- Chemoenzymatic Synthesis in Flow Reactors: A Rapid and Convenient Preparation of Captopril
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The chemoenzymatic flow synthesis of enantiomerically pure captopril, a widely used antihypertensive drug, is accomplished starting from simple, inexpensive, and readily available reagents. The first step is a heterogeneous biocatalyzed regio- and stereoselective oxidation of cheap prochiral 2-methyl-1,3-propandiol, performed in flow using immobilized whole cells of Acetobacter aceti MIM 2000/28, thus avoiding the use of aggressive and environmentally harmful chemical oxidants. The isolation of the highly hydrophilic intermediate (R)-3-hydroxy-2-methylpropanoic acid is achieved in-line by using a catch-and-release strategy. Then, three sequential high-throughput chemical steps lead to the isolation of captopril in only 75 min. In-line quenching and liquid–liquid separation enable breaks in the workflow and other manipulations to be avoided.
- De Vitis, Valerio,Dall'Oglio, Federica,Pinto, Andrea,De Micheli, Carlo,Molinari, Francesco,Conti, Paola,Romano, Diego,Tamborini, Lucia
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- Carnitine-esters from the mushroom Suillus laricinus
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Carnitine-esters (1-8) including, a compound (R)-3-hydroxybutanoyl-(R)-carnitine (5), were isolated from the mushroom Suillus laricinus. Their structures were determined by spectroscopic analyses and by total synthesis. One of these, (R)-3-hydroxy-2-methylpropanoyl-(R)-carnitine (4), promoted hyaluronan-degradation by human skin fibroblasts.
- Kawagishi, Hirokazu,Murakami, Hiroaki,Sakai, Shingo,Inoue, Shintaro
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- Enantioselective oxidation of prochiral 2-methyl-1,3-propandiol by Acetobacter pasteurianus
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The microbial oxidation of prochiral 2-methyl-1,3-propandiol into (R)-3-hydroxy-2-methyl propionic acid with Acetobacter pasteurianus DSM 8937 is reported. The biotransformation was optimised furnishing (R)-3-hydroxy-2-methyl propionic acid with 97% enantiomeric excess and 100% molar conversion of 5 g/L within 2 h. A simple fed-batch procedure allowed for the obtainment of 25 g/L of the enantiomerically enriched acid. (R)-3-Hydroxy-2-methyl propionic acid is an important building block for the synthesis of Captopril, a widely used antihypertensive drug.
- Molinari, Francesco,Gandolfi, Raffaella,Villa, Raffaella,Urban, Eva,Kiener, Andreas
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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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- Synthesis of Enantiomerically Enriched 2-Hydroxymethylalkanoic Acids by Oxidative Desymmetrisation of Achiral 1,3-Diols Mediated by Acetobacter aceti
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The stereoselective desymmetrisation of achiral 2-alkyl-1,3-diols is performed by oxidation of one of the two enantiotopic primary alcohol moieties by means of Acetobacter aceti MIM 2000/28 to afford the corresponding chiral 2-hydroxymethyl alkanoic acids (up to 94 % ee). The procedure, carried out in aqueous medium under mild conditions of pH, temperature and pressure, contributes to enlarge the portfolio of enzymatic oxidations available to organic chemists for the development of sustainable manufacturing processes.
- Brenna, Elisabetta,Cannavale, Flavia,Crotti, Michele,De Vitis, Valerio,Gatti, Francesco G.,Migliazza, Gaia,Molinari, Francesco,Parmeggiani, Fabio,Romano, Diego,Santangelo, Sara
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p. 3796 - 3803
(2016/12/24)
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- Palladium-catalyzed β-acyloxylation of simple amide via sp3 C-H activation
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β-Acyloxy amides are prepared in moderate to high yields by palladium-catalyzed acyloxylation of primary sp3 C-H bonds from simple amides without any special directing group. A catalytic system of Pd(OAc)2/CF3CO2H/ K2S2O8 is available to various amides with N-substituted by linear alkanes, cyclic alkanes, and electron-deficient benzyl compounds in this reaction. Acyloxylated products could be transformed easily to the corresponding β-hydroxy amides.
