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  • 1501.
    Wallin, Richard
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Kalek, Marcin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bartoszewicz, Agnieszka
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Thelin, Mats
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Stawinski, Jacek
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    On the sulfurization of H-phosphonate diesters and phosphite triesters using elemental sulfur2009Ingår i: Phosphorus Sulfur and Silicon and the Related Elements, ISSN 1042-6507, E-ISSN 1563-5325, Vol. 184, nr 4, s. 908-916Artikel i tidskrift (Refereegranskat)
  • 1502.
    Wallner, Olov
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Palladium-Catalyzed Synthesis and Transformations of Organometallic Compounds2006Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    This thesis is focused on two important fields of palladium catalysis: the development of electrophilic allylic substitution reactions via bis-allylpalladium intermediates; and application of palladium pincer-complexes in the synthesis and transformations of organometallic compounds.

    Palladium-catalyzed electrophilic allylation of aldehyde and imine substrates could be achieved using readily available allyl chlorides and acetates by employing hexamethylditin or bis(pinacolato)diboron reagents. The reaction proceeds under mild and neutral reaction conditions with high regioselectivity, providing the branched homoallylic products. The stereoselectivity of the reaction depends on the steric and electronic effects of the allylic substituents of the substrates. DFT modeling of the electrophilic attack on the bis-allylpalladium intermediate of the reaction revealed the origin of the regio- and stereoselectivity of the reaction.

    Palladium pincer-complexes were employed as catalysts in a variety of reactions such as stannylation, selenylation, allylation, and cross coupling reactions with various electrophiles. Allylic stannylation in the presence of hexamethylditin was achieved by use of an NCN palladium pincer-complex catalyst. In contrast to the reactions catalyzed by traditional palladium catalysts, isolation of functionalized allyl stannanes was possible due to the special features of the pincer-complex catalyst. Extension of the scope of the palladium pincer-complex catalyzed electrophilic allylation reactions was achieved by using potassium trifluoro(allyl)borate instead of allyl stannanes. In addition, asymmetric electrophilic allylation of sulfonimines was achieved by employment of novel BINOL-based palladium pincer-complexes. The enantioselectivity of the pincer-complex catalyst was fine-tuned by employment of substituted analogs of BINOL.

  • 1503.
    Wallner, Olov A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Potassium Trifluoro-2-propenylborate2007Ingår i: Encyclopedia of Reagents for Organic Synthesis, Wiley , 2007Kapitel i bok, del av antologi (Refereegranskat)
  • 1504.
    Wallner, Olov
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Olsson, Vilhelm J
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Eriksson, L.
    Szabó, Kálmán J
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Synthesis of New Chiral Pincer-Complex Catalysts for Asymmetric Allylation of Sulfonimines2006Ingår i: Inorganica Chimica Acta, ISSN 0020-1693, E-ISSN 1873-3255, Vol. 359, nr 6, s. 1767-1772Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Four new chiral pincer-complexes were prepared based on coupling of BINOL and TADDOL moieties with iodoresorcinol followed by oxidative addition of palladium(0). The X-ray analysis of complex 5a revealed that the BINOL rings form a well-defined chiral pocket around the palladium atom. This chiral environment can be further modified by γ-substitution of the BINOL rings. Preliminary studies for electrophilic allylation of sulfonimine 2 with allylstannane revealed that the presented chiral complexes are promising asymmetric catalysts for preparation of chiral homoallyl amines. The best result was achieved employing catalytic amounts of γ-Me BINOL complex 6 affording homoallyl amine 4 with 59% ee and 74% isolated yield.

  • 1505.
    Wallner, Olov
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán J
    Employment of Palladium Pincer-Complexes in Phenylselenylation of Organohalides2005Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, Vol. 70, nr 23, s. 9215-9221Artikel i tidskrift (Refereegranskat)
  • 1506.
    Wallner, Olov
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán J
    Origin of the Regio- and Stereoselectivity in Palladium-Catalyzed Electrophilic Substitution via Bis-allylpalladium Complexes2003Ingår i: Chemistry : a European journal, ISSN 0947-6539, Vol. 9, nr 17, s. 4025-4030Artikel i tidskrift (Refereegranskat)
  • 1507.
    Wallner, Olov
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán J
    Palladium Pincer Complex-Catalyzed Allylic Stannylation with Hexaalkylditin Reagents2004Ingår i: Organic Letters, ISSN 1523-7060, Vol. 6, nr 11, s. 1829-1831Artikel i tidskrift (Refereegranskat)
  • 1508.
    Wallner, Olov
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán J
    Palladium-Catalyzed Electrophilic Allylic Substitution of Allyl Chlorides and Acetates via Bis-allylpalladium Intermediates2003Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, Vol. 68, nr 7, s. 2934-2943Artikel i tidskrift (Refereegranskat)
  • 1509.
    Wallner, Olov
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán J
    Regioselective Palladium-Catalyzed Electrophilic Allylic Substitution in the Presence of Hexamethylditin2002Ingår i: Organic letters, ISSN 1523-7060, Vol. 4, nr 9, s. 1563-1566Artikel i tidskrift (Refereegranskat)
  • 1510.
    Wang, Dong
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    New Reactions with Allyl- and Allenylboron Reagents: Transition-Metal-Catalyzed and Transition-Metal-Free Carbon-Carbon Bond Formation Processes2018Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Organoboron compounds have been widely used in carbon-carbon bond formation reactions in organic synthesis and catalysis. This thesis is focused on cross-coupling reactions of allyl-, allenylboronic acids and their ester derivatives via transition metal catalysis or transition-metal-free processes.

    The first part of the thesis describes Cu-catalyzed C(sp3)-C(sp3) formation reactions involving allylboronic acids and α-diazoketones. This coupling process shows high γ-regioselectivity, resulting in branched allylic products. When stereodefined cyclic allylboronic acids were employed as the substrate, the relative facial configuration was retained in the reaction product.

    The second part involves Pd-catalyzed cross-coupling of allylboronic acid and α-diazoketones. The reaction proceeds with high α-regioselectivity, affording linear allylic products. Accordingly, the palladium- and copper-catalyzed cross-coupling of allylboronic acid and α-diazoketones occurs with opposite regioselectivity.

