- 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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- Novel cytotoxic amphiphilic nitro-compounds derived from a synthetic route for paraconic acids
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A series of precursors for bioactive paraconic acids (PA) were synthesized and their cytotoxicity assessed on human cells in vitro. Two amphiphilic nitro-containing precursors, Nitro-C15-EED and the butanolide Nitro-C12-GBL, were cytotoxic at the micromolar scale, with higher activity on tumor HeLa cells than on HEK-293T of non-tumor origin. The structure of these molecules is simple but different from reported bioactive nitro compounds. Nitro-C12-GBL was generally more cytotoxic, but after short-term (2 h) exposure both compounds reached maximum cytotoxicity. At 72 h post-treatments of HeLa cells the final dose-response for Nitro-C12-GBL (LC50 = 21.9 μmol L?1) was close to that for Nitro-C15-EED (LC50 = 25.3 μmol L?1), corresponding to LC50s ~ 3–3.6 times lower than those on HEK-293T. Short-term treatments with 50 μmol L?1 of these compounds promoted comparable outcomes, reducing tumor cells viability up to 27–36% of the controls and preserving ~70% of HEK-293T viability at 72 h post-treatments. Reduced cytotoxicity was observed in cultures continuously exposed to the compounds for longer periods (24–72 h), especially on tumor cells, underlining short-term treatments as alternatives to antiproliferative strategies. Due to their amphiphilic nature, these compounds show spontaneous surface activity and adsorption onto Langmuir monolayers of dipalmitoyl phosphatidyl choline (DPPC), especially Nitro-C12-GBL. The effects on DPPC monolayers are indicative of a possible physiological action that depends on the interaction with the cell membranes. Coarse-grained molecular dynamics indicate that individualized molecules of Nitro-C15-EED and the less toxic PA precursors are susceptible to trapping into phospholipid films. In contrast, Nitro-C12-GBL consistently forms large aggregates with outward polar domains, which could favor interaction with phospholipid polar heads of biological membranes.
- Ribeiro, Talita A.,Machado-Ferreira, Erik,Guimar?es, Lohaine F.,Cavaleiro, Jéssica,Britto, Alan Messala A.,Redua, Nátaly,de Souza, Lucas Miguel Pereira,Pimentel, André S.,Picciani, Paulo H.S.,Oliveira, Osvaldo N.,Barreto, Cléber Bonfim,Soares, Carlos Augusto G.
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- Total Synthesis of a Mycolic Acid from Mycobacterium tuberculosis
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In Mycobacterium tuberculosis, mycolic acids and their glycerol, glucose, and trehalose esters (“cord factor”) form the main part of the mycomembrane. Despite their first isolation almost a century ago, full stereochemical evaluation is lacking, as is a scalable synthesis required for accurate immunological, including vaccination, studies. Herein, we report an efficient, convergent, gram-scale synthesis of four stereo-isomers of a mycolic acid and its glucose ester. Binding to the antigen presenting protein CD1b and T cell activation studies are used to confirm the antigenicity of the synthetic material. The absolute stereochemistry of the syn-methoxy methyl moiety in natural material is evaluated by comparing its optical rotation with that of synthetic material.
- Buter, Jeffrey,Fodran, Peter,Jayaraman, Dhineshkumar,Minnaard, Adriaan J.,Moody, D. Branch,Ocampo, Tonatiuh A.,Tahiri, Nabil,Van Rhijn, Ildiko,Witte, Martin D.
