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  • 51. Arafa, Wael Abdelgayed Ahmed
    et al.
    Abdel-Magied, Ahmed Fawzy
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Nuclear Material Authority, Egypt.
    Utilization of ultrasonic irradiation as green and effective one-pot protocol to prepare a novel series of bis-2-amino-1,3,4-oxa(thia) diazoles and bis-tetrazoles2017In: ARKIVOC, ISSN 1551-7004, E-ISSN 1551-7012, p. 327-340Article in journal (Refereed)
    Abstract [en]

    In an effective and straightforward conversion, bis-semicarbazones and bis-thiosemicarbazones are transformed into a diversity of novel substituted bis-2-amino-1,3,4-oxadiazoles and bis-2-amino-1,3,4-thiadiazoles, respectively under ultrasonic irradiation. Bis-tetrazoles are obtained from the dialdehydes by sequential reaction with hydroxylamine hydrochloride, phosphorus pentoxide and sodium azide without isolation of the intermediates oximes and nitriles. All the reactions proceed cleanly and smoothly under mild conditions, with short reaction times and broad functional groups possibility. No side reactions were observed. [GRAPHICS]

  • 52. Ashour, Radwa M.
    et al.
    Abdel-Magied, Ahmed F.
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Nuclear Materials Authority, Egypt.
    Abdel-Khalek, Ahmed A.
    Helaly, O. S.
    Ali, M. M.
    Preparation and characterization of magnetic iron oxide nanoparticles functionalized by L-cysteine: Adsorption and desorption behavior for rare earth metal ions2016In: Journal of Environmental Chemical Engineering, ISSN 2160-6544, E-ISSN 2213-3437, Vol. 4, no 3, p. 3114-3121Article in journal (Refereed)
    Abstract [en]

    In this work, magnetic iron oxide nanoparticles functionalized with L-cysteine (Cys-Fe3O4 NPs) was synthesized and fully characterized by transmission electron microscopy (TEM), X-ray powder diffraction (XRD), Fourier transform infra-red (FTIR), thermogravimetric analysis (TGA) and zeta potential measurements. The synthesized Cys-Fe(3)O(4)NPs has been evaluated as a highly adsorbent for the adsorption of a mixture of four rare earths RE3+ ions (La3+, Nd3+, Gd3+ and Y3+) from digested monazite solutions. The influence of various factors on the adsorption efficiency such as, the contact time, sample pH, temperature, and concentration of the stripping solution were investigated. The results indicate that Cys-Fe3O4 NPs achieve high removal efficiency 96.7, 99.3, 96.5 and 87% for La3+, Nd3+, Gd3+ and Y3+ ions, respectively, at pH = 6 within 15 min, and the adsorbent affinity for metal ions was found to be in order of Nd3+ > La3+ > Gd3+ > Y3+ ions. Using the Langmuir model, a maximum adsorption capacity of La3+, Nd3+, Gd3+ and Y3+ at room temperature was found to be 71.5, 145.5, 64.5 and 13.6 mg g (1), respectively. The Langmuir isotherm and pseudo-second order model fitted much better than the other isotherms and kinetic models. The obtained results for the thermodynamic parameters confirmed the spontaneous and endothermic nature of the process. Moreover, the desorption was carried out with 0.1 M nitric acid solutions. In addition, Cys-Fe3O4 NPs can be used as a highly efficient adsorbent for the adsorption of La3+, Nd3+, Gd3+ and Y3+ ions from digested monazite solutions.

  • 53.
    Aydin, Juhanes
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Larsson, Johanna M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Selander, Nicklas
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Szabó, Kálmán J.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Pincer complex-catalyzed redox coupling of alkenes with iodonium salts via presumed palladium(IV) intermediates2009In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 11, no 13, p. 2852-2854Article in journal (Refereed)
    Abstract [en]

    Palladium pincer complexes directly catalyze the redox coupling reactions of functionalized alkenes and iodonium salts. The catalytic process, which is suitable for mild catalytic functionalization of allylic acetates and electron-rich alkenes, probably occurs through Pd(IV) intermediates. Due to the strong metal−ligand interactions, the oxidation of phosphine and amine ligands of the pincer complexes can be avoided in the presented reactions.

  • 54.
    Aydin, Juhanes
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Larsson, Johanna M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Szabó, Kálmán J.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Pincer Complex-Catalyzed Coupling Reactions via Palladium (IV) Intermediates2009In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 11, no 13, p. 2852-2854Article in journal (Refereed)
    Abstract [en]

    Palladium pincer complexes directly catalyze the redox coupling reactions of functionalized alkenes and iodonium salts. The catalytic process, which is suitable for mild catalytic functionalization of allylic acetates and electron-rich alkenes, probably occurs through Pd(IV) intermediates. Due to the strong metal−ligand interactions, the oxidation of phosphine and amine ligands of the pincer complexes can be avoided in the presented reactions.

  • 55.
    Aydin, Juhanes
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Szabó, Kálmán
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Enantioselective palladium pincer complex catalyzed carbon carbon coupling reactions between tosylimines and various nucleophiles2008In: Abstracts of Papers, 236th ACS National Meeting, Philadelphia, PA, United States, August 17-21, 2008, Washington, DC: American Chemical Society , 2008Conference paper (Other academic)
  • 56.
    Aydin, Juhanes
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Szabó, Kálmán J.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Mechanistic considerations for the enantioselective palladium pincer complex catalyzed carbon-carbon coupling reactions2008In: Abstracts of Papers, 236th ACS National Meeting, Philadelphia, PA, United States, August 17-21, 2008, Washington, DC: American Chemical Society , 2008Conference paper (Other academic)
  • 57.
    Ayesa, Susana
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Samuelsson, Bertil
    Classon, Björn
    A One-Pot, Solid-Phase Synthesis of Secondary Amines from Reactive Alkyl Halides and an Alkyl Azide2008In: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, no 1, p. 77-79Article in journal (Refereed)
  • 58.
    Babu, Beneesh P.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Endo, Yoshinori
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Bäckvall, Jan-E.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Biomimetic Aerobic Oxidation of Amino Alcohols to Lactams2012In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, no 37, p. 11524-11527Article in journal (Refereed)
  • 59.
    Babu, Beneesh P.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Meng, Xu
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Bäckvall, Jan-E.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Aerobic Oxidative Coupling of Arenes and Olefins through a Biomimetic Approach2013In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 13, p. 4140-4145Article in journal (Refereed)
  • 60. Back, Marcus
    et al.
    Nyhlen, Jonas
    Kvarnstrom, Ingemar
    Appelgren, Sara
    Borkakoti, Neera
    Jansson, Katarina
    Lindberg, Jimmy
    Nystrom, Susanne
    Hallberg, Anders
    Rosenquist, Asa
    Samuelsson, Bertil
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Design, synthesis and SAR of potent statine-based BACE-1 inhibitors: Exploration of P1 phenoxy and benzyloxy residues2008In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 16, no 21, p. 9471-9486Article in journal (Refereed)
    Abstract [en]

    Several BACE-1 inhibitors with low nanomolar level activities, encompassing a statine-based core structure with phenyloxymethyl- and benzyloxymethyl residues in the P1 position, are presented. The novel P1 modi. cation introduced to allow the facile exploration of the S1 binding pocket of BACE-1, delivered highly promising inhibitors.

