- A diastereoselective P450-catalyzed epoxidation reaction: Anti versus syn reactivity This Letter is dedicated to the memory of Harry Wasserman
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The achiral cyclohexene derivative dimethyl cis-1,2,3,6-tetrahydrophthalate has been subjected to oxidation catalyzed by cytochrome P450 monooxygenase P450-BM3, leading to diastereoselective epoxidation rather than oxidative hydroxylation. This reaction occurs with 94% diastereoselectivity in favor of the anti-epoxide, in contrast to m-CPBA which delivers unselectively a 70:30 mixture of anti/syn diastereomers. The experimental results are nicely explained on a molecular level by docking experiments and molecular dynamics computations.
- Ilie, Adriana,Lonsdale, Richard,Agudo, Rubén,Reetz, Manfred T.
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- Novel easily accessible glucosidase inhibitors: 4-hydroxy-5-alkoxy-1,2-cyclohexanedicarboxylic acids
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Glycosidases are very important enzymes involved in a variety of biochemical processes with a special importance to biotechnology, food industry, and pharmacology. Novel structurally simple inhibitors derived from cyclohexane-1,2-dicarboxylic acids were s
- Brazdova, Barbora,Tan, Nikmala S.,Samoshina, Nataliya M.,Samoshin, Vyacheslav V.
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- Novel 1,2,3-triazole compounds: Synthesis, In vitro xanthine oxidase inhibitory activity, and molecular docking studies
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In this study, novel 1,2,3-triazole compounds containing carbasugar frameworks (5 and 6) were synthesized by the copper-catalyzed azide-alkyne cycloaddition reactions and their in vitro inhibition effects on the enzyme xanthine oxidase were investigated. All of the synthesized compounds were characterized by spectroscopic methods. According to the enzyme inhibition results, compounds 5 (IC50 = 0.586 ± 0.017 μM) and 6 (IC50 = 0.751 ± 0.021 μM) showed stronger inhibition effects than allopurinol (IC50 = 1.143 ± 0.019 μM), which is a standard drug used for inhibition of xanthine oxidase. The binding modes of the 1,2,3-triazole compounds (5 and 6) with the active site of xanthine oxidase were explained based on molecular docking studies. The molecular docking studies showed that the aromatic structure, π-π interactions and hydrophobic interactions play a major role in xanthine oxidase inhibition for compounds 5 and 6.
- Tan, Ayse
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- Diastereoselective cis to trans desymmetrization of dimethyl succinates
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Meso-succinates, readily available by Diels-Alder cycloaddition of dimethyl maleate or maleic anhydride followed by esterification, can be isomerized quantitatively from the cis to the trans isomers in the presence of lithium alkoxides. The reaction performed with enantiopure chiral lithium alkoxides yields diastereomeric trans-succinates in good yield and selectivity.
- Michieletto, Ivan,Fabris, Fabrizio,De Lucchi, Ottorino
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- PHARMACEUTICAL COMPOUNDS FOR THE TREATMENT OF COMPLEMENT MEDIATED DISORDERS
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This disclosure provides pharmaceutical compounds to treat medical disorders, such as complement-mediated disorders, including complement Cl -mediated disorders.
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Page/Page column 299-300; 360-362
(2020/10/18)
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- Trans-hydrogenation: Application to a concise and scalable synthesis of brefeldin a
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The important biochemical probe molecule brefeldin A (1) has served as an inspirational target in the past, but none of the many routes has actually delivered more than just a few milligrams of product, where documented. The approach described herein is clearly more efficient; it hinges upon the first implementation of ruthenium-catalyzed trans-hydrogenation in natural products total synthesis. Because this unorthodox reaction is selective for the triple bond and does not touch the transannular alkene or the lactone site of the cycloalkyne, it outperforms the classical Birch-type reduction that could not be applied at such a late stage. Other key steps en route to 1 comprise an iron-catalyzed reductive formation of a non-terminal alkyne, an asymmetric propiolate carbonyl addition mediated by a bulky amino alcohol, and a macrocyclization by ring-closing alkyne metathesis catalyzed by a molybdenum alkylidyne.
