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  • 1.
    Adrian Meredith, Jenny
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Design and Synthesis of Inhibitors Targeting the Aspartic Proteases HIV-1 PR and BACE-12009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes the synthesis of molecules designed for inhibition of two aspartic proteases, viral HIV-1 PR and human BACE-1. It also reports on the structure activity relationships of the targeted enzyme inhibitors.

    It is estimated that currently 33 million people are infected with HIV, the causative agent of AIDS. The virus targets T-lymphocytes and macrophages of the human immune system. The HIV-1 PR plays an important role in the viral replication, and by inhibiting the enzyme the disease progression can be slowed down or even halted.

    Herein is reported the design and synthesis of a series of HIV-1 PR inhibitors with novel P2 substituents of which several inhibit the enzyme in the nanomolar range. The aim of the second work was to further develop the inhibitors by the introduction of fluorine. Several attempts were performed to fluorinate different P2-substituents.

    Alzheimer’s disease (AD) is neurodegenerative, progressive and fatal disorder of the brain. It is associated with accumulation of plaques and tangles that cause impairment and functional decline of brain tissue which result in loss of memory and cognition. The plaques are mainly constituted of amyloid-β peptides that are generated in two steps from the amyloid precursor protein (APP). The cleavage sequence is initiated by the aspartic protease BACE-1, which makes the enzyme a key target in the effort of finding a therapy that aim to slow down the progression of AD.

    Herein are enclosed the development of two series of potent BACE-1 inhibitors. In the first work a synthetic strategy was developed to truncate a previously reported hydroxyethylene core structure in order to generate more drug-like inhibitors. This generated a series of truncated inhibitors where two amide bonds have been replaced with an ether - or alternatively a secondary amine linkage. A number of these inhibitors show potency against BACE-1. In the second part of the work the aim was investigate the effect of alterations in the P1 position. Five scaffolds with new P1 substituents were designed, synthesized and coupled with two different P2-P3 substituents. This resulted in a series of potent inhibitors that inhibit BACE-1 in the nanomolar range.

  • 2.
    Ahlford, Katrin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Asymmetric transfer hydrogenation of ketones: Catalyst development and mechanistic investigation2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The development of ligands derived from natural amino acids for asymmetric transfer hydrogenation (ATH) of prochiral ketones is described herein. In the first part, reductions performed in alcoholic media are examined, where it is found that amino acid-derived hydroxamic acids and thioamides, respectively, are simple and versatile ligands that in combination with [RhCp*Cl2]2 efficiently catalyze this particular transformation. Selectivities up to 97% ee of the corresponding secondary alcohols are obtained, and it is furthermore observed that the two different ligand classes, albeit based on the same amino acid scaffold, give rise to products of opposite configuration.

    The highly interesting enantioswitchable nature of the two abovementioned catalysts is studied in detail by mechanistic investigations. A structure/activity correlation analysis is performed, which reveals that the diverse behavior of the catalysts arise from different interactions between the ligands and the metal. Kinetic studies furthermore stress the catalyst divergence, since a difference in the rate determining step is established from initial rate measurements. In addition, rate constants are determined for each step of the overall reduction process.

    In the last part, catalyst development for ATH executed in water is discussed. The applicability of hydroxamic acid ligands is further extended, and catalysts based on these compounds are found to be efficient and compatible with aqueous conditions. The structurally even simpler amino acid amide is also evaluated as a ligand, and selectivities up to 90% ee are obtained in the reduction of a number of aryl alkyl ketones. The very challenging reduction of dialkyl ketones is moreover examined in the Rh-catalyzed aqueous ATH, where a modified surfactant-resembling sulfonylated diamine is used as ligand, and the reaction is carried out in the presence of SDS-micelles. A positive effect is to some extent found on the catalyst performance upon addition of phase-transfer components, especially regarding the catalytic activity in the reduction of more hydrophobic substrates.

  • 3.
    Ahlsten, Nanna
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Transition metal-catalysed isomerisation of allylic alcohols: Applications to C−C, C−F and C−Cl bond formation2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The focus of this thesis has been to develop selective and atom-economical methods for carbon-carbon and carbon-heteroatom bond formation, and to some extent improve on existing findings in this area. More specifically, methods for the catalytic generation of enolates from allylic alcohols and their in situ functionalisation with electrophilic reagents are described.  

    In the first part of this thesis, a method for the Rh-catalysed redox-isomerisation of allylic alcohols into carbonyl compounds under environmentally benign conditions is described. The reaction takes place at room temperature, in the absence of acids or bases, using water as the only solvent, and it is applicable to both primary and secondary allylic alcohols.

    The second part describes the combination of an isomerisation reaction of allylic alcohols with a C−C bond formation, catalysed by a rhodium complex. In this way, allylic alcohols were coupled with aldehydes and N-tosylimines to give aldol and Mannich-type products. In addition to allylic alcohols, homoallylic and bishomoallylic alcohols could be used as enolate precursors, and this is the first report where the latter two substrate types have been used in such a reaction.       

    In the remaining parts of the thesis, an iridium-catalysed isomerisation of allylic alcohols has been combined with an electrophilic halogenation step to provide a conceptually new method for the synthesis of α-halogenated carbonyl compounds. In this way, α-fluoro and α-chloroketones have been synthesised as single constitutional isomers, with the regiochemistry of the final products determined by the position of the double bond in the allylic alcohols. The reactions are tolerant to air, run in water-organic solvent mixtures, and proceed at room temperature.