  • 61. Back, Marcus
    et al.
    Nyhlén, Jonas
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Kvarnström, Ingemar
    Rosenquist, Åsa
    Samuelsson, Bertil
    Design, synthesis and SAR of potent statin-based β-secretase inhibitors: Exploration of P1 phenoxy and benzyloxy residues2007Conference paper (Other academic)
  • 62.
    Balan, Daniela
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    The three-component aza-Baylis-Hillman reaction: development and application2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The current thesis presents the optimization and generalization of the Baylis-Hillman reaction applied to in situ generated imines, i.e. a three-component aza- Baylis-Hillman reaction. We found that the title reaction proceeds most efficiently in the presence of a combination of catalysts, i.e. 3-hydroxyquinuclidine (0.15 equiv) and titanium isopropoxide (0.02 equiv), together with molecular sieves (4 Å; activated powder; 200 mg/mmol substrate) at ambient temperature.

    Our study of the scope and limitations of this reaction, revealed that arylaldehydes and sulfonamides are the only imine precursors which both generate the corresponding imines in situ and facilitate a further reaction with the Michael acceptor in a Baylis-Hillman fashion. Among the Michael acceptors tested, acrylates and acrylonitrile demonstrate high reactivity, while acrylamides and β-substituted acrylates do not participate in the reaction.

    The optimized conditions applied to the above range of substrates results in good-to-excellent yields of the desired amine-products (53-94%) and very high chemoselectivity (83- >99%). Furthermore, the reaction times observed under these conditions are considerably shorter than those previously reported for the aza-Baylis-Hillman reaction.

    In the development of a stereoselective version of the title reaction, the use of a chiral catalyst proved to be most effective. Thus, an enantiomeric excess up to 74% can be obtained with β-Isocupreidine. With chiral imine precursors or chiral acrylates, the diastereoselectivity attained was poor. No asymmetric induction was observed when chiral Lewis acids were employed as a co-catalyst.

    The α-methylene-β-amino acid derivatives obtained via the three-component aza-Baylis-Hillman reaction were subjected to further transformation. Carbon chain elongation at the olefinic end of the amine-adduct was attempted. For this purpose, the Miyaura borylation protocol could be successfully applied. The subsequent Suzuki-type cross-coupling reaction resulted predominantly in hydrolysis of the boronate intermediate, together with formation of the amine-adduct via β-hydride elimination. The optimal conditions for this latter reaction remain to be found.

    Finally, 2,5-dihydropyrroles have been synthesized from aza-Baylis-Hillman adducts, via a short and efficient route in which the key step is a microwave-assisted ring-closing metathesis of the N-allylated amine-adducts.

  • 63. Barbion, Julien
    et al.
    Sorin, Geoffroy
    Selkti, Mohamed
    Kellenberger, Esther
    Baati, Rachid
    Santoro, Stefano
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Himo, Fahmi
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Pancrazi, Ange
    Lannou, Marie-Isabelle
    Ardisson, Janick
    Stereoselective functionalization of pyrrolidinone moiety towards the synthesis of salinosporamide A2012In: Tetrahedron, ISSN 0040-4020, E-ISSN 1464-5416, Vol. 68, no 32, p. 6504-6512Article in journal (Refereed)
    Abstract [en]

    An important feature of the synthesis of salinosporamide A. a potent proteasome inhibitor, is the establishment of the quaternary stereocenter at C3. A new route has been developed based on the methylation of a functionalized pyrrolidinone. Direct methylation reaction led to the unwanted diastereomer: however, by means of a Corey-Chaykovsky reaction followed by LiAlH4 epoxide opening, the desired alcohol was obtained. The pyrrolidinone was elaborated through a key allylation reaction between a tertiary allyltitanium reagent and an aldehyde bearing a spiroketal moiety in alpha-position.

  • 64.
    Bartholomeyzik, Teresa
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Investigation of Selectivity in Palladium-Catalyzed Oxidative Arylating Carbocyclization of Allenynes.Manuscript (preprint) (Other academic)
  • 65.
    Bartholomeyzik, Teresa
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Palladium(II)-Catalyzed Oxidative Carbocyclization/Functionalization of Allenynes2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The selective formation of carbon-carbon bonds constitutes a key transformation in organic synthesis with useful applications in pharmaceutical or material industry. A particularly versatile tool for carbon-carbon as well as carbon-heteroatom bond formation is palladium catalysis, which allows for mild and selective routes even towards complex structures.

    The work in this thesis describes the development and the mechanistic investigation of a palladium(II)-catalyzed oxidative carbocyclization/functionalization methodology, which converts 1,5-allenynes into either arylated or borylated carbocycles. To this end, either boronic acids or B2pin2 are employed and 1,4-benzoquinone serves as the stoichiometric oxidant. These protocols provide access to two products, a cyclic triene and a cyclic vinylallene. Their formation is dependent on the substrate structure as the latter product requires a propargylic C–H bond to be present in the substrate. Based on kinetic isotope effects, mechanisms involving either an initial allenic or propargylic C–H abstraction, respectively, were proposed. Full control of product selectivity to give either trienes or vinylallenes was achieved by modifying the reaction conditions with additives. Using substoichiometric amounts of BF3·OEt2 leads selectively to borylated or arylated vinylallenes. Under arylating conditions the reaction is zero order in allenyne and oxidant, and first order in phenylboronic acid. Transmetalation and, to some extent, propargylic C–H cleavage were found to be turnover-limiting. The selective reaction towards functionalized trienes was achieved by addition of either substoichiometric LiOAc·2H2O (borylation) or excess amounts of H2O (arylation). For the latter case, a kinetic study revealed an unusually slow catalyst activation. Lower concentrations of H2O gave product mixtures, and it was shown that vinylallenes are formed with either boronic acid or boroxine, whereas the formation of trienes requires boronic acid.