- Fuchs, Michael,Fürstner, Alois
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supporting information
p. 3978 - 3982
(2015/03/30)
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- Chemoenzymatic Sequential Multistep One-Pot Reaction for the Synthesis of (1S,2R)-1-(Methoxycarbonyl)cyclohex-4-ene-2-carboxylic Acid with Recombinant Pig Liver Esterase
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In this work, the development of a chemoenzymatic process for the production of (1S,2R)-1-(methoxycarbonyl)cyclohex-4-ene-2-carboxylic acid by ECS-PLE06 (recombinant pig liver esterase) is presented. Herein an optimized esterification protocol, starting f
- Süss, Philipp,Borchert, Sonja,Wardenga, Rainer,Hinze, Janine,Illner, Sabine,Von Langermann, Jan,Kragl, Udo,Bornscheuer, Uwe T.
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p. 2034 - 2038
(2016/02/26)
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- Scale-up of a recombinant pig liver esterase-catalyzed desymmetrization of dimethyl cyclohex-4-ene-cis-1,2-dicarboxylate
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A recombinant isoenzyme of pig liver esterase was used for the highly enantioselective desymmetrization of dimethyl cyclohex-4-ene-cis-1,2- dicarboxylate. The selected recombinant esterase showed a significant advantage in enantioselectivity over the comm
- Suess, Philipp,Illner, Sabine,Von Langermann, Jan,Borchert, Sonja,Bornscheuer, Uwe T.,Wardenga, Rainer,Kragl, Udo
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p. 897 - 903
(2014/08/05)
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- GLYCOMIMETIC-PEPTIDOMIMETIC INHIBITORS OF E-SELECTINS AND CXCR4 CHEMOKINE RECEPTORS
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Compounds, compositions and methods are provided for treating cancer and inflammatory diseases, and for releasing cells such as stem cells (e.g., bone marrow progenitor cells) into circulating blood and enhancing retention of the cells in the blood. More specifically, glycomimetic-peptidomimetic compounds that inhibit both E-selectins and CXCR4 chemokine receptors are described.
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Page/Page column 59
(2012/05/20)
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- Synthesis of a new 2,3-diaminoconduritol with conduritol F structure
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A new 2,3-diaminoconduritol derivative with the conduritol F structure was prepared starting from cyclohexa-1,4-diene. Initially, a lactam, prepared by the cycloaddition of chlorosulfonyl isocyanate (CSI) to cyclohexa-1,4-diene, was converted into an amino acid. The conversion of the acid functionality into an isocyanate resulted in the formation of an imidazolidinone derivative, formed by an intramolecular cyclization. In the second part of this work, the known anhydride, 3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione was successfully converted into the desired bis(carbamate). The bromination of the double bond in the six-membered ring followed by a DBU-induced (DBU = 1,8-diazabicyclo[5.4.0] undec-7-ene) HBr elimination furnished the symmetrical diene. The photooxygenation of the diene unit afforded the bicyclic endoperoxide. The reaction of the endoperoxide with thiourea followed by acetylation resulted in the formation of a syn-configured diacetate. The deprotection of the urethane and acetate groups gave the new 2,3-diaminoconduritol with the conduritol F structure. A new 2,3-diaminoconduritol with the conduritol F structure was prepared starting from the known anhydride 3a,4,7,7a-tetrahydroisobenzofuran-1, 3-dione, which was successfully converted into the desired diene with bis(carbamate) functional groups. The photooxygenation of the diene followed by cleavage of the peroxide linkage and removal of the protecting groups gave the new 2,3-diaminoconduritol. Copyright
- Ekmekci, Zeynep,Balci, Metin
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p. 4988 - 4995
(2013/01/14)
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- A convenient procedure for bis-esterification of cyclic anhydrides
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Aromatic and aliphatic cyclic anhydrides are chemoselectively and conveniently transformed to the corresponding diesters by the use of DBU and appropriate alkyl/allyl halides. This bis-esterification reaction has been exemplified mostly with dimethyl esters. But in some cases, mixed dialkyl esters are also prepared.