- Zhou, Lihong,Lu, Wenjun
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supporting information
p. 508 - 511
(2014/04/03)
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- Solvent effect and reactivity trend in the aerobic oxidation of 1,3-propanediols over gold supported on titania: Nmr diffusion and relaxation studies
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In recent work, it was reported that changes in solvent composition, precisely the addition of water, significantly inhibits the catalytic activity of Au/TiO2 catalyst in the aerobic oxidation of 1,4-butanediol in methanol due to changes in diffusion and adsorption properties of the reactant. In order to understand whether the inhibition mechanism of water on diol oxidation in methanol is generally valid, the solvent effect on the aerobic catalytic oxidation of 1,3-propanediol and its two methyl-substituted homologues, 2-methyl-1,3-propanediol and 2,2-dimethyl-1,3-propanediol, over a Au/TiO2 catalyst has been studied here using conventional catalytic reaction monitoring in combination with pulsed-field gradient nuclear magnetic resonance (PFG-NMR) diffusion and NMR relaxation time measurements. Diol conversion is significantly lower when water is present in the initial diol/methanol mixture. A reactivity trend within the group of diols was also observed. Combined NMR diffusion and relaxation time measurements suggest that molecular diffusion and, in particular, the relative strength of diol adsorption, are important factors in determining the conversion. These results highlight NMR diffusion and relaxation techniques as novel, non-invasive characterisation tools for catalytic materials, which complement conventional reaction data. In solvent company: The solvent effect on the aerobic catalytic oxidation of 1,3-propanediol and its two methyl-substituted homologues, 2-methyl-1,3-propanediol and 2,2-dimethyl-1,3-propanediol, over a Au/TiO 2 catalyst has been studied. The results show that diol conversion is significantly lower when water is present in the initial diol/methanol mixture. A reactivity trend within the group of diols was also observed. Copyright
- D'Agostino, Carmine,Kotionova, Tatyana,Mitchell, Jonathan,Miedziak, Peter J.,Knight, David W.,Taylor, Stuart H.,Hutchings, Graham J.,Gladden, Lynn F.,Mantle, Mick D.
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p. 11725 - 11732
(2013/09/12)
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- Oxidative esterification of homologous 1,3-propanediols
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The oxidative esterification of a homologous series of diols (1,3-propanediol,2-methyl-propanediol and 2,2-dimethyl-1,3-propanediol) with methanol has been investigated using titania-supported gold, palladium and gold-palladium catalysts using molecular oxygen. The gold-palladium catalysts showed the highest activity and 1,3-propanediol was the most reactive while the additional methyl groups decreased the reactivity. However, it is possible to achieve high selectivity to methyl 3-hydroxypropionate and 2-methyl-3- hydroxyisobutyrate by mono-oxidations. Graphical Abstract: [Figure not available: see fulltext.]
- Kotionova, Tatyana,Lee, Christopher,Miedziak, Peter J.,Dummer, Nicholas F.,Willock, David J.,Carley, Albert F.,Morgan, David J.,Knight, David W.,Taylor, Stuart H.,Hutchings, Graham J.
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p. 1114 - 1120
(2012/10/29)
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- Cu(I)-catalyzed oxidative cyclization of alkynyl oxiranes and oxetanes
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In the presence of a Cu(I) catalyst and a pyridine oxide, alkynyl oxiranes and oxetanes can be converted into functionalized five- or six-membered α,β-unsaturated lactones or dihydrofuranaldehydes. This new oxidative cyclization is proposed to proceed via an unusual allenyloxypyridinium intermediate.
