- Condensation of resorcinol with phosphorylated acetals, synthesis of calix[4]resorcinolarenes with phosphorus-containing alkyl fragments in the lower rim
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The reaction of resorcinol with phosphorylated acetals leads to formation of calix[4]resorcinolarenes having phosphonate, phosphinate, or (phosphinothioyl)sulfanylmethyl fragments in the lower rim of the molecule. Pleiades Publishing, Inc., 2006.
- Burilov,Volodina,Popova,Gazizov,Knyazeva,Pudovik,Habicher,Konovalov
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- Synthesis of calix[4]resorcinarenes, containing phosphoryl fragments at the lower rim of the molecule
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Reaction of resorcinol with phosphorylated acetals or ethoxyvinylphosphonic acid esters in acidic media leads to calix[4]resorcinarenes, containing dialkoxyphosphoryl fragments at the lower rim of the molecule. When the alkyl substituent in alkoxy groups at phosphorus atom is not very long, a partial hydrolysis of the initially formed products takes place to give calixarenes with alkoxyhydroxyphosphoryl fragments.
- Burilov,Knyazeva,Sadykova,Pudovik,Habicher,Baier,Konovalov
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- Phosphonodifluoropyruvate is a mechanism-based inhibitor of phosphonopyruvate decarboxylase from Bacteroides fragilis
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Bacteroides fragilis, a human pathogen, helps in the formation of intra-abdominal abscesses and is involved in 90% of anaerobic peritoneal infections. Phosphonopyruvate decarboxylase (PnPDC), a thiamin diphosphate (ThDP)-dependent enzyme, plays a key role in the formation of 2-aminoethylphosphonate, a component of the cell wall of B. fragilis. As such PnPDC is a possible target for therapeutic intervention in this, and other phosphonate producing organisms. However, the enzyme is of more general interest as it appears to be an evolutionary forerunner to the decarboxylase family of ThDP-dependent enzymes. To date, PnPDC has proved difficult to crystallize and no X-ray structures are available. In the past we have shown that ThDP-dependent enzymes will often crystallize if the cofactor has been irreversibly inactivated. To explore this possibility, and the utility of inhibitors of phosphonate biosynthesis as potential antibiotics, we synthesized phosphonodifluoropyruvate (PnDFP) as a prospective mechanism-based inhibitor of PnPDC. Here we provide evidence that PnDFP indeed inactivates the enzyme, that the inactivation is irreversible, and is accompanied by release of fluoride ion, i.e., PnDFP bears all the hallmarks of a mechanism-based inhibitor. Unfortunately, the enzyme remains refractive to crystallization.
- Pallitsch, Katharina,Rogers, Megan P.,Andrews, Forest H.,Hammerschmidt, Friedrich,McLeish, Michael J.
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supporting information
p. 4368 - 4374
(2017/07/22)
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- Determination of the Absolute Configuration of (?)-Hydroxynitrilaphos and Related Biosynthetic Questions
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The ongoing search for bioactive natural products has led to the development of new genome-based screening approaches to identify possible phosphonate producing microorganisms. From the identified phosphonate producers, several until now unknown phosphonic acid natural products were isolated, including (hydroxy)nitrilaphos (4 and 5) and (hydroxy)phosphonocystoximate (7 and 6). We present the synthesis of phosphonocystoximate via an aldoxime intermediate. Chlorination and coupling with methyl N-acetylcysteinate furnished 6 after global deprotection. The obtained experimental data confirm the previously assigned structure of the natural product. We were also able to determine the absolute configuration of (?)-hydroxynitrilaphos. Chiral resolution of diethyl cyanohydroxymethylphosphonate (24) with Noe's lactol furnished both enantiomers of 4. Conversion of (+)-24 to (R)-2-amino-1-hydroxyethylphosphonic acid by reduction of the cyano-group showed (?)-hydroxynitrilaphos ultimately to be S-configured. Further, we present a 13C-isotope labeling strategy for 4 and 5 that will possibly solve the question of whether hydroxynitrilaphos is a biosynthetic intermediate or a downstream product of hydroxyphosphonocystoximate biosynthesis.
- Pallitsch, Katharina,Happl, Barbara,Stieger, Christian
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p. 15655 - 15665
(2017/10/09)
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- Synthesis of a new family of acyclic nucleoside phosphonates, analogues of TPases transition states
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A 6-step procedure was developed for the synthesis of a new family of acyclic nucleoside phosphonates (ANPs), "PHEEPA" [(2-pyrimidinyl-2-(2- hydroxyethoxy)ethyl)phosphonic acids] in overall yields ranging from 4.5% to 32%. These compounds, which possess on one side a hydroxy function and on the other side a phosphonate group, can be considered either as potential antiviral agents or as transition state analogues of nucleoside phosphorylases such as thymidine phosphorylase.
