- MONOBACTAM COMPOUNDS AND USE THEREFOR
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Monobactam compounds and a use therefor. Specifically provided are chemical compounds represented by formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals, or prodrugs thereof, preparation methods therefor, pharmaceutical compositions containing said compounds, and a use of said compounds or compositions in treating bacterial infection. The present compounds feature excellent antibacterial activity, and have great hopes of becoming a therapeutic agent for bacterial infection.
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- Stereoselective synthesis and antiproliferative activity of the isomeric sphinganine analogues
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A flexible synthetic approach to biologically active sphingoid base-like compounds with a 3-amino-1,2-diol framework was achieved through a [3,3]-sigmatropic rearrangement and late stage olefin cross-metathesis as the key transformations. The stereochemistry of the newly created stereogenic centre was assigned via a single crystal X-ray analysis of the (4S,5R)-5-(hydroxymethyl)-4-vinyloxazolidine-2-thione. In order to rationalise the observed stereoselectivity of the aza-Claisen rearrangement, DFT calculations were carried out. The targeted isomeric sphingoid bases were screened in vitro for anticancer activity on a panel of seven human malignant cell lines. Cell viability experiments revealed that C17-homologues are more active than their C12 congeners.
- ?onková, Miroslava,Martinková, Miroslava,Gonda, Jozef,Jacková, Dominika,Pilátová, Martina Bago,Kupka, Daniel,Jáger, Dávid
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- Assignment of the relative and absolute stereochemistry of two novel epoxides using NMR and DFT-GIAO calculations
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Considering the potential biological application of isobenzofuranones, especially as agrochemical defensives, two novel epoxides, (1aR,2R,2aR,5S,5aS,6S,6aS)-5-(hydroxymethyl)hexahydro-2,6-methanooxireno[2,3-f]isobenzofuran-3(1aH)-one (9), and (1aS,2S,2aR,5S,5aS,6R,6aR)-5-(hydroxymethyl)hexahydro-2,6-methanooxireno[2,3-f]isobenzofuran-3(1aH)-one (10), were synthesized from the readily available D-mannitol in six steps. The multiplicities of the hydrogens located at the bridge of the bicycle are distinct for epoxides 9 and 10 due to W coupling, and this feature was employed to confirm the assignment of these nuclei. Besides analyses of the 2D NMR spectra, the assignments of the nuclei at the epoxide ring were also inferred from information obtained by theoretical calculations. The calculated 1H and 13C NMR chemical shifts for eight candidate structures were compared with the experimental chemical shifts of 9 and 10 by measuring the mean absolute errors (MAE) and by the DP4 statistical analysis. The structures and relative configurations of 9, and 10 were determined via NMR spectroscopy assisted with theoretical calculations. As consequence of the enantioselective syntheses starting from a natural polyol, the absolute configurations of the epoxides 9 and 10 were also defined.
- Moraes,Alvarenga,Demuner,Viana
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p. 109 - 115
(2018/05/03)
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- PROCESS FOR THE PREPARATION OF [(1 S,2R)-3-[[(4-AMINOPHENYL)SULFONYL] (2-METHYLPROPYL)AMINO]-2-HYDROXY-1 -(PHENYLMETHYL)PROPYL]-CARBAMIC ACID (3R,3AS,6AR)HEXAHYDRO FURO[2,3-B]FURAN-3-YL ESTER AND ITS AMORPHOUS FORM
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The present invention relates to an improved process for the preparation of [(1 S,2R)-3-[ [(4-aminophenyl)sulfonyl] (2-methylpropyl)amino]-2-hydroxy- 1 -(phenylmethyl)propyl] - carbamic acid (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl ester compound of formula- 1 represented by the following structural formula:
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- Synthesis and evaluation of eight- and four-membered iminosugar analogues as inhibitors of testicular ceramide-specific glucosyltransferase, testicular β-glucosidase 2, and other glycosidases
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Eight- and four-membered analogues of N-butyldeoxynojirimycin (NB-DNJ), a reversible male contraceptive in mice, were prepared and tested. A chiral pool approach was used for the synthesis of the target compounds. Key steps for the synthesis of the eight-membered analogues involve ring-closing metathesis and Sharpless asymmetric dihydroxylation and for the four-membered analogues Sharpless epoxidation, epoxide ring-opening (azide), and Mitsunobu reaction to form the four-membered ring. (3S,4R,5S,6R,7R)-1-Nonylazocane-3,4,5,6,7-pentaol (6) was moderately active against rat-derived ceramide-specific glucosyltransferase, and four of the other eight-membered analogues were weakly active against rat-derived β-glucosidase 2. Among the four-membered analogues, ((2R,3S,4S)-3-hydroxy-1-nonylazetidine-2,4-diyl)dimethanol (25) displayed selective inhibitory activity against mouse-derived ceramide-specific glucosyltransferase and was about half as potent as NB-DNJ against the rat-derived enzyme. ((2S,4S)-3-Hydroxy-1-nonylazetidine-2,4-diyl)dimethanol (27) was found to be a selective inhibitor of β-glucosidase 2, with potency similar to NB-DNJ. Additional glycosidase assays were performed to identify potential other therapeutic applications. The eight-membered iminosugars exhibited specificity for almond-derived β-glucosidase, and the 1-nonylazetidine 25 inhibited α-glucosidase (Saccharomyces cerevisiae) with an IC50 of 600 nM and β-glucosidase (almond) with an IC50 of 20 μM. Only N-nonyl derivatives were active, emphasizing the importance of a long lipophilic side chain for inhibitory activity of the analogues studied.
