- Asymmetric Total Synthesis of the Naturally Occurring Antibiotic Anthracimycin
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The first total synthesis of the potent antibiotic anthracimycin was achieved in 20 steps. The synthesis features an intramolecular Diels-Alder reaction to forge the trans-decalin moiety, and an unprecedented aldol reaction using a complex β-ketoester to provide the tricarbonyl motif. A Stork-Zhao olefination and Grubbs ring closing metathesis delivered the E/Z-diene and forged the macrocycle. The C2 configuration was set with a base-mediated epimerization, providing access to (-)-anthracimycin.
- Brimble, Margaret A.,Davison, Emma K.,Freeman, Jared L.,Furkert, Daniel P.,Wuest, William M.,Zhang, Wanli
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Read Online
- Essential role of the donor acyl carrier protein in stereoselective chain translocation to a fully reducing module of the nanchangmycin polyketide synthase
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Incubation of recombinant module 2 of the polyether nanchangmycin synthase (NANS), carrying an appended thioesterase domain, with the ACP-bound substrate (2RS)-2-methyl-3-ketobutyryl-NANS-ACP1 (2-ACP1) and methylmalonyl-CoA in the presence of NADPH gave diastereomerically pure (2S,4R)-2,4-dimethyl-5- ketohexanoic acid (4a). These results contrast with the previously reported weak discrimination by NANS module 2+TE between the enantiomers of the corresponding N-acetylcysteamine-conjugated substrate analogue (±)-2-methyl-3- ketobutyryl-SNAC (2-SNAC), which resulted in formation of a 5:3 mixture of 4a and its (2S,4S)-diastereomer 4b. Incubation of NANS module 2+TE with 2-ACP1 in the absence of NADPH gave unreduced 3,5,6-trimethyl-4-hydroxypyrone (3) with a kcat of 4.4 ± 0.9 min-1 and a kcat/ Km of 67 min-1 mM-1, corresponding to a ～2300-fold increase compared to the kcat/Km for the diffusive substrate 2-SNAC. Covalent tethering of the 2-methyl-3-ketobutyryl thioester substrate to the NANS ACP1 domain derived from the natural upstream PKS module of the nanchangmycin synthase significantly enhanced both the stereospecificity and the kinetic efficiency of the sequential polyketide chain translocation and condensation reactions catalyzed by the ketosynthase domain of NANS module 2.
- Guo, Xun,Liu, Tiangang,Deng, Zixin,Cane, David E.
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Read Online
- Preparation of Acidic 5-Hydroxy-1,2,3-triazoles via the Cycloaddition of Aryl Azides with β-Ketoesters
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Herein, a high-yielding cycloaddition reaction of β-ketoesters and azides to provide 1,2,3-triazoles is described. The reactions employing 2-unsubstituted β-ketoesters were found to provide 5-methyl-1,2,3-triazoles, whereas 2-alkyl-substituted β-ketoester
- Pacifico, Roberta,Destro, Dario,Gillick-Healy, Malachi W.,Kelly, Brian G.,Adamo, Mauro F. A.
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p. 11354 - 11360
(2021/08/20)
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- HEPATITIS B CORE PROTEIN MODULATORS
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The present disclosure provides, in part, compounds having allosteric effector properties against Hepatitis B virus Cp. Also provided herein are methods of treating viral infections, such as hepatitis B, comprising administering to a patient in need thereof a disclosed compound of formula:
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Page/Page column 103; 104
(2018/04/13)
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- Discovery and Engineering of Pathways for Production of α-Branched Organic Acids
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Cell-based synthesis offers many opportunities for preparing small molecules from simple renewable carbon sources by telescoping multiple reactions into a single fermentation step. One challenge in this area is the development of enzymatic carbon-carbon bond forming cycles that enable a modular disconnection of a target structure into cellular building blocks. In this regard, synthetic pathways based on thiolase enzymes to catalyze the initial carbon-carbon bond forming step between acyl coenzyme A (CoA) substrates offer a versatile route for biological synthesis, but the substrate diversity of such pathways is currently limited. In this report, we describe the identification and biochemical characterization of a thiolase-ketoreductase pair involved in production of branched acids in the roundworm, Ascaris suum, that demonstrates selectivity for forming products with an α-methyl branch using a propionyl-CoA extender unit. Engineering synthetic pathways for production of α-methyl acids in Escherichia coli using these enzymes allows the construction of microbial strains that produce either chiral 2-methyl-3-hydroxy acids (1.1 ± 0.2 g L-1) or branched enoic acids (1.12 ± 0.06 g L-1) in the presence of a dehydratase at 44% and 87% yield of fed propionate, respectively. In vitro characterization along with in vivo analysis indicates that the ketoreductase is the key driver for selectivity, forming predominantly α-branched products even when paired with a thiolase that highly prefers unbranched linear products. Our results expand the utility of thiolase-based pathways and provide biosynthetic access to α-branched compounds as precursors for polymers and other chemicals.
