- Visible-Light-Mediated Carbonyl Alkylative Amination to All-Alkyl α-Tertiary Amino Acid Derivatives
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The all-alkyl α-tertiary amino acid scaffold represents an important structural feature in many biologically and pharmaceutically relevant molecules. Syntheses of this class of molecule, however, often involve multiple steps and require activating auxiliary groups on the nitrogen atom or tailored building blocks. Here, we report a straightforward, single-step, and modular methodology for the synthesis of all-alkyl α-tertiary amino esters. This new strategy uses visible light and a silane reductant to bring about a carbonyl alkylative amination reaction that combines a wide range of primary amines, α-ketoesters, and alkyl iodides to form functionally diverse all-alkyl α-tertiary amino esters. Br?nsted acid-mediated in situ condensation of primary amine and α-ketoester delivers the corresponding ketiminium species, which undergoes rapid 1,2-addition of an alkyl radical (generated from an alkyl iodide by the action of visible light and silane reductant) to form an aminium radical cation. Upon a polarity-matched and irreversible hydrogen atom transfer from electron rich silane, the electrophilic aminium radical cation is converted to an all-alkyl α-tertiary amino ester product. The benign nature of this process allows for broad scope in all three components and generates structurally and functionally diverse suite of α-tertiary amino esters that will likely have widespread use in academic and industrial settings.
- Blackwell, J. Henry,Kumar, Roopender,Gaunt, Matthew J.
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- Enantioselective Synthesis of d- and l-α-Amino Acids by Enzymatic Transamination Using Glutamine as Smart Amine Donor
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Enzymatic transamination is a useful method for the green and highly enantioselective synthesis of chiral amines and non-canonical amino acids which are of major importance as intermediates in medicinal chemistry. However, transamination reactions are usually reversible and synthetic applications of transaminases often require the implementation of an equilibrium shift strategy. Herein, we report a highly effective approach using glutamine as smart amine donor. This amino acid is converted upon transamination into 2-oxoglutaramate which undergoes a fast cyclisation displacing the transamination equilibrium. We have developed a new activity assay in order to identify transaminases from biodiversity able to convert various α-keto acids into valuable amino acids of l- or d-series in the presence of glutamine as amine donor. Discovered transaminases were then used to prepare in high yield and with high enantioselectivity three amino acids of pharmaceutical importance, homophenylalanine, homoalanine and tert-leucine by simply using a nearly stoichiometric amount of glutamine as amine donor. (Figure presented.).
- Heuson, Egon,Charmantray, Franck,Petit, Jean-Louis,de Berardinis, Véronique,Gefflaut, Thierry
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supporting information
p. 778 - 785
(2019/01/04)
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- Evaluation of α-hydroxycinnamic acids as pyruvate carboxylase inhibitors
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Through a structure-based drug design project (SBDD), potent small molecule inhibitors of pyruvate carboxylase (PC) have been discovered. A series of α-keto acids (7) and α-hydroxycinnamic acids (8) were prepared and evaluated for inhibition of PC in two assays. The two most potent inhibitors were 3,3′-(1,4-phenylene)bis[2-hydroxy-2-propenoic acid] (8u) and 2-hydroxy-3-(quinoline-2-yl)propenoic acid (8v) with IC50 values of 3.0 ± 1.0 μM and 4.3 ± 1.5 μM respectively. Compound 8v is a competitive inhibitor with respect to pyruvate (Ki = 0.74 μM) and a mixed-type inhibitor with respect to ATP, indicating that it targets the unique carboxyltransferase (CT) domain of PC. Furthermore, compound 8v does not significantly inhibit human carbonic anhydrase II, matrix metalloproteinase-2, malate dehydrogenase or lactate dehydrogenase.
