- Screening for enhanced triacetic acid lactone production by recombinant Escherichia coli expressing a designed triacetic acid lactone reporter
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Triacetic acid lactone (TAL) is a signature byproduct of polyketide synthases (PKSs) and a valuable synthetic precursor. We have developed an endogenous TAL reporter by engineering the Escherichia coli regulatory protein AraC to activate gene expression in response to TAL. The reporter enabled in vivo directed evolution of Gerbera hybrida 2-pyrone synthase activity in E. coli. Two rounds of mutagenesis and high-throughput screening yielded a variant conferring ~20-fold increased TAL production. The catalytic efficiency (kcat/Km) of the variant toward the substrate malonyl-CoA was improved 19-fold. This study broadens the utility of engineered AraC variants as customized molecular reporters. In addition, the TAL reporter can find applications in other basic PKS activity screens.
- Tang, Shuang-Yan,Qian, Shuai,Akinterinwa, Olubolaji,Frei, Christopher S.,Gredell, Joseph A.,Cirino, Patrick C.
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- Activation of acyl condensation reaction of monomeric 6-hydroxymellein synthase, a multifunctional polyketide biosynthetic enzyme, by free coenzyme A
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6-Hydroxymellein (6HM) synthase is a multifunctional polyketide enzyme induced in carrot cells, whose fully active homodimer catalyzes condensation of acyl-CoAs and the NADPH-dependent ketoreduction of the enzyme-bound intermediate. 6HM-forming activity of the synthase was markedly decreased when the reaction mixture pH was adjusted from 7.5 to 6.0. However, under these slightly acidic conditions, the acyl condensation catalyzed by the dissociated monomer enzyme was appreciably stimulated by addition of free coenzyme A (CoA). In contrast, the condensation reaction at pH 6.0 was significantly inhibited in the presence of CoA when the reaction was carried out with the NADPH-omitted dimer synthase. Among the kinetic parameters of the acyl condensation, velocity of the monomer-catalyzing reaction at the acidic pH was appreciably increased upon addition of CoA while Kms did not show any significant change in the presence and absence of the compound. These results suggest that CoA associates with a specific site in the dissociated monomeric form of 6HM synthase, and the velocity of the acyl condensation reaction catalyzed by the CoA-synthase complex appreciably increases in acidic conditions.
- Kurosaki, Fumiya,Mitsuma, Satoru,Arisawa, Munehisa
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- The first example of the [4+2] cycloaddition reaction of silylketenes with 1,3-dienes: A convenient preparation of 2-pyranones and isochromenes
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Silylketenes easily undergo the [4+2] cycloaddition reaction with electron-rich 1,3-dienes and o-quinodimethanes to give the corresponding 2-pyranones and isochromenes, respectively.
- Ito, Tatsuya,Aoyama, Toyohiko,Shioiri, Takayuki
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- Note on the Synthesis of 4-Hydroxy-6-methyl-5,6-dihydro-2H-pyran-2-one
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Meldrum's acid (2) is acylated by diketen affording the acyl Meldrum's acid 3.In aqueous bicarbonate its 3-oxogroup is selectively reduced by sodium tetrahydroborate giving the alcohol 4, which readily undergoes cyclization in refluxing dioxane leading to the title pyrone 7.Under identical conditions 3 produces the pyrone 6 with the pyrone carboxylic acid 5 as intermediate. - Keywords: Acyl Meldrum's acid; Ring closure; Selective reduction
- Haeusler, Johannes
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- Synthesis, characterization and antimicrobial activity of some new azo dyes derived from 4-hydroxy-6-methyl-2H-pyran-2-one and its dihydro derivative
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A series of new azo disperse dyes was synthesized by coupling 4-hydroxy-6-methyl-2H-pyran-2-one (triacetic acid lactone, TAL) or its hydrogenated derivative 4-hydroxy-6-methyl-5,6-dihydro-2H-pyran-2-one (dihydro triacetic acid lactone, DHTAL) with diazonium salts derived from aniline, 4-bromoaniline, 4-nitroaniline, 4-methoxyaniline, 2,4-dimethoxyaniline and 2,5-dimethoxyaniline. Spectroscopic data of these dyes dissolved in five organic solvents were measured. The effects of solvent polarity, nucleophilic component and substituent nature on the visible absorption spectra of the dyes are also reported. The structures of all compounds were confirmed by FT-IR, electronic absorption in UV and visible regions, 1H, 13C and 2D NMR and high resolution mass spectroscopy (HRMS). In addition, in vitro antibacterial activity of the synthesized derivatives against Gram positive and Gram negative bacteria, both reference and clinical strains, was evaluated qualitatively and quantitatively by agar diffusion method.
