- Acylation studies with Meldrum's acid
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Meldrum's acid (1) on bisacylation with succinyl chloride afforded a neutral diketo product (2); however, the dimer enolic products (3) with acidic nature resulted in glutaryl and adipyl dichlorides. Monoacylation of (1) with acetyl chloride gave acidic 5-acetyl Meldrum's acid (4) in enol form. Copyright Taylor & Francis, Inc.
- Mahulikar,Mane
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Read Online
- A synthetic approach to 5/5/6-polycyclic tetramate macrolactams of the discodermide type
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A flexible synthetic route to the 16-membered tetramate-embedding macrocyclic scaffold present in various polycyclic tetramate macrolactams (PTMs) was developed which differs from the seminal synthesis of ikarugamycin by Boeckman Jr. in protecting groups and the order of connections. We also devised a short approach to various stereoisomers of the 5/5/6-tricarbocyclic motif found in discodermide and other PTMs, starting from the Weiss’ diketone.
- Bodenschatz, Kevin,St?ckl, Julia,Winterer, Markus,Schobert, Rainer
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- Electrochemical synthesis of versatile ammonium oxides under metal catalyst-, exogenous-oxidant-, and exogenous-electrolyte-free conditions
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An electrochemical oxidative cross-coupling reaction between 2.5-substituted-pyrazolin-5-ones and ammonium thiocyanate has been developed, which resulted in a series of unprecedented cross-coupling products under metal catalyst-, exogenous-oxidant-, and exogenous-electrolyte-free conditions. It is worth noting that since the resulting cross-coupling products are nearly insoluble in MeCN, the pure product could be afforded without silica gel column purification. In addition, the prepared ammonium oxides are versatile building blocks for synthesizing functionalized pyrazole derivatives.
- Yuan, Yong,Li, Liang-Sen,Zhang, Lin,Wang, Feng,Jiang, Lin,Zuo, Lin,Wang, Qi,Hu, Jian-Guo,Lei, Aiwen
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supporting information
p. 2768 - 2771
(2021/03/23)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF 4-({(1 R)-2-[5-(2-FLUORO-3METHOXYPHENYL)-3-{[2-FLUORO-6-(TRIFLUORO METHYL) PHENYL]METHYL}-4-METHYL-2,6-DIOXO-3,6DIHYDROPYRIMIDIN-1(2 H)-YL]-1-PHENYLETHYL}AMINO)BUTANOIC ACID OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention relates to an improved process for the preparation of 4- ({(1R) -2- [5- (2-fluoro- 3- methoxy phenyl) – 3 - {[ 2-fluoro- 6-(trifluoro methyl) phenyl] methyl} -4-methyl- 2,6-dioxo- 3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino) butanoic acid of formula (I) or its pharmaceutically acceptable salts. The compound of formula (I) is represented by the following structural formula.
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Page/Page column 17
(2021/07/02)
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- 5-Carbonyl-1,3-oxazine-2,4-diones from N-Cyanosulfoximines and Meldrum's Acid Derivatives
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At elevated temperatures, N-cyanosulfoximines react with Meldrum's acid derivatives to give sulfoximines with N-bound 5-carbonyl-1,3-oxazine-2,4-dione groups. A representative product was characterized by single-crystal X-ray structure analysis. The product formation involves an unexpected molecular reorientation requiring several sequential bond-forming and-cleaving processes.
- Brosge, Felix,Kochs, Johannes Florian,Bregu, Mariela,Truong, Khai-Nghi,Rissanen, Kari,Bolm, Carsten
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supporting information
p. 6667 - 6670
(2020/09/02)
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- Control of β-Branching in Kalimantacin Biosynthesis: Application of 13C NMR to Polyketide Programming
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The presence of β-branches in the structure of polyketides that possess potent biological activity underpins the widespread importance of this structural feature. Kalimantacin is a polyketide antibiotic with selective activity against staphylococci, and its biosynthesis involves the unprecedented incorporation of three different and sequential β-branching modifications. We use purified single and multi-domain enzyme components of the kalimantacin biosynthetic machinery to address in vitro how the pattern of β-branching in kalimantacin is controlled. Robust discrimination of enzyme products required the development of a generalisable assay that takes advantage of 13C NMR of a single 13C label incorporated into key biosynthetic mimics combined with favourable dynamic properties of an acyl carrier protein. We report a previously unassigned modular enoyl-CoA hydratase (mECH) domain and the assembly of enzyme constructs and cascades that are able to generate each specific β-branch.