    The third part concerns a new transition-metal-free carbon-carbon bond formation between allenylboronic acids and in situ generated diazo compounds. The diazo compounds are generated from tosylhydrazones in the presence of base. The reaction is suitable for synthesis of densely substituted conjugated dienes with high Z-selectivity.

    In the final part, the allylation of quinones with allylboronates is presented. The reaction was performed without any catalyst or additive. Various quinones can be employed as substrates, including unsubstituted, monosubstituted benzoquinones and naphthoquinones.

  • 1511.
    Wang, Dong
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    de Wit, Martin J. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Synthesis of Densely Substituted Conjugated Dienes by Transition-Metal-Free Reductive Coupling of Allenylboronic Acids and Tosylhydrazones2018Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 83, nr 15, s. 8786-8792Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tosylhydrazones and allenylboronic acids underwent a transition-metal-free reductive coupling reaction. This process is suitable for synthesis of tetra- and pentasubstituted conjugated dienes. The corresponding allenyl-Bpin substrate showed a very poor reactivity. The reaction is suggested to involve coupling of the in situ formed diazo compound and allenylboronic acid. The intermediate formed in this coupling undergoes allenyl migration followed by protodeboronation to furnish a conjugated diene as major product.

  • 1512.
    Wang, Dong
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Copper-Catalyzed, Stereoselective Cross-Coupling of Cyclic Allyl Boronic Acids with alpha-Diazoketones2017Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, nr 7, s. 1622-1625Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study; we present the synthesis of new, Stereodefined allylboronic adds employed to investigate the stereochemistry of the Cu-catalyzed cross-coupling of allylboronic acids with alpha-diazoketones. According to our results, this reaction proceeds with retention of the relative configurtion of the allylberonic acid substrate. We suggest that the stereoinduction step involves a syn S(E)2'-type transrnetalation of the allylboronic acid substrate with a Cu-carbene species.

  • 1513. Wang, Lei
    et al.
    Duan, Lele
    Stewart, Beverly
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Pu, Maoping
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Liu, Jianhui
    Privalov, Timofei
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Sun, Licheng
    Toward Controlling Water Oxidation Catalysis: Tunable Activity of Ruthenium Complexes with Axial Imidazole/DMSO Ligands2012Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 134, nr 45, s. 18868-18880Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Using the combinations of imidazole and dimethyl :sulfoxide (DMSO) as axial ligands and 2,2'-bipyridine-6,6'-dicarboxylate (bda) as the equatorial ligand, we have synthesized six novel ruthenium complexes with noticeably different activity as water oxidation catalysts (WOCs). In four C-s symmetric Ru-II(kappa(3)-bda)(DMSO)L-2 complexes L = imidazole (1), N-methylimidazole (2), 5-methylimidazole (3), and 5-bromo-N-methylimidazole (4). Additionally, in two C-2v symmetric Ru-II(kappa(4)-bda)L-2 complexes L = 5-nitroimidazole (5) and 5-bromo-N-methylimidazole (6), that is, fully equivalent axial imidazoles. A detailed characterization of all complexes and the mechanistic investigation of the catalytic water oxidation have been carried out with a number of experimental techniques, that is, kinetics, electrochemistry and high resolution mass spectrometry (HR-MS), and density functional theory (DFT) calculations. We have observed the in situ formation: of a Ru-II-complex with the accessible seventh coordination position. The measured catalytic activities and kinetics of complex 1-6 revealed details about an important structure activity relation: the connection between the nature of axial ligands in the combination and either the increase or decrease of the catalytic activity. In particular, an axial DMSO group substantially increases the turnover frequency of WOCs reported in article, with the ruthenium-complex having one axial 5-bromo-N-methylimidazole and one axial DMSO: (4), we have obtained a high initial turnover frequency of similar to 180 s(-1). DFT modeling Of the binuclear reaction pathway of the O-O bond formation in catalytic Water oxidation further corroborated the concept of the mechanistic significance of the axial ligands and rationalized the experimentally observed difference in the activity of complexes with imidazole/DMSO and imidazole/imidazole combinations of axial ligands.

  • 1514. Wang, Zhen
    et al.
    Jiang, Wenfeng
    Liu, Jianhui
    Jiang, Weina
    Wang, Yu
    Åkermark, Björn
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Sun, Licheng
    Pendant bases as proton transfer relays in diiron dithiolate complexes inspired by [Fe-Fe] hydrogenase active site2008Ingår i: Journal of Organometallic Chemistry, ISSN 0022-328X, Vol. 693, nr 17, s. 2828-2834Artikel i tidskrift (Refereegranskat)
  • 1515. Wang, Zhen
    et al.
    Liu, Jian-Hui
    He, Cheng-Jiang
    Jiang, Shi
    Åkermark, Björn
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Sun, Li-Cheng
    Azadithiolates cofactor of the iron-only hydrogenase and its PR3-monosubstituted derivatives: Synthesis, structure, electrochemistry and protonation2007Ingår i: Journal of Organometallic Chemistry, ISSN 0022-328X, E-ISSN 1872-8561, Vol. 692, nr 24, s. 5501-5507Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The core structure (mu-SCH2)(2)NH[Fe-2(CO)(6)](5) of Fe-only hydrogenases active site model has been synthesized by the condensation of iron carbonyl sulfides, formaldehyde and silyl protected amine. Its monosubstituted complexes (mu-SCH2)(2)NH[Fe-2(CO)(5)PR3] (R = Ph (6), Me (7)) were accordingly prepared. The coordination configurations of 5 and 6 were characterized by X-ray crystallography. Protonation of complex 7 to form the N-protonated product occurs in an acetonitrile solution upon addition of triflic acid. The redox properties of these model complexes were studied by cyclic voltammetry.

