- An unusual matrix of stereocomplementarity in the hydroxylation of monohydroxy fatty acids catalysed by cytochrome P450 from Bacillus megaterium with potential application in biotransformations
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Cytochrome P450 from Bacillus megaterium catalyses the diastereoselective hydroxylations of 13-hydroxymyristic acid, to predominantly erythro-12,13-dihydroxymyristic acid, and of 12-hydroxymyristic acid to give predominantly threo-12,13-dihydroxymyristic acid, in reactions that are stereocomplementary and with considerable potential application in biotransformations.
- Ahmed, Farjad,Al-Mutairi, Eiman H.,Avery, Kathryn L.,Cullis, Paul M.,Primrose, William U.,Roberts, Gordon C. K.,Willis, Christine L.
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Read Online
- Efficient Biosynthesis of (R)- or (S)-2-Hydroxybutyrate from l-Threonine through a Synthetic Biology Approach
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An efficient multi-enzyme cascade reaction for the synthesis of (R)- or (S)-2-hydroxybutyric acid [(R)- or (S)-2-HB] from l-threonine was developed by using recombinant Escherichia coli cells expressing separately or co-expressing l-threonine deaminase from Escherichia coli K-12 (ilvA), formate dehydrogenase (FDH) from Candida boidinii and l-lactate dehydrogenase (l-LDH) from Oryctolagus cuniculus or d-lactate dehydrogenase (d-LDH) from Staphylococcus epidermidis ATCC 12228. Up to 750 mM of l-threonine were completely transformed to (R)- or (S)-2-HB in optically pure form (>99% ee) with high isolated yields. This one-pot multi-enzyme transformation provides a new practical method for the synthesis of these important optically pure compounds. (Figure presented.).
- Yao, Peiyuan,Cui, Yunfeng,Yu, Shanshan,Du, Yuncheng,Feng, Jinhui,Wu, Qiaqing,Zhu, Dunming
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Read Online
- Highly Enantioselective O-H Bond Insertion Reaction of α-Alkyl- A nd α-Alkenyl-α-diazoacetates with Water
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Catalytic asymmetric reactions in which water is a substrate are rare. Enantioselective transition-metal-catalyzed insertion of carbenes into the O-H bond of water can be used to incorporate water into the stereogenic center, but the reported chiral catalysts give good results only when α-aryl-α-diazoesters are used as the carbene precursors. Herein we report the first highly enantioselective O-H bond insertion reactions between water and α-alkyl- A nd α-alkenyl-α-diazoesters as carbene precursors, with catalysis by a combination of achiral dirhodium complexes and chiral phosphoric acids or chiral phosphoramides. Participation of the phosphoric acids or phosphoramides in the carbene transfer reaction markedly suppressed competing side reactions, such as β-H migration, carbene dimerization, and olefin isomerization, and thus ensured good yields of the desired products. Fine-tuning of the ester moiety facilitated enantiocontrol of the proton transfer reactions of the enol intermediates and resulted in excellent enantioselectivity. This protocol represents an efficient new method for preparation of multifunctionalized chiral α-alkyl and α-alkenyl hydroxyl esters, which readily undergo various transformations and can thus be used for the synthesis of bioactive compounds. Mechanistic studies revealed that the phosphoric acids and phosphoramides promoted highly enantioselective [1,2]- A nd [1,3]-proton transfer reactions of the enol intermediates. Maximization of molecular orbital overlap in the transition states of the proton transfer reactions was the original driving force to involve the proton shuttle catalysts in this process.
- Li, You,Zhao, Yu-Tao,Zhou, Ting,Chen, Meng-Qing,Li, Yi-Pan,Huang, Ming-Yao,Xu, Zhen-Chuang,Zhu, Shou-Fei,Zhou, Qi-Lin
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supporting information
p. 10557 - 10566
(2020/07/27)
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- Chemical and Metagenomic Studies of the Lethal Black Band Disease of Corals Reveal Two Broadly Distributed, Redox-Sensitive Mixed Polyketide/Peptide Macrocycles
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Black band disease (BBD), a lethal, polymicrobial disease consortium dominated by the cyanobacterium Roseofilum reptotaenium, kills many species of corals worldwide. To uncover chemical signals or cytotoxins that could be important in proliferation of Roseofilum and the BBD layer, we examined the secondary metabolites present in geographically diverse collections of BBD from Caribbean and Pacific coral reefs. Looekeyolide A (1), a 20-membered macrocyclic compound formed by a 16-carbon polyketide chain, 2-deamino-2-hydroxymethionine, and d-leucine, and its autoxidation product looekeyolide B (2) were extracted as major compounds (～1 mg g-1 dry wt) from more than a dozen field-collected BBD samples. Looekeyolides A and B were also produced by a nonaxenic R. reptotaenium culture under laboratory conditions at similar concentrations. R. reptotaenium genomes that were constructed from four different metagenomic data sets contained a unique nonribosomal peptide/polyketide biosynthetic cluster that is likely responsible for the biosynthesis of the looekeyolides. Looekeyolide A, which readily oxidizes to looekeyolide B, may play a biological role in reducing H2O2 and other reactive oxygen species that could occur in the BBD layer as it overgrows and destroys coral tissue.