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supporting information
p. 7555 - 7560
(2020/03/23)
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- Synergistic Relay Reactions To Achieve Redox-Neutral α-Alkylations of Olefinic Alcohols with Ruthenium(II) Catalysis
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Herein, we report a ruthenium-catalyzed redox-neutral α-alkylation of unsaturated alcohols based on a synergistic relay process involving olefin isomerization (chain walking) and umpolung hydrazone addition, which takes advantage of the interaction between the two rather inefficient individual reaction steps to enable an efficient overall process. This transformation shows the compatibility of hydrazone-type “carbanions” and active protons in a one-pot reaction, and at the same time achieves the first Grignard-type nucleophilic addition using olefinic alcohols as latent carbonyl groups, providing a higher yield of the corresponding secondary alcohol than the classical hydrazone addition to aldehydes does. A broad scope of unsaturated alcohols and hydrazones, including some complex structures, can be successfully employed in this reaction, which shows the versatility of this approach and its suitability as an alternative, efficient means for the generation of secondary and tertiary alcohols.
- Kan, Jian,Li, Chao-Jun,Li, Chen-Chen,Li, Jianbin,Lv, Leiyang,Qiu, Zihang
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supporting information
p. 4544 - 4549
(2020/02/04)
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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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- Stereocontrolled Synthesis of Tetrafluoropentanols: Multivicinal Fluorinated Alkane Units for Drug Discovery
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A stereodivergent synthesis of four diastereomeric 2,3,4,5-tetrafluoropentanols is disclosed. X-ray crystallographic analysis reveals conformations that manifest sequential stereoelectronic gauche effects (σC-H/C → σC-F*), thereby generating topological diversity via subtle C(sp3)-H to C(sp3)-F exchange. Two representative tetrafluoro arrays have been incorporated into truncated analogues of Gilenya for the management of relapsing remitting multiple sclerosis. These closely similar multivicinal fluoroalkanes have notably different physicochemical profiles and were found to be stable in the presence of human microsomes.
- Bentler, Patrick,Erdeljac, Nathalie,Bussmann, Kathrin,Ahlqvist, Marie,Knerr, Laurent,Bergander, Klaus,Daniliuc, Constantin G.,Gilmour, Ryan
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p. 7741 - 7745
(2019/09/03)
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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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- Stereoselective formal synthesis of (-)-fumagillol
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A formal synthesis of fumagillol, a congener of fumagillin that possesses varied biological activity, is disclosed. Initial attempts at preparing an allylic sulfide via an α-chloro sulfide met with failure. The successful route involves a carbonyl-ene reaction, one-pot stannyl cupration, methylation of resulting alkenyl copper and further Stille-coupling of the alkenyl stannane as the key steps.
- Raghavan, Sadagopan,Yelleni, Mahesh Kumar Rao
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p. 4371 - 4379
(2017/07/03)
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- PROCESSES FOR PREPARING 2-DIHALO RIBOLACTONES
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Methods for forming 2-bromo, 2-fluoro ribofuranose intermediates and 2-chloro, 2- fluoro ribofuranose intermediates for use in preparing antiviral nucleosides are disclosed. Methods for forming nucleosides, and nucleoside prodrugs, using the intermediates, are also disclosed. The methods all produce intermediates, and the resulting nucleosides and prodrugs thereof, wherein the chirality of the carbon at the 2-position is controlled. In some embodiments, the chemistry involves using chiral auxiliaries, such as (R)-2,2-dimethyl-l,3- dioxolane-4-carbaldehyde, and in other embodiments, the chemistry involves using chiral starting materials, such as D-xylose.
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Page/Page column 83; 84; 92; 93
(2017/06/21)
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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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- Formal synthesis of nanaomycin D via a Hauser-Kraus annulation using a chiral enone-lactone
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Abstract A formal total synthesis of nanaomycin D has been achieved. The strategy employed made use of a one-pot cyclisation-stereoselective reduction of a hydroxyketone to install the pyranonaphthalene moiety after execution of a Hauser-Kraus annulation using a chiral enone-lactone as the Michael acceptor to append the γ-lactone ring. The chirality in the chiral enone-lactone was established using a Sharpless asymmetric dihydroxylation. The enone-lactone used herein represents an attractive chiral synthon for the construction of other γ-lactone containing pyranonaphthoquinones such as griseusin A and crisamicin A.