- Burkett, Daniel J.,Wyatt, Brittney N.,Mews, Mallory,Bautista, Anson,Engel, Ryan,Dockendorff, Chris,Donaldson, William A.,St. Maurice, Martin
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p. 4041 - 4047
(2019/08/26)
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- Enantioselective Organocatalyzed Consecutive Synthesis of Alkyl 4,5-Dihydrofuran-2-carboxylates from α-Keto Esters and (Z)-β-Chloro-β-nitrostyrenes
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Alkyl 4,5-dihydrofuran-2-carboxylates can be efficiently obtained via an enantioselective organocatalyzed consecutive reaction between α-keto esters and (Z)-(2-chloro-2-nitroethenyl)benzenes. The overall sequence combines a (R,R)-TUC-catalyzed Michael addition with a DABCO-promoted intramolecular O-alkylation leading to the title products as single diastereomers with enantiomeric excesses from 86% up to 97%.
- Becerra, Diana,Raimondi, Wilfried,Dauzonne, Daniel,Constantieux, Thierry,Bonne, Damien,Rodriguez, Jean
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supporting information
p. 195 - 201
(2016/12/24)
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- Novel Synthesis of α-Keto Esters and Amides by an sp3 C-H Oxidation of Nitromethyl Aryl Ketones Promoted by Ion-Supported (Diacetoxyiodo)benzene
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A simple and efficient method is described for the preparation of α-keto esters or amides from nitromethyl aryl ketones. In the presence of nucleophiles (alcohols or amines), the ion-supported (di-acetoxyiodo)benzene-promoted sp3 C-H oxidation of nitromethyl aryl ketones proceeded efficiently under mild conditions to give the corresponding α-keto esters and amides in moderate to good yields. This is the first reported use of (diacetoxyiodo)benzene in the synthesis of α-keto esters and amides. The reaction is ecofriendly and has the -advantages of mild conditions, short reaction times, and a recyclable reagent.
- Jiang, Xiaoying,Gan, Bing,Liu, Jiwei,Xie, Yuanyuan
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supporting information
p. 2737 - 2741
(2016/11/25)
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- Catalytic cyclization reactions of Huisgen zwitterion with -ketoesters by in situ chemoselective phosphine oxide reduction
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The first examples of catalytic cyclization reactions between the Huisgen zwitterion and α-ketoester derivatives are reported. The use of phenylsilane with a substoichiometric amount of bis(p-nitrophenyl)phosphate/diisopropylethylamine proved to be crucial for the in situ reduction of the phosphine oxide formed during the reaction. The optimized protocol is applied to alkyl or aryl ketoesters, furnishing either the corresponding cycloadducts or the hydrazone derivatives, depending on the substitution patterns of the substrates, in moderate to good yields (up to 80% yield, 18 examples).
- Fourmy, Kévin,Voituriez, Arnaud
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supporting information
p. 1537 - 1540
(2015/03/30)
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- A novel method for synthesis of α-keto esters with phenyliodine(III) diacetate
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A rapid and efficient synthesis of α-keto esters from β-ketonitriles using phenyliodine(III) diacetate is reported. This protocol gave α-keto esters in good yields. This is the first time to report the application of hypervalent iodine(III) reagents in the synthesis of α-keto esters. A plausible reaction mechanism is proposed.
- Xie, Yuanyuan,Liu, Jiwei,Huang, Yingyi,Yao, Lixia
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supporting information
p. 3793 - 3795
(2015/06/08)
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- Simplified procedure for TEMPO-catalyzed oxidation: Selective oxidation of alcohols, α-hydroxy esters, and amides using TEMPO and calcium hypochlorite
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A wide range of primary and secondary multifunctional alcohols, α-hydroxyamides, and α-hydroxyesters were oxidized to their corresponding aldehydes, ketones, α-ketoamides, and α-ketoesters under mild reaction conditions using 2,2,6,6-tetramethylpiperidine-1-oxyl as a catalyst with calcium hypochlorite as an oxidant [TEMPO-Ca(OCl)2]. This simplified method does not require any transition metals, acids, or bases and demonstrates controlled and selective oxidation of structurally diverse alcohols, affording moderate to excellent yields at room temperature.
