- Cyclobutanone mimics of penicillins: Effects of substitution on conformation and hemiketal stability
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(Chemical Equation Presented) The tendency for carbocyclic analogues of penicillins to undergo hydrate and hemiketal formation is central to their ability to function as β-lactamase inhibitors. 2-Thiabicyclo[3.2.0]heptan- 6-one-4-carboxylates with alkoxy functionality at C3 have been prepared through two complementary diastereoselective substitution reactions following a highly stereoselective chlorination with sulfuryl chloride. We have found that carbocyclic analogues with 3β substituents favor an endo envelope conformation in solution, the solid state, and the gas phase, whereas those with 3α substituents adopt an exo envelope. Evidence from X-ray crystal structures and ab initio calculations suggests that an anomeric effect contributes to the large conformational preference of the tetrahydrothiophene ring that favors the C3 substituent in an axial orientation. In addition, the envelope conformation of the bicycle, which is determined by the stereochemistry of the C3 substituent, has a dramatic effect on the ability of the cyclobutanone to undergo hemiketal formation in methanol-d4.
- Johnson, Jarrod W.,Evanoff, Darryl P.,Savard, Marc E.,Lange, Gerald,Ramadhar, Timothy R.,Assoud, Abdeljalil,Taylor, Nicholas J.,Dmitrienko, Gary I.
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Read Online
- Synthesis of a novel thiabicyclo[3.2.0]heptan-6-one analogue of penicillin
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Synthesis of (1SR, 4SR, 5SR, 7RS)-7-(tert-butoxycarbonylamino)-2-thiabicyclo[3.2.0]heptan-6-one-4- carboxylic acid ethyl ester, a novel cyclobutanone analogue of a β-lactam antibiotic is described. This was achieved by [2+2] cycloaddition of a 2,3-dihydrothiophene with dichloroketene, followed by conversion to a cyclobutanol and use of an intramolecular nitrene insertion strategy to install nitrogen functionality at C-7 with endo stereochemistry.
- Martyres, Domnic H,Baldwin, Jack E,Adlington, Robert M,Lee, Victor,Probert, Mike R,Watkin, David J
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Read Online
- Refining the structure?activity relationships of 2-phenylcyclopropane carboxylic acids as inhibitors of O-acetylserine sulfhydrylase isoforms
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The lack of efficacy of current antibacterials to treat multidrug resistant bacteria poses a life-threatening alarm. In order to develop enhancers of the antibacterial activity, we carried out a medicinal chemistry campaign aiming to develop inhibitors of
- Magalh?es, Joana,Franko, Nina,Annunziato, Giannamaria,Pieroni, Marco,Benoni, Roberto,Nikitjuka, Anna,Mozzarelli, Andrea,Bettati, Stefano,Karawajczyk, Anna,Jirgensons, Aigars,Campanini, Barbara,Costantino, Gabriele
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- Stereoisomers of oseltamivir-synthesis, in silico prediction and biological evaluation
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Oseltamivir is an important antiviral drug, which possess three chirality centers in its structure. From eight possible stereoisomers, only two have been synthesized and evaluated so far. We describe herein the stereoselective synthesis, computational activity prediction and biological testing of another three diastereoisomers of oseltamivir. These isomers have been synthesized using stereoselective organocatalytic Michael addition, cyclization and reduction. Their binding to viral neuraminidase N1 of influenza A virus was evaluated by quantum-chemical calculations and their anti-influenza activities were tested by an in vitro virus-inhibition assay. All three isomers displayed antiviral activity lower than that of oseltamivir, however, one of the stereoisomers, (3S,4R,5S)-isomer, of oseltamivir showed in vitro potency towards the Tamiflu-sensitive influenza viral strain A/Perth/265/2009(H5N1) comparable to Tamiflu.
- Hajzer, Viktória,Fi?era, Roman,Latika, Attila,Durmis, Július,Kollár, Jakub,Frecer, Vladimír,Tu?eková, Zuzana,Miertu?, Stanislav,Kostolansky, Franti?ek,Vare?ková, Eva,?ebesta, Radovan
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p. 1828 - 1841
(2017/03/09)
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- PAIN RELIEF COMPOUNDS
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The present invention relates to the use of compounds for the treatment or prevention of pain in mammals, in particularly in human beings, and also to a process for preparing these compounds.
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Paragraph 0482
(2015/02/19)
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- Synthesis and structure-activity relationship study of substituted caffeate esters as antinociceptive agents modulating the TREK-1 channel
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The TWIK-related K+ channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs. It has been reported that TREK-1 -/- mice were more sensitive than wild-type mice to painful stimuli, suggesting that activation of TREK-1 could result in pain inhibition. Here we report the synthesis of a series of substituted caffeate esters (12a-u) based on the hit compound CDC 2 (cinnamyl 3,4-dihydroxyl-α-cyanocinnamate). These analogs were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid induced-writhing assay) leading to the identification a series of novel molecules able to activate TREK-1 and displaying potent analgesic activity in vivo.
