- Rapid assembly of α-ketoamides through a decarboxylative strategy of isocyanates with α-oxocarboxylic acids under mild conditions
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A simple and practical method for α-ketoamide synthesis via a decarboxylative strategy of isocyanates with α-oxocarboxylic acids is described. The reaction proceeds at room temperature under mild conditions without an oxidant or an additive, showing good substrate scope and functional compatibility. Moreover, the applicability of this method was further demonstrated by the synthesis of various bioactive molecules and different application examples through a two-step one-pot operation.
- Huang, Junjie,Liang, Baihui,Chen, Xiuwen,Liu, Yifu,Li, Yawen,Liang, Jingwen,Zhu, Weidong,Tang, Xiaodong,Li, Yibiao,Zhu, Zhongzhi
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supporting information
p. 4783 - 4787
(2021/06/11)
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- Chemoenzymatic Production of Enantiocomplementary 2-Substituted 3-Hydroxycarboxylic Acids from l-α-Amino Acids
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A two-enzyme cascade reaction plus in situ oxidative decarboxylation for the transformation of readily available canonical and non-canonical l-α-amino acids into 2-substituted 3-hydroxycarboxylic acid derivatives is described. The biocatalytic cascade consisted of an oxidative deamination of l-α-amino acids by an l-α-amino acid deaminase from Cosenzaea myxofaciens, rendering 2-oxoacid intermediates, with an ensuing aldol addition reaction to formaldehyde, catalyzed by metal-dependent (R)- or (S)-selective carboligases namely 2-oxo-3-deoxy-l-rhamnonate aldolase (YfaU) and ketopantoate hydroxymethyltransferase (KPHMT), respectively, furnishing 3-substituted 4-hydroxy-2-oxoacids. The overall substrate conversion was optimized by balancing biocatalyst loading and amino acid and formaldehyde concentrations, yielding 36–98% aldol adduct formation and 91–98% ee for each enantiomer. Subsequent in situ follow-up chemistry via hydrogen peroxide-driven oxidative decarboxylation afforded the corresponding 2-substituted 3-hydroxycarboxylic acid derivatives. (Figure presented.).
- Pickl, Mathias,Marín-Valls, Roser,Joglar, Jesús,Bujons, Jordi,Clapés, Pere
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p. 2866 - 2876
(2021/04/14)
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- Structure-Activity Relationship Studies of α-Ketoamides as Inhibitors of the Phospholipase A and Acyltransferase Enzyme Family
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The phospholipase A and acyltransferase (PLAAT) family of cysteine hydrolases consists of five members, which are involved in the Ca2+-independent production of N-acylphosphatidylethanolamines (NAPEs). NAPEs are lipid precursors for bioactive N-acylethanolamines (NAEs) that are involved in various physiological processes such as food intake, pain, inflammation, stress, and anxiety. Recently, we identified α-ketoamides as the first pan-active PLAAT inhibitor scaffold that reduced arachidonic acid levels in PLAAT3-overexpressing U2OS cells and in HepG2 cells. Here, we report the structure-activity relationships of the α-ketoamide series using activity-based protein profiling. This led to the identification of LEI-301, a nanomolar potent inhibitor for the PLAAT family members. LEI-301 reduced the NAE levels, including anandamide, in cells overexpressing PLAAT2 or PLAAT5. Collectively, LEI-301 may help to dissect the physiological role of the PLAATs.
- Zhou, Juan,Mock, Elliot D.,Al Ayed, Karol,Di, Xinyu,Kantae, Vasudev,Burggraaff, Lindsey,Stevens, Anna F.,Martella, Andrea,Mohr, Florian,Jiang, Ming,Van Der Wel, Tom,Wendel, Tiemen J.,Ofman, Tim P.,Tran, Yvonne,De Koster, Nicky,Van Westen, Gerard J.P.,Hankemeier, Thomas,Van Der Stelt, Mario
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p. 9340 - 9359
(2020/10/19)
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- One-pot, two-step synthesis of unnatural α-amino acids involving the exhaustive aerobic oxidation of 1,2-diols
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Herein, we report the nor-AZADO-catalyzed exhaustive aerobic oxidations of 1,2-diols to α-keto acids. Combining oxidation with transamination using dl-2-phenylglycine led to the synthesis of free α-amino acids (AAs) in one pot. This method enables the rapid and flexible preparation of a variety of valuable unnatural AAs, such as fluorescent AAs, photoactivatable AAs, and other functional AAs for bioorthogonal reactions.