- Ben Mohamed-Smati, Soumaya,Faraj, Fadhil Lafta,Becheker, Imène,Berredjem, Hadjira,Le Bideau, Franck,Hamdi, Maamar,Dumas, Fran?oise,Rachedi, Yahia
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Read Online
- Regioselective functionalization of pyrones: Facile synthesis of 6-styrylpyrones via KHMDS-mediated aldol condensation
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Herein, we disclose our efforts directed toward the synthesis of the kavalactone-based natural product penstyrylpyrone and other related 4-OMe-2-pyrones possessing diverse substituents at the 3-, 5-, and 7-positions. Further, a facile approach to access 6-styrylpyrones via the KHMDS-mediated regioselective aldol condensation of 2-pyrones is described with moderate substrate scope and good to high yields (58–80%). The utility of this methodology was exemplified by the stereoselective construction of desmethoxyyangonin, asnipyrone A, and asnipyrone B.
- Basu, Manas K.,Mukkanti, K.,Samala, Ramakrishna
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- Synthesis and Herbicidal Activity against Buffelgrass (Cenchrus ciliaris) of (±)-3-deoxyradicinin
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A novel synthetic strategy for obtainment of (±)-3-deoxyradicinin (2) is reported. This synthetic methodology is more efficient than those previously reported in the literature and also shows higher versatility towards the introduction of different side-chains at both C-7 and C-2. The obtained compound (±)-2 shows phytotoxicity against the grass-weed buffelgrass comparable to that of the natural phytotoxin radicinin (1). Therefore, (±)-2 can constitute a more practical synthetic alternative to 1 as bioherbicide for buffelgrass control.
- Marsico, Giulia,Ciccone, Maria Sabrina,Masi, Marco,Freda, Fabrizio,Cristofaro, Massimo,Evidente, Antonio,Superchi, Stefano,Scafato, Patrizia
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- The Generation of a Library of Bromodomain-Containing Protein Modulators Expedited by Continuous Flow Synthesis
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A continuous flow process delivering key building blocks for a series of BCP modulator libraries is reported. A dynamically mixed flow reactor emerged as a pivotal technology in both synthesis and isolation phases enabling the processing of slurries and suspensions while maintaining high productivity and reliability. Accordingly, the synthesis of common intermediates in flow were employed to further build a pyridazone-based library (36 compounds) aimed at improving lead compound potency and selectivity while further enabling structure-activity relationship studies of a new BCP modulator family.
- Filipponi, Paolo,Baxendale, Ian R.
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p. 2000 - 2012
(2016/04/26)
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- Easy and green synthesis of 6-(arylvinyl)-4-hydroxy-3-(phenylsulfanyl)-2H-pyran-2-ones in aqueous potassium hydroxide
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A convenient green procedure have been proposed for the synthesis of 6-(2-arylvinyl)-4-hydroxy-3-(phenylsulfanyl)-2H-pyran-2-ones by condensation of 6-(arylvinyl)-4-hydroxy-2H-pyran-2-ones with S-phenyl benzenesulfonothioate in aqueous potassium hydroxide at room temperature.