  • 1516. Wang, Zhen
    et al.
    Liu, Jianhui
    He, Chengjiang
    Jiang, Shi
    Åkermark, Björn
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Sun, Licheng
    Diiron azadithiolates with hydrophilic phosphatriazaadamantane ligand as iron-only hydrogenase active site models: Synthesis, structure, and electrochemical study2007Ingår i: Inorganica Chimica Acta, ISSN 0020-1693, E-ISSN 1873-3255, Vol. 360, nr 7, s. 2411-2419Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Three novel complexes (mu-adt)[Fe-2(CO)(5)PTA] (2-PTA), (mu-adt)[Fe-2(CO)(4)PTA(2)](2-PTA(2)) and (mu-adt)[Fe-2(CO)(5)DAPTA] (2-DAPTA), where adt is SCH2N(CH2CH2CH3)CH2S, PTA stands for 1,3,5-triaza-7-phosphaadamantane and DAPTA is 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane, were prepared as the models of the iron hydrogenase active site through controlled CO displacement of (mu-adt)[Fe-2(CO)(6)] with PTA and DAPTA. The coordination configurations of 2-PTA and 2-PTA(2) were characterized by X-ray crystallography. The disubstituted diiron complex 2-PTA(2) features a basal/apical coordination mode, instead of the typical transoid basal/basal configuration. Protonation of three complexes only occurred at the bridging-N atom, rather than at the tertiary nitrogen atom on the PTA or DAPTA ligands. Electrochemical properties of the complexes were studied in acetonitrile or a mixture of acetonitrile and water in the presence of acetic acid, by cyclic voltammetry. The current sensitivity of the reduced species to acid concentration in the presence of H2O is greater than in the pure CH3CN solution.

  • 1517. Wangsell, Fredrik
    et al.
    Gustafsson, Karin
    Kvarnström, Ingemar
    Borkakoti, Neera
    Edlund, Michael
    Jansson, Katarina
    Lindberg, Jimmy
    Hallberg, Anders
    Rosenquist, Asa
    Samuelsson, Bertil
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core2010Ingår i: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 45, nr 3, s. 870-882Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxyl ethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the PI-position. The final inhibitors were optimized using three different amines to provide the residues in the P2'-P3' position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1'-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-I assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC50 Value of 3.1 nM.

  • 1518. Wangsell, Fredrik
    et al.
    Nordeman, Patrik
    Savmarker, Jonas
    Emanuelsson, Rikard
    Jansson, Katarina
    Lindberg, Jimmy
    Rosenquist, Asa
    Samuelsson, Bertil
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Larhed, Mats
    Investigation of alpha-phenylnorstatine and alpha-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors2011Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 19, nr 1, s. 145-155Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on alpha-phenylnorstatine, alpha-benzylnorstatine, iso-serine, and beta-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC(50) = 0.19 mu M) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids.

  • 1519.
    Warner, Madeleine
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Hydrogen transfer reactions catalyzed by a cyclopentadienyl ruthenium complex: Mechanistic studies and dynamic kinetic resolution.2010Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
  • 1520.
    Warner, Madeleine
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Racemization of Olefinic Alcohols by a Cyclopentadienyl Ruthenium Carbonyl Complex: Study of the Inhibiting Effect of the Carbon-Carbon Double BondManuskript (preprint) (Övrigt vetenskapligt)
  • 1521.
    Warner, Madeleine
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Ruthenium-Catalyzed Hydrogen Transfer Reactions: Mechanistic Studies and Chemoenzymatic Dynamic Kinetic Resolutions2013Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The main focus of this thesis lies on transition metal-catalyzed hydrogen transfer reactions. In the first part of the thesis, the mechanism for racemization of sec-alcohols with a ruthenium complex, Ru(CO)2Cl(η5-C5Ph5) was studied.

    The reaction between 5-hexen-2-ol and Ru(CO)2(Ot-Bu)(η5-C5Ph5) was studied with the aim to elucidate the origin of the slow racemization observed for this sec-alcohol. Two diastereomers of an alkoxycarbonyl complex, which has the double bond coordinated to ruthenium, were characterized by NMR and in situ FT-IR spectroscopy. The observed inhibition of the rate of racemization for substrates with double bonds provided further confirmation of the importance of a free coordination site on ruthenium for β-hydride elimination. Furthermore, we observed that CO exchange, monitored by 13C NMR using 13CO, occurs with both the precatalyst, Ru(CO)2Cl(η5-C5Ph5), and the active catalytic intermediate, Ru(CO)2(Ot-Bu)(η5-C5Ph5). It was also found that added CO has an inhibitory effect on the rate of racemization of (S)-1-phenylethanol. Both these observations provide strong support for reversible CO dissociation as a key step in the racemization mechanism.

    In the second part of this thesis, Ru(CO)2Cl(η5-C5Ph5) was combined with an enzymatic resolution catalyzed by a lipase, leading to several efficient dynamic kinetic resolutions (DKR). DKR of exocyclic allylic alcohols afforded the corresponding acetates in high yields and with excellent enantiomeric excess (ee). The products were utilized as synthetic precursors for α-substituted ketones and lactones. DKR of a wide range of homoallylic alcohols afforded the products in good to high yields and with high ee. The homoallylic acetates were transformed into 5,6-dihydropyran-2-ones in a short reaction sequence. Furthermore, DKR of a wide range of aromatic β-chloroalcohols afforded the products in high yields and with excellent ee. The β-chloro acetates were further transformed into chiral epoxides.

  • 1522.
    Warner, Madeleine C.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bäckvall, Jan-E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mechanistic Aspects on Cyclopentadienylruthenium Complexes in Catalytic Racemization of Alcohols2013Ingår i: Accounts of Chemical Research, ISSN 0001-4842, E-ISSN 1520-4898, Vol. 46, nr 11, s. 2545-2555Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Cyclopentadienylruthenium complexes commonly serve as efficient transition metal catalysts in the racemization of alcohols. The combination of the racemization reaction with enzymatic resolution leads to dynamic kinetic resolution (DKR). In DKR, a theoretical yield of 100% is possible, making it a powerful tool for enantioselective synthesis. In this Account, we summarize the most important mechanistic aspects of racemization of alcohols reported over the past decade based on both experimental and computational results. Precatalyst activation is often necessary, either by heating the reaction or by adding an alkoxide-type base. The subsequent alcohol-alkoxide exchange is rapid and introduces the substrate into the catalytic cycle. This exchange requires a free coordination site, which may be created via several different mechanisms. Following alkoxide formation, racemization occurs via beta-hydride elimination and subsequent readdition. In cyclopentadienyldicarbonylruthenium alkoxide complexes, which are 18-electron complexes, researchers originally considered two mechanisms for the creation of the free coordination site required for beta-hydride elimination: a change in hapticity of the cyclopentadienyl ligand from eta 5 to eta 3 and dissociation of a CO ligand. Based on computational and experimental results, we have found strong support for the pathway involving CO dissociation. Researchers had also wondered if the substrate remains coordinated to the metal center (the inner-sphere mechanism) during the hydrogen transfer step(s). Using competition and crossover experiments, we found strong evidence for an inner-sphere mechanism. In summary, we have obtained a detailed picture of the racemization of alcohols by cyclopentadienylruthenium catalysts, leading to the development of more efficient catalytic systems for racemization.