  • 66.
    Bartholomeyzik, Teresa
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Palladium(II)-Catalyzed Oxidative Carbocyclization/Functionalization of Allenynes2013Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Palladium catalysis has emerged as an outstanding tool in synthetic organic chemistry for the mild and selective formation of carbon-carbon and carbon-heteroatom bonds. This thesis has been directed towards the extension of palladium(II)-catalyzed carbocyclization chemistry under oxidative conditions. An oxidative carbocyclization/functionalization methodology utilizing boron-containing transmetalation reagents was exploited to convert 1,5-allenynes into either arylated or borylated carbocycles. Two protocols were developed that use minimal amounts of Pd(OAc)2, stoichiometric para-benzoquinone as the oxidant and either bis(pinacolato)diboron or different arylboronic acids under mild conditions. A wide substrate scope is applicable to both methods. When the allenyne substrate bears a propargylic hydrogen, two isomeric functionalized carbocycles can be formed. By controlling the reaction conditions the reaction can be directed towards either of these two isomeric products. Kinetic isotope effect studies suggest that the mechanism leading to the different products proceeds through allylic or propargylic C-H bond cleavage, respectively. Moreover, it was observed that water has an interesting effect on the product selectivity when arylboronic acids are used in the oxidative carbocyclization of allenynes.

  • 67.
    Bartholomeyzik, Teresa
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Deng, Youqian
    Bäckvall, Jan-E.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Selective Palladium-catalyzed oxidative carbocyclization of allenynes2013In: Abstracts of Papers of The American Chemical Society, American Chemical Society (ACS), 2013Conference paper (Other academic)
  • 68.
    Bartholomeyzik, Teresa
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Pendrill, Robert
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Jiang, Tuo
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Bäckvall, Jan-E.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Complex Kinetics in a Palladium(II)-Catalyzed Oxidative Carbocyclization: Untangling of Competing Pathways, Pre-Catalyst Activation, and Product MixturesManuscript (preprint) (Other academic)
  • 69.
    Bartholomeyzik, Teresa
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Pendrill, Robert
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Lihammar, Richard
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Jiang, Tuo
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Bäckvall, Jan-E.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Kinetics and Mechanism of the Palladium-Catalyzed Oxidative Arylating Carbocyclization of Allenynes2018In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 140, no 1, p. 298-309Article in journal (Refereed)
    Abstract [en]

    Pd-catalyzed C-C bond-forming reactions under oxidative conditions constitute a class of important and widely used synthetic protocols. This Article describes a mechanistic investigation of the arylating carbocyclization of allenynes using boronic acids and focuses on the correlation between reaction conditions and product selectivity. Isotope effects confirm that either allenic or propargylic C-H activation occurs directly after substrate binding. With an excess of H2O, a triene product is selectively formed via allenic C-H activation. The latter C-H activation was found to be turnover-limiting and the reaction zeroth order in reactants as well as the oxidant. A dominant feature is continuous catalyst activation, which was shown to occur even in the absence of substrate. Smaller amounts of H2O lead to mixtures of triene and vinylallene products, where the latter is formed via propargylic C-H activation. The formation of triene occurs only in the presence of ArB(OH)(2). Vinylallene, on the other hand, was shown to be formed by consumption of (ArBO)(3) as a first-order reactant. Conditions with sub-stoichiometric BF3 center dot OEt2 gave selectively the vinylallene product, and the reaction is first order in PhB(OH)(2). Both C-H activation and transmetalation influence the reaction rate. However, with electron-deficient ArB(OH)(2), C-H activation is turnover-limiting. It was difficult to establish the order of transmetalation vs C-H activation with certainty, but the results suggest that BF3 center dot OEt2 promotes an early transmetalation. The catalytically active species were found to be dependent on the reaction conditions, and H2O is a crucial parameter in the control of selectivity.

  • 70.
    Bartoszewicz, Agnieszka
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Building molecular complexity via tandem Ru-catalyzed reactions of allylic alcohols2009Licentiate thesis, comprehensive summary (Other academic)
  • 71.
    Bartoszewicz, Agnieszka
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Livendahl, Madeleine
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Martín-Matute, Belén
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Synthesis of b-Hydroxy Ketones from Allylic Alcohols via Catalytic Formation of Ruthenium Enolates2008In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 14, no 34, p. 10547-10550Article in journal (Refereed)
    Abstract [en]

    The most efficient Ru-catalyzed isomerization–aldol reaction from allylic alcohols has been achieved by using [η5-(Ph5Cp)Ru(CO)2Cl] as the catalyst. The bulky pentaphenylcyclopentadienyl ligand on the ruthenium atom prevents protonation at the oxygen of the Ru–enolate intermediate and completely suppresses the formation of unwanted ketone byproducts (see scheme). The domino transformation is as good as it can be: aldols are obtained in quantitative yields at ambient temperature.

  • 72. Bejhed, Rebecca S.
    et al.
    Tian, Bo
    Eriksson, Kristofer
    Brucas, Rimantas
    Oscarsson, Sven
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Strömberg, Mattias
    Svedlindh, Peter
    Gunnarsson, Klas
    Magnetophoretic Transport Line System for Rapid On-Chip Attomole Protein Detection2015In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 31, no 37, p. 10296-10302Article in journal (Refereed)
    Abstract [en]

    A lab-on-a-chip traveling wave magnetophoresis approach for sensitive and rapid protein detection is reported. In this method, a chip-based magnetic microarray comprising lines of micrometer-sized thin film magnetic elements was used to control the movement of magnetic beads (MBs). The MBs and the chip were functionalized, forming a sandwich-type assay. The MBs were transported across a detection area, and the presence of target molecules resulted in the immobilization of MBs within this area. Target quantification was accomplished by MB counting in the detection area using an optical microscope. In order to demonstrate the versatility of the microarray, biotinylated antiavidin was selected as the target protein. In this case, avidin-functionalized MBs and an avidin-functionalized detection area were used. With a total assay time of 1 to 1.5 h (depending on the labeling approach used), a limit of detection in the attomole range was achieved. Compared to on-chip surface plasmon resonance biodetection systems, our method has a larger dynamic range and is about a factor of 500 times more sensitive. Furthermore, our MB transportation system can operate in any chip-based biosensor platform, thereby significantly improving traditional biosensors.