- Reddy, Sabbasani Rajasekhara,Stella, Selvaraj,Chadha, Anju
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experimental part
p. 3493 - 3503
(2012/09/22)
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- Catalytic enantioselective protonation of α-oxygenated ester enolates prepared through phospha-brook rearrangement
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(Chemical Equation Presented) Phosphonates go chiral: The organocatalytic enantioselective reaction of α-ketoesters with phosphites using cinchona alkaloids and Na2CO3 has afforded α-phosphonyloxy esters with high enantioselectivities (see scheme). This process allows the formation of both enantiomers of the product. A catalyst loading of as low as 2 mol% does not result in a significant decrease of the enantioselectivity.
- Hayashi, Masashi,Nakamura, Shuichi
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supporting information; experimental part
p. 2249 - 2252
(2011/04/16)
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- Highly enantioselective hydrogenation of 2-oxo-4-arybutanoic acids to 2-hydroxy-4-arylbutanoic acids
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The Ru-catalyzed asymmetric hydrogenation of 2-oxo-4-arybutanoic acids to afford 2-hydroxy-4-arybutanoic acids was accomplished by employing SunPhos as chiral ligand and 1 M aq HBr as additive. The high enantioselectivities (88.4%-92.6% ee) and efficiency (TON=10,000, TOF=300 h-1) make this method efficient for the synthesis of an important intermediate, (R)-2-hydroxy-4-phenylbutanoic acid, for ACE inhibitors.
- Zhu, Lufeng,Chen, Houhe,Meng, Qinghua,Fan, Weizheng,Xie, Xiaomin,Zhang, Zhaoguo
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supporting information; experimental part
p. 6186 - 6190
(2011/09/19)
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- A high performance oxidation method for secondary alcohols by inductive activation of TEMPO in combination with pyridine-bromine complexes
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A new TEMPO-mediated catalytic oxidation method in combination with Py·HBr3 (stoichiometric) is developed for oxidation of secondary alcohols to the corresponding ketones. The performance of this oxidizing system is better compared with that of TEMPO method combined with R4NBr3. Poly(4-vinylpyridine)·HBr3 can be used in place of Py·HBr3. The electron-withdrawing substituent at the C-4 position of TEMPO increases the reactivity of TEMPO significantly in the oxidation of electron-deficient alcohols such as polyhaloalkylmethanols. Inductive effect of the substituent of TEMPO is discussed through the characterization of the redox potential of N-O radical by cyclic voltammetry.
- Mei, Zhen-Wu,Omote, Takumi,Mansour, Mounir,Kawafuchi, Hiroyuki,Takaguchi, Yutaka,Jutand, Anny,Tsuboi, Sadao,Inokuchi, Tsutomu
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experimental part
p. 10761 - 10766
(2009/04/11)
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- PROCESS FOR PRODUCING ALPHA-OXOCARBONYL COMPOUND
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A process by which an α-oxocarbonyl compound useful as an intermediate for pharmaceuticals/agricultural chemicals can be industrially advantageously and efficiently produced in a high yield. The process, which is for producing an α-oxocarbonyl compound represented by the general formula (I) wherein R1 and R2 are as defined in the description, comprises oxidizing an α-hydroxycarbonyl compound represented by the general formula (II) , with oxygen or air in the presence of a carboxylic acid and at least one vanadium compound selected from divanadium pentaoxide, divanadium trioxide, divanadium tetraoxide, ammonium metavanadate, sodium metavanadate, potassium metavanadate, triethoxyoxovanadium, tripropoxyoxovanadium, triisopropoxyoxovanadium, vanadium oxobis(acetylacetonate) and vanadium tris(acetylacetonate).
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Page/Page column 8
(2008/06/13)
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- Method for transferring amino acid into ketone acid(ester)
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A method for transferring amino acid into ketone acid (ester) may obtain ketone acid (ester) at low cost. The method uses sodium hypochlorous acid as oxidizing agent and proceeds oxidation reaction with amino acid or its derivatives so as to obtain ketone acid and its derivatives. The sodium hypochlorous acid is easily to get with low cost and the conditions of the reaction are mild so that the method meets the needs of the industry.