- Benferrah,Hammadi,Berthiol
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p. 2881 - 2886
(2017/03/22)
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- An Efficient Synthetic Access to Substituted Thiazolyl-pyrazolyl-chromene-2-ones from Dehydroacetic Acid and Coumarin Derivatives by a Multicomponent Approach
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Two new series of pyran- or coumarin-substituted thiazolyl-pyrazole-chromen-2-one derivatives 10a-10d and 11a-11d were efficiently synthesized under environmentally friendly reaction conditions through a convenient one-pot multicomponent reaction of a heterocyclic bromoacetyl derivative 3 or 4 with thiosemicarbazide and a substituted 3-(acetoacetyl)coumarin derivative 5a-5d in anhydrous ethanol. The reaction proceeds through Hantzsch thiazole and Knorr pyrazole syntheses in refluxing ethanol. The key features of this approach are its operational simplicity, the quick access to the desired products, and the good to excellent yields. The structures of the newly synthesized compounds were established by IR spectroscopy, 1H, 13C, and 2D NMR spectroscopy, and mass spectrometry. Two new series of pyran- or coumarin-substituted (thiazolyl-pyrazole-chromen-2-ones) may be efficiently accessed from bromoacetyl derivatives of dehydroacetic acid or coumarin, thiosemicarbazide, and substituted 3-(acetoacetyl)coumarins by green multicomponent reactions. The newly synthesized structures were established by IR spectroscopy, 1H, 13C, and 2D NMR spectroscopy, and mass spectrometry.
- Ben Mohamed, Soumaya,Rachedi, Yahia,Hamdi, Maamar,Le Bideau, Franck,Dejean, Camille,Dumas, Fran?oise
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p. 2628 - 2636
(2016/06/08)
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- Potassium fluoride-barium oxide catalysis in an easy and efficient synthesis of methysticin from piperonal under microwave irradiation
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Condensation of compounds containing active methylene group with aromatic aldehyde (piperonal) in the presence of BaO on KF without a solvent under microwave irradiation is an efficient synthetic approach to methysticin and derivatives of kavalactones (4-methoxy-6-styryl-pyran-2-ones).
- Benferrah,Hammadi,Berthiol
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p. 1939 - 1944
(2015/10/12)
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- Reaction of pyran-2-one with 5-amino-1H-pyrazoles: Synthesis and characterization of 5,7-dimethylpyrazolo[1,5-a] pyrimidines and their regioisomeric ethyl esters
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In this work, the reaction of 4-hydroxy-6-methylpyran-2-one, a bifunctional compound, with various 5-amino-3/4-aryl-1H-pyrazoles in ethanol has been studied. While the reaction with 5-amino-3-aryl-1H-pyrazoles affords three products namely 5,7-dimethylpyrazolo[1,5-a]pyrimidines 3, ethyl 2-(7-methylpyrazolo [1,5-a]pyrimidin- 5-yl)acetates 4 and its regioisomer ethyl 2-(5-methylpyrazolo[1,5-a]pyrimidin-7- yl)acetates 5, 5-amino-4-aryl-1H-pyrazoles led to the formation of two products 5,7- dimethylpyrazolo[1,5-a] pyrimidines 7 and ethyl 2-(5-methylpyrazolo[1,5-a]pyrimidin- 7-yl)acetates 8. The products were characterized unambiguously by rigorous analysis of IR, NMR (1H and 13C) and mass spectrometry and a mechanism is proposed for their formation.
- Aggarwal, Ranjana,Rani, Chinu,Kumar, Rajiv
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p. 419 - 428
(2019/01/21)
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- Expanding the structural diversity of polyketides by exploring the cofactor tolerance of an inline methyltransferase domain
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A strategy for introducing structural diversity into polyketides by exploiting the promiscuity of an in-line methyltransferase domain in a multidomain polyketide synthase is reported. In vitro investigations using the highly-reducing fungal polyketide synthase CazF revealed that its methyltransferase domain accepts the nonnatural cofactor propargylic Se-adenosyl-l-methionine and can transfer the propargyl moiety onto its growing polyketide chain. This propargylated polyketide product can then be further chain-extended and cyclized to form propargyl-α pyrone or be processed fully into the alkyne-containing 4′-propargyl-chaetoviridin A.