- Jana, Amit Kumar,Karmakar, Raju,Dinda, Bidyut Kumar,Mitra, Prithiba,Ghosh, Ketaki,Karmakar, Rajdip,Mal, Dipakranjan
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p. 975 - 979
(2012/10/29)
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- Pre-organization of the core structure of E-selectin antagonists
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A new class of N-acetyl-dglucosamine (GlcNAc) mimics for Eselectin antagonists was designed and synthesized. The mimic consists of a cyclohexane ring substituted with alkyl substituents adjacent to the linking position of the fucose moiety. Incorporation into E-selectin antagonists led to the test compounds 8 and the 2'-benzoylated analogues 21, which exhibit affinities in the low micromolar range. By using saturation transfer difference (STD)-NMR it could be shown that the increase in affinity does not result from an additional hydrophobic contact of the alkyl substituent with the target protein E-selectin, but rather from a steric effect stabilizing the antagonist in its bioactive conformation. The loss of affinity found for antagonists 10 and 35 containing a methyl substituent in a remote position (and therefore unable to support to the stabilization of the core) further supports this hypothesis. Finally, when a GlcNAc mimetic containing two methyl substituents (52 and 53) was used, in which one methyl was positioned adjacent to the fucose linking position and the other was in a remote position, the affinity was regained.
- Schwizer, Daniel,Patton, John T.,Cutting, Brian,Smiesko, Martin,Wagner, Beatrice,Kato, Ako,Weckerle, Celine,Binder, Florian P. C.,Rabbani, Said,Schwardt, Oliver,Magnani, John L.,Ernst, Beat
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supporting information; experimental part
p. 1342 - 1351
(2012/04/04)
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- GLYCOMIMETIC COMPOUNDS AND METHODS TO INHIBIT INFECTION BY HIV
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Compounds, compositions and methods are provided for use to inhibit infection by human immunodeficiency virus (HIV). More specifically, the present invention relates to glycomimetic compounds that inhibit HIV infection, and uses thereof.
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(2011/10/19)
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- HETEROBIFUNCTIONAL INHIBITORS OF E-SELECTINS AND CXCR4 CHEMOKINE RECEPTORS
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Compounds, compositions and methods are provided for treating cancer and inflammatory diseases, and for releasing cells such as stem cells (e.g., bone marrow progenitor cells) into circulating blood and enhancing retention of the cells in the blood. More specifically, heterobifunctional compounds that inhibit both E-selectins and CXCR4 chemokine receptors are described.
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Page/Page column 12; 29
(2010/11/17)
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- Enantioselective synthesis of an advanced intermediate for the synthesis of brefeldin A and analogues
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A synthesis of methyl (1R,2R,4S)-2-[(E)-2-iodovinyl]-4-(methoxymethoxy) cyclopentanecarboxylate is described in nine steps from a prochiral anhydride. A desymmetrization reaction followed by an epimerization and a Takai reaction are the key steps of the t
- Legrand, Frédéric,Archambaud, Sylvie,Collet, Sylvain,Aphecetche-Julienne, Karine,Guingant, André,Evain, Michel
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p. 389 - 393
(2008/09/17)
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- Glycomimetic replacements for hexoses and N-acetyl hexosamines
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Compounds and methods are provided for obtaining oligosaccharide mimics. More specifically, compounds and methods are described wherein oligosaccharide mimics are obtained by incorporating or substituting in a cyclohexane derivative.
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Page/Page column 17; title page
(2008/12/06)
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- Methods of use of glycomimetics with replacements for hexoses and n-acetyl hexosamines
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Methods are provided for using a compound to treat, for example, endothelial dysfunction including vascular abnormalities. More specifically, methods are described for using an oligosaccharide compound or glycomimetic compound wherein a cyclohexane derivative is incorporated in either.