  • 1523.
    Warner, Madeleine C.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bäckvall, Jan-E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Racemization of Olefinic Alcohols by a Carbonyl(cyclopentadienyl)ruthenium Complex: Inhibition by the Carbon-Carbon Double Bond2015Ingår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, nr 11, s. 2388-2393Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this article, racemization of various olefinic sec-alcohols by Ru(CO)(2)((5)-C5Ph5)Cl was investigated. The racemization of three aliphatic sec-alcohols with different chain lengths containing terminal double bonds was studied. A dramatic decrease of the racemization rate was found for these sec-alcohols compared to that of the corresponding saturated substrates. The slow racemization rate of the former alcohols is ascribed to coordination of the double bond to the ruthenium centre, which blocks the free site needed for -hydride elimination. This mechanism was supported by a recent study, in which 5-hexen-2-ol was found to form an alkoxycarbonyl complex having the double bond coordinated to the ruthenium atom. Aliphatic sec-alcohol substrates with a di- or trisubstituted double bond were found to give a lower degree of inhibition of the racemization rate than the substrates with a monosubstituted double bond.

  • 1524.
    Warner, Madeleine C.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Casey, Charles P.
    Bäckvall, Jan-E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Shvo's Catalyst in Hydrogen Transfer Reactions2011Ingår i: BIFUNCTIONAL MOLECULAR CATALYSIS, 2011, s. 85-125Konferensbidrag (Refereegranskat)
    Abstract [en]

    This chapter reviews the use of Shvo's catalyst in various hydrogen transfer reactions and also discusses the mechanism of the hydrogen transfer. The Shvo catalyst is very mild to use since no activation by base is required in the transfer hydrogenation of ketones or imines or in the transfer dehydrogenation of alcohols and amines. The Shvo catalyst has also been used as an efficient racemization catalyst for alcohols and amines. Many applications of the racemization reaction are found in the combination with enzymatic resolution leading to a dynamic kinetic resolution (DKR). In these dynamic resolutions, the yield based on the starting material can theoretically reach 100%. The mechanism of the hydrogen transfer from the Shvo catalyst to ketones (aldehydes) and imines as well as the dehydrogenation of alcohols and amines has been studied in detail over the past decade. It has been found that for ketones (aldehydes) and alcohols, there is a concerted transfer of the two hydrogens involved, whereas for typical amines and imines, there is a stepwise transfer of the two hydrogens. One important question is whether the substrate is coordinated to the metal or not in the hydrogen transfer step(s). The pathway involving coordination to activate the substrate is called the inner-sphere mechanism, whereas transfer of hydrogen without coordination is called the outer-sphere mechanism. These mechanistic proposals together with experimental and theoretical studies are discussed.

  • 1525.
    Warner, Madeleine C.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Nagendiran, Anuja
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bogár, Krisztián
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bäckvall, Jan-E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Enantioselective Route to Ketones and Lactones from Exocyclic Allylic Alcohols via Metal and Enzyme Catalysis2012Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 14, nr 19, s. 5094-5097Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A general and efficient route for the synthesis of enantiomerically pure a-substituted ketones and the corresponding lactones has been developed. Ruthenium- and enzyme-catalyzed dynamic kinetic resolution (DKR) with a subsequent Cu-catalyzed alpha-allylic substitution are the key steps of the route. The a-substituted ketones were obtained in high yields and with excellent enantiomeric excess. The methodology was applied to the synthesis of a naturally occurring caprolactone, (R)-10-methyl-6-undecanolide, via a subsequent Baeyer-Villiger oxidation.

  • 1526.
    Warner, Madeleine C.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Shevchenko, Grigory A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Jouda, Suzan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bogar, Krisztian
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bäckvall, Jan-E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Dynamic Kinetic Resolution of Homoallylic Alcohols: Application to the Synthesis of Enantiomerically Pure 5,6-Dihydropyran-2-ones and delta-Lactones2013Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, nr 41, s. 13859-13864Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Dynamic kinetic resolution of various homoallylic alcohols with the use of Candida antarctica lipaseB and ruthenium catalyst 2 afforded homoallylic acetates in high yields and with high enantioselectivity. These enantiopure acetates were further transformed into homoallylic acrylates after hydrolysis of the ester function and subsequent DMAP-catalyzed esterification with acryloyl chloride. After ring-closing metathesis 5,6-dihydropyran-2-ones were obtained in good yields. Selective hydrogenation of the carboncarbon double bond afforded the corresponding -lactones without loss of chiral information.

  • 1527.
    Warner, Madeleine C
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Verho, Oscar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bäckvall, Jan-E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    CO dissociation mechanism in racemization of alcohols by a cyclopentadienyl ruthenium dicarbonyl catalyst2011Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 133, nr 9, s. 2820-2823Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    13CO exchange studies of racemization catalyst (η5-Ph5C5)Ru(CO)2Cl and (η5-Ph5C5)Ru(CO)2(Ot-Bu) by 13C NMR spectroscopy are reported. CO exchange for the active catalyst form, (η5-Ph5C5)Ru(CO)2(Ot-Bu) is approximately 20 times faster than that for the precatalyst (η5-Ph5C5)Ru(CO)2Cl. An inhibition on the rate of racemization of (S)-1-phenylethanol was observed on addition of CO. These results support the hypothesis that CO dissociation is a key step in the racemization of sec-alcohols by (η5-Ph5C5)Ru(CO)2Cl, as also predicted by DFT calculations.