- Winter, Jaclyn M.,Chiou, Grace,Bothwell, Ian R.,Xu, Wei,Garg, Neil K.,Luo, Minkui,Tang, Yi
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supporting information
p. 3774 - 3777
(2013/08/23)
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- The Botrytis cinerea type III polyketide synthase shows unprecedented high catalytic efficiency toward long chain acyl-CoAs
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BPKS from Botrytis cinerea is a novel type III polyketide synthase that accepts C4-C18 aliphatic acyl-CoAs and benzoyl-CoA as the starters to form pyrones, resorcylic acids and resorcinols through sequential condensation with malonyl-CoA. The catalytic efficiency (kcat/K m) of BPKS was 2.8 × 105 s-1 M -1 for palmitoyl-CoA, the highest ever reported. Substrate docking analyses addressed the unique features of BPKS such as its high activity and high specificity toward long chain acyl-CoAs.
- Jeya, Marimuthu,Kim, Tae-Su,Tiwari, Manish Kumar,Li, Jinglin,Lee, Jung-Kul,Zhao, Huimin
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p. 2864 - 2867,4
(2020/09/16)
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- Heck-matsuda arylation as a strategy to access kavalactones isolated from polygala sabulosa, piper methysticum, and analogues
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Herein, we describe the total syntheses of three bioactive pyrones isolated from Polygala sabulosa (i.e., 1, 4, and 7) and eight isolated from Piper methysticum (i.e., 8-10, 13, 15, and 18-20) using the Heck-Matsuda arylation as the key strategy. The evaluation of this methodology by employing different arenediazonium tetrafluoroborates revealed that the Heck arylation was more efficient when the olefin undergoing arylation possessed the vinyl-2-pyrone structural unit instead of the vinyl dihydro-2-pyrone moiety. The Heck-Matsuda arylation of many of the examined olefins proceeded in a practical manner with total regio- and stereocontrol.
- Soldi, Cristian,Moro, Angelica V.,Pizzolatti, Moacir G.,Correia, Carlos R. D.
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experimental part
p. 3607 - 3616
(2012/07/31)
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- Antitumor agents 287. Substituted 4-amino-2H-pyran-2-one (APO) analogs reveal a new scaffold from neo-tanshinlactone with in vitro anticancer activity
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4-Amino-2H-benzo[h]chromen-2-one (ABO) and 4-amino-7,8,9,10-tetrahydro-2H- benzo[h]chromen-2-one (ATBO) analogs were found to be significant in vitro anticancer agents in our previous research. Our continuing study has now discovered a new simplified (monocyclic rather than tricyclic) class of cytotoxic agents, 4-amino-2H-pyran-2-one (APO) analogs. By incorporating various substituents on the pyranone ring, we have established preliminary structure-activity relationships (SAR). Analogs 19, 20, 23, and 26-30 displayed significant tumor cell growth inhibitory activity in vitro. The most active compound 27 exhibited ED50 values of 0.059-0.090 μM.
- Dong, Yizhou,Nakagawa-Goto, Kyoko,Lai, Chin-Yu,Morris-Natschke, Susan L.,Bastow, Kenneth F.,Lee, Kuo-Hsiung
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scheme or table
p. 2341 - 2344
(2011/05/15)
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- Production of octaketide polyenes by the calicheamicin polyketide synthase CalE8: Implications for the biosynthesis of enediyne core structures
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(Chemical Equation Presented) Enediyne antibiotics are categorized according to the presence of either a 9- or 10-membered ring within their polyketide-derived core structures. Recent literature reports have favored the notion that biosynthetic divergence
- Belecki, Katherine,Crawford, Jason M.,Townsend, Craig A.