- Gunasekera, Sarath P.,Meyer, Julie L.,Ding, Yousong,Abboud, Khalil A.,Luo, Danmeng,Campbell, Justin E.,Angerhofer, Alexander,Goodsell, Justin L.,Raymundo, Laurie J.,Liu, Junyang,Ye, Tao,Luesch, Hendrik,Teplitski, Max,Paul, Valerie J.
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p. 111 - 121
(2019/01/21)
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- Method for Improving Optical Purity of 2-Hydroxycarboxylic Acid or Derivative Thereof
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To provide a method for improving optical purity of an optically active 2-hydroxycarboxylic acid or a derivative thereof, which is useful as a raw material in the manufacture of medicines, agrochemicais, and industrial products. The method of the invention for improving purity of a hydroxycarboxylic acid of the following formula (1a) or (1b) or a derivative thereof includes the steps of reacting the hydroxycarboxylic acid of the following formula (1a) or (1b) with at least one optically inactive base selected from the group consisting of an alkali metal, alkoxide and a secondary amine in the presence of a solvent and, subsequently, performing recrystallization, to thereby form a hydroxycarboxylic acid salt of the following formula (IIIa) or (IIIb): wherein R1 represents a C1-8 alkyl group, and R2 represents an alkali metal or a secondary amine.
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Paragraph 0082; 0083
(2016/04/20)
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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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- Glutathione-analogous peptidyl phosphorus esters as mechanism-based inhibitors of γ-glutamyl transpeptidase for probing cysteinyl-glycine binding site
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γ-Glutamyl transpeptidase (GGT) catalyzing the cleavage of γ-glutamyl bond of glutathione and its S-conjugates is involved in a number of physiological and pathological processes through glutathione homeostasis Defining its Cys-Gly binding site is extremely important not only in defining the physiological function of GGT, but also in designing specific and effective inhibitors for pharmaceutical purposes Here we report the synthesis and evaluation of a series of glutathione-analogous peptidyl phosphorus esters as mechanism-based inhibitors of human and Escherichia coli GGTs to probe the structural and stereochemical preferences in the Cys-Gly binding site Both enzymes were inhibited strongly and irreversibly by the peptidyl phosphorus esters with a good leaving group (phenoxide) Human GGT was highly selective for l-aliphatic amino acid such as l-2-aminobutyrate (l-Cys mimic) at the Cys binding site, whereas E coli GGT significantly preferred l-Phe mimic at this site The C-terminal Gly and a l-amino acid analogue at the Cys binding site were necessary for inhibition, suggesting that human GGT was highly selective for glutathione (γ-Glu-l-Cys-Gly), whereas E coli GGT are not selective for glutathione, but still retained the dipeptide (l-AA-Gly) binding site The diastereoisomers with respect to the chiral phosphorus were separated Both GGTs were inactivated by only one of the stereoisomers with the same stereochemistry at phosphorus The strict recognition of phosphorus stereochemistry gave insights into the stereochemical course of the catalyzed reaction Ion-spray mass analysis of the inhibited E coli GGT confirmed the formation of a 1:1 covalent adduct with the catalytic subunit (small subunit) with concomitant loss of phenoxide, leaving the peptidyl moiety that presumably occupies the Cys-Gly binding site The peptidyl phosphonate inhibitors are highly useful as a ligand for X-ray structural analysis of GGT for defining hitherto unidentified Cys-Gly binding site to design specific inhibitors
- Nakajima, Mado,Watanabe, Bunta,Han, Liyou,Shimizu, Bun-Ichi,Wada, Kei,Fukuyama, Keiichi,Suzuki, Hideyuki,Hiratake, Jun
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p. 1176 - 1194
(2014/02/14)
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- Bridging racemic lactate esters with stereoselective polylactic acid using commercial lipase catalysis
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A productive and enantioselective hydrolysis of racemic mixtures of lactate esters with commercial Candida rugosa lipase was performed. This step contributes to a novel envisioned route for stereoselective PLA production by combining recent chemocatalytic developments with this biocatalytic contribution, foreseeing two separate l- and d-lactate enantiomer streams. A study of the hydrolysis kinetics identified an unexpected rate determining step at the origin of an unprecedented ester reactivity order.
