIII catalytic cycle is merged with an IrIII-IrIII-IrII photoredox cycle, in which PdIII is responsible for oxidizing IrII to complete the photoredox cycle.
- Cheng, Wan-Min,Shang, Rui,Yu, Hai-Zhu,Fu, Yao
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p. 13191 - 13195
(2015/09/15)
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- Direct asymmetric hydrogenation of α-keto acids by using the highly efficient chiral spiro iridium catalysts
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A new efficient and highly enantioselective direct asymmetric hydrogenation of α-keto acids employing the Ir/SpiroPAP catalyst under mild reaction conditions has been developed. This method might be feasible for the preparation of a series of chiral α-hydroxy acids on a large scale.
- Yan, Pu-Cha,Xie, Jian-Hua,Zhang, Xiang-Dong,Chen, Kang,Li, Yuan-Qiang,Zhou, Qi-Lin,Che, Da-Qing
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p. 15987 - 15990
(2015/02/19)
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- Enantio- and chemoselective Br?nsted-acid/Mg(nBu) 2 catalysed reduction of α-keto esters with catecholborane
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The first enantio- and chemoselective Br?nsted-acid catalysed reduction of α-keto esters with catecholborane has been developed. The α-hydroxy esters were obtained under mild reaction conditions in virtually quantitative yields and excellent enantioselectivities. With slight modifications both enantiomers can be obtained without any loss of selectivity. This journal is the Partner Organisations 2014.
- Enders, Dieter,St?ckel, Bianca A.,Rembiak, Andreas
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supporting information
p. 4489 - 4491
(2014/04/17)
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- PIPECOLATE-DIKETOAMIDES FOR TREATMENT OF PSYCHIATRIC DISORDERS
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The present invention relates to compounds having a pipecolate diketoamide scaffold, pharmaceutically acceptable salts of these compounds and pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said pipecolate diketoamide compounds can be used for prophylaxis and/or treatment of psychiatric disorders and neurodegenerative diseases, disorders and conditions.
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Page/Page column 36; 37; 38
(2013/07/05)
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- Discovery and initial optimization of 5,5′-disubstituted aminohydantoins as potent β-secretase (BACE1) inhibitors
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8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S1 to the S3 pocket.
- Nowak, Pawel,Cole, Derek C.,Aulabaugh, Ann,Bard, Jonathan,Chopra, Rajiv,Cowling, Rebecca,Fan, Kristi Y.,Hu, Baihua,Jacobsen, Steve,Jani, Minakshi,Jin, Guixan,Lo, Mei-Chu,Malamas, Michael S.,Manas, Eric S.,Narasimhan, Rani,Reinhart, Peter,Robichaud, Albert J.,Stock, Joseph R.,Subrath, Joan,Svenson, Kristine,Turner, Jim,Wagner, Erik,Zhou, Ping,Ellingboe, John W.
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scheme or table
p. 632 - 635
(2010/06/12)
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- Non-steroidal progesterone receptor modulators
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The present invention relates to non-steroidal progesterone receptor modulators of the general formula I, the use of the progesterone receptor modulators for the manufacture of medicaments, and pharmaceutical compositions which comprise these compounds. The compounds according to the invention are suitable for the therapy and prophylaxis of gynecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea, and for the therapy and prophylaxis of hormone-dependent tumours and for use for female fertility control and for hormone replacement therapy.
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Page/Page column 211
(2009/10/31)
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- An efficient new synthesis of racemic cetiedil and a novel route to α-ketocarboxylic acids utilising mild conditions
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We describe a new efficient synthesis of the prescribed racemic drug cetiedil [(±)-2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1H-azepin-1-yl)ethylester], Additionally, we report herein a high yielding large scale, route to its acid precursor 7, subsequently enabling large-scale synthesis of the chiral forms of cetiedil, and detailed pharmacological investigations. Additionally, we describe a novel route to α-ketocarboxylic acids, starting from readily available or easily obtainable aldehydes: The mild conditions utilised opens up its applicability for use on molecules of biological interest. Georg Thieme Verlag Stuttgart.
- Roxburgh, Craig J.,Ganellin, C. Robin,Thorpe, Andrew J.
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p. 1211 - 1214
(2008/02/07)
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- Asymmetric grignard synthesis with cyclic 1,2 aminoalcohols
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Processes for preparing a single enantiomer of an alpha , alpha -disubstituted- alpha -hydroxy acetic acid, especially cyclohexylphenylglycolic acid (CHPGA), is disclosed. The processes employ cyclic 1,2-aminoalcohols as chiral auxiliaries by forming diastereomeric esters of aminoalcohols or diastereomeric amides of oxazolidines. Intermediates useful in the process are also disclosed.
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- Rigid aminoalcohol backbone as a highly defined chiral template for the preparation of optically active tertiary α-hydroxyl acids
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Constrained aminoalcohol derived-ketoester or amides have provided a new entry for the production of enantiopure acid 1 for (S)-oxybutynin.
- Senanayake, Chris H.,Fang, Kevin,Grover, Paul,Bakale, Roger P.,Vandenbossche, Charles P.,Wald, Stephen A.