- Walker, Paul D.,Williams, Christopher,Weir, Angus N. M.,Wang, Luoyi,Crosby, John,Race, Paul R.,Simpson, Thomas J.,Willis, Christine L.,Crump, Matthew P.
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supporting information
p. 12446 - 12450
(2019/08/16)
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- Acyl/aroyl Meldrum's acid as an enol surrogate for the direct organocatalytic synthesis of α,β-unsaturated ketones
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The operationally simple, robust and straightforward organocatalytic protocol is developed for the synthesis of E-selective α,β-unsaturated ketones. The method utilizes simple and easily accessible starting materials such as Meldrum's acid, carboxylic acid, aldehyde and simple bifunctional amine catalyst. The tandem organocatalytic process utilizes acyl/aroyl Meldrum's acid as an enol surrogate for the effective Doebner-Knoevenagel type condensation reactions. A wide variety of aldehydes, carboxylic acids and base sensitive functional groups are well tolerated under the mild reaction conditions.
- Khopade, Tushar M.,Warghude, Prakash K.,Mete, Trimbak B.,Bhat, Ramakrishna G.
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supporting information
p. 197 - 200
(2018/12/13)
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- 3-Oxoisoxazole-2(3H)-carboxamides and isoxazol-3-yl carbamates: Resistance-breaking acetylcholinesterase inhibitors targeting the malaria mosquito, Anopheles gambiae
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To identify potential selective and resistance-breaking mosquitocides against the African malaria vector Anopheles gambiae, we investigated the acetylcholinesterase (AChE) inhibitory and mosquitocidal properties of isoxazol-3-yl dimethylcarbamates (15), and the corresponding 3-oxoisoxazole-2(3H)-dimethylcarboxamide isomers (14). In both series, compounds were found with excellent contact toxicity to wild-type susceptible (G3) strain and multiply resistant (Akron) strain mosquitoes that carry the G119S resistance mutation of AChE. Compounds possessing good to excellent toxicity to Akron strain mosquitoes inhibit the G119S mutant of An. gambiae AChE (AgAChE) with ki values at least 10- to 600-fold higher than that of propoxur, a compound that does not kill Akron mosquitoes at the highest concentration tested. On average, inactivation of WT AgAChE by dimethylcarboxamides 14 was 10-20 fold faster than that of the corresponding isoxazol-3-yl dimethylcarbamates 15. X-ray crystallography of dimethylcarboxamide 14d provided insight into that reactivity, a finding that may explain the inhibitory power of structurally-related inhibitors of hormone-sensitive lipase. Finally, human/An. gambiae AChE inhibition selectivities of these compounds were low, suggesting the need for additional structural modification.
- Verma, Astha,Wong, Dawn M.,Islam, Rafique,Tong, Fan,Ghavami, Maryam,Mutunga, James M.,Slebodnick, Carla,Li, Jianyong,Viayna, Elisabet,Lam, Polo C.-H.,Totrov, Maxim M.,Bloomquist, Jeffrey R.,Carlier, Paul R.