- Inada, Haruki,Furukawa, Keisuke,Shibuya, Masatoshi,Yamamoto, Yoshihiko
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supporting information
p. 15105 - 15108
(2019/12/26)
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- Direct Synthesis of Free α-Amino Acids by Telescoping Three-Step Process from 1,2-Diols
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A practical telescoping three-step process for the syntheses of α-amino acids from the corresponding 1,2-diols has been developed. This process enables the direct synthesis of free α-amino acids without any protection/deprotection step. This method was also effective for the preparation of a 15N-labeled α-amino acid. 1,2-Diols bearing α,β-unsaturated ester moieties afforded bicyclic α-amino acids through intramolecular [3 + 2] cycloadditions. A preliminary study suggests that the resultant α-amino acids are resolvable by aminoacylases with almost complete selectivity.
- Inada, Haruki,Shibuya, Masatoshi,Yamamoto, Yoshihiko
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supporting information
p. 709 - 713
(2019/01/25)
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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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- Deracemization and Stereoinversion of α-Amino Acids by l-Amino Acid Deaminase
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Enantiomerically pure α-amino acids are compounds of primary interest for the fine chemical, pharmaceutical, and agrochemical sectors. Amino acid oxidases are used for resolving d,l-amino acids in biocatalysis. We recently demonstrated that l-amino acid deaminase from Proteus myxofaciens (PmaLAAD) shows peculiar features for biotechnological applications, such as a high production level as soluble protein in Escherichia coli and a stable binding with the flavin cofactor. Since l-amino acid deaminases are membrane-bound enzymes, previous applications were mainly based on the use of cell-based methods. Now, taking advantage of the broad substrate specificity of PmaLAAD, a number of natural and synthetic l-amino acids were fully converted by the purified enzyme into the corresponding α-keto acids: the fastest conversion was obtained for 4-nitrophenylalanine. Analogously, starting from racemic solutions, the full resolution (ee >99%) was also achieved. Notably, d,l-1-naphthylalanine was resolved either into the d- or the l-enantiomer by using PmaLAAD or the d-amino acid oxidase variant having a glycine at position 213, respectively, and was fully deracemized when the two enzymes were used jointly. Moreover, the complete stereoinversion of l-4-nitrophenylalanine was achieved using PmaLAAD and a small molar excess of borane tert-butylamine complex. Taken together, recombinant PmaLAAD represents an l-specific amino acid deaminase suitable for producing the pure enantiomers of several natural and synthetic amino acids or the corresponding keto acids, compounds of biotechnological or pharmaceutical relevance. (Figure presented.).
- Rosini, Elena,Melis, Roberta,Molla, Gianluca,Tessaro, Davide,Pollegioni, Loredano
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p. 3773 - 3781
(2017/11/13)
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- Enzymatic Resolution by a d-Lactate Oxidase Catalyzed Reaction for (S)-2-Hydroxycarboxylic Acids
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Oxidase-catalyzed kinetic resolution is important for the production of enantiopure 2-hydroxycarboxylic acids (2-HAs), which are versatile building blocks for the synthesis of many significant compounds. However, in contrast to that of (R)-2-HAs, the production of (S)-2-HA is challenging because of the lack of related oxidases. Herein, suitable enzymes were screened systematically through the analysis of numerous putative d-lactate oxidase sequences and identification of several required properties. Finally, a d-lactate oxidase from Gluconobacter oxydans 621H with advantageous characteristics, such as good solubility, broad substrate spectrum, and high stereoselectivity, was selected to resolve 2-HAs into (S)-2-HAs. A variety of (S)-2-HAs was produced successfully using this d-lactate oxidase with excellent enantiomeric excess values (>99 %). The presented screening criteria and approach for target biocatalysis suggested a guideline for the production of optically active chemicals such as (S)-2-HAs.