- Van Wouwe, Pieter,Dusselier, Michiel,Basic, Aurelie,Sels, Bert F.
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supporting information
p. 2817 - 2824
(2013/10/08)
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- On the conversion of structural analogues of (S)-2-hydroxypropylphosphonic acid to epoxides by the final enzyme of fosfomycin biosynthesis in S. fradiae
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2-Hydroxyethyl- and (S)-2-hydroxybutylphosphonic acid were prepared, starting in the latter case from (S)-2-aminobutyric acid. They were fed to cultures of Streptomyces fradiae producing fosfomycin. Only the latter (150 μg/mL of medium) was converted to the ethyl analogue of fosfomycin, isolated as 2-amino-1-hydroxybutylphosphonic acid (3%) in admixture with 2-amino-1-hydroxypropylphosphonic acid (97%) derived from fosfomycin.
- Schweifer, Anna,Hammerschmidt, Friedrich
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p. 3056 - 3059
(2008/12/23)
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- Synthetic studies towards ptilomycalin A: total synthesis of crambescidin 359
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A potentially biomimetic synthesis of the guanidine-containing marine natural product crambescidin 359 via a double Michael addition of guanidine to a suitably functionalised bis-enone is reported.
- Moore, Christopher G.,Murphy, Patrick J.,Williams, Harri L.,McGown, Alan T.,Smith, Nigel K.
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p. 11771 - 11780
(2008/03/13)
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- Asymmetric hydrolysis of 2-hydroxy-carboxylic esters using recombinant Escherichia coli
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Optically active 2-hydroxy-carboxylates are important compounds for their use as intermediates in the synthesis of pharmaceuticals and stereoblock polymers. Enterobacter sp. DS-S-75 and the recombinant Escherichia coli harbouring the 4-chloro-3-hydroxybutyrate (CHB) hydrolase gene from the strain DS-S-75 showed asymmetric hydrolytic activity towards 2-hydroxy-carboxylates, as well as towards CHB. It was discussed that the hydroxyl group in the substrate was particularly important for the asymmetric hydrolytic activity of the CHB hydrolase, and as such, it was re-designated to EnHCH (hydroxy-carboxylic ester hydrolase derived from Enterobacter sp.). Using the recombinant cell, both the reaction rate and the concentration of the substrates were significantly improved upon when compared to that of DS-S-75. Optically active 2-hydroxy-carboxylates could be synthesized on a practical basis for industrial production in this report.
- Nakagawa, Atsushi,Kato, Ko,Shinmyo, Atsuhiko,Suzuki, Toshio
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p. 2394 - 2398
(2008/03/13)
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- Storage stable perfusion solution for dihydropteridinones
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Disclosed are storage stable aqueous infusible or injectable solutions containing an active substance of general formula (I) wherein the groups L, R1, R2, R3, R4 and R5 have the meanings given in the claims and in the specification, and an amount of a physiologically acceptable acid or mixture of acids sufficient to dissolve the active substance and act as a stabiliser, optionally together with other formulating excipients suitable for parenteral administration, and a process for preparing the infusible or injectable solutions according to the invention.
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Page/Page column 16
(2008/06/13)
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- NOVEL CRYSTALLINE FORMS OF ANTIDIABETIC COMPOUNDS
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Novel crystalline forms of two indole compounds connected to phenoxyalkylcarboxylic acid groups are selective PPAR gamma partial agonists that are useful in the treatment of type 2 diabetes, hyperglycemia, obesity, dyslipidemia, and the metabolic syndrome. The novel crystal forms include a crystalline free acid dihydrate and crystalline free acid anhydrate of one compound and several crystalline forms of the free acid and the sodium salt of the second compound. The invention also relates to pharmaceutical compositions comprising these novel crystal forms, processes to prepare the crystal forms and their pharmaceutical compositions, and uses of the crystal forms in the treatment of type 2 diabetes and other PPAR gamma modulated diseases.
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(2010/11/23)
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- DIHYDROPTERIDINONES, METHOD FOR THE PRODUCTION AND USE THEREOF IN THE FORM OF DRUGS
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The invention relates to novel dihydropteridinones of general formula (I), wherein rests L, R1-R5 have the significance indicated in claims and a specification, in the isomers thereof, in a method for producing and using said dihydropteridinones in the form of drugs.
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Page/Page column 34
(2010/02/08)
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- A synthesis of crambescidin 359
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A potentially biomimetic synthesis of the guanidine-containing marine natural product crambescidin 359 via a double Michael addition of guanidine to a suitably functionalised bis-enone is reported.