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p. 1321 - 1340
(2015/03/04)
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- ORGANOCOPPER COMPLEX, ORGANOCOPPER COMPLEX SOLUTION, COPPER OXIDE THIN FILM, METHOD FOR PRODUCING COPPER OXIDE THIN FILM, AND COMPOUND
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Provided are: an organocopper complex having a structure represented by general formula (1); a copper oxide thin film comprising the organocopper complex; a method for producing the copper oxide thin film; and a compound constituting the organocopper comp
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Paragraph 0278-0280; 0283
(2016/10/08)
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- A novel method for the one-pot five-component synthesis of highly functionalized pyranopyrazoles catalyzed by CuI nanoparticles
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A novel one-pot, five-component reaction for the synthesis of highly functionalized pyranopyrazoles from acid chlorides, Meldrum's acid, hydrazine hydrate, aromatic aldehydes and malononitrile in the presence of catalytic amount of CuI nanoparticles in aq
- Safaei-Ghomi, Javad,Ziarati, Abolfazl,Tamimi, Mehrnoush
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p. 403 - 410
(2013/08/23)
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- Synthesis and dynamic NMR study of new stable ylides derived from the reaction of triphenylphosphine, dialkyl acetylenedicarboxylates, and 5-ACYL meldrums acid
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Triphenylphosphine and dialkyl acetylenedicarboxylate react smoothly in the presence of 5-acyl Meldrum's acid in dichloromethane at room temperature and lead to synthesis of new stable ylide derivatives of dimethyl (5-acetyl-2,2-dimethyl-4,6-dioxo-1,3-dio
- Habibi, Azizollah,Eskandari, Khalil,Alizadeh, Abdolali
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body text
p. 1109 - 1117
(2012/08/13)
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- Development of N-substituted hydroxylamines as efficient nitroxyl (HNO) donors
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Due to its inherent reactivity, nitroxyl (HNO), must be generated in situ through the use of donor compounds, but very few physiologically useful HNO donors exist. Novel N-substituted hydroxylamines with carbon-based leaving groups have been synthesized, and their structures confirmed by X-ray crystallography. These compounds generate HNO under nonenzymatic, physiological conditions, with the rate and amount of HNO released being dependent mainly on the nature of the leaving group. A barbituric acid and a pyrazolone derivative have been developed as efficient HNO donors with half-lives at pH 7.4, 37 °C of 0.7 and 9.5 min, respectively.
- Guthrie, Daryl A.,Kim, Nam Y.,Siegler, Maxime A.,Moore, Cathy D.,Toscano, John P.
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supporting information; experimental part
p. 1962 - 1965
(2012/03/12)
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- Asymmetric total synthesis of the indole alkaloid cyclopiazonic acid and first structure-activity data
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The indole alkaloid α-cyclopiazonic acid (CPA) is one of the few known inhibitors of sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) besides the terpenoids thapsigargin and artemisinin. We report here the first asymmetric total synthesis of cy
- Beyer, W.R. Christian,Woithe, Katharina,Lüke, Bettina,Schindler, Michael,Antonicek, Horst,Scherkenbeck, Jürgen
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experimental part
p. 3062 - 3070
(2011/05/17)
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- A facile synthesis of pyrimidin-4-ones
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A facile synthesis of 2,6-disubstituted pyrimidin-4-ones and 2,5,6-trisubstituted pyrimidin-4-ones from commercially available materials with application of microwave technology in key steps is described.
- Guo, Cheng
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scheme or table
p. 548 - 549
(2010/10/02)
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- Structure-activity relationships of 1,4-dihydropyridines that act as enhancers of the vanilloid receptor 1 (TRPV1)
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Vanilloid agonists such as capsaicin activate ion flux through the TRPV1 channel, a heat- and ligand-gated cation channel that transduces painful chemical or thermal stimuli applied to peripheral nerve endings in skin or deep tissues. We have probed the SAR of a variety of 1,4-dihydropyridine (DHP) derivatives as novel 'enhancers' of TRPV1 activity by examining changes in capsaicin-induced elevations in 45Ca2+-uptake in either cells ectopically expressing TRPV1 or in cultured dorsal root ganglion (DRG) neurons. The enhancers increased the maximal capsaicin effect on 45Ca2+-uptake by typically 2- to 3-fold without producing an action when used alone. The DHP enhancers contained 6-aryl substitution and small alkyl groups at the 1 and 4 positions, and a 3-phenylalkylthioester was tolerated. Levels of free intracellular Ca2+, as measured by calcium imaging, were also increased in DRG neurons when exposed to the combination of capsaicin and the most efficacious enhancer 23 compared to capsaicin alone. Thus, DHPs can modulate TRPV1 channels in a positive fashion.
- Roh, Eun Joo,Keller, Jason M.,Olah, Zoltan,Iadarola, Michael J.,Jacobson, Kenneth A.
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scheme or table
p. 9349 - 9358
(2009/04/06)
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- Synthetic libraries of tyrosine-derived bacterial metabolites
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The preparation of a collection of 131 small molecules, reminiscent of families of long chain N-acyl tyrosines, enamides and enol esters that have been isolated from heterologous expression of environmental DNA (eDNA) in Escherichia coli, is reported. The synthetic libraries of N-acyl tyrosines and their 3-keto counterparts were prepared via solid-phase routes, whereas the enamides and enol esters were synthesized in solution-phase.