  • 4.
    Alam, Rauful
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Catalytic Regio- and Stereoselective Reactions for the Synthesis of Allylic and Homoallylic Compounds2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is focused on two main areas of organic synthesis, palladium-catalyzed functionalization of alkenes and allylic alcohols, as well as development of new allylboration reactions.

    We have developed a palladium-catalyzed selective allylic trifluoroacetoxylation reaction based on C−H functionalization. Allylic trifluoroacetates were synthesized from functionalized olefins under oxidative conditions. The reactions proceed under mild conditions with a high level of diastereoselectivity. Mechanistic studies of the allylic C−H trifluoroacetoxylation indicate that the reaction proceeds via (η3-allyl)palladium(IV) intermediate.

    Palladium-catalyzed regio- and stereoselective synthesis of allylboronic acids from allylic alcohols has been demonstrated. Diboronic acid B2(OH)4 was used as the boron source in this process.

    The reactivity of the allylboronic acids were studied in three types of allylboration reactions: allylboration of ketones, imines and acyl hydrazones. All three processes are conducted under mild conditions without any additives. The reactions proceeded with remarkably high regio- and stereoselectivity.

    An asymmetric version of the allylboration of ketones was also developed. In this process chiral BINOL derivatives were used as catalysts. The reaction using γ-disubstituted allylboronic acids and various aromatic and aliphatic ketones afforded homoallylic alcohols bearing two adjacent quaternary stereocenters with excellent regio-, diastereo- and enantioselectivity (up to 97:3 er) in high yield. The stereoselectivity in the allylboration reactions could be rationalized on the basis of the Zimmerman-Traxler TS model.

  • 5.
    Almer, Helena
    Stockholm University, Faculty of Science.
    Studies on formation and stability of phosphorothioate RNA1995Doctoral thesis, comprehensive summary (Other academic)
  • 6.
    Alpe, Marianne
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Synthesis of oligosaccharides related to the capsular polysaccharides of Streptococcus pneumoniae serotype 9 and of Cryptococcus neoformans2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In the present investigation, synthesis of oligosaccharides corresponding to structural elements present in the capsular polysaccharides of Streptococcus pneumoniae and Cryptococcus neoformans has been achieved. The first two sections describe the synthesis of spacer-equipped oligosaccharides corresponding to structures from the CPS of Streptococcus pneumoniae serotypes 9N, 9A and 9L, the production of which involved synthetic challenges such as the construction of β-ManNAc and α-GlcA linkages. The former challenge was met by employing azide displacement of a 2-O-triflate substituent on a β-glucoside, whereas the latter task was accomplished utilizing thioethyl glucuronic acid donors in the presence of various promoters. The pentasaccharide product obtained correspond to the complete repeating unit of the CPS of serotype 9A.

    The last two sections of this thesis describe the construction of thioglycoside di- and trisaccharide building blocks containing α-Man, β-Xyl, β-GlcA and 6-O-acetyl motifs, as well as subsequent assembly of these building blocks into oligosaccharides corresponding to the repeating units of the capsular polysaccharide of the yeast Cryptococcus neoformans. The GlcA moiety was introduced via trichloroacetimidate coupling involving the peracetylated glucuronic acid methyl ester donor, after which the subsequent necessary benzylation was performed with the di- and trisaccharides. All of the target oligosaccharides were synthesized as amino-spacer glycosides in order to make conjugation to a carrier protein possible.

  • 7.
    Anderlund, Magnus
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Dinuclear Manganese Complexes for Artificial Photosynthesis: Synthesis and Properties2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis deals with the synthesis and characterisation of a series of dinuclear manganese complexes. Their ability to donate electrons to photo-generated ruthenium(III) has been investigated in flash photolysis experiments followed by EPR-spectroscopy. These experiment shows several consecutive one-electron transfer steps from the manganese moiety to ruthenium(III), that mimics the electron transfer from the oxygen evolving centre in photosystem II.

    The redox properties of these complexes have been investigated with electro chemical methods and the structure of the complexes has been investigated with different X-ray techniques. Structural aspects and the effect of water on the redox properties have been shown.

    One of the manganese complexes has been covalently linked in a triad donor-photosensitizer-acceptor (D–P–A) system. The kinetics of this triad has been investigated in detail after photo excitation with both optical and EPR spectroscopy. The formed charge separated state (D–P–A+) showed an unusual long lifetime for triad based on ruthenium photosensitizers.

    The thesis also includes a study of manganese-salen epoxidation reactions that we believe can give an insight in the oxygen transfer mechanism in the water oxidising complex in photosystem II.

  • 8.
    Andersson, Mats
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Determination of the structures of three bacterial polysaccharides and synthesis and use of new spacers for glycoconjugate formation1993Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The first part of this work describes studies on the structures of three bacterial polysaccharides, i.e., the extracellular polysaccharides of Streptococcus pneumoniae type 2 and Butyrivibrio fibrisolvens strain X6C61 and the O-antigenic side-chain of the lipopolysaccharide of Escherichia coli 086.

    The second part describes the synthesis of new spacer molecules for oligosaccharide immobilization and their use in glycoconjugate formation.