  • 73.
    Belhomme, Marie-Charlotte
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Wang, Dong
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Szabó, Kálmán J.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Formation of C(sp(3))-C(sp(3)) Bonds by Palladium Catalyzed Cross-Coupling of alpha-Diazoketones and Allylboronic Acids2016In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 18, no 10, p. 2503-2506Article in journal (Refereed)
    Abstract [en]

    Palladium catalyzed cross-coupling of allylboronic acids with a-diazoketones was studied. The reaction selectively affords the linear allylic product. The reaction proceeds with formation of a new C(sp(3))-C(sp(3)) bond. The reaction was performed without an external oxidant, likely without the Pd-catalyst undergoing redox reactions.

  • 74. Bergenstråhle-Wohlert, Malin
    et al.
    Angles d'Ortoli, Thibault
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Sjöberg, Nils A.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Wohlert, Jakob
    On the anomalous temperature dependence of cellulose aqueous solubility2016In: Cellulose (London), ISSN 0969-0239, E-ISSN 1572-882X, Vol. 23, no 4, p. 2375-2387Article in journal (Refereed)
    Abstract [en]

    The solubility of cellulose in water-based media is promoted by low temperature, which may appear counter-intuitive. An explanation to this phenomenon has been proposed that is based on a temperature-dependent orientation of the hydroxymethyl group. In this paper, this hypothesis is investigated using molecular dynamics computer simulations and NMR spectroscopy, and is discussed in conjunction with alternative explanations based on solvent–solute and solvent–solvent hydrogen bond formation respectively. It is shown that neither simulations nor experiments lend support to the proposed mechanism based on the hydroxymethyl orientation, whereas the two alternative explanations give rise to two distinct contributions to the hydration free energy of cellooligomers.

  • 75. Berglund, Jennie
    et al.
    Angles d'Ortoli, Thibault
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Vilaplana, Francisco
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Bergenstråhle-Wohlert, Malin
    Lawoko, Martin
    Henriksson, Gunnar
    Lindström, Mikael
    Wohlert, Jakob
    A molecular dynamics study of the effect of glycosidic linkage type in the hemicellulose backbone on the molecular chain flexibility2016In: The Plant Journal, ISSN 0960-7412, E-ISSN 1365-313X, Vol. 88, no 1, p. 56-70Article in journal (Refereed)
    Abstract [en]

    The macromolecular conformation of the constituent polysaccharides in lignocellulosic biomass influences their supramolecular interactions, and therefore their function in plants and their performance in technical products. The flexibility of glycosidic linkages from the backbone of hemicelluloses was studied by evaluating the conformational freedom of the φ and ψ dihedral angles using molecular dynamic simulations, additionally selected molecules were correlated with experimental data by NMR spectroscopy. Three types of β-(1→4) glycosidic linkages involving the monosaccharides (Glcp, Xylp and Manp) present in the backbone of hemicelluloses were defined. Different di- and tetrasaccharides with combinations of such sugar monomers from hemicelluloses were simulated and free energy maps of the φ - ψ space and hydrogen bonding patterns were obtained. The glycosidic linkage between Glc-Glc or Glc-Man (C-type) was the stiffest with mainly one probable conformation; the linkage from Man-Man or Man-Glc (M-type) was similar but with an increased probability for an alternative conformation making it more flexible, and the linkage between two Xyl-units (X-type) was the most flexible with two almost equally populated conformations. Glycosidic linkages of the same type showed essentially the same conformational space in both disaccharides and in the central region of tetrasaccharides. Different probabilities of glycosidic linkage conformations in the backbone of hemicelluloses can be directly estimated from the free energy maps, which to a large degree affect the overall macromolecular conformations of these polymers. The information gained contributes to an increased understanding of hemicelluloses’ function both in the cell wall and in technical products.

  • 76. Bermejo Góme, Antonio
    et al.
    Cortés González, Miguel A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Karolinska Intitutet, Sweden.
    Lübcke, Marvin
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Karolinska Intitutet, Sweden.
    Johansson, Magnus J.
    Schou, Magnus
    Szabó, Kálmán J.
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Karolinska Intitutet, Sweden.
    Synthesis of trifluoromethyl moieties by late-stage copper (I) mediated nucleophilic fluorination2017In: Journal of fluorine chemistry, ISSN 0022-1139, E-ISSN 1873-3328, Vol. 194, p. 51-57Article in journal (Refereed)
    Abstract [en]

    The nucleophilic fluorination of bromodifluoromethyl derivatives mediated by the complex (PPh3)(3)CuF is described. Under the reaction conditions, different trifluoroacetates, trifluorolcetones, trifluoroarenes and trifluoroacetamides were obtained in good yields.

  • 77.
    Bermejo Gómez, Antonio
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Ahlsten, Nanna
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Platero-Prats, Ana E.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Martín-Matute, Belén
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Synthesis of 4,5-disubstituted 2-aminothiazoles from a,b-unsaturated ketones: Preparation of 5-benzyl-4-methyl-2-aminothiazolium hydrochloride salt2014In: Organic Syntheses, ISSN 0078-6209, Vol. 91, p. 185-200Article in journal (Refereed)
  • 78.
    Bermejo Gómez, Antonio
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Karolinska Universitetssjukhuset, Sweden; Karolinska Institutet, Sweden.
    Cortés González, Miguel A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Karolinska Institutet, Sweden.
    Lübcke, Marvin
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Karolinska Institutet, Sweden.
    Johansson, Magnus J.
    Halldin, Christer
    Szabó, Kálmán J.
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Karolinska Insitutet, Sweden.
    Schou, Magnus
    Efficient DBU accelerated synthesis of F-18-labelled trifluoroacetamides2016In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 52, no 97, p. 13963-13966Article in journal (Refereed)
    Abstract [en]

    Nucleophilic F-18-fluorination of bromodifluoromethyl derivatives was performed using [F-18] Bu4NF in the presence of DBU(1,8-diazabicyclo[5.4.0]undec-7-ene). This novel procedure provided a diverse set of [F-18] trifluoroacetamides in good to excellent radiochemical conversions. A mechanism where DBU acts as organomediator in this transformation is proposed.