  • 1528. Watcharinyanon, Somsakul
    et al.
    Puglia, Carla
    Göthelid, Emmanuelle
    Bäckvall, Jan-Erling
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Moons, Ellen
    Johansson, Lars S.O.
    Molecular orientation of thiol-derivatized tetraphenylporphyrin on gold studied by XPS and NEXAFS2009Ingår i: Surface Science, ISSN 0039-6028, E-ISSN 1879-2758, Vol. 603, nr 7, s. 1026-1033Artikel i tidskrift (Refereegranskat)
  • 1529. Wei, Wen-Jie
    et al.
    Siegbahn, Per E. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Liao, Rong-Zhen
    Theoretical Study of the Mechanism of the Nonheme Iron Enzyme EgtB2017Ingår i: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 56, nr 6, s. 3589-3599Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    EgtB is a nonheme iron enzyme catalyzing the C - S bond formation between gamma-glutamyl cysteine (gamma GC) and N-alpha-trimethyl histidine (TMH) in the ergothioneine biosynthesis. Density functional calculations were performed to elucidate and delineate the reaction mechanism of this enzyme. Two different mechanisms were considered, depending on whether the sulfoxidation or the S C bond formation takes place first. The calculations suggest that the S - O bond formation occurs first between the thiolate and the ferric superoxide, followed by homolytic O-O bond cleavage, very similar to the case of cysteine dioxygenase. Subsequently, proton transfer from a second-shell residue Tyr377 to the newly generated iron - oxo moiety takes place, which is followed by proton transfer from the TMH imidazole to Tyr377, facilitated by two crystallographically observed water molecules. Next, the S C bond is formed between gamma GC and TMH, followed by proton transfer from the imidazole CH moiety to Tyr377, which was calculated to be the rate-limiting step for the whole reaction, with a barrier of 17.9 kcal/mol in the quintet state. The calculated barrier for the rate-limiting step agrees quite well with experimental kinetic data. Finally, this proton is transferred back to the imidazole nitrogen to form the product. The alternative thiyl radical attack mechanism has a very high barrier, being 25.8 kcal/mol, ruling out this possibility.

  • 1530. Wellens, Adinda
    et al.
    Garofalo, Corinne
    Nguyen, Hien
    Van Gerven, Nani
    Slättegård, Rikard
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Hernalsteens, Jean-Pierre
    Wyns, Lode
    Oscarson, Stefan
    De Greve, Henri
    Hultgren, Scott
    Bouckaert, Julie
    Intervening with urinary tract infections using anti-adhesives based on the crystal structure of the FimH-oligomannose-3 complex2008Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 3, nr 4, s. e2040; 1-13Artikel i tidskrift (Refereegranskat)
  • 1531.
    Wettergren, Jenny
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Selective transfer hydrogenations: Catalyst development and mechanistic investigations2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    By generating a library of amino acid-based ligands, pseudo-dipeptides, and combining them with transition metals, we have created selective and efficient ruthenium and rhodium catalysts for the asymmetric transfer hydrogenation of ketones. The ruthenium-catalyzed reaction was studied in detail, and we found that alkali metals play a crucial role for the reactivity and selectivity of the reaction. Furthermore, we have performed kinetic studies on the catalytic system, and the experimental data does neither support the established inner-sphere nor the classical outer-sphere mechanism. Hence, a novel mechanism for the ruthenium-pseudo-dipeptide-catalyzed transfer hydrogenation is proposed. In this unprecedented outer-sphere mechanism, a hydride and an alkali metal ion are transferred from the donor to the ruthenium complex in the rate determining step.

    In addition, the pseudo-dipeptide ligands were employed in the rhodium-catalyzed transfer hydrogenation of aryl alkyl ketones to yield the corresponding alcohols in high yields and excellent enantioselectivities (up to 98% ee). The study revealed that the alkali metals, so important in the ruthenium analogue of the reaction, do not improve the enantioselectivity of the reaction. Deuterium labeling experiments showed that the reaction follows the mono hydridic route.

    Furthermore, a novel method for efficient catalyst screening has been developed. We have demonstrated that ligand synthesis, catalyst formation, and enantioselective catalysis can be performed using an in situ one-pot procedure. The efficacy of the concept was demonstrated in the enantioselective reduction of ketones. In addition to the simplification of the catalyst formation, this approach resulted in improvement of the product ee.

    Finally, the development of a reduction protocol for the transfer hydrogenation of ketones to alcohols without the involvement of transition metal catalysts is described. Using microwave irradiation, a range of ketones was efficiently reduced in high yields using catalytic amounts of lithium 2-propoxide in 2-propanol.

  • 1532.
    Wettergren, Jenny
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    In Situ Formation of Ligand and Catalyst: Application in Ruthenium-Catalyzed Enantioselective Reduction of Ketones2007Ingår i: Regio- and Stereo-Controlled Oxidations and Reductions, Wiley, England , 2007, s. 121-124Kapitel i bok, del av antologi (Refereegranskat)
  • 1533.
    Wettergren, Jenny
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Buitrago, Elina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Ryberg, Per
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mechanistic Investigation on the Asymmetric Transfer Hydrogenation of Ketones Catalyzed by Pseudo-Dipeptides Ruthenium complexes2009Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, nr 23, s. 5709-5718Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lithium-powered: A kinetic investigation into the asymmetric transfer hydrogenation of non-activated aryl alkyl ketones, catalyzed by N-Boc-protected -amino acid hydroxyamide ruthenium–arene complexes, has revealed that the reactions proceed through an unprecedented bimetallic outer-sphere mechanism. Under optimized conditions, these catalysts provide access to secondary alcohols in high yields and with excellent enantioselectivities (>99 % ee).

    The combination of N-Boc-protected -amino acid hydroxyamides (pseudo-dipeptides) and [{Ru(p-cymene)Cl2}2] resulted in the formation of superior catalysts for the asymmetric transfer hydrogenation (ATH) of non-activated aryl alkyl ketones in propan-2-ol. The overall kinetics of the ATH of acetophenone to form 1-phenylethanol in the presence of ruthenium pseudo-dipeptide catalysts were studied, and the individual rate constants for the processes were determined. Addition of lithium chloride to the reaction mixtures had a strong influence on the rates and selectivities of the processes. Kinetic isotope effects (KIEs) for the reduction were determined and the results clearly show that the hydride transfer is rate-determining, whereas no KIEs were detected for the proton transfer. From these observations a novel bimetallic outer-sphere-type mechanism for these ATH process is proposed, in which the bifunctional catalysts mediate the transfer of a hydride and an alkali metal ion between the hydrogen donor and the substrate. Furthermore, the use of a mixture of propan-2-ol and THF (1:1) proved to enhance the rates of the ATH reactions. A series of aryl alkyl ketones were reduced under these conditions in the presence of 0.5 mol % of catalyst, and the corresponding secondary alcohols were formed in high yields and with excellent enantioselectivities (>99 % ee) in short reaction times.