  • 9.
    Andersson, Nina
    Stockholm University, Faculty of Science, Department of Physical, Inorganic and Structural Chemistry.
    Mesostructured materials: Synthesis towards applications2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A new class of materials with well-defined structures on mesoscopic (2-50 nm) length scales has attracted considerable interest during the last decade. These mesostructured mataterials are formed from the self-assembly of amphiphillic molecules and inorganic precursors. The aim of this thesis has been to develop preparation methods that are scalable, and at the same time allow for efficient structural control coupled with possibility to incorporate different functionalities.

    Two different industrial processes for production of particles with spherical morphology were successfully tailored for synthesis of well-ordered mesostructured particles. An existing spray drying method for a fast and continuous production was further developed, and for the first time, an emulsion-based method was implemented. The latter method resulted in superior control of both particle size and internal mesostructure.

    Mesostructured photochromic pigments were synthesised by incorporating photochromic dyes in the organic domains of the surfactant templated inorganic/organic mesostructured silica particles. The pigments were produced using a one-pot synthesis method employing an aerosol reactor, allowing control over both the internal mesostructure and the dye content. We show that transparent photochromic films can be prepared using latex binders and conventional coating technology.

    Mesoporous magnetic carrier materials were prepared by adding iron oxide nanoparticles during either the emulsion- or aerosol processing. The surfactant templated silica matrix displayed well-ordered internal pore architecture with limited pore blocking caused by the incorporated iron oxide nanoparticles. The iron oxide content was precisely controlled, and the magnetic properties were preserved during the processing. Finally we demonstrate that these materials can be used to magnetically separate water-soluble dyes from solution.

  • 10.
    Angles d'Ortoli, Thibault
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Assembling and Unraveling Carbohydrates Structures: Conformational analysis of synthesized branched oligosaccharides2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Advances in the elaboration of vaccines and enzyme inhibitors rely on acquiring more knowledge about protein-carbohydrate binding events. Furthermore, the relationships between biological function and the three-dimensional properties of large glycans can be studied by focusing on the structural components they contained, namely, by scaling down the system under analysis. Chemical methods are useful assets as they allow the isolation and determination of epitopes; these small and recognizable fragments that lead to very specific interactions. In this thesis, biologically relevant saccharides were obtained using recently developed concepts in carbohydrate synthesis and NMR spectroscopy was used to unravel their conformational preferences.

    In paper I, the convergent synthesis of the tetrasaccharide found in the natural product solaradixine is described. Reactivity enhanced disaccharide glycosyl donors were coupled to a disaccharide acceptor in a 2 + 2 fashion. The computer program CASPER was subsequently used to verify the synthesized structure.

    The conformation arming concept employed in paper I was further investigated in paper II. An NMR-based methodology enabled the determination of the ring conformations of a set of donors. Subsequently, glycosylation reactions were performed and yields were correlated to donors ring shapes. Perturbations in the rings shape caused by bulky silyl ether protective groups were sufficient to boost the potency of several donors. As a matter of fact, complex branched oligosaccharides could be obtained in good to excellent yields.

    In paper III, NMR spectroscopy observables were measured to elucidate the ring shape, the mutual orientation of the rings across the glycosidic bond and the positions of the side chains of 5 trisaccharides found in larger structures. With the aid of molecular dynamics simulations, their overall conformational propensities were revealed.

    Finally, the software CASPER prediction skills were improved by adding, inter alia, NMR information of synthesized mono- and disaccharides to its database. Unassigned chemical shifts from polysaccharides served as input to challenge its ability to solve large carbohydrate structures.

  • 11.
    Ayesa Alvarez, Susana
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Design and Synthesis of Amine Building Blocks and Protease Inhibitors2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The first part of this thesis addresses the design and synthesis of amine building blocks accomplished by applying two different synthetic procedures, both of which were developed using solid-phase chemistry. Chapter 1 presents the first of these methods, entailing a practical solid-phase parallel synthesis route to N-monoalkylated aminopiperidines and aminopyrrolidines achieved by selective reductive alkylation of primary and/or secondary amines. Solid-phase NMR spectroscopy was used to monitor the reactions for which a new pulse sequence was developed. The second method, reported in Chapter 2, involves a novel approach to the synthesis of secondary amines starting from reactive alkyl halides and azides. The convenient solid-phase protocol that was devised made use of the Staudinger reaction in order to accomplish highly efficient alkylations of N-alkyl phosphimines or N-aryl phosphimines with reactive alkyl halides.

    The second part of the thesis describes the design and synthesis of three classes of protease inhibitors targeting the cysteine proteases cathepsins S and K, and the serine protease hepatitis C virus (HCV) NS3 protease. Chapter 4 covers the design, solid-phase synthesis, and structure-activity relationships of 4-amidofurane-3-one P1-containing inhibitors of cathepsin S and the effects of P3 sulfonamide groups on the potency and selectivity towards related cathepsin proteases. This work resulted in the discovery of highly potent and selective inhibitors of cathepsin S. Two parallel solid-phase approaches to the synthesis of a series of aminoethylamide inhibitors of cathepsin K are presented in Chapter 5. Finally, Chapter 6 reports peptide-based HCV NS3 protease inhibitors containing a non-electrophilic allylic alcohol moiety as P1 group and also outlines efforts to incorporate this new template into low-molecular-weight drug-like molecules.

  • 12.
    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.

  • 13.
    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.