- Dayde, Benedicte,Benzaria, Samira,Pierra, Claire,Gosselin, Gilles,Surleraux, Dominique,Volle, Jean-Noel,Pirat, Jean-Luc,Virieux, David
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experimental part
p. 3448 - 3454
(2012/05/31)
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- Novel 1β-methylcarbapenems with isoxazoloethenyl moieties containing carboxylic acid sodium salt
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The synthesis of novel 1β-methylcarbapenems 1a,b having sodium 5-(3- and 5-carboxylic acid)isoxazoloethenyl moieties at C-5 position of pyrrolidine ring and their biological evaluation are described. Both compounds showed potent and well-balanced antibacterial activity as well as high stability to DHP-I. The selected sodium 3-carboxylic acid derivative 1a possessed excellent DHP-I stability and advanced pharmacokinetic parameters in comparison with 2 and meropenem. The synthesis of novel 1β-methylcarbapenems 1a,b having sodium 5-(3- and 5-carboxylic acid)isoxazoloethenyl moieties at C-5 position of pyrrolidine ring and their biological evaluation are described. Both compounds showed potent and well-balanced antibacterial activity as well as high stability to DHP-I. The selected sodium 3-carboxylic acid derivative 1a possessed excellent DHP-I stability and advanced pharmacokinetic parameters in comparison with 2 and meropenem.
- Lee, Kyung Seok,Kang, Yong Koo,Yoo, Kyung Ho,Kim, Dong Chan,Shin, Kye Jung,Paik, Young-Sook,Kim, Dong Jin
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p. 231 - 234
(2007/10/03)
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- Synthesis and biological evaluation of cycloalkylidene carboxylic acids as novel effectors of Ras/Raf interaction
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The protooncogenes Ras and Raf play important roles in signal transduction pathways regulated by mitogen-activated protein kinases. Mutations of Ras that arrest the protein in its active state are frequently implicated in tumor formation. We used Ras and Raf proteins in the yeast two-hybrid system to search for natural or synthesized substances capable of modulating Ras/Raf interaction by specifically binding to one of the interacting partners. We found that cycloalkylidene carboxylic acids enhanced Ras/Raf interaction by acting on the cysteine-rich domain of Raf. Several analogues of the active substance 2-cyclohexylidene propanoic acid were synthesized and the importance of the semicyclic double bond in the stabilization of Ras/Raf interaction was demonstrated. Variation of the size and the substituents of the cyclic system as well as the length of the carboxylic acid resulted in enhanced Ras/Raf interaction.
- Friese, Anke,Hell-Momeni, Katja,Zündorf, Ilse,Winckler, Thomas,Dingermann, Theodor,Dannhardt, Gerd
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p. 1535 - 1542
(2007/10/03)
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- Synthesis and Synthetic Utilization of α-Functionalized Vinylphosphonates Bearing β-Oxy or β-Thio Substituents
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The β-hetero-substituted vinylphosphonates la-c on treatment with LDA or LTMP were readily lithiated at the α-position of the phosphono group, and the resulting α-lithiovinylphosphonates were trapped with various electrophiles to afford the corresponding α-functionalized vinylphosphonates 2-14 in 55-96% yields. The Friedel-Crafts reaction of α-(silyl)- or a-(germyl)-phosphonoketene dithioacetals 2, 9, or 4 with acid chlorides gave α-acylated phosphonoketene dithioacetals 15-19 in 53-91% yields. The palladium-catalyzed cross-coupling reaction of β-ethoxy-α-(tributylstannyl)vinylphosphonate 13 with a variety of organic halides (R = acyl, allyl, aryl, etc.) provided β-ethoxy-α-substituted vinylphosphonates 21-26 in good to moderate yields. The palladium-mediated cross-coupling reaction of α-(iodo)vinylphosphonates 7 and 14 with terminal acetylenes afforded α-alkynylated vinylphosphonates 41-44 in 69-83% yields. Several α-functionalized β-hetero-substituted vinylphosphonates were applied to the synthesis of pyrazoles and an isoxazole possessing a phosphono function.
- Kouno, Ryoji,Okauchi, Tatsuo,Nakamura, Mitsuharu,Ichikawa, Junji,Minami, Toru
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p. 6239 - 6246
(2007/10/03)
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- Water soluble phosphorylated polysiloxanes
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This invention relates to a novel family of phosphorylated polysiloxanes which are non-ionic and water soluble. When these polysiloxanes are dissolved in water, the resulting solutions exhibit low surface tensions. The invention also relates to phosphorylated polysiloxanes which are gels or hydrogels. The invention further contemplates methods of synthesizing the phosphorylated polysiloxanes.