  • 1534.
    Wettergren, Jenny
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Buitrago, Elina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Ryberg, Per
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mechanistic investigations into the asymmetric transfer hydrogenation of ketones catalyzed by pseudo-dipeptide ruthenium complexes2009Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, nr 23, s. 5709-5718Artikel i tidskrift (Refereegranskat)
  • 1535.
    Wettergren, Jenny
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bøgevig, Anders
    Portier, Maude
    Adolfsson, Hans
    Ruthenium-Catalyzed Enantioselective Reduction of Electron-Rich Aryl Alkyl Ketones2006Ingår i: Advanced Synthesis and Catalysis, ISSN 1615-4150, Vol. 348, nr 10-11, s. 1277-1282Artikel i tidskrift (Refereegranskat)
  • 1536.
    Wettergren, Jenny
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Zaitsev, Alexey
    Adolfsson, Hans
    Rhodium-Catalyzed Asymmetric Transfer Hydrogenation of Aryl Alkyl Ketones Employing Ligands Derived from Amino Acids2007Ingår i: Advanced Synthesis and Catalysis, ISSN 1615-4150, Vol. 349, nr 17-18, s. 2556-2562Artikel i tidskrift (Refereegranskat)
  • 1537.
    Wettergren, Jenny
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Zaitsev, Alexey B.
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Asymmetric transfer hydrogenation of ketones: development of amino acid derived transition metal catalysts2008Ingår i: Abstracts of Papers, 235th ACS National Meeting, New Orleans, LA, United States, April 6-10, 2008, 2008Konferensbidrag (Övrigt vetenskapligt)
  • 1538.
    Wettergren, Jenny
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Zaitsev, Alexey B.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Rhodium-catalyzed asymmetric transfer hydrogenation of aryl alkyl ketones employing ligands derived from amino acids2007Ingår i: Advanced Synthesis & Catalysis, ISSN 1615-4150, Vol. 349, s. 2556-2562Artikel i tidskrift (Refereegranskat)
  • 1539.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    A perspective on the primary and three-dimensional structures of carbohydrates2013Ingår i: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 378, s. 123-132Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Carbohydrates, in more biologically oriented areas referred to as glycans, constitute one of the four groups of biomolecules. The glycans, often present as glycoproteins or glycolipids, form highly complex structures. In mammals ten monosaccharides are utilized in building glycoconjugates in the form of oligo-(up to about a dozen monomers) and polysaccharides. Subsequent modifications and additions create a large number of different compounds. In bacteria, more than a hundred monosaccharides have been reported to be constituents of lipopolysaccharides, capsular polysaccharides, and exopolysaccharides. Thus, the number of polysaccharide structures possible to create is huge. NMR spectroscopy plays an essential part in elucidating the primary structure, that is, monosaccharide identity and ring size, anomeric configuration, linkage position, and sequence, of the sugar residues. The structural studies may also employ computational approaches for NMR chemical shift predictions (CASPER program). Once the components and sequence of sugar residues have been unraveled, the three-dimensional arrangement of the sugar residues relative to each other (conformation), their flexibility (transitions between and populations of conformational states), together with the dynamics (timescales) should be addressed. To shed light on these aspects we have utilized a combination of experimental liquid state NMR techniques together with molecular dynamics simulations. For the latter a molecular mechanics force field such as our CHARMM-based PARM22/SU01 has been used. The experimental NMR parameters acquired are typically H-1, H-1 cross-relaxation rates (related to NOEs), (3)JCH and (3)JCC trans-glycosidic coupling constants and H-1, C-13-and H-1, H-1-residual dipolar couplings. At a glycosidic linkage two torsion angles phi and psi are defined and for 6-substituted residues also the omega torsion angle is required. Major conformers can be identified for which highly populated states are present. Thus, in many cases a well-defined albeit not rigid structure can be identified. However, on longer timescales, oligosaccharides must be considered as highly flexible molecules since also anti-conformations have been shown to exist with H-C-O-C torsion angles of similar to 180 degrees, compared to syn-conformations in which the protons at the carbon atoms forming the glycosidic linkage are in close proximity. The accessible conformational space governs possible interactions with proteins and both minor changes and significant alterations occur for the oligosaccharides in these interaction processes. Transferred NOE NMR experiments give information on the conformation of the glycan ligand when bound to the proteins whereas saturation transfer difference NMR experiments report on the carbohydrate part in contact with the protein. It is anticipated that the subtle differences in conformational preferences for glycan structures facilitate a means to regulate biochemical processes in different environments. Further developments in the analysis of glycan structure and in particular its role in interactions with other molecules, will lead to clarifications of the importance of structure in biochemical regulation processes essential to health and disease.

  • 1540.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Computational and experimental analysis of oligosaccharide conformation and dynamics2011Ingår i: Abstracts of Papers, 241st ACS National Meeting & Exposition, Anaheim, CA, United States, March 27-31, 2011, American Chemical Society (ACS), 2011Konferensbidrag (Refereegranskat)
    Abstract [en]

    Carbohydrate structures in the form of glycoconjugates are found in Nature, e.g., as N- and O-linked glycoproteins, glycolipids, short-chain lipopolysaccharides also referred to as lipooligosaccharides and saponins.  The carbohydrate constituent may be studied as part of the glycoconjugate or as oligosaccharides. A number of experimental biophysical techniques are available in order to investigate their conformation and dynamics, in particular, NMR spectroscopy, both in solution and in the solid state, X-ray diffraction on crystals, neutron diffraction with isotopic substitution carried out in the solution state, optical rotation, ultrasonic relaxation and more recently Raman optical activity. Computational approaches including molecular mechanics,1 molecular dynamics simulations,2 ab initio and DFT methods3 may subsequently be employed to study and interpret conformational equilibria based on experimental data. The use of carbon-13 site-specifically synthesized oligosaccharides for obtaining, in particular, conformationally dependent trans-glycosidic homo- and heteronuclear coupling constants and interpretation of conformational equilibria from these based on recently developed Karplus-type relationships for spin-spin coupling constants over three bonds4 will be presented for different oligosaccharides in quest for a description of the population distribution of the torsion angles at the glycosidic linkage.