- Sheng, Binbin,Xu, Jing,Ge, Yongsheng,Zhang, Shuo,Wang, Danqi,Gao, Chao,Ma, Cuiqing,Xu, Ping
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p. 2630 - 2633
(2016/08/30)
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- Chemoselective conversion from α-hydroxy acids to α-keto acids enabled by nitroxyl-radical-catalyzed aerobic oxidation
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The chemoselective oxidation of α-hydroxy acids to α-keto acids catalyzed by 2-azaadamantane N-oxyl (AZADO), a nitroxyl radical catalyst, is described. Although α-keto acids are labile and can easily release CO2 under oxidation conditions, the use of molecular oxygen as a cooxidant enables the desired chemoselective oxidation.
- Furukawa, Keisuke,Inada, Haruki,Shibuya, Masatoshi,Yamamoto, Yoshihiko
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supporting information
p. 4230 - 4233
(2016/09/09)
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- Chemoselective catalytic oxidation of 1,2-diols to α-hydroxy acids controlled by TEMPO-ClO2 charge-transfer complex
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Chemoselective catalytic oxidation from 1,2-diols to α-hydroxy acids in a cat. TEMPO/cat. NaOCl/NaClO2 system has been achieved. The use of a two-phase condition consisting of hydrophobic toluene and water suppresses the concomitant oxidative cleavage. A study of the mechanism suggests that the observed selectivity is derived from the precise solubility control of diols and hydroxy acids as well as the active species of TEMPO. Although the oxoammonium species TEMPO+Cl- is hydrophilic, the active species dissolves into the organic layer by the formation of the charge-transfer (CT) complex TEMPO-ClO2 under the reaction conditions.
- Furukawa, Keisuke,Shibuya, Masatoshi,Yamamoto, Yoshihiko
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supporting information
p. 2282 - 2285
(2015/05/13)
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- Asymmetric friedel-crafts alkylation of α-substituted β-nitroacrylates: Access to β2,2-amino acids bearing indolic all-carbon quaternary stereocenters
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A highly enantioselective Friedel-Crafts alkylation reaction of indoles with acyclic α-substituted β-nitroacrylates is developed under the catalysis of Ni(ClO4)2-bisoxazoline complex at 1 mol % catalyst loading, affording chiral indolic β-nitroesters bearing all-carbon quaternary stereocenters in excellent yields and ees of up to 97%. Transformation of one of the products to β2,2-amino ester and tetrahydro-β-carboline through nitro reduction and sequential Pictet-Spengler cyclization was exemplified.
- Weng, Jian-Quan,Deng, Qiao-Man,Wu, Liang,Xu, Kai,Wu, Hao,Liu, Ren-Rong,Gao, Jian-Rong,Jia, Yi-Xia
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supporting information
p. 776 - 779
(2014/03/21)
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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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- Microwave-assisted domino access to C2-chain functionalized furans from tertiary propargyl vinyl ethers
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Tertiary propargyl vinyl ethers armed with an electron-withdrawing group (amide or ester) at the tertiary propargylic position have been efficiently transformed into trisubstituted C2-chain functionalized furans. The metal-free domino transformation involves a microwave-assisted tandem [3,3]-propargyl Claisen rearrangement/5-exo-dig O-cyclization reaction. The manifold can be performed in a one-pot fashion from the primary components (1,2-ketoester/1,2-ketoamide or tertiary propargyl alcohols).