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Page/Page column 24; sheet 1
(2008/12/08)
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- Synthesis of novel potent hepatitis C virus NS3 protease inhibitors: Discovery of 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid as a N-acyl-l-hydroxyproline bioisostere
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Potent tetrapeptidic inhibitors of the HCV NS3 protease have been developed incorporating 4-hydroxy-cyclopent-2-ene-1,2-dicarboxylic acid as a new N-acyl-l-hydroxyproline mimic. The hydroxycyclopentene template was synthesized in eight steps from commercially available (syn)-tetrahydrophthalic anhydride. Three different amino acids were explored in the P1-position and in the P2-position the hydroxyl group of the cyclopentene template was substituted with 7-methoxy-2-phenyl-quinolin-4-ol. The P3/P4-positions were then optimized from a set of six amino acid derivatives. All inhibitors were evaluated in an in vitro assay using the full-length NS3 protease. Several potent inhibitors were identified, the most promising exhibiting a Ki value of 1.1 nM.
- Thorstensson, Fredrik,Wangsell, Fredrik,Kvarnstroem, Ingemar,Vrang, Lotta,Hamelink, Elizabeth,Jansson, Katarina,Hallberg, Anders,Rosenquist, Asa,Samuelsson, Bertil
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p. 827 - 838
(2007/10/03)
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- Novel Versatile Synthesis of Substituted Tetrabenzoporphyrins
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A novel general synthetic route to tetraaryltetrabenzoporphyrins (Ar 4TBP) with various peripheral functional groups is developed. The procedure includes (i) Barton-Zard condensation of 1-nitro- or 1-phenylsulfonylcyclohexenes with isocyanoacet
- Finikova, Olga S.,Cheprakov, Andrei V.,Beletskaya, Irina P.,Carroll, Patrick J.,Vinogradov, Sergei A.
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p. 522 - 535
(2007/10/03)
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- Toward the total synthesis of variecolin
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(matrix presented) An annulative approach toward the total synthesis of the sesterterpenoid variecolin (1) is presented. Synthesis of the key hemiketal, containing the core ABC ring skeleton, has been achieved on a model system by an expeditious route uti
- Molander, Gary A.,Quirmbach, Michael S.,Silva Jr., Luiz F.,Spencer, Keith C.,Balsells, Jaume
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p. 2257 - 2260
(2007/10/03)
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- Asymmetric hydrolysis of a meso-diester using pig liver esterase immobilised in hollow fibre ultrafiltration membrane
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Pig liver esterase (PLE) was physically immobilised in a polysulphone ultrafiltration hollow fibre membrane reactor and used for the repetitive batch two-phase hydrolysis and separation, on a multigram scale, of the meso-diester dimethyl cis-cycloxex-4-en
- Sousa, Helena A.,Crespo, Joao G.,Afonso, Carlos A.M.
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p. 929 - 934
(2007/10/03)
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- Conversion of Fatty Acids and Derivatives, IV. Conversion of Fatty Acid Methyl Esters into Dialkylated Succinic Esters by Oxidative Coupling of Their Enolates
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The enolates of fatty acid methyl esters 1a-g are dimerized in good yields (56 to 73percent) by means of oxidative coupling with copper(II) bromide to dialkylated succinic esters 2a-g.The configuration of meso-2a was established by independent synthesis.O
- Quermann, Rolf,Maletz, Reinhard,Schaefer, Hans J.
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p. 1219 - 1224
(2007/10/02)
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- Micellar Effects upon Alkene Bromination. 2. The Role of Alkene Hydrophobicity
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Surface polarity of cettyltrimethylammonium bromide (CTAB) aqueous micelles was checked by use of as a probe the bromination reaction of a series of 1-alkenes and a water-soluble alkene, cis-4-cyclohexene-1,2-dicarboxylic acid dimethyl ester (I).There was
- Cerichelli, Giorgio,Grande, Celeste,Luchetti, Luciana,Mancini, Giovanna
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p. 3025 - 3030
(2007/10/02)
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- Dimethyl cis- and trans-1,2-Dimethylcyclohexane-1,2-dicarboxylate
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1-Methoxy-3-trimethylsilyloxybuta-1,3-diene adds readily to dimethylmaleic anhydride, and the product can be converted into dimethyl cis-1,2-dimethylcyclohex-4-ene-1,2-dicarboxylate (3).The several steps required mean that this route compares unfavourably
- Rae, Ian D.,Serelis, Algirdas K.