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p. 819 - 822
(2007/10/03)
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- The synthesis and some pharmacological actions of the enantiomers of the K+-channel blocker cetiedil
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Cetiedil ((±)-2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1H-azepin-1-yl) ethyl ester) possesses anti-sickling and analgesic, antispasmodic, local anaesthetic and vasodilator activities. A total synthesis and circular dichroism spectra of the enantiomers of cetiedil is described, together with a comparison of their effectiveness as blockers of the Ca2+-activated K+ permeability of rabbit erythrocytes; the contractile response of intestinal smooth muscle to acetylcholine; the Ca2+-dependent contraction of depolarized intestinal muscle; and the cell volume-sensitive K+ permeability (K(vol)) of liver cells. The enantiomers did not differ substantially in their ability to block the Ca2+-activated K+ permeability of rabbit red cells or in their effectiveness as blockers of the contractile response of depolarized smooth muscle to externally applied Ca2+. There was a clear difference in the muscarinic blocking activity of the enantiomers, as assessed by inhibition of the contractile response of intestinal smooth muscle to acetylcholine; (+)-cetiedil was 7.7 ± 0.2 (s.d.) times more active than the (-) form. The enantiomers also differed in their potency as blockers of the increase in membrane conductance which occurs when liver cells swell. The concentration of (+)-cetiedil needed to reduce the conductance increase by 50% was 2.04 ± 0.54 (s.d.) μM; (-)-cetiedil was 2.6 ± 0.8 (s.d.) times less active (IC50 of 5.2 ± 1.2 μM). Differences in the biological actions of the enantiomers of cetiedil indicate that a more extensive study could be rewarding in relation to the use of the enantiomers both in therapeutics and in the study of K+ channels.
- Roxburgh, Craig J.,Ganellin, C. Robin,Shiner, Mark A. R.,Benton, David C. H.,Dunn, Philip M.,Ayalew, Yeshi,Jenkinson, Donald H.
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p. 851 - 857
(2007/10/03)
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- An Evaluation of the Substrate Specificity, and of Its Modification by Site-Directed Mutagenesis, of the Cloned L-Lactate Dehydrogenase from Bacillus stearothermophilus
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The L-lactate dehydrogenase of Bacillus stearothermophilus (BSLDH) is a stable, thermophilic oxidoreductase.It has been selected as a model of enzymes with considerable future promise in assymetric synthesis in that it has been cloned to ensure a plentiful and inexpensive supply and because of the potential for tailoring its specificity to accept unnatural substrate structures via the site-directed mutagenesis techniques of moleculer biology.In this study, the specificity of BSLDH toward representative α-keto acids possessing straight- and branched-chain alkyl,cycloalkyl, or aromatic side chains has been evaluated.The results show that substrates that are sterically bulky in the region of the α-keto group to be reduced are poorly accepted by the enzyme.Graphics analyses indicated that the low activities of these hindered substrates might be partly due to a bad interaction of the active site residue Gln102 with large or branched substituents adjacent to the α-keto group.Accordingly, Gln102 has been replaced by the smaller Asn residue by site-directed mutagenesis in an attempt to expand the active site volume available to receive substrates larger than the natural pyruvate.However, the kinetic data show that bulky α-keto acids are only marginally better accommodated by the Gln102 -> Asn mutant than by the wild-type enzyme.
- Luyten, Marcel A.,Bur, Daniel,Wynn, Hla,Parris, Wendy,Glod, Marvin,et al.
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p. 6800 - 6804
(2007/10/02)
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- Process for preparing α-keto-carboxylic acids from acyl halides
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A process for the production of α-keto-carboxylic acids of the general formula: STR1 wherein R1 and R2 are the same or different and are hydrogen, hydrocarbyl radicals, substituted hydrocarbyl radicals or hydrocarbyloxy radicals by reacting an acyl halide of the formula: STR2 wherein R1 and R2 are as defined above and X represents halogen, in a liquid solvent medium, with an alkali metal tetracarbonyl cobaltate complex of the formula: wherein M is an alkali metal to form the corresponding acylcobaltcarbonyl complex of the formula: STR3 wherein R1 and R2 are as defined above, reacting the acylcobaltcarbonyl complex thus formed with carbon monoxide and an alkali metal hydroxide or an alkaline earth metal hydroxide at elevated temperature and elevated pressure in a liquid solvent medium to form the corresponding alkali metal salt or alkaline earth metal salt of the product α-keto-carboxylic acid and thereafter acidifying the salt of the α-keto-carboxylic acid to form the product α-keto-carboxylic acid.
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- Preparation of α-keto-carboxylic acids from acyl halides
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A process for the production of α-keto-carboxylic acids of the general formula: STR1 wherein R1 and R2 are the same or different and are hydrogen, hydrocarbyl radicals, substituted hydrocarbyl radicals or hydrocarbyloxy radicals by reacting an acyl halide of the formula: STR2 wherein R1 and R2 are as defined above and X represents halogen, in a liquid solvent medium, with an alkali metal tricarbonyl[triphenylphosphine]cobaltate complex of the formula: wherein M is an alkali metal to form the corresponding phenylacetyl tricarbonyl[triphenylphosphine]cobalt complex of the formula: STR3 wherein R1 and R2 are as defined above, reacting the acylcobaltcarbonyl complex thus formed with carbon monoxide and an alkali metal hydroxide or an alkaline earth metal hydroxide at elevated temperature and elevated pressure in a liquid solvent medium to form the corresponding alkali metal salt or alkaline earth metal salt of the product α-keto-carboxylic acid and thereafter acidifying the salt of the α-keto-carboxylic acid to form the product α-keto-carboxylic acid.
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