- Georgiades, Savvas N.,Clardy, Jon
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supporting information; experimental part
p. 3117 - 3121
(2009/04/03)
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- On the synthesis of 5-ethyl Meldrum's acid
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Reductive alkylation of Meldrum's acid with acetaldehyde can give, depending on the experimental conditions, e ither a new dimer (5-[3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)butyl]-2,2-dimethyl-1,3-dioxane-4, 6-dione) or ethyl Meldrum's acid (2,2-dimethyl-1,3-dioxane-4,6-dione). A best way to obtain this latter product is synthesis of 1-ethoxyethylidene Meldrum's acid from reaction of Meldrum's acid with triethyl orthoacetate, followed by a sodium borohydride reduction.
- Akue-Gedu, Rufine,El-Hafidi, Hayate,Rigo, Benoit,Couturier, Daniel
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p. 365 - 369
(2007/10/03)
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- Hydrolysis of α-alkyl-α-(methylthio)methylene Meldrum's acids. A kinetic and computational investigation of steric effects
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The rates of hydrolysis of α-R-α-(methylthio)methylene Meldrum's acids (8-R with R = H, Me, Et, s-Bu, and t-Bu) were determined in basic and acidic solution in 50% DMSO-50% water (v/v) at 20 °C. In basic solution (KOH), nucleophilic attack to form a tetrahedral intermediate (T OH-) is rate limiting for all substrates (κ1OH). In acidic solution (HCl) and at intermediate pH values (acetate buffers), water attack (κ1H2O) is rate limiting for 8-Me, 8-Et, and 8-t-Bu; the same is presumably the case for 8-t-Bu, but rates were too slow for accurate measurements at low pH. For 8-H, water attack is rate limiting at intermediate pH but at pH OH- to products, two of which being unique to hydrolysis reactions and taking advantage of the acidic nature of the OH group in TOH-. This scheme provides an explanation why even at high [KOH] TOH- does not accumulate to detectable levels even though the equilibrium for OH - addition to 8-R is expected to favor TOH, and why at low pH water attack is rate limiting for R = Me, Et, s-Bu, and t-Bu but leaving group departure becomes rate limiting with the sterically small R = H. The trend in the k1OH and k1H2O indicates increasing steric crowding at the transition state with increasing size of R, but this effect is partially offset by a sterically induced twisting of the C=C double bond in 8-R which leads to its elongation and makes the substrate less stable and hence more reactive. Our computational results suggest that this effect becomes particularly pronounced for R = t-Bu and explains why k 1OH for 8-t-Bu is somewhat higher than for the less crowded 8-s-Bu.
- Bernasconi, Claude F.,Brown, Shoshana D.,Ali, Mahammad,Rappoport, Zvi,Yamataka, Hiroshi,Salim, Hatim
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p. 4795 - 4802
(2007/10/03)
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- Structural requirements of dictyopyrones isolated from Dictyostelium spp. in the regulation of Dictyostelium development and in anti-leukemic activity
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Cellular slime molds are fascinating to the field of developmental biology, and have long been used as excellent model organisms for the study of various aspects of multicellular development. We have recently isolated α-pyronoids, named dictyopyrones A-D (1-4), from various species of Dictyostelium cellular slime molds, and it was shown that compound 3 may regulate Dictyostelium development. In this study, we synthesized dictyopyrones A-D (1-4) and their analogues, investigated the physiological role of the molecules in cell growth and morphogenesis in D. discoideum, and further verified their effects on human leukemia K562 cells. Nitrogen-containing compounds 22 and 37 strongly inhibited cell growth in K562 leukemia cells, indicating that these compounds may be utilized as novel lead compounds for anti-leukemic agents.