- Hassan, Najmah P.S.,Naysmith, Briar J.,Sperry, Jonathan,Brimble, Margaret A.
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p. 7137 - 7143
(2015/08/24)
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- Reversal of facial selectivity in a thia-Claisen rearrangement by incorporation of a vinylic bromine substituent
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Thia-Claisen rearrangements have been carried out using N-benzylpyrrolidine-2-thione and chiral allylic bromides derived from d-mannitol. Introduction of a bromine atom onto the double bond of the allylic bromide reverses the sense of diastereoselectivity in the [3,3]-sigmatropic rearrangement. Density functional theory calculations lead us to rationalise the observed selectivity in terms of a Cieplak effect.
- Ellwood, Adam R.,Mortimer, Anne J. Price,Goodman, Jonathan M.,Porter, Michael J.
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p. 7530 - 7539
(2013/11/06)
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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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- A newly-designed PE-supported arsine for efficient and practical catalytic Wittig olefination
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A newly designed PE-supported arsine has been developed as an excellent catalyst for catalytic Wittig-type olefination. Simple ketones, in particular inactive ketones prove to be suitable substrates for the first time. This reaction provides an easy access to di-, tri-, and tetra-substituted olefins in high yield.
- Wang, Peng,Liu, Chun-Rong,Sun, Xiu-Li,Chen, Shuai-Shuai,Li, Jun-Fang,Xie, Zuowei,Tang, Yong
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supporting information; experimental part
p. 290 - 292
(2012/01/06)
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- Iterative asymmetric allylic substitutions: Syn- and anti-1,2-diols through catalyst control
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A copper-catalyzed asymmetric allylic boronation (AAB) gives access to syn- and anti-1,2-diols. The method facilitates an iterative strategy for the preparation of polyols (see scheme), such as the fully differentiated L-ribo-tetrol and protected D-arabin
- Park, Jin Kyoon,McQuade, D. Tyler
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supporting information; scheme or table
p. 2717 - 2721
(2012/04/17)
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- Chromium-mediated stereoselective synthesis of carbohydrate-derived (E)-α,β-unsaturated esters or amides
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A chromium-mediated novel synthesis of carbohydrate-derived di- and trisubstituted (E)-α,β-unsaturated esters or amides from a range of dichloroesters or amides and a variety of sugar aldehydes is reported. The process took place with total stereoselectiv
- Rodriguez-Solla, Humberto,Concellon, Carmen,Blanco, Elena G.,Sarmiento, Juan Ignacio,Diaz, Pamela,Soengas, Raquel G.
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experimental part
p. 5461 - 5465
(2011/08/09)
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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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- Ring-closing metathesis (RCM) based synthesis of the macrolactone core of amphidinolactone A
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A convergent synthesis of the macrolactone core of amphidinolactone A has been achieved, in a 10 step linear sequence with 32% overall yield, through a ring-closing metathesis reaction as the macrolactonization step. The RCM precursor was obtained by the
- Mohapatra, Debendra K.,Pattanayak, Manas R.,Das, Pragna P.,Pradhan, Tapas R.,Yadav
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scheme or table
p. 5630 - 5632
(2011/09/16)
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- An improved two-step synthetic route to primary allylic alcohols from aldehydes
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An improved two-step synthetic route to allylic alcohols from aldehydes has been developed. A modification of the HWE reaction in H2O-2-PrOH (1 : 1) and a convenient protocol to prepare AlH3 in THF from LiAlH 4 and n-BuBr are the key factors in the improvement.
- Liu, Zheng,Gong, Yaqiong,Byun, Hoe-Sup,Bittman, Robert
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experimental part
p. 470 - 475
(2010/06/14)
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- Enantioselective total synthesis of (-)-Clavosolide A and B
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Enantioselective total synthesis of (-)-clavosolide A and B was reported in full including the synthesis of proposed structure of (-)-clavosoldie A (1), revised structure of (-)-clavosoldie A (5), and revised structure of (-)-clavosoldie B (6). The relative and absolute stereochemistries of the natural products were confirmed unambiguously by comparing the optical rotation values and 1H and 13C NMR spectra of them.