- Tejedor, David,Cotos, Leandro,Garcia-Tellado, Fernando
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supporting information; scheme or table
p. 4422 - 4425
(2011/10/08)
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- Asymmetrie aerobic oxidation of α-hydroxy acid derivatives by C 4-symmetric, vanadate-centered, tetrakisvanadyl(V) clusters derived from N-salicylidene-α-aminocarboxylates
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(Chemical Equation Presented) A series of chiral vanadyl(V) methoxides bearing 3-t-butyl-5-substituted N-salicylene-L-valinate and L-t-leucinate as chiral auxiliaries has been prepared. In all cases except the 3,5-di-t-butyl analogue, they exist as monomers both in solution and in the single crystal state. In the case of the 3,5-di-t-butyl analogue, the architectural nature of the vanadyl(V) complex highly depends on the base used during the complex formation event. A pentanuclear C4-symmetric complex was formed when potassium salts were employed instead of the corresponding sodium salts. A central vanadate(V) unit serves to grip four identical chiral monomelic vanadyl(V) units together, by which a potassium ion sits on top of the four flanking units through carbonyl coordinations and serves to hold the whole cluster by cooperation with the central vanadate(V) unit. In comparison with the corresponding monomelic vanadyl(V) methoxide complex, the cluster complex was utilized to facilitate the asymmetric aerobic oxidations of various racemic α-hydroxyesters, -amides, and -thioesters with excellent selectivity factors (krel 40 to >500).
- Chen, Chien-Tien,Bettigeri, Sampada,Weng, Shiue-Shien,Pawar, Vijay D.,Lin, Ya-Hui,Liu, Cheng-Yuan,Lee, Way-Zen
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p. 8175 - 8185
(2008/02/13)
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- Hydrogenation of α-oxo carboxylic acid derivatives over nickel and palladium catalysts
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Hydrogenation of a number of α-oxo carboxylic acid derivatives over nickel catalysts and palladium black at 20-90°C has been studied. Hydrogenation of sodium 2-oxo-4-phenyl-3-butenoate over nickel catalysts results in reduction of the double bond and keto group to afford sodium 2-hydroxy-4-phenylbutanoate. Hydrogenation of the same substrate over palladium black can be stopped at the stage of formation of sodium 2-oxo-4-phenylbutanoate. Under similar conditions, ethyl 2,2-diethoxy-4-phenyl-3-butenoate shows a low reactivity. Sodium 2-oxo-4-(3-pyridyl)-3-butenoate is hydrogenated over palladium catalysts with formation of sodium 2-hydroxy-4-(3-pyridyl)-3-butenoate, whereas the reaction with analogous furan derivatives is accompanied by cleavage of the furan ring. One-step procedures have been developed for preparation of (9-fluorenyl)hydroxyacetic acid and 1-(9-fluorenyl)-1,2-ethanediol by hydrogenation of (9-fluorenyl)oxo-acetic acid (or its sodium salt) and methyl (9-ffuorenyl)oxoacetate, respectively. 1998 MAHK "Hayka/Interperiodica".
- Slavinskaya,Sile,Korchagova,Katkevich,Lipsbergs,Lukevits
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p. 1750 - 1754
(2007/10/03)
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- Stereochemical Control in Microbial Reduction. 30. Reduction of Alkyl 2-Oxo-4-phenylbutyrate as Precursors of Angiotensin Converting Enzyme (ACE) Inhibitors
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Alkyl 2-oxo-4-phenylbutyrates are reduced to the corresponding alkyl (R)-2-hydroxy-4-phenylbutyrates, versatile chiral building blocks in organic synthesis, in high chemical yield (80-90%) with excellent stereoselectivity (>90%ee). The reaction has been run in aqueous diethyl ether at 30 °C for 24 h under the catalysis of bakers' yeast (Saccharomyces cerevisiae) which was preincubated for 6 h in the presence of phenacyl chloride. The amount of water in the medium should be controlled strictly not to exceed 0.8 mL (g yeast)-1.