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supporting information; experimental part
p. 12564 - 12566
(2010/01/29)
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- Synthesis and phytotoxic activity of new pyridones derived from 4-hydroxy-6-methylpyridin-2(1H)-one
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Commercial dehydroacetic acid was converted into 4-hydroxy-6-methylpyridin- 2(1 H)-one (3), which was then condensed with several aliphatic aldehydes to produce seven new title compounds in variable yields (35-92%). Reaction of 3 with α,β-unsaturated aldehydes resulted in the formation of condensed pyran derivatives 4g′ and 4h′. A mechanism is proposed to explain the formation of such compounds. The effects of all methylpyridin-2(1 H)-one derivatives on the development of the dicotyledonous species Ipomoea grandifolia and Cucumis sativus and the monocotyledonous species Sorghum bicolor were evaluated. At the dose of 6.7 × 10-8 mol a.i./g substrate the compounds showed some phytotoxic selectivity, being more active against the dicotyledonous species. These compounds can be used as lead structures for the development of more active phytotoxic products.
- Demuner, Antonio Jacinto,Valente, Vania Maria Moreira,Barbosa, Luiz Claudio Almeida,Rathi, Akshat H.,Donohoe, Timothy J.,Thompson, Amber L.
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experimental part
p. 4973 - 4986
(2010/04/05)
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- Pyrone polyketides synthesized by a type III polyketide synthase from Drosophyllum lusitanicum
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To isolate cDNAs involved in the biosynthesis of acetate-derived naphthoquinones in Drosophyllum lusitanicum, an expressed sequence tag analysis was performed. RNA from callus cultures was used to create a cDNA library from which 2004 expressed sequence tags were generated. One cDNA with similarity to known type III polyketide synthases was isolated as full-length sequence and termed DluHKS. The translated polypeptide sequence of DluHKS showed 51-67% identity with other plant type III PKSs. Recombinant DluHKS expressed in Escherichia coli accepted acetyl-coenzyme A (CoA) as starter and carried out sequential decarboxylative condensations with malonyl-CoA yielding α-pyrones from three to six acetate units. However, naphthalenes, the expected products, were not isolated. Since the main compound produced by DluHKS is a hexaketide α-pyrone, and the naphthoquinones in D. lusitanicum are composed of six acetate units, we propose that the enzyme provides the backbone of these secondary metabolites. An involvement of accessory proteins in this biosynthetic pathway is discussed.
- Jindaprasert, Aphacha,Springob, Karin,Schmidt, Juergen,De-Eknamkul, Wanchai,Kutchan, Toni M.
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experimental part
p. 3043 - 3053
(2009/04/11)
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- Exploiting the reaction flexibility of a type III polyketide synthase through in vitro pathway manipulation
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A synthetic metabolic pathway has been constructed in vitro consisting of the type III polyketide synthase from Streptomyces coelicolor and peroxidases from soybean and Caldariomyces fumago (chloroperoxidase). This has resulted in the synthesis of the pentaketide flaviolin and its dimeric derivative, and a wide range of pyrones and their coupled derivatives with flaviolin, as well as their halogenated derivatives. The addition of acyl-CoA oxidase to the pathway prior to the polyketide synthase resulted in unsaturated pyrone side chains, further broadening the product spectrum that can be achieved. The approach developed in this work, therefore, provides a new model to exploit biocatalysis in the synthesis of complex natural product derivatives. Copyright
- Jeong, Jae-Cheol,Srinivasan, Aravind,Grueschow, Sabine,Bach, Horacio,Sherman, David H.,Dordick, Jonathan S.
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- Engineered biosynthesis of plant polyketides: Chain length control in an octaketide-producing plant type III polyketide synthase
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The chalcone synthase (CHS) superfamily of type III polyketide syntheses (PKSs) produces a variety of plant secondary metabolites with remarkable structural diversity and biological activities (e.g., chalcones, stilbenes, benzophenones, acrydones, phloroglucinols, resorcinols, pyrones, and chromones). Here we describe an octaketide-producing novel plant-specific type III PKS from aloe (Aloe arborescens) sharing 50-60% amino acid sequence identity with other plant CHS-superfamily enzymes. A recombinant enzyme expressed in Escherichia coli catalyzed seven successive decarboxylative condensations of malonyl-CoA to yield aromatic octaketides SEK4 and SEK4b, the longest polyketides known to be synthesized by the structurally simple type III PKS. Surprisingly, site-directed mutagenesis revealed that a single residue Gly207 (corresponding to the CHS's active site Thr197) determines the polyketide chain length and product specificity. Small-to-large substitutions (G207A, G207T, G207M, G207L, G207F, and G207W) resulted in loss of the octaketide-forming activity and concomitant formation of shorter chain length polyketides (from triketide to heptaketide) including a pentaketide chromone, 2,7-dihydroxy-5-methylchromone, and a hexaketide pyrone, 6-(2,4-dihydroxy-6-methylphenyl)-4-hydroxy-2-pyrone, depending on the size of the side chain. Notably, the functional diversity of the type III PKS was shown to evolve from simple steric modulation of the chemically inert single residue lining the active-site cavity accompanied by conservation of the Cys-His-Asn catalytic triad. This provided novel strategies for the engineered biosynthesis of pharmaceutically important plant polyketides.