  • 14.
    Bartoszewicz, Agnieszka
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Transition metal-catalysed hydrogen transfer processes for C-C and C-N bond formation: Synthetic studies and mechanistic investigations2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis focusses on synthetic studies and mechanistic investigations into reactions involving hydrogen-transfer processes.

    In the first part, the development of an efficient method for the synthesis of β-hydroxy ketones (aldols) and β-amino ketones (Mannich products) from allylic alcohols and aldehydes is described. These reactions use  Ru(η5-C5Ph5)(CO)2Cl as the catalyst. The reaction parameters were optimised in order to suppress the formation of undesired by-products. Neutral and mild reaction conditions enabled the synthesis of a variety of aldol products in up to 99% yield, with a good syn/anti ratio. The influence of the stereoelectronic properties of the catalyst on the reaction outcome was also studied. Based on the results obtained, a plausible reaction mechanism has been proposed, involving as the key steps the 1,4-addition of hydride to α,β-unsaturated ketones and the formation of ruthenium (Z)-enolates.

    In the second part of this thesis, a ruthenium-catalysed tandem isomerisation/C-H activation reaction is presented. A number of ruthenium complexes, phosphine ligands, and additives were evaluated in order to establish the optimal reaction conditions. It was found that the use of a stable ruthenium catalyst, Ru(PPh3)3Cl2, together with PtBu3 and HCO2Na resulted in an efficient tandem transformation. Using this procedure, a variety of ortho-alkylated ketones were obtained in excellent yields. Moreover, homoallylic alcohols could also be used as starting materials for the reaction, which further expands the substrate scope. Mechanistic investigations into the isomerisation part of the process were carried out.

    The last project described in the thesis deals with the design and preparation of novel bifunctional iridium complexes containing an N-(2-hydroxy-isobutyl)-N-Heterocyclic carbene ligand. These complexes were used as catalysts to alkylate amines using alcohols as latent electrophiles. The catalytic system developed here was found to be one of the most active systems reported to date, allowing the reaction to be performed at temperatures as low as 50 °C for the first time. A broad substrate scope was examined. Combined experimental and theoretical studies into the reaction mechanism are consistent with a metal-ligand bifunctional activity of the new catalyst.

  • 15.
    Baumann, Herbert
    Stockholm University, Faculty of Science.
    Synthesis of and NMR and conformational studies on some 3-O-, 4-O- and 3,4-di-O-glycopyranosyl-substituted methyl d-glycopyranosides1988Doctoral thesis, comprehensive summary (Other academic)
  • 16.
    Bedecs, Katarina
    Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
    Galanin in the rat dorsal spinal cord: an inhibitor peptide in sensory processing1995Doctoral thesis, comprehensive summary (Other academic)
  • 17.
    Bernlind, Christian
    Stockholm University, Faculty of Science.
    Synthesis of LPS epitopes containing Kdo, L-, and D-Glycero-D-manno-heptose to be used in potential conjugate vaccines against Haemophilus species1998Doctoral thesis, comprehensive summary (Other academic)
  • 18.
    Berthold, Malin
    Stockholm University, Faculty of Science.
    Galanin: ligand - receptor interactions1997Doctoral thesis, comprehensive summary (Other academic)
  • 19.
    Bielawski, Marcin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Diaryliodonium Salts: Development of Synthetic Methodologies and α-Arylation of Enolates2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes novel reaction protocols for the synthesis of diaryliodonium salts and also provides an insight to the mechanism of α-arylation of carbonyl compounds with diaryliodonium salts.

     The first chapter gives a general introduction to the field of hypervalent iodine chemistry, mainly focusing on recent developments and applications of diaryliodonium salts.

    Chapter two describes the synthesis of electron-rich to electron-poor diaryliodonium triflates, in moderate to excellent yields from a range of arenes and iodoarenes.

    In chapter three, it is described that molecular iodine can be used together with arenes in a direct one-pot, three-step synthesis of symmetric diaryliodonium triflates. A large scale synthesis of bis(4-tert-butylphenyl)iodonium triflate is also described, controlled and verified by an external research group, further demonstrating the reliability of this methodology.

    The fourth chapter describes the development of a sequential one-pot synthesis of diaryliodonium salts from aryl iodides and boronic acids, furnishing symmetric and unsymmetric, electron-rich to electron-poor diaryliodonium tetrafluoroborates in moderate to excellent yields. This method was developed to overcome the regiochemical limitations imposed by the reaction mechanism in the protocols described in the preceding chapters.

    Chapter five describes a one-pot synthesis of heteroaromatic iodonium salts under similar conditions described in chapter two.

    The final chapter describes the reaction of enolates with chiral diaryliodonium salts or together with a phase transfer catalyst yielding racemic products. DFT calculations were performed, which revealed a low lying energy transition state (TS) between intermediates, which is believed to be responsible for the lack of selectivity observed in the experimental work. It is also proposed that a [2,3] rearrangement is preferred over a [1,2] rearrangement in the α-arylation of carbonyl compounds.

    The synthetic methodology described in this thesis is the most generally applicable, efficient and high-yielding to date for the synthesis of diaryliodonium salts, making these reagents readily available for various applications in synthesis.

  • 20.
    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.

  • 21.
    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)
  • 22.
    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.