- Lee, Jae Chul,Francis, Subhashree,Dutta, Dinah,Gupta, Vijayalaxmi,Yang, Yan,Zhu, Jin-Yi,Tash, Joseph S.,Schoenbrunn, Ernst,Georg, Gunda I.
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experimental part
p. 3082 - 3098
(2012/05/31)
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- Practical one-pot synthesis of protected l-glyceraldehyde derivatives
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A large-scale, simple, economic, and safe procedure for the preparation of l-glyceraldehyde acetonide under conditions, which allow its direct transformation (one-pot) into the desired products (acetylene, imine, nitrone, unsaturated ester) is reported. l-Glyceraldehyde acetonide is obtained from the corresponding ester, which is readily available from l-serine. Georg Thieme Verlag Stuttgart New York.
- Stecko, Sebastian,Michalak, Micha,Stodulski, MacIej,Muchal, Lukasz,Parda, Kamil,Furman, Bartlomiej,Chmielewski, Marek
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p. 2695 - 2698
(2012/11/07)
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- Total synthesis of branimycin: An evolutionary approach
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The first total synthesis of the macrolactone antibiotic branimycin (4) has been described. The key disconnection leads to a cis-dehydrodecalone core and a polyketide side chain which are connected via organometallic addition. The dehydrodecalone core was targeted via altogether five different approaches featuring various kinds of chiral elements and ring-closing methodology. In the end the most successful method starting from diepoxynaphthalene 109 was chosen to carry on with the synthesis. Thus the oxygen functions and carbon appendages were introduced via organometallic desymmetrization reactions to generate epoxy ketone 107, to which vinyl iodide 11 was added after conversion into the organolithium species. The synthesis was completed by introducing the ester side chain via Michael addition and subsequent macrolactonization. Competitive approach: The first total synthesis of the macrolactone antibiotic branimycin is described (see figure). The dehydrodecalin core was targeted via five competing approaches featuring various kinds of chiral elements and ring-closing methodology. In this "Darwinian" struggle the most successful route emerged and led to the completion of the synthesis. Copyright
- Enev, Valentin S.,Felzmann, Wolfgang,Gromov, Alexey,Marchart, Stefan,Mulzer, Johann
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p. 9651 - 9668
(2012/09/21)
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- Design, synthesis, and X-ray structure of substituted bis-tetrahydrofuran (bis-THF)-derived potent HIV-1 protease inhibitors
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We investigated substituted bis-THF-derived HIV-1 protease inhibitors in order to enhance ligand-binding site interactions in the HIV-1 protease active site. In this context, we have carried out convenient syntheses of optically active bis-THF and C4-substituted bis-THF ligands using a [2,3]-sigmatropic rearrangement as the key step. The synthesis provided convenient access to a number of substituted bis-THF derivatives. Incorporation of these ligands led to a series of potent HIV-1 protease inhibitors. Inhibitor 23c turned out to be the most potent (Ki = 2.9 pM; IC50 = 2.4 nM) among the inhibitors. An X-ray structure of 23c-bound HIV-1 protease showed extensive interactions of the inhibitor with the protease active site, including a unique water-mediated hydrogen bond to the Gly-48 amide NH in the S2 site.