- Abe, Ikuro,Oguro, Satoshi,Utsumi, Yoriko,Sano, Yukie,Noguchi, Hiroshi
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p. 12709 - 12716
(2007/10/03)
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- Synthesis of new series of 1-Aryl-1,4-dihydro-4-oxo-6-methyl pyridazine-3-carboxylic acid as potential antibacterial agents
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New series of 1-aryl-1,4-dihydro-4-oxo-6-methyl pyridazine-3-carboxylic acid has been synthesized and the structures of the new compounds were established on the basis of 1H-NMR, mass (ES/MS), elemental analysis and IR spectral data. In vitro antibacterial activity (MIC activity) was evaluated and compared with standard drugs ciprofloxacin, sparfloxacin and trovafloxacin. Most of the compounds in the series have shown very interesting antibacterial activity against both Gram-positive and Gram-negative organisms. In this paper, we describe studies leading to identification of antibacterial agents incorporating novel pyridazine ring surrogate. In a gratifying result, the initial pyridazine-3-carboxylic acid analogues prepared were found to exhibit in vitro antibacterial activity approaching that of corresponding fluoroquinolone progenitor.
- Nagawade, Rahul R.,Khanna, Vijay V.,Bhagwat, Sachin S.,Shinde, Devanand B.
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p. 1325 - 1330
(2007/10/03)
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- Ketone derivatives and medical application thereof
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The present invention relates to ketone derivatives represented by the following formula and medical agents containing the ketone derivatives or pharmacologically acceptable salts thereof as an active ingredient, and in particular, relates to a hematopoietic agent; it is shown that the present invention increases blood cells, such as platelets, white blood cells, and red blood cells, and is effective in preventing and treating cytopenia caused by cancer chemotherapy, radiation therapy, and the like.
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- A new approach to the synthesis of 3,6- and 5,6-dialkyl derivatives of 4-hydroxy-2-pyrone. Synthesis of rac-germicidin
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A new approach to the synthesis of 3,6- and 5,6-dialkyl-4-hydroxy-2- pyrones has been developed. The method includes the formation of acylated Meldrum's acids (5-(2-alkyl-3-oxoacyl)-2,2-dimethyl-1,3-dioxane-4,6-diones) followed by their thermal transformation. Introduction of 3-alkyl substituents was accomplished by acylation of 4-hydroxy-2-pyrones and ionic hydrogenation of the 3-acyl derivatives obtained. The effectiveness of this new approach has been demonstrated in the synthesis of rac-germicidin, an autoregulative germination inhibitor of Streptomyces viridochromogenes NRRL B-1551.
- Lokot, Igor P.,Pashkovsky, Felix S.,Lakhvich, Fedor A.
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p. 4783 - 4792
(2007/10/03)
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- Synthetic hispidin, a PKC inhibitor, is more cytotoxic toward cancer cells than normal cells in vitro
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The trypanocidal activity of naturally occurring 6-(3,4-dihydroxystyryl)-4-hydroxy-2-pyrone (hispidin) prompted us to examine its cytotoxic activity toward normal and cancerous cells in culture. Hispidin synthesized in our laboratory to a high degree of purity (checked by 1H and 13C NMR spectroscopy) was shown to be cytotoxic (between 10-3 mol/L and 10-7 mol/L) toward normal human MRC-5 fibroblasts, human cancerous keratinocytes (SCL-1 cell line), and human cancerous pancreatic duct cells (Capan-1 cell line). Interestingly, addition of hispidin in three successive doses (between 10-5 mol/L and 10-7 mol/L) led to a 100-fold increase in activity with an enhanced activity on cancer cells compared to normal cells (50%). Synthetic hispidin was found to inhibit isoform β of protein kinase C (IC50 of 2 x 10-6 mol/L), but not E. coli and placental type XV alkaline phosphatases. The enhanced activity of hispidin toward the cancerous cell lines is discussed.