- Moore, Christopher G.,Murphy, Patrick J.,Williams, Harri L.,McGown, Alan T.,Smith, Nigel K.
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p. 251 - 254
(2007/10/03)
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- Quantitative transformation of racemic 2-hydroxy acids into (R)-2-hydroxy acids by enantioselective oxidation with glycolate oxidase and subsequent reduction of 2-keto acids with D-lactate dehydrogenase
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The enzymatic resolution of chiral 2-hydroxy acids 1 by enantioselective oxidation with molecular oxygen in the presence of glycolate oxidase from spinach (Spinacia oleracea) and subsequent asymmetric reduction of 2-oxo acids 2 with D-lactate dehydrogenase from Lactobacillus leichmannii leads to enantiomerically pure (R)-2-hydroxy acids in up to 89% yield based on the racemate.
- Adam, Waldemar,Lazarus, Michael,Saha-Moeller, Chantu R.,Schreier, Peter
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p. 351 - 355
(2007/10/03)
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- α-(Arylsulfonamido)borneols as Auxiliaries in Asymmetric Synthesis: An Efficient and Highly Stereoselective Method for the Reduction of α-Keto Esters
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A method for preparation of enantiomerically pure α-hydroxy esters by stereoselective reduction of chiral α-keto esters under convenient conditions (LiAlH(OCEt3)3, THF, 0 deg C) has been developed.The compounds exo,exo-3-(arylsulfonamido)-2-borneol and exo,exo-2-(arylsulfonamido)-3-borneol have been used as novel auxiliaries to achieve highly diastereoselective reductions.The auxiliaries can be removed by mild saponification (LiOH, THF-H2O, rt) without racemization of the reduced products.
- Xiang, Yi Bin,Snow, Ken,Belley, Michel
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p. 993 - 994
(2007/10/02)
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- On the factors controlling the structural specificity and stereospecificity of the L-lactate dehydrogenase from Bacillus stearothermophilus: Effects of Gln102→Arg and Arg171→Trp/Tyr double mutations
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The factors determining the L-stereospecificity of the L-lactate dehydrogenase from Bacillus stearolhermophilus have been probed by introducing Arg171Trp/Tyr and Gln 102Arg mutations. These changes preclude normal 2-keto acid substrate binding via an Arg171-COO- electrostatic interaction and are positioned to induce a reversal of the natural substrate binding mode, thereby leading to D-2-hydroxy acid formation. However, the L-stereospecificities of the mutant enzymes remain unchanged, showing that there are important fail-safe stereospecificity determinants that take over when the key Arg171-COO- binding interaction is removed. The effects of the mutations on structural specificity are approximately additive, resulting in the broad 2-keto acid specificity of the wild-type enzyme being changed to give catalysts highly selective for the dicarboxylic substrate oxalacetate.
- Kallwass, Helmut K.W.,Hogan, James K.,Macfarlane, Emma L.A.,Martichonok, Valeri,Partis, Wendy,Kay, Cyril M.,Gold, Marvin,Bryan Jones
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p. 10704 - 10710
(2007/10/02)
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- Stereochemical Control on Yeast Reduction of α-Keto Esters. Reduction by Immobilized Bakers' Yeast in Hexane
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Ethyl 2-oxoheptanoate has been reduced by three methods: free bakers' yeast (FBY) in water, immobilized bakers' yeast (IMBY) in water, and IMBY in hexane.It has been found that the stereochemistry of reduction of α-keto esters by bakers' yeast is controlled by appropiate choice of reaction conditions.
- Nakamura, Kaoru,Inoue, Kiyoko,Ushio, Kazutoshi,Oka, Shinzaburo,Ohno, Atsuyoshi
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p. 2589 - 2593
(2007/10/02)
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- PREPARATION OF CHIRAL SULFONES BY ASYMMETRIC ADDITION OF ARENESULFONYL CARBANIONS TO ACETONE
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In the presence of a chiral diamine, the magnesium salt of tolyl sulfone reacts with acetone at the α-carbon to afford the corresponding β-hydroxy adduct in good optical purity.
- Akiyama, Takahiko,Shimizu, Makoto,Mukaiyama, Teruaki
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p. 611 - 614
(2007/10/02)
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- A SYNTHON FOR CHIRAL GLYCOLATE ENOLATE (ROC-HCOOR'): A CAMPHOR-BASED OXAZOLINE
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Alkylations of the anion (7a) derived from a camphor-based oxazoline proceed in good yield.Hydrolysis affords the corresponding α-hydroxy acids in high ee.
- Kelly, T. Ross,Arvanitis, Argyrios
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