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Page/Page column 2
(2008/06/13)
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- Facile Synthesis of α-Ketocarbonyl Compounds from α-Hydroxycarbonyl Compounds
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Various α-ketocarbonyl compounds were obtained in excellent yields under mild condition from the reaction of the corresponding α-hydroxycarbonyl compounds with sodium hypobromite in the presence of HCl catalyst.
- Chang, Hae Sung,Woo, Jae Chun,Lee, Kyoung Mo,Ko, Young Kwan,Moon, Surk-Sik,Kim, Dae-Whang
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- An efficient synthesis of chiral homophenylalanine derivatives via enantioselective hydrogenation
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Chiral homophenylalanine derivatives were synthesized via enantioselective hydrogenation of 5a and 5b catalyzed by rhodium complexes bearing chiral phosphine and phosphinite legands. Enantiomeric excesses up to 96.2% were achieved when S-spiroOP(S-1) was used as a chiral ligand under 500 psi of H2 pressure in acetone.
- Li, Xingshu,Yeung, Chi-Hung,Chan, Albert S. C.,Lee, Dong-Sheng,Yang, Teng-Kuei
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p. 3863 - 3867
(2007/10/03)
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- A convenient preparation of α-keto esters by the Grignard reaction on N-acylpyrazoles
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The α-keto esters were prepared by the formation of N-acylpyrazole followed by the appropriate Grignard reaction. These short step reaction conveniently afforded various α-keto esters in good yields.
- Kashima, Choji,Shirahata, Yoshie,Tsukamoto, Yoshihiro
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p. 459 - 464
(2007/10/03)
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- New way for the preparation of 4-phenyl-2-oxobutyric acid ethyl ester
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New way for the preparation of 4-phenyl-2-oxobutyric acid ethyl ester 1 has been elaborated. The four-steps synthesis from ethyl pyruvate involves the consecutive condensation of ethyl pyruvate with benzaldehyde, hydrogenation of benzylidenepyruvic acid sodium salt 2a to 4-phenyl-2-hydroxybutyric acid 3 on Ni catalysts, esterification of 3 and oxidation of the ester to 1 with CrO3.
- Siavinska,Sile,Korchagova,Katkevich,Lukevics
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p. 2229 - 2233
(2007/10/03)
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- Oxidations of Dihydroxyalkanoates to Vicinal Tricarbonyl Compounds with a 4-BzoTEMPO-Sodium Bromite System or by Indirect Electrolysis Using 4-BzoTEMPO and Bromide Ion
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An efficient access to vicinal dioxoalkanoates, one of structural elements of potent competitive inhibitors of hydrolytic enzyme, from 2,3-dihydroxyalkanoates has been developed, which features an one-step procedure with a mild oxidizing system using recyclable 2, 2, 6, 6-tetramethylpiperidine-1-oxyl in combination with NaBrO2*3H2O or electrogenerated active bromine species as a real oxidant.
- Inokuchi, Tsutomu,Liu, Ping,Torii, Sigeru
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p. 1411 - 1414
(2007/10/02)
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- Process for producing α-keto-carboxylic acid ester
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The invention provides a novel process for produing α -keto-carboxylic acid esters that are useful as intermediates for the preparation of pharmaceutical drugs in high yield by oxidizing α -hydroxycarbocylic acid esters with hypochlorous acid in the presence of nitroxy radical.
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- OXIDATION OF α-HYDROXY ESTERS TO α-KETO ESTERS USING THE DESS-MARTIN PERIODINANE REAGENT
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The oxidation of α-hydroxy esters, including peptidyl α-hydroxy esters, with the Dess-Martin periodinane reagent is a useful and general method for the preparation of α-keto esters.