- Kikuchi, Haruhisa,Sasaki, Kazunori,Sekiya, Jun'ichi,Maeda, Yasuo,Amagai, Aiko,Kubohara, Yuzuru,Oshima, Yoshiteru
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p. 3203 - 3214
(2007/10/03)
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- Microwave-assisted solution-phase synthesis of 1,4,5-trisubstituted pyrazoles
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A small parallel library of 1,4,5-trisubstituted pyrazoles was prepared in solution using a three-step procedure starting from Meldrum acid. The Meldrum acid was acylated with different acyl chlorides and the products opened with different alcohols and amines to give substituted β-keto esters and β-keto amines. Further reaction with N,N-dimethylformamide dimethylacetal and the final cyclisation were effectively carried out under microwave irradiation. Scavenger resins were employed exclusively in the first step, whereas use of microwaves allowed complete conversion of the starting materials in the other two steps. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
- Giacomelli, Giampaolo,Porcheddu, Andrea,Salaris, Margherita,Taddei, Maurizio
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p. 537 - 541
(2007/10/03)
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- A novel route to 5-substituted 3-isoxazolols. Cyclization of N,O-diBoc β-keto hydroxamic acids synthesized via acyl Meldrum's acids
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3-Isoxazolols are most often synthesized from a β-keto ester and hydroxylamine. This cyclization typically gives rise to a major byproduct, the corresponding 5-isoxazolone. We have found that N,O-diBoc-protected β- keto hydroxamic acids can be synthesized and cyclized to 5-substituted 3- isoxazolols without formation of any byproduct. We present a novel and versatile three-step procedure in which carboxylic acid derivatives are converted into acyl Meldrum's acids which, upon aminolysis with N,O-bis(tert- butoxycarbonyl)hydroxylamine, lead to the N,O-diBoc-protected β-keto hydroxamic acids. These hydroxamic acid analogues were then, upon treatment with hydrochloric acid, cyclized to the corresponding 5-substituted 3- isoxazolols.
- Sorensen, Ulrik S.,Falch, Erik,Krogsgaard-Larsen, Povl
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p. 1003 - 1007
(2007/10/03)
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- Decarboxylative elimination of enol triflates as a general synthesis of acetylenes
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Decarboxylative elimination of a range of enol triflates of β-keto esters gives acetylenes.
- Fleming, Ian,Ramarao, Chandrashekar
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p. 1113 - 1114
(2007/10/03)
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- Synthesis of the AB spiroketal subunit of spongistatin 1 (Altohyrtin A): The pyrone approach
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The synthesis of the AB spiroketal fragment of spongistatin 1 (altohyrtin A) has been accomplished utilizing the addition of a metalated pyrone to an aldehyde followed by acid catalyzed spirocyclization. A stereoselective copper (I) promoted conjugate add
- Crimmins, Michael T.,Washburn, David G.
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p. 7487 - 7490
(2007/10/03)
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- Solid-phase synthesis of polymer-bound β-ketoesters and their application in the synthesis of structurally diverse pyrazolones
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An efficient solid-phase synthesis of different polymer-bound β-ketoesters 7 is described using readily available acid chlorides 1 and haloalkanes 6 as building blocks. The corresponding pyrazolones 9 and 10 were obtained by mild acid catalyzed reaction with phenylhydrazine or by treatment with hydrazine under cyclisation and cleavage from the resin in high purity and good yield.
- Tietze, Lutz F.,Steinmetz, Adrian,Balkenhohl, Friedhelm
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p. 1303 - 1306
(2007/10/03)
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- The synthesis of β-keto lactones via cyclization of β-keto ester dianions or the cyclization of Meldrum's acid derivatives
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Two new methods to synthesize macrocyclic β-keto lactones have been developed.The first involves the synthesis of ω-halo-β-keto esters and an intramolecular alkylation of the dianions to these compounds.The reaction is complicated by elimination in the small and medium ring systems and by difficulties in purifying the final products.However, it is possible to obtain modest yields of the desired β-keto lactones.This procedure was used to synthesize the 25- and 27-membered ring β-hydroxy lactones that are the constituents of termite defense compounds.The second method involves the thermolysis of acylated Meldrum's acid derivatives, which leads directly to β-keto lactones.This process gives modest yields of macrocyclic systems and good yield of the unsubstituted 3-oxopentan-5-olide (25) .The 14-membered macrocyclic β-keto lactone 9j has a complex 1H NMR spectrum, which has been interpreted in terms of multiple conformations.The temperature dependence of the NMR spectrum of 9j is consistent with entropic, rather than enthalpic, control of the equilibrium.Quasiharmonic entropy calculations are consistent with this model.
- Lermer, Leonard,Neeland, Edward G.,Ounsworth, James P.,Sims, Russell J.,Tischler, Samuel A.,Weiler, Larry
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p. 1427 - 1445
(2007/10/02)
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