  • 79.
    Bermejo-Gómez, Antonio
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Ahlsten, Nanna
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Martín-Matute, Belén
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Synthesis of 4,5-disubstituted 2-amino-1,3-thiazoles from α,β-unsaturated ketones: Preparation of 5-Benzyl-4-methyl-1,3-thiazol-2-amine hydrochlorideManuscript (preprint) (Other academic)
  • 80. Betterley, Nolan M.
    et al.
    Kerdphon, Sutthichat
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Chaturonrutsamee, Suppisak
    Kongsriprapan, Sopanat
    Surawatanawong, Panida
    Soorukram, Darunee
    Pohmakotr, Manat
    Andersson, Pher G.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Reutrakul, Vichai
    Kuhakarn, Chutima
    Bi(OTf)(3) Enabled C-F Bond Cleavage in HFIP: Electrophilic Aromatic Formylation with Difluoro(phenylsulfanyl)methane2018In: Asian Journal of Organic Chemistry, ISSN 2193-5807, Vol. 7, no 8, p. 1642-1647Article in journal (Refereed)
    Abstract [en]

    Bismuth(III) trifluoromethanesulfonate [Bi(OTf)(3)] mediated mild electrophilic aromatic formylation utilizing difluoro(phenylsulfanyl)methane (PhSCF2H) as a formylating agent in hexafluoro-2-propanol (HFIP) as a recyclable ionizing solvent has been developed. The active formylating species was generated via C-F bond cleavage and was characterized to be a bis(phenylsulfanyl)methyl cation by experimental and computational H-1 and C-13 NMR.

  • 81.
    Bielawski, Marcin
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Aili, David
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Olofsson, Berit
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Regiospecific One-Pot Synthesis of Diaryliodonium Tetrafluoroborates from Arylboronic Acids and Aryl Iodides2008In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 73, no 12, p. 4602-4607Article in journal (Refereed)
    Abstract [en]

    Diaryliodonium salts have recently received considerable attention as mild arylation reagents in organic synthesis. This paper describes a regiospecific, sequential one-pot synthesis of symmetrical and unsymmetrical diaryliodonium tetrafluoroborates, which are the most popular salts in metal-catalyzed arylations. The protocol is fast and high-yielding and has a large substrate scope. Furthermore, the corresponding diaryliodonium triflates can conveniently be obtained via an in situ anion exchange.

  • 82.
    Bielawski, Marcin
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Zhu, Mingzhao
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Olofsson, Berit
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Efficient and General One-Pot Synthesis of Diaryliodonium Triflates: Optimization, Scope and Limitations2007In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 349, no 17-18, p. 2610-2618Article in journal (Refereed)
    Abstract [en]

    Symmetrical and unsymmetrical diaryliodonium triflates have been synthesized from both electron-deficient and electron-rich arenes and aryl iodides with mCPBA and triflic acid. A thorough investigation of the optimization, scope and limitations has resulted in an improved one-pot protocol that is fast, high-yielding, and operationally simple. The reaction has been extended to the direct synthesis of symmetrical iodonium salts from iodine and arenes, conveniently circumventing the need for aryl iodides.

  • 83.
    Binh, Khanh Mai
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Szabó, Kálmán J
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Himo, Fahmi
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Mechanisms of Rh-Catalyzed Oxyfluorination and Oxytrifluoromethylation of Diazocarbonyl Compounds with Hypervalent Fluoroiodine2018In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 8, no 5, p. 4483-4492Article in journal (Refereed)
    Abstract [en]

    The reaction mechanisms of rhodium-catalyzed geminal oxyfluorination and oxytrifluoromethylation of diazo-carbonyl compounds with fluoro-benziodoxole and Togni reagents are investigated by means of density functional theory calculations. It is shown that the two reactions follow very similar mechanisms, involving N-2 dissociation to form a Rh-carbene intermediate, alcohol insertion and proton transfer resulting in a stable Rh-enol intermediate, and concerted proton transfer/electrophilic addition of the hypervalent iodine reagent to the enol. Isomerization of the hypervalent iodine takes then place before a ligand coupling affords the final product. The role of the dirhodium catalyst in facilitating the various steps of the reaction is discussed. The presented mechanisms are consistent with available experimental information, and the obtained insights allow for extension to other reactions involving hypervalent iodine reagents.

  • 84. Biswas, Srijit
    et al.
    Dahlstrand, Christian
    Watile, Rahul A.
    Kalek, Marcin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Himo, Fahmi
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Samec, Joseph S. M.
    Atom-Efficient Gold(I)-Chloride-Catalyzed Synthesis of alpha-Sulfenylated Carbonyl Compounds from Propargylic Alcohols and Aryl Thiols: Substrate Scope and Experimental and Theoretical Mechanistic Investigation2013In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 52, p. 17939-17950Article in journal (Refereed)
    Abstract [en]

    Gold(I)-chloride-catalyzed synthesis of -sulfenylated carbonyl compounds from propargylic alcohols and aryl thiols showed a wide substrate scope with respect to both propargylic alcohols and aryl thiols. Primary and secondary aromatic propargylic alcohols generated -sulfenylated aldehydes and ketones in 60-97% yield. Secondary aliphatic propargylic alcohols generated -sulfenylated ketones in yields of 47-71%. Different gold sources and ligand effects were studied, and it was shown that gold(I) chloride gave the highest product yields. Experimental and theoretical studies demonstrated that the reaction proceeds in two separate steps. A sulfenylated allylic alcohol, generated by initial regioselective attack of the aryl thiol on the triple bond of the propargylic alcohol, was isolated, evaluated, and found to be an intermediate in the reaction. Deuterium labeling experiments showed that the protons from the propargylic alcohol and aryl thiol were transferred to the 3-position, and that the hydride from the alcohol was transferred to the 2-position of the product. Density functional theory (DFT) calculations showed that the observed regioselectivity of the aryl thiol attack towards the 2-position of propargylic alcohol was determined by a low-energy, five-membered cyclic protodeauration transition state instead of the strained, four-membered cyclic transition state found for attack at the 3-position. Experimental data and DFT calculations supported that the second step of the reaction is initiated by protonation of the double bond of the sulfenylated allylic alcohol with a proton donor coordinated to gold(I) chloride. This in turn allows for a 1,2-hydride shift, generating the final product of the reaction.

  • 85.
    Björklund, Catarina
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Design and Synthesis of BACE-1 Inhibitors: Novel Compounds Targeting an Aspartic Protease Important in the Pathogenesis of Alzheimer’s Disease2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis deals with the design and synthesis of protease inhibitors targeting the aspartic protease BACE-1 (β-site APP cleaving enzyme-1), an enzyme important in the pathogenesis of Alzheimer’s disease. The inhibitors are evaluated with respect to inhibition data, in a structure-activity relationship part.