- Dao, Duc Hai,Kawai, Yasushi,Hida, Kouichi,Bornes, Sander,Nakamura, Kaoru,Ohno, Atsuyoshi,Okamura, Mutsuo,Akasaka, Takeshi
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p. 425 - 432
(2007/10/03)
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- Palladium-Catalyzed Double and Single Carbonylations of β-Amino Alcohols. Selective Synthesis of Morpholine-2,3-diones and Oxazolidin-2-ones and Applications for Synthesis of α-Oxo Carboxylic Acids
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Catalytic cross double carbonylation of secondary amines and alcohols proceeds in the presence of [PdCl2(MeCN)2] and CuI under carbon monoxide (80 atm) and oxygen (5 atm). Catalytic intramolecular double carbonylation of β-amino alcohols gives morpholine-2,3-diones, which are excellent protecting compounds of amino alcohols and important precursors for biologically active nitrogen compounds. In contrast, catalytic single carbonylation of β-amino alcohols under a mixture (1 : 1) of carbon monoxide and oxygen (1.0 atm) proceeds to give oxazolidin-2-ones selectively. The reaction can be explained by assuming a mechanism which includes intramolecular nucleophilic attack of the hydroxy group of (hydroxyethyl)aminocarbonyl ligands on the CO ligand of the carbamoylpalladium(II) complexes, followed by reductive elimination to give morpholine-2,3-diones. In contrast, direct nucleophilic attack of the hydroxy group to the carbamoyl group affords oxazolidin-2-ones. As a common intermediate for the double and single carbonylations, carbamoylpalladium(II) complex has been isolated by the reaction of [PdCl2(PMe3)2] with β-amino alcohol under CO. The present double carbonylation of amino alcohols provides a novel and convenient method for synthesis of α-oxo carboxylic acids. Thus, the morpholine-2,3-diones obtained undergo reaction with Grignard reagents chemoselectively at the ester positions to give 2-substituted 2-hydroxymorpholin-3-ones, which undergo acid hydrolysis to give α-oxo carboxylic acids.
- Imada, Yasushi,Mitsue, Yo,Ike, Kazuo,Washizuka, Ken-Ichi,Murahashi, Shun-Ichi
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p. 2079 - 2090
(2007/10/03)
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- Pyruvic Acid Dimethylhydrazone. A Synthetic Equivalent of the Pyruvic Acid Dianion
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The pyruvic acid dimethyl hydrazone can be easily prepared in ether.This compound, after deprotonation with alkyllithium, forms a strong nucleophile which on tratment with electrophiles and acidic work up yield α-ketoacids, α-hydroxybutenolides or α,γ-diketoacids.
- Tapia, Ines,Alcazar, Victoria,Moran, Joaquin R.,Caballero, Cruz,Grande, Manuel
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p. 697 - 700
(2007/10/02)
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- Facile Synthesis of α-Keto Acids and Esters by Palladium-Catalyzed Decarboxylation Reactions of Diallyl α-Oxalcarboxylates
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Reaction of diallyl α-oxalcarboxylates with formic acid in the presence of palladium catalyst gave α-keto acid in good yields.When the reaction was carried out without formic acid, decarboxylation-allylation took place to give allyl β-allyl-α-keto carboxylates.
- Shimizu, Isao,Makuta, Toshiyuki,Oshima, Masato
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p. 1457 - 1460
(2007/10/02)
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- Process for preparing arylalkylpyruvic acids
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A process for the production of an arylalkylpyruvic acid of the general formula: wherein: A represents an aromatic hydrocarbon radical containing 1 or 2 condensed benzene rings, each R, which may be the same or different, represents hydrogen or a linear or branched alkyl radical with up to 4 carbon atoms which is unsubstituted or substituted by a nitro group or by an alkoxy group containing 1 to 4 carbon atoms, or an alkoxy group containing 1 to 4 carbon atoms, or a halogeno, nitrile, nitro or alkylcarbonyloxy group, n is 0 or an integer from 1-3 when A contains one benzene ring, and n is 0 or an integer from 1-5 when A contains two condensed benzene rings and m is 1-20, which comprises carbonylating an arylalkyl halide of the general formula: where R, n, A and m are defined above and X represents halogen, by reacting the arylalkyl halide in a liquid solvent medium, with carbon monoxide at elevated temperature and pressure in the presence of a catalytic amount of a metal carbonyl compound and an alkali or an alkaline earth metal inorganic base.
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- DIPEPTIDES CONTAINING THIALYSINE AND RELATED AMINO ACIDS AS ANTIHYPERTENSIVES
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The invention relates to dipeptide compounds containing thialysine and related amino acids which are useful as converting enzyme inhibitors and as antihypertensives.
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- AMINOACYL-CONTAINING DIPEPTIDE DERIVATIVES USEFUL AS ANTIHYPERTENSIVES
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The invention relates to aminoacyl-containing dipeptide derivatives and related compounds which are useful angiotensin converting enzyme inhibitors and as antihypertensives.
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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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