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- Approaches to the Synthesis of Retronecine from Some Pyrrolidine Precursors
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Procedures are described for the attempted conversion of the pyrrolidine (2) into a bicyclic system that would ultimately lead to retronecine (3). The only molecule to be isolated from these attempts was the epimeric ketone (6), and AM1 and MM2 calculations were used to probe this apparently favoured isomerization. Alternative procedures were then investigated that sought to convert the pyrrolidine (1) into precursors to retronecine, and notable successes were obtained with the addition of the amine (21) to both nitroethene and ethyl 2-diethylphosphonoacrylate. However, not only were these precursors resistant to further transformations into retronecine, but also the problem of epimerization again arose. Consequently, AM1 calculations were again employed, and an X-ray structure determination of ethyl (7R,8R)-7-benzyloxy-1-benzyloxymethyl-5,6,7,8-tetrahydro-3H-pyrrolizine-2-carboxylate (39) is reported. Attempts to convert (39) into a diastereoisomer of retronecine were unsuccessful.
- Clare, Brian W.,Ferro, Vito,Skelton, Brian W.,Stick, Robert V.,White, Allan H.
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p. 805 - 824
(2007/10/02)
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- An Isoxazole Route to Unsaturated α-Alkoxycarbonyl-β-diketones
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Cycloaddition of diethylphosphonomethyl nitrile oxide to the enamine from ethyl acetoacetate produces 4-ethoxycarbonyl-3-diethoxyphosphonylmethyl-5-methylisoxazole; condensation of the phosphonate with aldehydes and ketones gives 3-alkenylisoxazoles that are cleaved by hexacarbonylmolybdenum to afford unsaturated α-alkoxycarbonyl-β-diketones.
- Jones, Raymond C. F.,Bhalay, Gurdip,Carter, Paul A.
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p. 1715 - 1716
(2007/10/02)
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- PREPARATION ET CONVERSION D'ω-FORMYLALKYLPHOSPHONATES EN ACIDES AMINOCARBOXYALKYLPHOSPHONIQUES
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ω-Formylalkylphosphonates by acid hydrolysis of the corresponding acetals obtained from triethylphosphite and bromoacetals has been described.In aqueous solution in the presence of cyanide and amines these compounds give aminonitriles (Strecker) or hydantoins (Bucherer).These reactions give access to a large variety of compounds which by acid hydrolysis (Strecker) or basic then acid hydrolysis (Bucherer) lead to pure aminocarboxalkylphosphonic acids (phosphonoalanine, etc.).
- Varlet, J. M.,Fabre, G.,Sauveur, F.,Collignon, N.,Savignac, Ph.
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p. 1377 - 1384
(2007/10/02)
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- AMINATION REDUCTRICE D'ALDEHYDES PHOSPHONIQUES. Un Reexamen
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The reactivity of diethyl-2-oxo ethyl- and 3-oxo propylphosphonates with ammonia, methyl and dimethylamine at pH 7 in the presence of sodium cyanohydridoborate via reductive amination of the carbonyl group has been reexamined.Reactions of diethyl-2-oxoethyl- and 3-oxopropylphosphonates with ammonia give imino-bis-(alkylphosphonates); methyl and dimethylamine give monocondensation products thus permitting the synthesis of N-substituted aminoalkylphosphonates.
- Collignon, N.,Fabre, G.,Varlet, J. M.,Savignac, Ph.
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- LE POUVOIR EXTRACTANT DES PHOSPHONATES β CARBONYLES VIS-A-VIS DU CUIVRE, DU COBALT ET DU NICKEL
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The copper-cobalt-nickel separation being an nowadays industrial problem, this work was aimed to correlate the structure of some β carbonyl phosphonate compounds with the extractibility of three corresponding cations (4).The generalised formula of these compounds is: (RO)2P(O)-CH2-C(O)-R' and the way to synthesise them depends upon the nature of R and R' (R is always a saturated hydrocarbon radical).The different samples are described in table I.Toluen has been chosen as the dilutant and the studied pH domain extends from the pH of first contact between phases to the pH of precipitation of the metal hydroxides.The following compounds exhibit a slight affinity for copper, cobalt and nickel: E1 : R' is the phenyl radical.E2, E3 : R' is the parafluorophenyl radical.E5 : R' is a saturated hydrocarbon radical.E9 : R' is a partially fluorine substituted aliphatic radical.The compounds are not interesting for solving the industrial problem with which we are concerned.On the contrary, the following compounds exhibit, in certain conditions (pH, concentration) an excellent affinity for one or another of the three metals, allowing sometimes a complete extraction : E4 (figure 1) : R' is the hydrogen atom.E6, E7, E8 (table II, figure 2 and table III) : R' is a completely fluorine substituted aliphatic radical, by way of example E6 extracts well nickel or cobalt and E7, E8 extract well copper.One can notice the formation of a third phase with E7 (R = -C2H5).The substitution of the ethyl group by the normal butyl (E8, R = -C4H9) increases the lipophilicity of the complex metal phosphonate and the compound E8 is able to realise the purification of diluted cobalt or nickel aqueous solutions towards copper.
- Sturz, G.,Clement, J. C.,Daniel, A.,Molinier, J.,Lenzi, M.
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p. 161 - 172
(2007/10/02)
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