    Alzheimer’s disease is a disabling, progressive and ultimately fatal form of dementia afflicting approximately 40 percent of the population over 80 years, with over 30 million people suffering from Alzheimer’s disease worldwide. This makes Alzheimer’s disease the most common form of dementia. The identification of the amyloid-β peptide (Aβ) as the main constituent of extracellular plaques, which characterize Alzheimer’s disease, suggests that Aβ plays a vital role in the pathology of Alzheimer’s disease. The formation of Aβ occurs when amyloid-β precursor protein (APP) is cleaved by β-secretase (BACE-1) and γ-secretase, which differ in length by 39-42 amino acids. This suggests that β-secretase is a suitable target for the development of therapeutics against Alzheimer’s disease.

    The synthetic work of this thesis comprises development of BACE-1 inhibitors containing a hydroxyethylene (HE) central core transition state isostere. The target molecules were readily synthesized from chiral carbohydrate starting materials. Highly potent inhibitors were produced by varying the substituents coupled to the HE central core. Selecting an aryloxymethyl P1 side-chain and a methoxy P1’ side-chain resulted in exceptionally potent BACE-1 inhibitors that also exhibit high selectivity over cathepsin D. In a further development, the ether oxygen linkage in the P1 side-chain was removed, resulting in a carba analogue, providing improved potency in a cell-based assay.

  • 86.
    Björsne, Magnus
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Synthesis of potential candidates for therapeutic intervention against the human immunodeficiency virus1995Doctoral thesis, comprehensive summary (Other academic)
  • 87.
    Blasco, Pilar
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Patel, Dhilon S.
    Engström, Olof
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Im, Wonpil
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Conformational Dynamics of the Lipopolysaccharide from Escherichia coli O91 Revealed by Nuclear Magnetic Resonance Spectroscopy and Molecular Simulations2017In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 56, no 29, p. 3826-3839Article in journal (Refereed)
    Abstract [en]

    The outer leaflet of the outer membrane in Gram-negative bacteria contains lipopolysaccharides (LPS) as a major component, and the outer membrane provides a physical barrier and protection against hostile environments. The enterohemorrhagic Escherichia coli of serogroup O91 has an O-antigen polysaccharide (PS) with five sugar residues in the repeating unit (RU), and the herein studied O-antigen PS contains similar to 10 RUs. H-1-C-13 HSQC-NOESY experiments on a 1-C-13-labeled PS were employed to deduce H-1-H-1 cross-relaxation rates and transglycosidic (3)J(CH) related to the psi torsional angles were obtained by H-1-H-1 NOESY experiments. Dynamical parameters were calculated from the molecular dynamics (MD) simulations of the PS in solution and compared to those from C-13 nuclear magnetic resonance (NMR) relaxation studies. Importantly, the MD simulations can reproduce the dynamical behavior of internal correlation times along the PS chain. Two-dimensional free energy surfaces of glycosidic torsion angles delineate the conformational space available to the O-antigen. Although similar with respect to populated states in solution, the O-antigen in LPS bilayers has more extended chains as a result of spatial limitations due to close packing. Calcium ions are highly abundant in the phosphate-containing core region mediating LPS LPS association that is crucial for maintaining bilayer integrity, and the negatively charged O-antigen promotes a high concentration of counterbalancing potassium ions. The ensemble of structures present for the PS in solution is captured by the NMR experiments, and the similarities between the O-antigen on its own and as a constituent of the full LPS in a bilayer environment make it possible to realistically describe the LPS conformation and dynamics from the MD simulations.

  • 88.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Can Reduction of NO to N2O in Cytochrome c Dependent Nitric Oxide Reductase Proceed through a Trans-Mechanism?2017In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 56, no 1, p. 120-131Article in journal (Refereed)
    Abstract [en]

    As part of microbial denitrification, NO is reduced to N2O in the membrane bound enzyme nitric oxide reductase, NOR The N N coupling occurs in the diiron binuclear active site, BNC, and different mechanisms for this reaction step have been suggested. Computational studies have supported a so-called cis:b(3)-mechanism, in which the hyponitrite product of the reductive N N bond formation coordinates with one nitrogen to the heme iron and with both oxygens to the non-heme iron in the BNC. In contrast, experimental results have been interpreted to support a so-called trans-mechanism, in which the hyponitrite intermediate coordinates with one nitrogen atom to each of the two iron ions. Hybrid density functional theory is used here to perform an extensive search for possible intermediates of the NO reduction in the cNOR enzyme. It is found that hyponitrite structures coordinating with their negatively charged oxygens to the positively charged iron ions are the most stable ones. The hyponitrite intermediate involved in the suggested trans-mechanism, which only coordinates with the nitrogens to the iron ions, is found to be prohibitively high in energy, leading to a too slow reaction, which should rule out this mechanism. Furthermore, intermediates binding one NO molecule to each iron ion in the BNC, which have been suggested to initiate the trans-mechanism, are found to be too high in energy to be observable, indicating that the experimentally observed electron paramagnetic resonance signals, taken to support such an iron-nitrosyl dimer intermediate, should be reinterpreted.

  • 89.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    How Quantum Chemistry Can Solve Fundamental Problems in Bioenergetics2015In: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 115, no 18, p. 1197-1201Article in journal (Refereed)
    Abstract [en]

    Three different enzymes are discussed, cytochrome c oxidase, involved in aerobic respiration, cytochrome c dependent nitric oxide reductase, involved in denitrification (anaerobic respiration), and photosystem II, involved in photosynthesis. For all three systems, free energy profiles for the entire catalytic cycle are obtained from quantum mechanical calculations on large cluster models of the active sites, using hybrid density functional theory with the B3LYP* functional. The free energy pro-files are used to solve different fundamental problems concerning energy conservation, enzymatic reaction mechanisms and structure, and also to explain experimental results that seem to be in conflict with each other. Possible future applications to related problems using similar methodology are suggested.