- Son, Jung Beom,Kim, Si Nae,Kim, Na Yeong,Hwang, Min-Ho,Lee, Wonsun,Lee, Duck Hyung
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scheme or table
p. 653 - 663
(2010/08/19)
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- Stereoselective triplet-sensitised radical reactions of furanone derivatives
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The stereo- and regioselectivity of triplet-sensitised radical reactions of furanone derivatives have been investigated. Furanones 7a,b were excited to the 3ππ* state by triplet energy transfer from acetone. Intramolecular hydrogen abstraction then occurred such that hydrogen was transferred from the tetrahydropyran to the β position of the furanone moiety. Radical combination of the tetrahydropyranyl and the oxoallyl radicals led to the final products 8a,b. In the intramolecular reaction, overall, a pyranyl group adds to the a position of the furanone. The effect of conformation was first investigated with compounds 9a,b carrying an additional substituent on the tether between the furanone and pyranyl moiety. Further information on the effect of conformation and the relative configuration at the pyranyl anomeric centre and the furanone moiety was obtained from the transformations of the glucose derivatives 12, 14, 17 and 18. Radical abstraction occurred at the anomeric centre and at the S′-position of the glucosyl moiety. Computational studies of the hydrogen-abstraction step were carried out with model structures. The activation barriers of this step for different stereoisomers and the abstraction at the anomeric centre and at the 6' -position of the tetrahydropyranyl moiety were calculated. The results of this investigation are in accordance with experimental observations. Furthermore, they reveal that the reactivity and regioselectivity are mainly determined in the hydrogen-abstraction step. Intramolecular hydrogen abstraction (almost simultaneous electron and proton transfer) in 3ππ * excited furanones only takes place under restricted structural conditions in a limited number of conformations that are defined by the relative configuration of the substrates. It is observed that in the biradical intermediate, back-hydrogen transfer occurs leading to the starting compound. In the case of glucose derivatives, this reaction led to epimerisation at the anomeric centre.
- Jahjah, Rabih,Gassama, Abdoulaye,Bulach, Veronique,Suzuki, Chikako,Abe, Manabu,Hoffmann, Norbert,Martinez, Agathe,Nuzillard, Jean-Marc
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supporting information; scheme or table
p. 3341 - 3354
(2010/06/19)
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- Total synthesis of diastereomeric marine butenolides possessing a syn-aldol subunit at C10 and C11 and the related C11-ketone
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Two diastereomeric marine butenolides, (4S,10R,11R)- and (4S,10S,11S)-4,11-dihydroxy-10-methyldodec-2-en-1,4-olide, possessing a syn-aldol subunit at C10 and C11 have been efficiently synthesized by using a three-module coupling strategy. The enantiomeric syn-aldol modules prepared by the syn-selective aldol reaction of the norephedrine-derived chiral propionates were coupled with the chiral C3-C7 module via 1,3-dithiane bisalkylation. The butenolide ring was then installed via a high-yielding ring-closing metathesis (RCM) reaction. Oxidation of the diastereomeric C11-alcohols furnished the corresponding C11-ketones, which are produced by the same marine microorganism.
- Wang, Yan,Dai, Wei-Min
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supporting information; experimental part
p. 187 - 196
(2010/03/04)
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- One-pot, fluoride-promoted wittig reaction
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A one-pot, fluoride-promoted Wittig reaction was developed. The reactions of ethyl -bromoacetate with aliphatic, aromatic, and heteroaromatic aldehydes in the presence of tri-n-butylphosphine and tetrabutylammonium fluoride produced ,-unsaturated esters in good to excellent yields and E-stereoselectivity. Under the same conditions, reactions of ethyl -bromopropionate, -bromo acetonitrile, and -bromoacetophenone with aliphatic and aromatic aldehydes in the presence of tri-n-butylphosphine and tetrabutylammonium fluoride produced the expected ,-unsaturated derivatives in good E-stereoselectivity. The protocol was extended to semistabilized ylides and applied to the synthesis of some combretastatin analogs.