  • 23.
    Bollmark, Martin
    Stockholm University.
    Studies on the synthesis of nucleotide analogues containing P-F and P-Se bonds2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In the present work, new synthetic approaches to the synthesis of nucleoside phosphorofluoridate and phosphorofluoridothioate diesters have been developed. These procedures involve either oxidative transformation of the corresponding H-phosphonate or H-phosphonothioate diesters in the presence of fluoride anion or iodine-promoted desulfurization of phosphorothioate or phosphorodithioate diesters in the presence of fluoride anion. Also, efficient protocols for the synthesis of nucleoside phosphorofluoridate, nucleoside phosphorofluoridothioate and nucleoside phosphorofluoridodithioate monoesters were developed.

    Furthermore, the chemistry of a new class of P(III) compounds containing selenium, i. e. H-phosphonoselenoate monoesters was developed and synthetic procedures for the conversion of these compounds into the corresponding diesters were designed. In addition, the usefulness of H-phosphonoselenoate diesters for the preparation of various selenium-containing nucleotide analogues was demonstrated.

    Finally, the possibility of employing triphenylphosphine selenide as a reagent for selenizing P(III) compounds was examined. Under mild conditions, this commercially available reagent was found to convert phosphite triesters and H-phosphonate diesters efficiently into the corresponding phosphoroselenoate derivatives.

  • 24.
    Borén, Linnéa
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Enantioselective Synthesis of Sec-Alcohol Derivatives and Diols via Combined Ruthenium and Enzyme Catalysis2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The first part of this thesis describes the synthesis of enantiopure secondary alcohol derivatives. These syntheses are carried out via the combination of an enzyme as a resolution catalyst and a ruthenium catalyst as a racemization catalyst, in what is called dynamic kinetic resolution (DKR). By varying the resolution catalyst enantio-complementary processes can be obtained. A lipase (PS-C II) catalyzed DKR of γ-hydroxyamides gave the corresponding (R)-acetates in high yields and with high enantioselectivity. The synthetic usefulness of these obtained (R)-acetates was demonstrated by the synthesis of (R)-5-methyltetrahydrofurane-2-one. A protease (Subtilisin Carlsberg) catalyzed DKR of various secondary alcohols gave the corresponding (S)-acetates in high yields and with high enantioselectivity. In the second part of this thesis the DKR process has been extended into a dynamic kinetic asymmetric transformation (DYKAT) of diols. Various 1,5- and 1,4-diols were transformed into enantiopure diacetates in a lipase (CALB and PS-C II) catalyzed DYKAT. The synthetic utility of the obtained enantiopure diacetates were demonstrated by the synthesis of various enantiopure disubstituted heterocycles.

  • 25.
    Bowden, Tim
    Stockholm University.
    Studies on glycosylation mechanisms and synthesis of structures related to inositolphosphoglycans2000Doctoral thesis, comprehensive summary (Other academic)
  • 26.
    Buitrago, Elina
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Transition metal-catalyzed reduction of carbonyl compounds: Fe, Ru and Rh complexes as powerful hydride mediators2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A detailed mechanistic investigation of the previously reported ruthenium pseudo-dipeptide-catalyzed asymmetric transfer hydrogenation (ATH) of aromatic ketones was performed. It was found that the addition of alkali metals has a large influence on both the reaction rate and the selectivity, and that the rate of the reaction was substantially increased when THF was used as a co-solvent. A novel bimetallic mechanism for the ruthenium pseudo-dipeptide-catalyzed asymmetric reduction of prochiral ketones was proposed.

    There is a demand for a larger substrate scope in the ATH reaction, and heteroaromatic ketones are traditionally more challenging substrates. Normally a catalyst is developed for one benchmark substrate, and a substrate screen is carried out with the best performing catalyst. There is a high probability that for different substrates, another catalyst could outperform the one used. To circumvent this issue, a multiple screen was executed, employing a variety of ligands from different families within our group’s ligand library, and different heteroaromatic ketones to fine-tune and to find the optimum catalyst depending on the substrate. The acquired information was used in the formal total syntheses of (R)-fluoxetine and (S)-duloxetine, where the key reduction step was performed with high enantioselectivities and high yield, in each case.

    Furthermore, a new iron-N-heterocyclic carbene (NHC)-catalyzed hydrosilylation (HS) protocol was developed. An active catalyst was formed in situ from readily available imidazolium salts together with an iron source, and the inexpensive and benign polymethylhydrosiloxane (PMHS) was used as hydride donor. A set of sterically less demanding, potentially bidentate NHC precursors was prepared. The effect proved to be remarkable, and an unprecedented activity was observed when combining them with iron. The same system was also explored in the reduction of amides to amines with satisfactory results.

  • 27.
    Bunrit, Anon
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University.
    Direct Catalytic Nucleophilic Substitution of Non-Derivatized Alcohols2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis focuses on the development of methods for the activation of the hydroxyl group in non-derivatized alcohols in substitution reactions. The thesis is divided into two parts, describing three different catalytic systems.

    The first part of the thesis (Chapter 2) describes nucleophilic allylation of amines with allylic alcohols, using a palladium catalyst to generate unsymmetrical diallylated amines. The corresponding amines were further transformed by a one-pot ring-closing metathesis and aromatization reaction to afford β-substituted pyrroles with linear and branched alkyl, benzyl, and aryl groups in overall moderate to good yields.