  • 90.
    Blomberg, Margareta R. A.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Mechanism of Oxygen Reduction in Cytochrome c Oxidase and the Role of the Active Site Tyrosine2016In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 55, no 3, p. 489-500Article in journal (Refereed)
    Abstract [en]

    Cytochrome c oxidase, the terminal enzyme in the respiratory chain, reduces molecular oxygen to water and stores the released energy through electrogenic chemistry and proton pumping across the membrane. Apart from the heme-copper binuclear center, there is a conserved tyrosine residue in the active site (BNC). The tyrosine delivers both an electron and a proton during the O-O bond cleavage step, forming a tyrosyl radical. The catalytic cycle then occurs in four reduction steps, each taking up one proton for the chemistry (water formation) and one proton to be pumped. It is here suggested that in three of the reduction steps the chemical proton enters the center of the BNC, leaving the tyrosine unprotonated with radical character. The reproprotonation of the tyrosine occurs first in the final reduction step before binding the next oxygen molecule. It is also suggested that this reduction mechanism and the presence of the tyrosine are essential for the proton pumping. Density functional theory calculations on large cluster models of the active site show that only the intermediates with the proton in the center of the BNC and with an unprotonated tyrosyl radical have a high electron affinity of similar size as the electron donor, which is essential for the ability to take up two protons per electron and thus for the proton pumping. This type of reduction mechanism is also the only one that gives a free energy profile in accordance with experimental observations for the amount of proton pumping in the working enzyme.

  • 91.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Borowski, Tomasz
    Himo, Fahmi
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Liao, Rong-Zhen
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Quantum Chemical Studies of Mechanisms for Metalloenzymes2014In: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 114, no 7, p. 3601-3658Article, review/survey (Refereed)
  • 92.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    How cytochrome c oxidase can pump four protons per oxygen molecule at high electrochemical gradient2015In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1847, no 3, p. 364-376Article in journal (Refereed)
    Abstract [en]

    Experiments have shown that the A-family cytochrome c oxidases pump four protons per oxygen molecule, also at a high electrochemical gradient. This has been considered a puzzle, since two of the reduction potentials involved, Cu(II) and Fe(III), were estimated from experiments to be too low to afford proton pumping at a high gradient The present quantum mechanical study (using hybrid density functional theory) suggests a solution to this puzzle. First, the calculations show that the charge compensated Cu(II) potential for Cu-B is actually much higher than estimated from experiment, of the same order as the reduction potentials for the tyrosyl radical and the ferryl group, which are also involved in the catalytic cycle. The reason for the discrepancy between theory and experiment is the very large uncertainty in the experimental observations used to estimate the equilibrium potentials, mainly caused by the lack of methods for direct determination of reduced Cu-B. Second, the calculations show that a high energy metastable state, labeled E-H, is involved during catalytic turnover. The E-H state mixes the low reduction potential of Fe(III) in heme a(3) with another, higher potential, here suggested to be that of the tyrosyl radical, resulting in enough exergonicity to allow proton pumping at a high gradient In contrast, the corresponding metastable oxidized state, O-H, is not significantly higher in energy than the resting state, O. Finally, to secure the involvement of the high energy E-H state it is suggested that only one proton is taken up via the K-channel during catalytic turnover.

  • 93.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Improved free energy profile for reduction of NO in cytochrome c dependent nitric oxide reductase (cNOR)2016In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 37, no 19, p. 1810-1818Article in journal (Refereed)
    Abstract [en]

    Quantum chemical calculations play an essential role in the elucidation of reaction mechanisms for redox-active metalloenzymes. For example, the cleavage and the formation of covalent bonds can usually not be described only on the basis of experimental information, but can be followed by the calculations. Conversely, there are properties, like reduction potentials, which cannot be accurately calculated. Therefore, computational and experimental data has to be carefully combined to obtain reliable descriptions of entire catalytic cycles involving electron and proton uptake from donors outside the enzyme. Such a procedure is illustrated here, for the reduction of nitric oxide (NO) to nitrous oxide and water in the membrane enzyme, cytochrome c dependent nitric oxide reductase (cNOR). A surprising experimental observation is that this reaction is nonelectrogenic, which means that no energy is conserved. On the basis of hybrid density functional calculations a free energy profile for the entire catalytic cycle is obtained, which agrees much better with experimental information on the active site reduction potentials than previous ones. Most importantly the energy profile shows that the reduction steps are endergonic and that the entire process is rate-limited by high proton uptake barriers during the reduction steps. This result implies that, if the reaction were electrogenic, it would become too slow when the gradient is present across the membrane. This explains why this enzyme does not conserve any of the free energy released.

  • 94.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Proton pumping in cytochrome c oxidase: Energetic requirements and the role of two proton channels2014In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1837, no 7, p. 1165-1177Article in journal (Refereed)
    Abstract [en]

    Cytochrome c oxidase is a superfamily of membrane bound enzymes catalyzing the exergonic reduction of molecular oxygen to water, producing an electrochemical gradient across the membrane. The gradient is formed both by the electrogenic chemistry, taking electrons and protons from opposite sides of the membrane, and by proton pumping across the entire membrane. In the most efficient subfamily, the A-family of oxidases, one proton is pumped in each reduction step, which is surprising considering the fact that two of the reduction steps most likely are only weakly exergonic. Based on a combination of quantum chemical calculations and experimental information, it is here shown that from both a thermodynamic and a kinetic point of view, it should be possible to pump one proton per electron also with such an uneven distribution of the free energy release over the reduction steps, at least up to half the maximum gradient. A previously suggested pumping mechanism is developed further to suggest a reason for the use of two proton transfer channels in the A-family. Since the rate of proton transfer to the binuclear center through the D-channel is redox dependent, it might become too slow for the steps with low exergonicity. Therefore, a second channel, the K-channel, where the rate is redox-independent is needed. A redox-dependent leakage possibility is also suggested, which might be important for efficient energy conservation at a high gradient. A mechanism for the variation in proton pumping stoichiometry over the different subfamilies of cytochrome oxidase is also suggested. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference.

  • 95.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Protonation of the binuclear active site in cytochrome c oxidase decreases the reduction potential of Cu-B2015In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1847, no 10, p. 1173-1180Article in journal (Refereed)
    Abstract [en]

    One of the remaining mysteries regarding the respiratory enzyme cytochrome c oxidase is how proton pumping can occur in all reduction steps in spite of the low reduction potentials observed in equilibrium titration experiments for two of the active site cofactors, CUB(II) and Fe-a3(III). It has been speculated that, at least the copper cofactor can acquire two different states, one metastable activated state occurring during enzyme turnover, and one relaxed state with lower energy, reached only when the supply of electrons stops. The activated state should have a transiently increased Cu-B(II) reduction potential, allowing proton pumping. The relaxed state should have a lower reduction potential, as measured in the titration experiments. However, the structures of these two states are not known. Quantum mechanical calculations show that the proton coupled reduction potential for Cu-B is inherently high in the active site as it appears after reaction with oxygen, which explains the observed proton pumping. It is suggested here that, when the flow of electrons ceases, a relaxed resting state is formed by the uptake of one extra proton, on top of the charge compensating protons delivered in each reduction step. The extra proton in the active site decreases the proton coupled reduction potential for Cu-B by almost half a volt, leading to agreement with titration experiments. Furthermore, the structure for the resting state with an extra proton is found to have a hydroxo-bridge between Cu-B(II) and Fe-a3(III), yielding a magnetic coupling that can explain the experimentally observed EPR silence.