- Blaisse, Michael R.,Dong, Hongjun,Fu, Beverly,Chang, Michelle C. Y.
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supporting information
p. 14526 - 14532
(2017/10/24)
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- Substrate range of the titanium TADDOLate catalyzed asymmetric fluorination of activated carbonyl compounds
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The substrate range of the [TiCl2(TADDOLate)] (TADDOL=α,α,α′,α′-tetraaryl-1,3-dioxolane-4, 5-dimethanol)-catalyzed asymmetric α-fluorination of activated β-carbonyl compounds has been investigated. Optimal conditions for catalysis are characterized by using 5 mol-% of TiCl2(naphthalen-1- yl)-TADDOLate) as catalyst in a saturated (0.14 mol/l) MeCN solution of F-TEDA (1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis- [tetrafluoroborate]) at room temperature. A series of α-methylated β-keto esters (3-oxobutanoates, 3-oxopentanoates) with bulky benzyl ester groups (60-90% ee) or phenyl ester (67-88% ee) have been fluorinated readily, whereas α-acyl lactones were also readily fluorinated, but gave lower inductions (13-46% ee). Double stereochemical differentiation in β-keto esters with chiral ester groups raised the stereoselectivity to a diastereomeric ratio (dr) of up to 96.5:3.5. For the first time, β-keto S-thioesters were asymmetrically fluorinated (62-91.5% ee) and chlorinated (83% ee). Lower inductions were observed in fluorinations of 1,3-diketones (up to 40% ee) and β-keto amides (up to 59% ee). General strategies for preparing activated β-carbonyl compounds as important model substrates for asymmetric catalytic α-functionalizations are presented (>60 examples). Copyright
- Bertogg, Andreas,Hintermann, Lukas,Huber, Dominique P.,Perseghini, Mauro,Sanna, Maria,Togni, Antonio
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scheme or table
p. 353 - 403
(2012/05/07)
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- Novel chiral pyrrolidinone scaffolds derived from threonine with antibacterial activity
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The synthesis of chiral pyrrolidinones derived from threonine, making use of a Dieckmann or aldol ring closure, is described. Compounds were found to exhibit antibacterial activity, for which the correlation with various physiochemical parameters was examined. This chiral tetramate scaffold may provide a useful template for fragment-based drug design providing rapid access to novel antibacterial compound libraries.
- Anwar, Muhammad,Cowley, Andrew R.,Moloney, Mark G.
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experimental part
p. 1758 - 1770
(2010/10/18)
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- Structural studies on bioactive compounds. 1 Heck reactions on 4-methylenepyrazolo[5,1-c][1,2,4]triazines
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1-(3-Methyl-4-methylenepyrazolo[5,1-c][1,2,4]triazin-6(4H-yl)ethanone 9a and its 7-methyl- 9b and 7-phenylderivative 9c undergo Heck coupling to afford (Z)-1-{4-benzylidene-3-methylpyrazolo[5,1-c][1,2,4]triazin-6(4H)- yl}ethanones 10a-c and substituted benzylidene analogues 10d-m as the major geometrical isomers in low yields. The most potent agent in a human tumour screen in vitro was 10b (mean GI50 value 4.9 mM in a panel of 60 human cancer cell lines), with evidence of selective action against colon KM12 (GI50 0.02 mM) and breast MCF-7 tumour cell lines (GI501.35 mM).
- Iwashita, Eiichiro,Williams, Huw E. L.,Hutchinson, Ian,Stevens, Malcolm F. G.
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experimental part
p. 115 - 120
(2009/08/15)
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- SILVER β-KETOCARBOXYLATE, MATERIAL COMPRISING THE SAME FOR FORMING SILVER METAL, AND USE THEREOF
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A new material from which silver metal can be rapidly formed even at a temperature as low as about 210°C or below. The material for silver metal formation comprises a silver β-ketocarboxylate. Heating this forming material can rapidly form silver metal even at a temperature as low as about 210°C or below. Examples of the silver β-ketocarboxylate include silver isobutyrylacetate, silver benzoylacetate, silver acetoacetate, silver propionylacetate, silver α-methylacetoacetate, and silver α-ethylacetoacetate.