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p. 1941 - 1948
(2007/10/02)
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- CHEMICAL REPERCUSSIONS OF ORBITAL INTERACTIONS THROUGH BOND AND THROUGH SPACE. EFFECT OF REMOTE SUBSTITUENTS ON THE ADDITION OF NITRENES TO BICYCLIC OLEFINS
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The reactivity of a series of bicyclic olefins with nitrenes is profoundly influenced by the nature of remote functional groups.There is a marked lack of reactivity for reactions with carboethoxynitrene as compared to phthalimidonitrene which is distinctly nucleophilic in character.An explanation for the reluctance to form aziridines is offered in terms of orbital interactions between the distant groups and the olefinic bond, making the latter remarkably electron deficient as evidenced by UV-photoelectron spectroscopy.Because of the complexity of the spectra, identification of the Ip associated with the reactive ?-centre was made by recourse to ab initio configuration interaction calculations for key members of the series.
- Aitken, R. Alan,Gosney, Ian,Farries, Hugh,Palmer, Michael H.,Simpson, Isobel,et. al.
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p. 1329 - 1346
(2007/10/02)
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- CREATION OF NOVEL CHIRAL SYNTHONS WITH ENZYMES AND APPLICATIONS TO NATURAL PRODUCT SYNTHESIS. 15. EFFICIENT INTRODUCTION OF CHIRAL CENTERS INTO CYCLOHEXANE RING.
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The chiral half-ester 2 obtained by asymmetric hydrolysis of the symmetric diester 1 with pig liver esterase has been shown to be a versatile synthon for various chiral cyclohexane derivatives.
- Kobayashi, Susumu,Kamiyama, Keiji,Iimori, Takamasa,Ohno, Masaji
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p. 2557 - 2560
(2007/10/02)
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- A Study of Stereoselective Hydrolysis of Symmetrical Diesters with Pig Liver Esterase
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Pig liver esterase (PLE) catalyzed hydrolysis of dimethyl esters of symmetrical dicarboxylic acids, including meso-diacids, cis-1,2-cycloalkanedicarboxylic acids, and diacids with a prochiral center, was studied with 14 substrates.The products of these stereoselective hydrolyses are chiral monoesters of dicarboxylic acids, with an enantiomeric excess (e.e.) from 10percent to 100percent.Some of these optically active monoesters are valuable synthons in natural products synthesis.An additivity pattern of α- and β-substituents with the glutaric esters on the stereoselectivity of enzymatic hydrolysis was observed.Analysis of the experimental results leads to a model of enzyme stereoselectivity of diester hydrolysis in which the substitution pattern at α- and β-C-atoms is found to determine the absolute configuration of the resulting monoester.
- Mohr, Peter,Waespe-Sarcevic, Nada,Tamm, Christoph,Gawronska, Krystyna,Gawronsky, Jacek K.
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p. 2501 - 2511
(2007/10/02)
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- Electrophilic additions to strained alkenes. II. The reaction of benzeneselenenyl chloride with tricyclo2,5>deca-3,7-diene derivatives
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The reactions of benzeneselenenyl chloride with three derivatives of tricyclo2,5>deca-3,7-diene have been investigated in four solvent systems: methylene chloride, acetic acid, acetic acid/LiClO4, and methanol.Under conditions of kinetic control only products of exo-anti attack upon the cyclobutene moiety are isolable when the solvent system is methylene chloride or acetic aicd.This observation also holds in acetic acid/LiClO4 except in the case of dimethyl tricyclo2,5>deca-3,7,9-triene-7,8-dicarboxylate where the major product is that of cross-bonding with solvent incorporation.In methanol products of solvent incorporation, transannular cross-bonding and lactonization (where possible) are observed.A general mechanistic scheme is proposed to account for these observations in accord with earlier results for the analogous arenesulphenylations.
- Garratt, Dennis G.,Ryan, Dominic M.,Kabo, Ann
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p. 2329 - 2339
(2007/10/02)
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