    The second part (Chapters 3 and 4) describes the direct intramolecular stereospecific nucleophilic substitution of the hydroxyl group in enantioenriched alcohols by Lewis acid and Brønsted acid/base catalysis.

    In Chapter 3, the direct intramolecular substitution of non-derivatized alcohols has been developed using Fe(OTf)3 as catalyst. The hydroxyl groups of aryl, allyl, and alkyl alcohols were substituted by the attack of O- and N-centered nucleophiles, to provide five- and six-membered heterocycles in up to excellent yields with high enantiospecificities. Experimental studies showed that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile of the substrate. Competition and catalyst-substrate interaction experiments demonstrated that this transformation proceeds via an SN2-type reaction pathway.

    In Chapter 4, a Brønsted acid/base catalyzed intramolecular substitution of non-derivatized alcohols was developed. The direct intramolecular and stereospecific substitution of different alcohols was successfully catalyzed by phosphinic acid (H3PO2). The hydroxyl groups of aryl, allyl, propargyl, and alkyl alcohols were substituted by O-, N-, and S-centered nucleophiles to generate five- and six-membered heterocycles in good to excellent yields with high enantiospecificities. Mechanistic studies (both experiments and density functional theory calculations) have been performed on the reaction forming five-membered heterocyclic compounds. Experimental studies showed that phosphinic acid does not promote SN1 reactivity. Rate-order determination indicated that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile. DFT calculations corroborated with a reaction pathway in which the phosphinic acid has a dual activation mode and operates as a bifunctional Brønsted acid/Brønsted base to simultaneously activate both the nucleophile and nucleofuge, resulting in a unique bridging transition state in an SN2-type reaction mechanism.

  • 28.
    Buskas, Therese
    Stockholm University.
    Synthesis of lactosamine-containing carbohydrate structures and development for their easy assembly and conjugation1999Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is based on four publications. The first chapter describes preparation of anomerically pure thioethyl-, thiophenyl-, and n-pentenyl 2-azido-2-deoxy glycosyl building blocks from easily accessible per-acetylated glycosamines.

    In the second part, acetylated, benzylated and non-protected n-pentenyl glycosides are used as substrates for preparing various spacer functionalities, which are obtained by means of radical elongations, oxidations and reductions.

    The syntheses of a trisaccharide,a-D-GlcpNAc-(1-->4)-b-D-Galp-(1-->4)-b-D-GlcpNAc, and fragments thereof, linked to a long lipophilic aglycon, are described in the third part. For the formation of theb-D-Galp-(1-->4)-D-GlcpNAc bond, several differently protected glucosamine acceptors were prepared and their reactivity towards a disaccharide donor evaluated.

    Finally, lactosamine derivatives were prepared by regioselective galactosylation and used as building blocks in the chemical synthesis of various oligosaccharides. The syntheses of polylactosamine di-, tri- and tetramers were achieved by regioselective glycosylation. Also spacer containing sulfated N-acetyllactosamine and Lewis x structures were synthesised.

  • 29.
    Chai, Guocai
    Stockholm University, Faculty of Science.
    Dendrite coherency during equiaxed solidification in aluminium alloys1994Doctoral thesis, comprehensive summary (Other academic)
  • 30.
    Colas, Kilian
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    New C-C coupling Reactions Enabled by Main-group Organometallics2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The carbon-carbon bond has always been at the very core of chemical research. Strategies for the creation of C−C bonds are one of the keys to the construction game that organic chemists play with the building blocks provided by Nature, with the ultimate goal of producing useful molecular structures that will serve society as medicines, materials, imaging tools, catalysts, and ligands (to mention but a few). While very different in their structure, all of these molecules are often prepared by the same methods. However, efficiency could be improved with tailored chemical strategies that would serve an individual purpose. Ideally, these chemical manipulations should be efficient, selective, environmentally friendly and economic, in order to truly fulfill their final objective.

    However, despite the ever-expanding rule-book of chemical reactions, target molecules of increasing complexity often face chemists with daunting challenges, whose success rely on multi-step synthetic sequences. There is therefore a permanent need for new, specific methods and strategies that are capable of seamlessly creating C−C bonds, evading the synthesis of difficult or expensive substrates. In this regard, common organometallic reagents display a unique behavior as carbon precursors, in particular as powerful nucleophiles. Reagents based on main-group elements such as lithium or magnesium have therefore played a central role in organic synthesis ever since their discovery. The challenge often lies in controlling their high reactivity, as well as their basic character. Tuning and taming these properties provides chemists with a wide range of unique strategies for the selective synthesis of countless molecular targets.

    In the first part of this thesis, a scalable and stereoselective [3+3] homocoupling of imines in which two C−C bonds are formed in a single step is reported. This reaction relies on an unusual combination of visible-light irradiation and aluminum organometallics. This photochemical process enables the circumvention of the native [3+2] reactivity of these readily available starting materials, thus enabling rapid access to densely functionalized piperazines. Thanks to the congested environment they provide, these heterocyclic scaffolds can be used as ligands to prevent catalyst deactivation through oligomerization.

    The next chapter presents a novel Pummerer-type redox-neutral coupling of sulfoxides and Grignard reagents. This reaction is enabled by a unique turbo-magnesium amide base, and allows the use of a wide range of carbon nucleophiles in intermolecular Pummerer C−C coupling for the streamlined preparation of thioethers. Given the central character of sulfur in organic chemistry, these compounds can then be converted to a variety of unrelated functional groups for the streamlined preparation of diverse building blocks.