- Burkhart, Joseph P.,Peet, Norton P.,Bey, Philippe
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p. 3433 - 3436
(2007/10/02)
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- Highly Selective Photoinduced Dimerization of Alkyl Pyruvates Catalyzed by Cobaloxime
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Alkyl pyruvates with an electron-withdrawing group, an α-methyl group, and a group that can react with hydridocobaloxime were dimerized selectively to dialkyl 4-hydroxy-4-methyl-2-oxopentanedioates in the presence of a catalytic amount of benzyl(pyridine)cobaloxime under irradiation by a tungsten lamp.Hydridocobaloxime is the active species produced by the reaction of photoactivated benzylcobaloxime and alkyl pyruvate in the initiation step.The hydridocobaloxime induced the dimerization reaction catalytically via the insertion of enol pyruvate into the Co-H bond of the hydridocobaloxime to give an intermediate alkylcobaloxime, which, in the catalytic cycle, reacted with the second alkyl pyruvate.
- Kijima, Masashi,Miyamori, Kiyokatsu,Sato, Takeo
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p. 1719 - 1722
(2007/10/02)
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- NAD(P)H MODELS 20 CHEMOSELECTIVE METAL ION CATALYZED REDUCTION OF α-KETO-β,γ-UNSATURATED ESTERS BY 1,4-DIHYDROPYRIDINE DERIVATIVES
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Ethyl 2-oxo-4-aryl-3-butene-1-oates (1a-c) are reduced by NAD(P)H models (1-n-propyl-1,4-dihydronicotinamide (4) and Hantzsch ester (5)), in presence of magnesium perchlorate.One equivalent of the reductant reduces the substrates selectively to the corresponding 2-oxo-4-arylbutanoates (6, 10a, b).An additional equivalent and higher temperature, converts ethyl 2-oxo-4-phenylbutanoate (6) to ethyl 2-hydroxy-4-phenylbutanoate (7).Reduction of ethyl 2-oxo-4-phenyl-3-buten-1-oate (1a) by Hantzsch ester in C2H5OD or by Hantzsch ester-4,4-d2 in C2H5OH, leads to direct transfer of the hydrogen or deuterium, respectively, without isotopic scrambling.These results have been interpreted to support the hydride transfer mechanism.
- Meijer, Louis H. P.,Pandit, Upendra K.
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p. 467 - 472
(2007/10/02)
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- Studies on Conjugated Nitriles. IV. Reaction of Ethyl Cyanoformate with Organomagnesium, -zinc, and - cadmium Reagents, and Phosphonium Ylide
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The reaction of ethyl cyanoformate (1a) with phenylcadmium bromide (3a) gave ethyl benzoate (4), ethyl 2-phenyl-2-oxoacetate (5a), and 2-ethoxycarbonyl-2,4-diphenyl-3-imidazoline-5-one (6).In the presence of zinc chloride, the addition of 3a to the cyano group of 1a occured to give only 5a.The similar reaction of 1a with other organocadmium reagents (3b-f) in the presence of zinc chloride gave the corresponding α-ketoesters (5b-f) in moderate yields.The reactions of 1a with other organometallic reagents, e.g. phenylmagnesium (2a), -zinc (8) and -mercuric bromide (9) in the presence or in the absence of zinc chloride were examined.Furthermore, the addition of phosphonium ylide 13a to the cyano group of 1a in the presence of stannic chloride occured exclusively to give the phosphonium salt 14.The results are discussed in terms of the hard and soft acids and bases (HSAB) principle.Keywords - ethyl cyanoformate; benzoyl cyanide; organocadmium reagent; organozinc reagent; phosphonium ylide; cyano group addition; α-ketoester; α-dehydroamino ester; Lewis acid
- Akiyama, Yasunobu,Takebayashi, Shoko,Kawasaki, Tomomi,Sakamoto, Masanori
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p. 1800 - 1807
(2007/10/02)
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- CONVERSION OF α-AMINOESTERS TO α-KETOESTERS
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A one-pot method for converting α-aminoesters to α-ketoesters via peracid oxidation of diazoesters is described.
- Thorsett, E. D.
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p. 1875 - 1876
(2007/10/02)
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