- Gronnier, Colombe,Kramer, Soren,Odabachian, Yann,Gagosz, Fabien
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supporting information; experimental part
p. 828 - 831
(2012/03/07)
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- Bioactive constituents from chinese natural medicines. XXXI.1 hepatoprotective principles from sinocrassula indica: Structures of sinocrassosides A8, A9, A10, A11, and A12
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The methanolic extract from the whole plant of Sinocrassula indica (Crassulaceae) was found to show hepatoprotective effect on D-galactosamineinduced cytotoxicity in primary cultured mouse hepatocytes. From the methanolic extract, five new acylated flavon
- Ninomiya, Kiyofumi,Morikawa, Toshio,Xie, Haihui,Matsuda, Hisashi,Yoshikawa, Masayuki
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experimental part
p. 1983 - 1995
(2009/04/06)
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- 14-Membered cyclodepsipeptides with alternating β-hydroxy and α-amino acids by cyclodimerization
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The cyclodimerization (twinning) of β-hydroxy acid amides of type 1 under 'direct amide cyclization' (DAC) conditions is described. Although other coupling methods also gave moderate results, best yields were obtained via DAC, reaching 88% for the cyclodi
- Iliev, Boyan,Linden, Anthony,Kunz, Roland,Heimgartner, Heinz
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p. 1079 - 1094
(2007/10/03)
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- Mapping the substrate selectivity of new hydrolases using colorimetric screening: Lipases from Bacillus thermocatenulatus and Ophiostoma piliferum, esterases from Pseudomonas fluorescens and Streptomyces diastatochromogenes
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Recent advances in biochemistry and molecular biology have simplified the discovery and preparation of new hydrolases. Although these hydrolases might solve problems in organic synthesis, measuring their selectivity, especially enantioselectivity, remains tedious and time consuming. Recently, we developed a colorimetric screening method to measure the enantioselectivity of hydrolases. Here we apply this rapid screening method to map the substrate selectivity of four new hydrolases: lipases from the thermophilic Bacillus thermocatenulatus (DSM 730, BTL2) and a filamentous fungus Ophiostoma piliferum (NRRL 18917, OPL) and esterases from two bacteria, Pseudomonas fluorescens (SIK-W1, esterase I, PFE) and Streptomyces diastatochromogenes (Tue 20, SDE). We screened a general library of 29 substrates and a chiral library of 23 pairs of enantiomers. All four hydrolases catalysed the hydrolysis of unnatural substrates, but the two lipases accepted a broader range of substrates than the two esterases. As expected, the two lipases favoured more hydrophobic substrates, while the two esterases showed a preference for smaller substrates. Several moderately enantioselective reactions were identified for the solketal esters: BTL2, butyrate, E = 7.9 (R); octanoate, E = 4.9 (R) and 3-bromo-2-methyl propionate methyl esters, PFE, E = 12 (S); SDE, E = 5.6 (S). OPL showed low enantioselectivity toward all substrates tested. The current colorimetric screen could not measure the selectivity for several slow-reacting substrates. Traditional screening identified high enantioselectivity of BTL2 and PFE toward one of these slow substrates, 1-phenylethyl acetate (E>50).
- Liu, Andrew Man Fai,Somers, Neil A.,Kazlauskas, Romas J.,Brush, Terry S.,Zocher, Frank,Enzelberger, Markus M.,Bornscheuer, Uwe T.,Horsman, Geoff P.,Mezzetti, Alessandra,Schmidt-Dannert, Claudia,Schmid, Rolf D.
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p. 545 - 556
(2007/10/03)
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- A practical method for the conversion of β-hydroxy carboxylic acids into the corresponding β-amino acids
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Optically active α- or β-substituted βamino acids were synthesized from the corresponding β-hydroxy acids in 4 steps in excellent yield. Stereochemistry was retained at the α-position and reversed at the β-position during the conversion.
- Jin, Yonghao,Kim, Dong H.
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p. 1189 - 1190
(2007/10/03)
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- Enantiotopically Selective Oxidation of α,ω-Diols with the Enzyme Systems of Microorganisms
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Gluconobacter were found to be capable of oxidizing prochiral diols such as 2-substituted propane-1,3-diols 1 and 3-substituted pentane-1,5-diols 4 with distinction of pro-R and pro-S sites of the molecules, in that (-)-(R)-α-substituted β-hydroxypropionic acids 2 and (+)-(3S)-3-substituted δ-valerolactones 5 were obtained, respectively.Oxidation of 3-methylpentane-1,3,5-triol 11 afforded unnatural (+)-(S)-mevalonolactone 12.The steric bulkiness of the substituents on the prochiral center and the distance from the hydroxy group greatly affected the rate and the enantioselectivity of the reaction.
- Ohta, Hiromichi,Tetsukawa, Hatsuki,Noto, Naoko
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p. 2400 - 2404
(2007/10/02)
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- ENANTIOSELECTIVE SYNTHESIS OF β-HYDROXYISOBUTYRIC ACID: A USEFUL SYNTHON IN THE SYNTHESIS OF POLYPROPIONATE-TYPE NATURAL PRODUCTS
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The aldol reaction of formaldehyde with the dicyclopentylborinyl enolate derived from S-(or R-) 1-tert-butyldimethylsilyloxy-1-cyclohexylbutan-2-one, followed by desilylation and sodium meta-periodate oxidation, provides R-(or S-) β-hydroxyisobutyric acid.
- Choy, William,Ma, Philip,Masamune, Satoru
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p. 3555 - 3556
(2007/10/02)
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