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Page/Page column 25
(2008/06/13)
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- Synthesis of 1,2,4-triazole-fused heterocycles by tandem appel dehydration/thermal rearrangement methodology
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The reaction of α-substituted benzophenone 1-acetamidoethylidenehydrazones 6b,c and 13a-d with a mixture of triphenylphosphine, carbon tetrachloride, and triethylamine in dichloromethane (Appel's condition) provides a general route to a variety of 1,2,4-triazole-fused heterocycles such as compounds 9-11, 16a-d, 17b-d, and 18 via the thermal rearrangement of the expected amino ketenimine intermediates.
- Lee, Kee-Jung,Kim, Seong Heon,Kwon, Jong Hyuk
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p. 1461 - 1466
(2007/10/03)
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- DURCH STERISCHE EFFEKTE STABILISIERTE β-KETOCARBONSAEUREN
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Increasing steric hindrance in β-keto carboxylic acids leads to an increasing kinetic stability towards decarboxylation, till systems are reached wich are completely stable at room temperature.Simultaneously the tautomeric equilibrium is changed in favour of the (Z)-enol, and finally in favour of the (E)-configurated enol.
- Meier, Herbert,Wengenroth, Horst,Lauer, Wolfgang,Krause, Volker
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p. 5253 - 5256
(2007/10/02)
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- The Knoevenagel Reactions of Aldehydes with Carboxy Compounds. I. Reactions of p-Nitrobenzaldehyde with Active Methine Compounds
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The Knoenvenagel reactions of p-nitrobenzaldehyde (1) with β-keto acids, methylmalonic (2a) and α-methylacetoacetic acids (2b) were carried out in the presence of a tertiary amine such as pyridine.We have isolated the corresponding β-hydroxy intermediate
- Tanaka, Mayumi,Oota, Osamu,Hiramatsu, Hideo,Fujiwara, Kazuyoshi
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p. 2473 - 2480
(2007/10/02)
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- Knoevenagel Reactions with β-Oxo Acids. Regiospecific Enol Equivalents for Syntheses of α,β-Unsaturated Ketones and of Some β-Ketols
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3-Oxobutanoic acid reacts with aliphatic aldehydes in the presence of pyridine to give α,β-unsaturated methyl ketones in good yields.Analogous results were obtained with a series of other β-oxo acids.Synthesis of (E)-7-methyloct-4-en-3-one, a major constituent of the marine sponge Plakortis zygompha, has been carried out using this methodology.Aromatic aldehydes are generally less reactive under these conditions but give β-ketols when the phenyl ring bears an electron-withdrawing substituent.Some observations on the mechanism of the reaction between 3-oxobutanoic acid and benzaldehyde are presented.
- Grayson, David H.,Tuite, Mathew R. J.
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p. 2137 - 2142
(2007/10/02)
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- Carboxylation of Ketones Using Triethylamine and Magnesium Halides
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Procedures for the carboxylation of ketones with carbon dioxide at atmospheric pressure in the presence of magnesium halides and triethylamine are described.A variety of ketones are converted to the corresponding β-keto acids in satisfactory yields by using magnesium chloride-sodium iodide mixtures in acetonitrile.This carboxylation reaction exhibits little regioselectivity with 2-butanone.
- Tirpak, Robin E.,Olsen, Richard, S.,Rathke, Michael W.
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p. 4877 - 4879
(2007/10/02)
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- Synthesis of 1,3-dioxin-4-one Derivatives
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A facile and general synthesis of 2,2-dimethyl-1,3-dioxin-4-one derivatives (1) is reported.Treatment of β-keto acids with a mixture of isopropenyl acetate and conc. sulfuric acid gave 2,2-dimethyl-1,3-dioxin-4-ones (1).Similar treatment of tert-butyl esters of β-keto acids also gave 1.KEYWORDS - 2,2-dimethyl-1,3-dioxin-4-one derivative; diketene-acetone adduct; diketene; acylketene; β-keto acid; β-keto ester
- Sato, Masayuki,Ogasawara, Hiromichi,Oi, Keiichi,Kato, Tetsuzo
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p. 1896 - 1901
(2007/10/02)
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