- Fumagalli, Tiziano,Sello, Guido,Orsini, Fulvia
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experimental part
p. 2178 - 2195
(2009/12/01)
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- Stereoselective Reformatskii-Claisen rearrangement: Synthesis of 2′,3′-dideoxy-6′,6′-difluoro-2′-thionucleosides
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A new approach for the stereoselective synthesis of 2′,3′- dideoxy-6′,6′-difluoro-2′-thionucleosides, analogues of highly bioactive L-OddC and 3TC, has been developed via TMSCl/pyridine induced stereoselective Reformatskii-Claisen rearragement of secondar
- Zheng, Feng,Zhang, Xingang,Qing, Feng-Ling
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scheme or table
p. 1505 - 1507
(2009/09/06)
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- Process for the enantioselective preparation of pregabalin
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The invention provides a new enantioselective process for the preparation of (S)-pregabalin, or a pharmaceutical acceptable addition acid salt comprising: acid hydrolysis of the dioxolan ring of a chiral compound of general formula (I) to obtain compound
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Page/Page column 8; 10-11
(2009/02/10)
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- Stereoselective and efficient synthesis of (S)-pregabalin from d-mannitol
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A straightforward synthesis of (S)-pregabalin in 28% overall yield starting from d-mannitol acetonide, as a primary source of chirality, is presented. The process is suitable for large-scale synthesis and involves simple and high-yielding chemical transformations as well as low-cost commercially available reagents.
- Izquierdo, Sandra,Aguilera, Jordi,Buschmann, Helmut H.,Garcia, Monica,Torrens, Antoni,Ortuno, Rosa M.
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p. 651 - 653
(2008/09/20)
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- Diastereoselective Thia-Claisen rearrangement of pyrrolidinone-derived ketene N,S-acetals
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Thia-Claisen rearrangements of S-allylic ketene N,S-acetals were carried out using substrates with an external allylic stereogenic centre. High levels of diastereoselectivity were observed only when a bromine substituent was introduced onto the double bon
- Ellwood, Adam R.,Price Mortimer, Anne J.,Tocher, Derek A.,Porter, Michael J.
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scheme or table
p. 2199 - 2203
(2009/04/10)
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- The formal synthesis of isofebrifugine using stereoselective intramolecular Michael addition
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The formal synthesis of isofebrifugine, a bioactive alkaloid, was achieved via a stereoselective intramolecular Michael addition reaction from d-mannitol.
- Sudhakar, Neela,Srinivasulu, Gannoju,Rao, Ganipisetti Srinivas,Rao, Batchu Venkateswara
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experimental part
p. 2153 - 2158
(2009/04/05)
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- Diazo reagents in copper(I)-catalyzed olefination of aldehydes
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The olefination of aldehydes to synthesize unsaturated ketones, esters, amides and phosphonates using diazo reagents and triphenylphosphine in the presence of copper(I) iodide as catalyst, is described. Good to excellent E:Z selectivities as well as yields were obtained for a large variety of aliphatic, aromatic and heteroaromatic aldehydes. The reaction showed also an excellent functional group compatibility and aldehydes were selectively reacted in the presence of ketone, nitro, amine, ether, acetal, thioether and halide groups. The use of a cost-effective copper salt as a catalyst is advantageous compared to previously reported expensive transition metal complexes. The method was used in the total synthesis of the scutifoliamide A, a biologically active compound that exhibits antifungal activity.