    In the final two chapters, the development of a method for the direct conversion of carboxylic acids to ketones with Grignard reagents is described. Using the above-mentioned combination of organometallics, a wide variety of carboxylic acids substrates and Grignard reagents can be coupled in a convenient, scalable and highly selective method that suppresses the need for activation and offers a straightforward approach to ketones from readily available starting materials.

  • 31.
    Cotton, Hanna
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Chiral metallocene ligands for transition metal-catalysed reactions2004Doctoral thesis, comprehensive summary (Other academic)
  • 32.
    Csjernyik, Gábor
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Studies of Biomimtic Oxidations and Racemizations2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis deals with studies of ruthenium-catalyzed hydrogen transfer reactions for oxidations and racemization.

    Through optimisation of the substrate-selective redox catalyst, the electron and proton transfer mediator (a benzoquinone derivative), and the oxygen-activating metal macrocycle a highly efficient biomimetic oxidation of secondary alcohols was obtained. Several alcohols were subjected to the new oxidation protocol and the corresponding ketones were isolated in high yield.

    The deactivation of the oxygen-activating metal macrocycle retarded the aerobic oxidation of primary alcohols. Encapsulation of the metal macrocycle into zeolite, described in chapter 3, proved to be an efficient method to solve this problem and comparable conversion of alcohols was achieved. The immobilization of the oxygen-activating porphyrin to a surface can be an alternative approach to solve the deactivation problem. Therefore as the first step towards studies of immobilized porphyrins on a metal surface (of gold or silver), S-thioacetyl derivatized porphyrins were synthesized; two alternative syntheses are described in chapter 4.

    A new and effecient ruthenium-catalyzed racemization protocol was established by proper ligand tuning. The racemization of the enantiomerically pure alcohols was increased significantly; this work is reported in chapter 5.

  • 33.
    Daver, Henrik
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Quantum Chemical Modeling of Phosphoesterase Mimics and Chemistry in Confined Spaces2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, density functional theory is employed in the study of two kinds of systems that can be considered to be biomimetic in their own ways. First, three binuclear metal complexes, synthesized by the group of Prof. Ebbe Nordlander, have been investigated. The complexes are designed to resemble the active sites of phosphatase enzymes and have been examined in complexes where either two Zn(II) ions or one Fe(III) and one Mn(II) ion are bound. These dinuclear compounds were studied as catalysts for the hydrolysis of bis(2,4-dinitrophenyl) phosphate and the transesterification of 2-hydroxypropyl p-nitrophenyl phosphate, which are model systems for the same reactions occurring in DNA or RNA. It was found that the two reactions take place in similar ways: a hydroxide ion that is terminally bound to one of the metal centers acts either as a nucleophile in the hydrolysis reaction or as a base in the transesterification. The leaving groups depart in an effectively concerted manner, and the formed catalyst-product complexes are predicted to be the resting states of the catalytic cycles. The rate-determining free energy barriers are identified from the catalyst-product complex in one catalytic cycle to the transition state of nucleophilic attack in the next.

    Another type of biomimetic modeling is made with an aim of imitating the conceptual features of selective binding of guests and screening them from solute-solvent interactions. Such features are found in so-called nanocontainers, and this thesis is concerned with studies of two capsules synthesized by the group of Prof. Julius Rebek, Jr. First, the cycloaddition of phenyl acetylene and phenyl azide has experimentally been observed to be accelerated in the presence of a capsule. Computational studies were herein performed on this system, and a previously unrecognized structure of the capsule is discovered. Two main factors are then identified as sources of the rate acceleration compared to the uncatalyzed reaction, namely the reduction of the entropic component and the selective destabilization of the reactant supercomplex over the transition state.

    In the second capsule study, the alkane binding trends of a water-soluble cavitand was studied. It is found that implicit solvation models fail severely in reproducing the experimental equilibrium observed between binding of n-decane by the cavitand monomer and encapsulation in the capsule dimer. A mixed explicit/implicit solvation protocol is developed to better quantify the effect of hydrating the cavitand, and a simple correction to the hydration free energy of a single water molecule is proposed to remedy this. The resulting scheme is used to predict new hydration free energies of the cavitand complexes, resulting in significant improvement vis-à-vis experiments.

    The computational results presented in this thesis show the usefulness of the quantum chemical calculations to develop understanding of experimental trends observed for substrate binding and catalysis. In particular, the methodology is shown to be versatile enough such that experimental observations can be reproduced for such diverse systems as studied herein.

  • 34.
    Deiana, Luca
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Development of Catalytic Enantioselective Approaches for the Synthesis of Carbocycles and Heterocycles2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In biological systems, most of the active organic molecules are chiral. Some of the main constituents of living organisms are amino acids and sugars. They exist predominantly in only one enantiomerically pure form. For example, our proteins are built-up by L-amino acids and as a consequence they are enatiomerically pure and will interact in different ways with enantiomers of chiral molecules. Indeed, different enantiomers or diastereomers of a molecule could often have a drastically different biological activity. It is of paramount importance in organic synthesis to develop new routes to control and direct the stereochemical outcome of reactions. The aim of this thesis is to investigate new protocols for the synthesis of complex chiral molecules using simple, environmentally friendly proline-based organocatalysts. We have investigated, the aziridination of linear and branched enals, the stereoselective synthesis of β-amino acids with a carbene co-catalyst, the synthesis of pyrazolidines, the combination of heterogeneous transition metal catalysis and amine catalysis to deliver cyclopentenes bearing an all-carbon quaternary stereocenter and a new heterogeneous dual catalyst system for the carbocyclization of enals. The reactions presented in this thesis afforded the corresponding products with high levels of chemo-, diastero- and enantioselectivity.