- Rodrigues, Nuno,Bennis, Khalil,Vivier, Delphine,Pereira, Vanessa,Chatelain, Franck C.,Chapuy, Eric,Deokar, Hemantkumar,Busserolles, Jér?me,Lesage, Florian,Eschalier, Alain,Ducki, Sylvie
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supporting information
p. 391 - 402
(2014/03/21)
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- N-heterocyclic carbene catalyzed umpolung of Michael acceptors for intermolecular reactions
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leahciM! The N-heterocyclic carbene catalyzed umpolung of Michael acceptors proceeds through the formation of a deoxy-Breslow intermediate (see scheme; EWG=electron-withdrawing group). This nucleophilic species can react with other Michael acceptors in an intermolecular fashion, thereby resulting in the formation of homo- or heterodimeric olefins. This "Michael umpolung" should become a valuable method for the formation of densely functionalized olefins.
- Biju, Akkattu T.,Padmanaban, Mohan,Wurz, Nathalie E.,Glorius, Frank
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supporting information; experimental part
p. 8412 - 8415
(2011/10/31)
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- Investigation on lewis acid mediated diels-alder reactions of 2-phosphono-2-alkenoates. Application to total synthesis of (±)-α- alasken-8-one via reductive alkylation of resulting adduct
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(Chemical Equation Presented) The Lewis acid mediated Diels-Alder reactions of three 2-phosphono-2-alkenoates including triethyl 2-phosphonoacrylate (1), triethyl 2-phosphonobut-2-enoate (2), and ethyl 2-(diethoxyphosphono)-3- methylbut-2-enoate (3) have been investigated. Of several Lewis acids tested, tin(IV) chloride was shown to be the most effective at enhancing the regio- and stereoselectivity of the reactions of 1 with the electron-rich dienes to result in the formation of the single regio- and/or stereoisomers in good yields. Bearing the β methyl group(s), 2 displayedmuch less reactivity than 1 while 3 was completely unreactive under the study's conditions. Throughout the investigation, we found that the cycloadditions of 2, especially of the Z-isomer, could be efficiently induced by using zinc chloride at elevated temperatures. Furthermore, a lithium naphthalenide (LN)-induced reductive alkylation process was applied to the resulting Diels-Alder adducts 4 to allow the phosphono group at the quaternary carbon centers to be replaced by various alkyl groups to afford the alkyl-substituted esters 12, therefore practically turning 1 and 2 into the useful synthetic equivalents of the corresponding 2-alkyl 2-alkenoates that usually display poor Diels-Alder reactivity. Application of this combined operation has facilitated the total synthesis of the sesquiterpene natural product α-alasken-8-one (8) in racemic form.
- Liao, Chuan-Cheng,Zhu, Jia-Liang
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body text
p. 7873 - 7884
(2010/01/16)
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- An approach to amino ester subunits of tamiflu
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A two-step synthesis of amino cyclohexene carboxylic acid esters has been achieved in good overall yield from nitro phosphonate and unsaturated aldehydes. Georg Thieme Verlag Stuttgart.
- Kraus, George A.,Goronga, Tinopiwa
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p. 1765 - 1767
(2008/02/10)
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- 2-Diethoxyphosphoryl-4-nitroalkanoates - Versatile intermediates in the synthesis of α-alkylidene-γ-lactones and lactams
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Michael addition of various nitroalkanes 7a-f to ethyl (2- diethoxyphosphoryl)acrylate (6) gave 2-diethoxyphosphoryl-4-nitroalkanoates 8a-f. Transformation of the nitro functionality into hydroxy or amino group and cyclization yielded 3-(diethoxyphosphory
- B?aszczyk, Edyta,Krawczyk, Henryk,Janecki, Tomasz
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p. 2685 - 2688
(2007/10/03)
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- Synthesis of isomeric 1,4-[13C]2-labeled 2-ethoxycarbonyl-1,4-diphenylbutadienes
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The 1,4-bis-13C-labeled isomeric compounds (Z,E)- and (E,E)-2-ethoxycarbonyl-1,4-diphenylbutadiene have been synthesized by two different methods. A double Horner-Wadsworth-Emmons (HWE) strategy was employed for the synthesis of the Z,E isomer. On the other hand, synthesis of the E,E isomer was achieved by Baylis-Hillman reaction of benzaldehyde with ethyl acrylate and subsequent rearrangement, followed by Wittig olefination with benzaldehyde. The routes provide stereoselective access to labeled compounds in good yields.