- Lebel, Helene,Davi, Michael
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supporting information; experimental part
p. 2352 - 2358
(2009/10/02)
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- Synthesis of 3′,3′-difluoro-2′-hydroxymethyl-4′, 5′-unsaturated carbocyclic nucleosides
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3′,3′-Difluoro-2′-hydroxymethyl-4′, 5′-unsaturated carbocyclic nucleosides 1-3 have been stereoselectively synthesized from ester 10, which can be conveniently prepared from 2,3-isopropylidene-D-glyceraldehyde 7 in five steps. The whole synthesis highligh
- Yang, Yan-Yan,Xu, Jun,You, Zheng-Wei,Xu, Xiu-Hua,Qiu, Xiao-Long,Qing, Feng-Ling
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p. 5437 - 5440
(2008/09/18)
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- Process for preparing alpha, beta - unsaturated ester
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A process for preparing an α,β-unsaturated ester of the compound (4), wherein R7 and R8 are the same or different and hydrogen atom, C1-6alkyl group or phenyl group, which comprises oxidizing a glycerol derivative (2), wherein R7 and R8 are the same as defined above, in the presence of a nitroxyl radical compound and a co-oxidant to prepare a glyceraldehyde and then reacting the compound with a phosphonoacetic acid alkyl ester or a (triphenylphosphoranylidene)acetic acid alkyl ester to give the compound (4).
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Page/Page column 5
(2008/06/13)
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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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- Stereoselective synthesis of (+)-SCH 351448: A unique ligand system for sodium, calcium, and other cations
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(+)-SCH 351448 (Na+ salt A) was synthesized employing ring-closing olefin metathesis reaction of an open diene diester intermediate for construction of the 28-membered macrodiolide structure. The open diene diester was prepared from the monomeric hydroxy carboxylic acid and two different olefin fragments. The monomeric hydroxy acid was synthesized via Julia-Julia coupling reaction of intermediates derived from the same olefinic fragments. Oxane units in these fragments were prepared by radical cyclization reactions of β-alkoxyacrylates. Analogous SCH 351448 salts incorporating other mono- and divalent cations may be prepared. Under acidic conditions, SCH 351448 (Na+ salt A) was the most stable complex, but SCH 351448 (Ca2+ salt) and (Na+ salt B) appear to be physiologically important species.
- Kang, Eun Joo,Cho, Eun Jin,Ji, Mi Kyung,Lee, Young Eun,Shin, Dong Mok,Choi, Soo Young,Chung, Young Keun,Kim, Jong-Seo,Kim, Hie-Joon,Lee, Sueg-Geun,Lah, Myoung Soo,Lee, Eun
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p. 6321 - 6329
(2007/10/03)
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- Claisen self-condensation/decarboxylation as the key steps in the synthesis of C2-symmetrical 1,7-dioxaspiro[5.5]undecanes
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A convenient method for the synthesis of functionalised 1,7-dioxaspiro[5.5]undecanes using acid-catalysed spiroketalisations of substituted dihydroxyketones is described. The dihydroxyketones were readily prepared from appropriately substituted hydroxy es
- Lastdrager, Bas,Timmer, Mattie S. M.,Van Der Marel, Gijsbert A.,Overkleeft, Herman S.
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p. 6195 - 6198
(2007/10/03)
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- Synthesis of diastereomerically and enantiomerically pure 2,3-disubstituted tetrahydrofurans using a sulfoxonium ylide
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Nucleophilic substitution reactions of 2,3-epoxy alcohols, easily prepared via Sharpless asymmetric epoxidation chemistry, offer access to a wide variety of enantiomerically pure compounds. In this communication, we describe the use of a Payne rearrangement to control regioselectivity in the ring-opening of a series of 2,3-epoxy alcohols with dimethylsulfoxonium methylide to yield diastereomerically and/or enantiomerically pure disubstituted tetrahydrofuran rings. The factors influencing the success and substitution pattern of the THF ring products are discussed, including steric, electronic, and solvent effects. Copyright
- Schomaker, Jennifer M.,Pulgam, Veera Reddy,Borhan, Babak
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p. 13600 - 13601
(2007/10/03)
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- Crude D-(+)-Glyceraldehyde Obtained from D-Mannitol-Diacetonide by Oxidative Cleavage with Sodium Periodate: Its Reactions with Nucleophilic Species
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The oxidative cleavage of D-(+)-mannitol-diacetonide with sodium periodate lead to a mixture of D-(+)-glyceraldehyde, its hydrate and oligomeric derivatives. In spite of the low concentration of free glyceraldehyde (estimated in ~20%, by NMR), good yields were obtained in nucleophilic additions involving this mixture and a variety of nucleophiles (amines, phosphonates, phosphoranes, nitronates, organometallic compounds).