- Ghosh, Arun K.,Martyr, Cuthbert D.,Steffey, Melinda,Wang, Yuan-Fang,Agniswamy, Johnson,Amano, Masayuki,Weber, Irene T.,Mitsuya, Hiroaki
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body text
p. 298 - 302
(2011/06/21)
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- Stereoselective synthesis of chiral tetrahydrofurans with potent 5-LO inhibitory activity
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Chiral glyceraldehydes have been exploited for the design of convenient and scalable synthetic approaches to chiral tetrahydrofurans, which have potential as potent 5-lipoxygenase (5-LO) inhibitors. The synthesis of all four possible stereoisomers by a general methodology is reported; wherein the chirons derived from the glyceraldehyde derivatives on reaction with homopropargyl ether, cyclization and further reactions gave the targets.
- Sharma,Punna, Sreenivas,Krishna, Palakodety Radha,Chorghade, Mukund S.,Ley, Steven V.
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p. 1125 - 1133
(2007/10/03)
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- Stereoselective and efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3- b]furan-3-ol
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(Chemical Equation Presented) Two short and efficient synthesis routes have been developed for bis-THF-alcohol 2, a key building block of the investigational HIV protease inhibitor TMC114 (1). Using S-2,3-O- isopropylideneglyceraldehyde (4) as the source of chirality, both routes are based on a diastereoselective Michael addition of nitromethane to give predominantly the syn congeners 6 followed by a Nef oxidation and cyclization to afford lactone acetals 8, which are reduced and cyclized to give 2.
- Quaedflieg, Peter J. L. M.,Kesteleyn, Bart R. R.,Wigerinck, Piet B. T. P.,Goyvaerts, Nicolaas M. F.,Vijn, Robert Jan,Liebregts, Constantinus S. M.,Kooistra, Jaap H. M. H.,Cusan, Claudia
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p. 5917 - 5920
(2007/10/03)
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- PROCESS FOR THE PREPARATION OF GLYCERALDEHYDE ACETONIDE
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The invention relates to a process for the preparation of glyceraldehyde acetonide by oxidation of 2,2-dimethyl-1,3-dioxolane-4-methanol by an oxidizing agent, wherein the 2,2-dimethyl-1,3-dioxolane-4-methanol is oxidized by an organic N-chloro compound in the presence of an inert base and TEMPO or a TEMPO-derivative. In one embodiment of the invention enantiomerically enriched glyceraldehyde acetonide is prepared from the corresponding enantiomerically enriched 2,2-dimethyl-1,3-dioxolane-4-methanol. Preferably, the organic N-chloro compount is trichloroisocyanuric acid or dichlorodimethyl hydantoin. Preferably, the inert base is sodium acetate or sodium bicarbonate.
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Page/Page column 21
(2008/06/13)
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- METHODS FOR THE PREPARATION OF (3R,3aS,6aR) HEXAHYDRO-FURO[2,3-b]FURAN-3-OL
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The present invention relates to methods for the preparation of diastereomerically pure (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol (6) as well as a novel intermediate, (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one (4) for use in said methods. More in particular the invention relates to a stereoselective method for the preparation of diastereomerically pure (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol, as well as methods for the crystallization of (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan- 2-one and for the epimerization of (3aR,4R,6aS) 4-methoxy-tetrahydro-furo[3,4-b]-furan-2-one to (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one.
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Page/Page column 39
(2008/06/13)
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- Stereoselective syntheses of pharmaceutically relevant chiral tetrahydrofurans from (S)- and (R)-glyceraldehyde derivatives
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A practically simple and flexible method of making chiral tetrahydrofurans of therapeutic relevance is reported from glyceraldehyde derivatives as chiral synthons. One of the stereocentres is derived from glyceraldehyde derivatives, while the other one is introduced by Sharpless asymmetric epoxidation using either (+)- or (-)-DIPT.
- Sharma,Punna, Sreenivas,Rajendra Prasad,Krishna, Palakodety Radna,Chorghade, Mukund S.,Ley, Steven V.