  • 1541.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    General NMR Spectroscopy of Carbohydrates and Conformational Analysis in Solution2007Ingår i: Molecular Interactions Biochemistry of Glycans, Elsevier Ltd , 2007, s. 101-132Kapitel i bok, del av antologi (Refereegranskat)
  • 1542. Wieczorek, Birgit
    et al.
    Träff, Annika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Krumlinde, Patrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Dijkstra, Harm P.
    Egmond, Maarten R.
    van Koten, Gerard
    Bäckvall, Jan-Erling
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Klein Gebbink, Robertus J. M.
    Covalent anchoring of a racemization catalyst to CALB-beads: towards dual immobilization of DKR catalysts2011Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 52, nr 14, s. 1601-1604Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The preparation of a heterogeneous bifunctional catalytic system, combining the catalytic properties of an organometallic catalyst (racemization) with those of an enzyme (enantioselective acylation) is described. A novel ruthenium phosphonate inhibitor was synthesized and covalently anchored to a lipase immobilized on a solid support (CALB, Novozym® 435). The immobilized bifunctional catalytic system showed activity in both racemization of (S)-1-phenylethanol and selective acylation of 1-phenylethanol.

  • 1543. Wieczorek, Birgit
    et al.
    Träff, Annika
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Krumlinde, Patrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Dijkstra, Harm P.
    Egmond, Maarten R.
    van Koten, Gerard
    Bäckvall, Jan-Erling
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Klein Gebbink, Robertus J.M.
    Site-Specific Covalent Immobilization of a Racemization Catalyst onto Lipase-containing BeadsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The synthesis and application of the novel heterogeneous bifunctional catalyst CALB-5 as a racemization and resolution catalyst for the dynamic kinetic resolution is described. The semisynthetic ruthenium lipase hybrid CALB-5 was obtained by inhibiting CALB beads with the novel ruthenium phosphonate complex 5 possessing a lipase active site-directed phosphonate group. By partially inhibiting the lipase beads with 5, a bifunctional catalytic system was obtained. Racemization, by the Ru-catalytic site, gave 0% ee after 24 h, and the kinetic resolution, enzymatic acylation by the uninhibited CALB sites, gave 28% conversion of 1-phenylethanol after 3 h with >99% ee of the acetylated product. A dynamic kinetic resolution experiment of (S)-1-phenylethanol with CALB-5 gave the acylated (R)-product in 18% yield and with >99% ee.

  • 1544.
    Wikmark, Ylva
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Engineering Candida antarctica Lipase A for Enantioselective Transformations in Organic Synthesis: Design, Immobilization and Organic Solvent Screening of Smart Enzyme Libraries2015Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    The use of enzymes as catalysts in organic synthesis constitutes an attractive alternative to conventional chemical catalysis. Enzymes are non-toxic and biodegradable and they can operate under mild reaction conditions. Furthermore, they often display high chemo-, regio- and stereoselectivity, enabling specific reactions with single product outcome.

    By the use of protein engineering, enzymes can be altered for the specific needs of the researcher. The major part of this thesis describes engineering of lipase A from Candida antarctica (CalA), for improved enantioselectivity in organic synthetic transformations.

    The first part of the thesis describes a highly combinatorial method for the introduction of mutation sites in an enzyme library. By the simultaneous introduction of nine mutations, we found an enzyme variant with five out of the nine possible mutations. This quintuple variant had an enlarged active site pocket and was enantioselective and active for our model substrate, an ibuprofen ester. This is a bulky substrate for which the wild-type enzyme shows no enantioselectivity and very poor activity.

    In the second part of the thesis, we continued our approach of combinatorial, focused enzyme libraries. This time we aimed at decreasing the alcohol pocket of CalA, in order to increase the enantioselectivity for small and medium-sized secondary alcohols. The enzyme library was bound on microtiter plates and screened by a transacylation reaction in organic solvent. This library yielded an enzyme variant with high enantioselectivity for the model substrate 1-phenyl ethanol, and high to excellent selectivity for other alcohols tested. Screening in organic solvent is advantageous since a potential hit is more synthetically useful.

    In the third part of the thesis, we used manipulated beads of controlled porosity glass (EziG™) for enzyme immobilization, and demonstrated the generality of this carrier for several enzyme classes. EziG™ allowed fast enzyme immobilization with simultaneous purification and yielded active biocatalysts in all cases.

    The last project describes the function of the proposed active site flap in CalA. In our study, we removed this motif. The engineered variant was compared to the wild-type enzyme by testing the amount of interfacial activation and the selectivity for certain alcohols. We showed that the motif is indeed controlling the entrance to the active site and that the flap is not part of the enantioselectivity determining machinery. 

  • 1545.
    Wikmark, Ylva
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Engelmark Cassimjee, Karim
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Lihammar, Richard
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bäckvall, Jan-E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Removing the Active-Site Flap in Lipase A from Candida antarctica Produces a Functional Enzyme without Interfacial Activation2016Ingår i: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 17, nr 2, s. 141-145Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A mobile region is proposed to be a flap that covers the active site of Candida antarctica lipase A. Removal of the mobile region retains the functional properties of the enzyme. Interestingly interfacial activation, required for the wild-type enzyme, was not observed for the truncated variant, although stability, activity, and stereoselectivity were very similar for the wild-type and variant enzymes. The variant followed classical Michaelis-Menten kinetics, unlike the wild type. Both gave the same relative specificity in the transacylation of a primary and a secondary alcohol in organic solvent. Furthermore, both showed the same enantioselectivity in transacylation of alcohols and the hydrolysis of alcohol esters, as well as in the hydrolysis of esters chiral at the acid part.