  • 96.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Siegbahn, Per E. M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Why is the reduction of NO in cytochrome c dependent nitric oxide reductase (cNOR) not electrogenic?2013In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1827, no 7, p. 826-833Article in journal (Refereed)
    Abstract [en]

    The membrane-bound enzyme cNOR (cytochrome c dependent nitric oxide reductase) catalyzes the reduction of NO in a non-electrogenic process. This is in contrast to the reduction of O-2 in cytochrome c oxidase (CcO), the other member of the heme-copper oxidase family, which stores energy by the generation of a membrane gradient. This difference between the two enzymes has not been understood, but it has been speculated to be of kinetic origin, since per electron the NO reduction is more exergonic than the O-2 reduction, and the energy should thus be enough for an electrogenic process. However, it has not been clear how and why electrogenicity, which mainly affects the thermodynamics, would slow down the very exergonic NO reduction. Quantum chemical calculations are used to construct a free energy profile for the catalytic reduction of NO in the active site of cNOR. The energy profile shows that the reduction of the NO molecules by the enzyme and the formation of N2O are very exergonic steps, making the rereduction of the enzyme endergonic and rate-limiting for the entire catalytic cycle. Therefore the NO reduction cannot be electrogenic, i.e. cannot take electrons and protons from the opposite sides of the membrane, since it would increase the endergonicity of the rereduction when the gradient is present, thereby increasing the rate-limiting barrier, and the reaction would become too slow. It also means that proton pumping coupled to electron transfer is not possible in cNOR In CcO the corresponding rereduction of the enzyme is very exergonic.

  • 97.
    Blomberg, Margareta R. A.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Ädelroth, Pia
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The mechanism for oxygen reduction in cytochrome c dependent nitric oxide reductase (cNOR) as obtained from a combination of theoretical and experimental results2017In: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1858, no 11, p. 884-894Article in journal (Refereed)
    Abstract [en]

    Bacterial NO-reductases (NOR) belong to the heme-copper oxidase (HCuO) superfamily, in which most members are O-2-reducing, proton-pumping enzymes. This study is one in a series aiming to elucidate the reaction mechanisms of the HCuOs, including the mechanisms for cellular energy conservation. One approach towards this goal is to compare the mechanisms for the different types of HCuOs, cytochrome c oxidase (CcO) and NOR, reducing the two substrates O-2 and NO. Specifically in this study, we describe the mechanism for oxygen reduction in cytochrome c dependent NOR (cNOR). Hybrid density functional calculations were performed on large cluster models of the cNOR binuclear active site. Our results are used, together with published experimental information, to construct a free energy profile for the entire catalytic cycle. Although the overall reaction is quite exergonic, we show that during the reduction of molecular oxygen in cNOR, two of the reduction steps are endergonic with high barriers for proton uptake, which is in contrast to oxygen reduction in CcO, where all reduction steps are exergonic. This difference between the two enzymes is suggested to be important for their differing capabilities for energy conservation. An additional result from this study is that at least three of the four reduction steps are initiated by proton transfer to the active site, which is in contrast to CcO, where electrons always arrive before the protons to the active site. The roles of the non-heme metal ion and the redox-active tyrosine in the active site are also discussed.

  • 98.
    Bogár, Krisztián
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Synthetic Transformations via Metal- and Enzyme-Catalyzed Dynamic Kinetic Resolution2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis deals with the preparation of a new half-sandwich type ruthenium(II)- catalyst for racemization of optically active secondary alcohols and the development of a highly efficient method in combination with lipases such as Candida antarctica lipase B and Pseudomonas cepacia lipase for dynamic kinetic resolution of various functionalized alcohols under mild reaction conditions.

    It was shown that the RuCl(CO)25-C5Ph5) complex can racemize optically active aliphatic and aromatic secondary alcohols at room temperature in rather short times. Different parameters, such as the nature of the catalyst, catalyst loading and solvent effect were studied. After the optimization steps, the Ru-catalyzed racemization of (S)-1-phenylethanol in the presence of Candida antarctica lipase B was also investigated. The compatibility of the metal- and enzyme-catalyzed reactions led to a highly efficient coupled catalytic system for transformation of racemic alcohols to their enantiomerically pure acetates. This protocol was applied for a wide range of secondary alcohols. It was shown that in the case of allylic alcohols the obtained enantiopure allylic acetates are useful compounds for synthesis of α-methyl carboxylic acids such as (R)-Flurbiprofen and acyloin acetates. Highly selective dynamic kinetic asymmetric transformation of 3,5-piperidine diol to deliver various 3,5-dioxygenated piperidines is also described.

  • 99.
    Bogár, Krisztián
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Bäckvall, Jan-E.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    High-yielding metalloenzymatic dynamic kinetic resolution of fluorinated aryl alcohols2007In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 48, no 31, p. 5471-5474Article in journal (Refereed)
    Abstract [en]

    Dynamic kinetic resolution (DKR) of various fluorinated aryl alcohols by a combination of lipase-catalyzed enzymatic resolution with in situ ruthenium-catalyzed alcohol racemization is described. (R)-Selective Candida antarctica lipase B (CALB) was employed for transesterification of different fluoroaryl alcohols in DKR reactions delivering the corresponding acetates in high yield (97%) with excellent enantiomeric excess (98%).

  • 100.
    Bogár, Krisztián
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Hoyos Vidal, Pilar
    Alcántara León, Andrés R.
    Bäckvall, Jan-E.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Chemoenzymatic Dynamic Kinetic Resolution of Allylic Alcohols: A Highly Enantioselective Route to Acyloin Acetates2007In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 9, no 17, p. 3401-3404Article in journal (Refereed)
    Abstract [en]

    Dynamic kinetic resolution (DKR) of a series of sterically hindered allylic alcohols has been conducted with Candida antarctica lipase B (CALB) and ruthenium catalyst 1. The optically pure allylic acetates obtained were subjected to oxidative cleavage to give the corresponding acylated acyloins in high yields without loss of chiral information.

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