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p. 1113 - 1123
(2007/10/03)
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- Utilization of 1-Oxa-2,2-(dimesityl)silacyclopentane acetals in the stereoselective synthesis of polyols
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We have developed a route for the stereoselective synthesis of 1-oxa-2,2-(dimesityl)silacyclopentane acetals, intermediates in the synthesis of highly functionalized 1,3-diols. This route involves a diastereoselective conjugate addition reaction of a hydrosilyl anion, a subsequent diastereoselective enolate alkylation, and a fluoride-catalyzed intramolecular hydrosilylation reaction to afford the oxasilacyclopentane acetal. A highly selective nucleophilic substitution reaction, followed by oxidation of the C-Si bond, leads to the desired polyol. Copyright
- Powell, Sharon A.,Tenenbaum, Jason M.,Woerpel
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p. 12648 - 12649
(2007/10/03)
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- Substituted oxygen alicyclic compounds, including methods for synthesis thereof
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The invention provides new methods for preparation of cyclic oxygen compounds, including 2,5-disubstituted tetahydrofurans, 2,6-disubstituted tetrahydropyrans, 2,7-disubstituted oxepanes and 2,8-oxocanes. The invention also provides new cyclic oxygen compounds and pharmaceutical compositions and therapeutic methods that comprise such compounds.
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- Methods for synthesis of substituted tetrahydrofuran compound
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The invention includes inter alia new methods for preparation of the pharmaceutically active compound 2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran and precursors thereof.
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- Cycloaddition Reaction of 2,2-Dimethyl-3,4-dihydro-2H-pyrrole N-Oxide With Unsaturated Sugar Lactones and Esters
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Intermolecular asymmetric 1,3-dipolar cycloaddition of 2,2-dimethyl-3,4-dihydro-2H-pyrrole N-oxide with optically active α,β-unsaturated esters 1,2 gave the diastereomers 8,9,10 and with sugar lactones 3 and 6 gave stereoselectively the cycloadduct 11 and 12.The stereochemistry of the products has been established using high field nmr techniques.The major adducts 11 and 12 arise from an exo transition state and anti-approach, indicating the dominance of steric factors over secondary orbital interactions.
- Baskaran, S.,Trivedi, Girish.K.
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p. 1853 - 1864
(2007/10/03)
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- New routes to isomerically pure cyclopentanes. Synthesis of (3S,4S)-3,4-bis(benzoyloxymethyl)cyclopentan-1-ol using palladium-catalyzed [2 + 3] cycloaddition
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Two different routes to the enantiomerically pure (3S,4S)-3,4-bis(benzoyloxymethyl)cyclopentan-1-ol (6), a useful intermediate for the synthesis of a number of natural products, are described. Formation of the chiral five-membered ring was achieved using a palladium-catalyzed [2 + 3] cycloaddition between 2-(acetoxymethyl)-3-(trimethylsilyl)propene and optically active methyl (E)-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene-α-D-xylo-hept-5- enofuranuronate or ethyl (4R,Z)-4,5-(isopropylidenedioxy)pent-2-enoate.
- Janson,Kvarnstrom,Svensson,Classon,Samuelsson
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p. 129 - 133
(2007/10/02)
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- Asymmetric dihydroxylation of acrolein acetals: Synthesis of stable equivalents of Enantiopure glyceraldehyde and glycidaldehyde
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Asymmetric dihydroxylation (ADH) of acrolein acetals afforded optically active glyceraldehyde equivalents. Enantiopure 3-(1,2-dihydroxyethyl)-1,5-dihydro-3H-2,4-benzodioxepine 3, a protected glyceraldehyde, was obtained from the corresponding acrolein acetal 2 by ADH and subsequent recrystallization. Enantiopure 3-(1,2-epoxyethyl)-1,5-dihydro-3H-2,4-benzodioxepine 5, a protected glycidaldehyde, was produced in two steps from 3.
- Oi, Ryu,Sharpless, K. Barry
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p. 2095 - 2098
(2007/10/02)
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- Efficient Procedures for in situ Trapping of (R)- and (S)-Glyceraldehyde acetonides by Stabilized Wittig Reagents
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Practical, high yielding procedures are described whereby useful chiral enones and enoates can be prepared from either (R)- or (S)-glyceraldehyde acetonide.The labile aldehydes, formed from their precursors by lead tetraacetate cleavage, are reacted with stabilized Wittig reagents in situ.
- Leonard, John,Mohialdin, Soad,Swain, Philip
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p. 3529 - 3534
(2007/10/02)
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- A Convenient Synthesis of L-(S)-Glyceraldehyde Acetonide from L-Ascorbic Acid
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L-(S)-glyceraldehyde acetonide is easily obtained from L-ascorbic acid by three-step procedure.Since the aldehyde is rather unstable in pure form it is more convenient to use it as an aqueous solution.It was used to synthesize L-(R)-glycerol acetonide, monocyclic-β-lactams, and olefins (by Wittig reaction).
- Hubschwerlen, Christian
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p. 962 - 964
(2007/10/02)
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