  • 1546.
    Wikmark, Ylva
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Humble, Maria Svedendahl
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bäckvall, Jan-E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Combinatorial Library Based Engineering of Candida antarctica Lipase A for Enantioselective Transacylation of sec-Alcohols in Organic Solvent2015Ingår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 54, nr 14, s. 4284-4288Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A method for determining lipase enantioselectivity in the transacylation of sec-alcohols in organic solvent was developed. The method was applied to a model library of Candida antarctica lipase A (CalA) variants for improved enantioselectivity (E values) in the kinetic resolution of 1-phenylethanol in isooctane. A focused combinatorial gene library simultaneously targeting seven positions in the enzyme active site was designed. Enzyme variants were immobilized on nickel-coated 96-well microtiter plates through a histidine tag (His6 -tag), screened for transacylation of 1-phenylethanol in isooctane, and analyzed by GC. The highest enantioselectivity was shown by the double mutant Y93L/L367I. This enzyme variant gave an E value of 100 (R), which is a dramatic improvement on the wild-type CalA (E=3). This variant also showed high to excellent enantioselectivity for other secondary alcohols tested.

  • 1547.
    Willy, Benjamin
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Szabó, Kálmán J
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Development of pincer complex-catalyzed oxidative C-H activation borylation reactions: Synthetic applications and mechanistic studies2010Ingår i: Abstracts of Papers, 239th ACS National Meeting, San Francisco, CA, United States, March 21-25, 2010, Washington D C: American Chemical Society , 2010Konferensbidrag (Övrigt vetenskapligt)
  • 1548.
    Winqvist, Anna
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Studies towards a method for incorporation of 3'-deoxy-3'-C-methylenephosphonate linkages into oligonucleotides2002Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Synthetic strategies towards 3’-deoxy-3’-C-methylenephosphinate building blocks were explored. The key transformations involved stereoselective hydroboration of 1-[2-O-(tert-butyldimethylsilyl-5-O-(4-methoxytrityl)-3-deoxy-3-C-methylene- ß -D-erythro-pentofuranosyl]uracil to give the corresponding 3’-deoxy-3’-C- hydroxymethyl derivative with ribo-configuration, as well as the further conversion into a precursor with a suitable leaving group, e. g., triflate, for subsequent substitution with the phosphinic acid synthon bis(trimethylsilyl)hypophosphite. Improvements of these steps enabled synthesis of 2’-O-(tert-butyldimethylsilyl-5’-O-( 4-methoxytrityl)-3’-deoxy-3’-C-methylenephosphinate uridine in a respectable overall yield of 40% over 6 steps, from the corresponding 2’-O-(tert-butyldimethylsilyl- 5’-O-(4-methoxytrityl)uridine.

    For the introduction of internucleosidic 3’-deoxy-3’-C-methylenephosphonate linkages into oligonucleotides, a preparatory study of the elongation steps, i. e., coupling of the phosphinate building block to the 5’-hydroxyl function of a nucleoside derivative and subsequent oxidation, was performed. Of several coupling reagents studied for the activation of the phosphinate building block prior to coupling, the most promising proved to be N,N-bis(2-oxo-3-oxazolidin-1-yl)phosphinic chloride. The oxidation of the resulting 3’-deoxy-3’-C-methylenephosphinate ester to the corresponding 3’-deoxy-3’-C-methylenephosphonate linkage was achieved using iodine in pyridine-water, in the presence of a catalyst, i. e., either a base (triethylamine) or an acid (pyridinium salt).

  • 1549. Wojcik, Anna
    et al.
    Broclawik, Ewa
    Siegbahn, Per E. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Lundberg, Marcus
    Moran, Graham
    Borowski, Tomasz
    Role of Substrate Positioning in the Catalytic Reaction of 4-Hydroxyphenylpyruvate Dioxygenase-A QM/MM Study2014Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 136, nr 41, s. 14472-14485Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ring hydroxylation and coupled rearrangement reactions catalyzed by 4-hydroxyphenylpyruvate dioxygenase were studied with the QM/MM method ONIOM(B3LYP:AMBER). For electrophilic attack of the ferryl species on the aromatic ring, five channels were considered: attacks on the three ring atoms closest to the oxo ligand (C1, C2, C6) and insertion of oxygen across two bonds formed by them (C1-C2, C1-C6). For the subsequent migration of the carboxymethyl substituent, two possible directions were tested (C1-C2, C1-C6), and two different mechanisms were sought (stepwise radical, single-step heterolytic). In addition, formation of an epoxide (side)product and benzylic hydroxylation, as catalyzed by the closely related hydroxymandelate synthase, were investigated. From the computed reaction free energy profiles it follows that the most likely mechanism of 4-hydroxyphenylpyruvate dioxygenase involves electrophilic attack on the C1 carbon of the ring and subsequent single-step heterolytic migration of the substituent. Computed values of the kinetic isotope effect for this step are inverse, consistent with available experimental data. Electronic structure arguments for the preferred mechanism of attack on the ring are also presented.

  • 1550.
    Wolpher, Henriette
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Ruthenium(II) Polypyridyl Complexes in Supramolecular Systems relevant to Artificial Photosynthesis2005Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    This thesis describes the synthesis and properties of ruthenium complexes relevant to artificial photosynthesis. The work includes preparation of RuIIpolypyridine complexes as well as multi component systems where RuII(bpy)3 or RuII(tpy)2 type complexes are used as photosesnsitizers.

    In the first part, the synthesis and characterisation of bipyridyl(pyridyl)methane type ligands and the corresponding ruthenium(II) bistridentate polypyridyl complexes is described. The bipyridyl-pyridyl methane type ligands were designed to increase the excited state lifetime of ruthenium(II) bisterpyridine-type complexes by altering the ligand field as compared to normal terpyridine ligands.

    In the second part photoinduced electron transfer and formation of charge separated states in donor-photosensitizer dyads or donor-photosensitizer-acceptor triads is studied. The first covalently linked donor-photosensitizer-acceptor triad with tyrosine as electron donor was prepared, and long lived light induced charge separation was observed. RuIIterpyridine complexes linked to carotenoid or tyrosine were also prepared, for studies of light induced charge separation on a TiO2 surface. Tryptofan was covalently linked to Ru(bpy)3 and proton coupled electron transfer from tryptophan to photogenerated ruthenium(III) was demonstrated. A pH-dependent study of the electron transfer rate gave insight into the mechanism of proton coupled electron transfer in amino acids.

    Finally, the last part of the thesis presents the preparation and properties of the first complex containing a photosensitizer covalently linked to a Fe-hydrogenase active site model.

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