- Gonindard,Bergonzi,Denier,Sergheraert,Klaebe,Chavant,Hollande
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p. 141 - 153
(2007/10/03)
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- Pyranones
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A process for the separation of at least one isomer from a mixture of isomers of a tetrahydropyran-2-one, having at least two chiral centers which comprises selective reaction of at least one isomer with a reagent catalyzed by a hydrolase enzyme whereby at least one isomer is preferentially converted into a distinct chemical species from the other isomers so that it is susceptible of separation by an appropriate chemical or physical separation process in which the tetrahydropyran-2-one is of Formula (1): STR1 wherein: Z is --H or a protecting group susceptible of reaction with the reagent under the influence of the enzyme; and Y is formyl or protected formyl.
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- Reactions of fused and unfused α-pyrones with magnesium alkoxide, sodium alkoxide and water as the nucleophile: effects of chelation
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The reactions between a series of α-pyrones (two mono- and three fused) and the non-chelating base sodium alkoxide, the chelating base magnesium alkoxide and water as the nucleophile, have been studied.Aromatic and other products formed reflect the points of attack on the pyrone systems and when sodium methoxide is used the ensuing cyclisation is preferentially by aldol mechanisms.The employment of excess magnesium methoxide or ethoxide gives magnesium-chelated precursors and the nature of products now depends on these intermediates, and the protection afforded by such magnesium chelation to the reaction products.In the case of structures containing chelated β-keto ester features the chelates are screened from attack as aldol acceptors, but are effective Claisen acceptors.In such chelates an adjacent methylene is activated by further magnesium alkoxide to act as an aldol or Claisen donor.These contrasting aldol/Claisen reactivities, as between a non-chelating and a chelating base, are illustrated in the ensuing chemistry of the pyrones.Treatment with water releases the main carbon chain with decarboxylation, from which new products may form.
- Crombie, Leslie,Games, David E.,James, Alun W. G.
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p. 2715 - 2724
(2007/10/03)
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- Cyclization Reactions of Tricarbonylmethane Thiosemicarbazones: Formation of 1,3,4-Thiadiazole Derivatives with Concomitant C-C Bond Cleavage
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Under acylating conditions 3-acetyl-4-hydroxy-2H-pyran-2-one thiosemicarbazones (1a, b and 2a, b) are transformed into 2-(acylamino)-5-methyl-1,3,4-thiadiazoles 3b, c, e, f and 2H-pyran-2-ones 1c and 2c via C-C bond cleavage.Similarly, the reaction of 1b with RCO2H/EtOH (R = Me, Et) affords 2-anilino-5-methyl-1,3,4-thiadiazole (3d) and triacetic acid lactone 1c.Upon treatment with Ac2O/Et3N the dehydroacetic acid derivative 1b is transformed into the thiadiazoline 4, while the benzo derivative 2b is converted into thiadiazole 3e and 4-acetoxycoumarin (2c). - Key Words: 2H-Pyran-2-ones / Coumarins / 1,3,4-Thiadiazoles / Thiosemicarbazones
- Somogyi, Laszlo
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p. 721 - 724
(2007/10/02)
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- TWO LACTONE FORMATION REACTIONS FROM 1,3-DIOXIN-4-ONES HAVING HYDROXYALKYL GROUP AT THE 6-POSITION: DIFFERENCE IN RING OPENING AND CLOSURE
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Two methods (A: ring opening to acylketenes followed by intramolecular ketene trapping and B: methoxide-mediated ring opening followed by cyclization of the hydroxy esters thus formed) have become available for the synthesis of lactones and/or cyclic ethers from 1,3-dioxin-4-ones having 1- 4-hydroxyalkyl group at the 6-position.Mechanism and scope of both methods have been clarified.