- Domingos, Jorge L. De O.,Vilela, Guilherme V. M. De A.,Costa, Paulo R. R.,Dias, Ayres G.
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p. 589 - 598
(2007/10/03)
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- Synthesis of (-)-tetrodotoxin: Preparation of an advanced cyclohexenone intermediate
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The preparation of an advanced intermediate toward the enantioselective synthesis of tetrodotoxin is outlined. The enantiomerically pure cyclopentene 15 was generated from ketone 14 by alkylidene carbene insertion with retention of absolute configuration. An ozonolysis/aldol sequence first produced the trans cyclohexenone, which upon epimerization gave the more stable cis enone 18.
- Taber, Douglass F.,Storck, Pierre H.
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p. 7768 - 7771
(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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- A general procedure for a one-pot oxidative cleavage/Wittig reaction of glycols
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Oxidative cleavage of a series of glycols using NaIO4 on silica gel in the presence of a series of stabilized ylides provides access to a number of synthetically useful alkenes. The ease and general utility of this reaction is demonstrated here using several carbohydrates and amino acid derived glycols.
- Dunlap, Norma K.,Mergo, Wosenu,Jones, James M.,Carrick, Jesse D.
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p. 3923 - 3925
(2007/10/03)
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- In situ oxidative diol cleavage - Wittig processes
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1,2-Diol cleavage followed by in situ trapping of the resulting aldehyde with a stabilised phosphorane is described; both manganese dioxide and silica-supported sodium periodate can be used as the heterogeneous oxidant, but the latter reagent is generally the most efficient.
- Outram, Helen S.,Raw, Steven A.,Taylor, Richard J.K.
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p. 6185 - 6187
(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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- The synthesis of a sulfone containing analogue of the esperamicin-A1 aglycone: A hetero Diels-Alder approach
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The hetero Diels-Alder reaction of methyl/ethyl thioglyoxylate, generated in situ from the corresponding anthracene adduct, with a series of dienes was studied as a route to a key 3,4-dihydro-2H-thiopyran derivative bearing an acetylene function at C-2, a
- Prabhakaran, Jaya,Lhermitte, Hervé,Das, Jagattaran,Sasi-Kumar,Grierson, David S.
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p. 658 - 662
(2007/10/03)
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- Synthesis of polyhydroxylated pyrrolizidine alkaloids of the alexine family by tandem ring-closing metathesis-transannular cyclization. (+)-Australine
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Dienes 23 and 54, prepared from epoxy alcohol 9 via oxazolidinones 15 and 51, respectively, underwent ring-closing metathesis with Grubbs's catalyst to give azacyclooctenes 26 and 55. Treatment of each azacyclooctene with m-chloroperoxybenzoic acid afforded β-epoxide 28 from 26 and α-epoxide 61 from 60. Basic hydrolysis of each of these oxazolidinones was accompanied by transannular attack at the epoxide by nitrogen, resulting in 2-(O-benzyl)-7-deoxyalexine (29) and 1,2-di-(O-benzyl)australine (62). The latter was converted to the alkaloid australine (3) upon hydrogenolysis. Attempts to effect ring-closing metathesis of dienes 37, 38, and 46 were unsuccessful, suggesting that, while one allylic oxygen substituent can be tolerated by Grubbs's catalyst, two cannot.
- White,Hrnciar
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p. 9129 - 9142
(2007/10/03)
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