- Crist, Rachael M.,Reddy, Pulgam Veera,Borhan, Babak
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p. 619 - 621
(2007/10/03)
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- Lewis Acid-Promoted [2 + 1] Cycloaddition Reactions of a 1-Seleno-2-silylethene to 2-Phosphonoacrylates: Stereoselective Synthesis of a Novel Functionalized α-Aminocyclopropanephosphonic Acid
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Stereoselective SnCl4-promoted [2 + 1] cycloaddition reactions of 1-seleno-2-silylethene 1 with 2-phosphonoacrylates 2 lead to highly functionalized cyclopropanephosphonate esters 3 in high yields. The cyclopropane products 3 are potentially versatile starting materials for biologically important compounds. Stereoselective synthesis of a novel functionalized α-aminophosphonic acid derivative, an analogue of (Z)-2,3-methanohomoserine 13, from the cycloadduct 3b was achieved. Stereoselectivity in the [2 + 1] cycloaddition was explained by consideration of the structure of the 2-SnCl4 complex.
- Yamazaki, Shoko,Takada, Takashi,Imanishi, Tomomi,Moriguchi, Yumiko,Yamabe, Shinichi
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p. 5919 - 5928
(2007/10/03)
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- Cycloaddition of N-Buta-1,3-dienyl-succinimide to gem-Substituted Vinyl Phosphonates
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N-Buta-1,3-dienylsuccinimide 3 reacted with trimethyl 2-phosphonoacrylate 4, triethyl 2-phosphonoacrylate 5, α-(diethylphosphono)acrylonitrile 6, α-(diethylphosphono)vinyl methylsulfone 7 and tetraethyl ethenylidene bis(phosphonate) 8 to give the ortho-cy
- Defacqz, Nathalie,Touillaux, Roland,Marchand-Brynaert, Jacqueline
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p. 2273 - 2286
(2007/10/03)
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- OXIDATIONS OF TRIETHYL α-PHOSPHONOACRYLATE. EPOXIDATION TO TRIETHYL α-PHOSPHONOACRYLATE OXIDE BY HYPOCHLORITE AND FORMATION OF TRIETHYL DIHYDROXYPHOSPHONOACETATE WITH RuO4-PERIODATE
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Oxidation of the methylidene double bond in triethyl α-phosphonoacrylate 2 by O3, catalytic RuO4 (RuO2/NaOCl, RuO2/NaIO4) and stoichiometric RuO4 was investigated as a route to α-oxygenated phosphonoacetate derivatives.Ozonation of 2 gave a mixture of products containing, in one experiment, triethyl phosphonoglyoxylate 1 as a minor (5percent) component.Efforts to prepare ethylidene compounds analogous to 2 (as alternative ozonation substrates) using known routes for synthesis of corresponding diethyl oxomalonate derivatives were unsuccessful.Treatment of 2 in biphasic H2O/CCl4 with catalytic RuO4 using NaOCl as co-oxidant or with NaOCl alone produced a novel epoxide product, triethyl α-phosphonoacrylate oxide (7) in up to 79percent isolated yield.When NaOCl was replaced with NaIO4 as the RuO2 reoxidant (H2O/CHCl3), the major reaction product in the aqueous phase was identified by 13C and 31P NMR as triethyl dihydroxyphosphonoacetate 8, the hydrate of the ketone 1.Reaction of 2 with stoichiometric RuO4 in CCl4 did not provide 1.A convenient modification in the synthesis of 2 is also described, and its 13C and 31P NMR spectra are reported. Key words: Oxidation; epoxide; sodium hypochlorite; sodium periodate; ruthenium tetroxide; triethyl α-phosphonoacrylate oxide; dihydroxyphosphonoacetate.
- Levy, Jeffrey N.,Mckenna, Charles E.
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- The chemistry of substituted pyrazolidinones; applications to the synthesis of bicyclic derivatives
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Methodology for the selective chemical derivatizations of substituted pyrazolidinones is described. The application of these methods to the preparation of [4.3.0] and [3.3.0] bicyclic systems is also discussed. The importance of these latter systems as nuclei of antibacterial agents with potential utility in the treatment of infectious disease provides the motivation for these investigations.
- Ternansky,Draheim
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p. 777 - 796
(2007/10/02)
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- A SHORT SYNTHESIS OF THE Δ1-CARBOPENEM RING SYSTEM
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Michael addition of N-lithio-4-vinyl-azetidin-2-one to several vinyl phosphonates gave adducts which were converted to Δ1-carbopenems via ozonolysis and an intramolecular Horner-Wittig reaction.
- Venugopalan, B.,Hamlet, A. Bevin,Durst, Tony
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p. 191 - 194
(2007/10/02)
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