- Sato, Masayuki,Sakaki, Jun-ichi,Sugita, Yoshiaki,Yasuda, Sanae,Sakoda, Hiroko,Kaneko, Chikara
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p. 5689 - 5708
(2007/10/02)
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- An Improved Method for γ-Carboxylation of β-Diketones. Synthesis of 4-Alkyl-3,5-dioxohexanoic Acids and 5-Alkyl Derivatives of Triacetic Acid Lactone
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γ-Carboxylation of β-diketones, 1, can be improved using samples containing 100percent of ketoenol tautomers, 3, prepared by mild hydrolysis of the corresponding copper(II) complexes 2.Cyclization of the so formed 4-alkyl-3,5-dioxohexanoic acids, 4, affords 5-alkyl-4-hydroxy-6-methyl-2-pyrones, 5.
- Cervello, Jordi,Marquet, Jorge,Moreno-Manas, Marcial
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p. 1931 - 1941
(2007/10/02)
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- AN INVESTIGATION OF THE BIOSYNTHESIS OF CITROMYCETIN IN PENICILLIUM FREQUENTANS USING (13)C- AND (14)C-LABELLED PRECURSORS
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Citromycetin (1) has been shown by (13)C n.m.r. to incorporate seven intact acetate units from -, -, and -acetates in accordance with a polyketide biosynthesis.The distribution of radioactivity following incorporation of malonate was consistent with the utilisation of two starter units.The following possible advanced precursors, labelled with (14)C, were not incorporated : 2,4-dihydroxy-6-methylbenzoic acid (14), 4,5,7-trihydroxyphthalide (16), and 4,7-dihydroxy-5-methylcoumarin (18).Two compounds, 2,4,5-trihydroxy-6-methylbenzoic acid (15) and triacetic acid lactone (17), were degraded to radiolabelled acetate prior to incorporation.
- Evans, Geoffrey E.,Staunton, James
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p. 755 - 762
(2007/10/02)
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- Alkylation of Position C-5 of Triacetic Acid Lactone by Sigmatropic Rearrangement of Sulphonium Ylides
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Reactions of the 4-methoxy-6-(phenylthiomethyl)-2H-pyran-2-ones 4 with three different diazo compounds under copper or rhodium catalysis give the corresponding sulphonium ylides, which through sigmatropic rearrangement and further prototropy afford the pyrones 6, functionalized at the difficultly accessible position C-5.Desulphurations of products 6 with deactivated Raney nickel give the pyrones 17-19.The influence of the experimental conditions on the competition between sigmatropic and Stevens rearrangement has been studied for the reaction of 4-methoxy-6-(phenylthiomethyl)-2H-pyran-2-one (4a) and dimethyl diazomalonate.Several products (9, 10, and 11) arising from sulphonium ylides equilibration and radical recombination have been found in addition to the sigmatropic and the Stevens rearrangement products 6d and 8.
- March, Pedro de,Moreno-Manas, Marcial,Ripoll, Isabel
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p. 1413 - 1420
(2007/10/02)
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- Enol Ethers, XIV. Acylation of Keto Enol Ethers with Malonyl Dichloride - A New Synthesis of Phloroglucinols
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Phloroglucinols 4 and/or 4-hydroxy-2H-pyran-2-ones 5 are formed from keto enol ethers 1 and malonyl dichloride (2a) in high yields.Since the pyranones 5 can be smoothly converted into phloroglucinols, the reaction of 1 with 2a represents a new, facile synthetic route to phloroglucinols.The reaction proceeds via formation of a chloro carbonyl ketene 8 and its subsequent reaction with 1.The product ratio 4:5 is rationalized in terms of substituent effects in the enol ether substrate.
- Effenberger, Franz,Schoenwaelder, Karl-Heinz
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p. 3270 - 3279
(2007/10/02)
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