  • 35.
    Eklund, Robert
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Computational Analysis of Carbohydrates: Dynamical Properties and Interactions2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis a computational complement to experimental observables will be presented. Computational tools such as molecular dynamics and quantum chemical tools will be used to aid in the interpretation of experimentally (NMR) obtained structural data. The techniques are applied to study the dynamical features of biologically important carbohydrates and their interaction with proteins. When evaluating conformations, molecular mechanical methods are commonly used. Paper I, highlights some important considerations and focuses on the force field parameters pertaining to carbohydrate moieties. Testing of the new parameters on a trisaccharide showed promising results. In Paper II, a conformational analysis of a part of the repeating unit of a Shigella flexneri bacterium lipopolysaccharide using the modified force field revealed two major conformational states. The results showed good agreement with experimental data. In Paper III, a trisaccharide using Langevin dynamics was investigated. The approach used in the population analysis included a least-square fit technique to match T1 elaxation parameters. The results showed good agreement with experimental T-ROE build-up curves, and three states were concluded to be involved. In Paper IV, carbohydrate moieties were used in the development of prodrug candidates, to “hide” peptide opioid receptor agonists. Langevin dynamics and quantum chemical methods were employed to elucidate the structural preference of the compound. The results showed a chemical shift difference between hydrogens across the ring for the two isomers as well as a difference in the coupling constant, when taking the dynamics into account. In Paper V, the interaction of the Salmonella enteritidis bacteriophage P22 with its host bacterium, involves an initial hydrolysis of the O-antigenic polysaccharide (O-PS). Docking calculations were used to examine the binding between the Phage P22 tail-spike protein and the O-PS repeating unit. Results indicated a possible active site in conjunction with NMR measurements.

  • 36.
    Ekström, Jesper
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Transition Metal Hydrides: Biomimetic Studies and Catalytic Applications2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, studies of the nature of different transition metal-hydride complexes are described. The first part deals with the enantioswitchable behaviour of rhodium complexes derived from amino acids, applied in asymmetric transfer hydrogenation of ketones. We found that the use of amino acid thio amide ligands resulted in the formation of the R-configured product, whereas the use of the corresponding hydroxamic acid- or hydrazide ligands selectively gave the S-alcohol.

    Structure/activity investigations revealed that the stereochemical outcome of the catalytic reaction depends on the ligand mode of coordination.

    In the second part, an Fe hydrogenase active site model complex with a labile amine ligand has been synthesized and studied. The aim of this study was to find a complex that efficiently catalyzes the reduction of protons to molecular hydrogen under mild conditions. We found that the amine ligand functions as a mimic of the loosely bound ligand which is part of the active site in the hydrogenase.

    Further, an Fe hydrogenase active site model complex has been coupled to a photosensitizer with the aim of achieving light induced hydrogen production. The redox properties of the produced complex are such that no electron transfer from the photosensitizer part to the Fe moiety occurs.

    In the last part of this thesis, the development of a protocol for the transfer hydrogenation of ketones to secondary alcohols without the involvement of transition metal catalysts is described. A variety of ketones were efficiently reduced in 2-propanol using catalytic amounts of alkali alkoxide under microwave irradiation.

  • 37.
    Engqvist, Magnus
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Direct Amino Acid-Catalyzed Enantioselective α-Oxidation Reactions and Asymmetric de novo Synthesis of Carbohydrates2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The ability of amino acids to form nucleophilic enamines with aldehydes and ketones has been used in the development of asymmetric α-oxidation reactions with electrophilic oxidizing agents. Singlet molecular oxygen has for the first time been asymmetrically incorporated into aldehydes and ketones, and the products were isolated as their corresponding diols in good yields and ee’s. Organocatalytic α-oxidations of cyclic ketones with iodosobenzene and N-sulfonyloxaziridine were also possible and furnished after reduction the product diols in generally low yields and in low to good ee’s. Amino acids have also been shown to catalyze the formation of carbohydrates by sequential aldol reactions. For example, proline and hydroxy proline mediate a highly selective trimerisation of α-benzyloxyacetaldehyde into allose, which was obtained in >99 % ee. Non linear effect studies of this reaction revealed the largest permanent nonlinear effect observed in a proline-catalyzed reaction to date. Moreover, polyketides were also assembled in a similar fashion by an amino acid-catalyzed one-pot reaction, and was successful for the trimerisation of propionaldehyde, however the sequential cross aldol reactions suffered from lower selectivities. This problem was overcome by the development of a two-step synthesis that enabled the formation of a range of polyketides with excellent selectivities from a variety of aldehydes. The method furnishes the polyketides via the shortest route reported and in comparable product yields to most multi-step synthesis. All polyketides were isolated as single diastereomers with >99 % ee. Based on the observed amino acid-catalysis, amino acids are thought to have taken part in the prebiotic formation of tetroses and hexoses.

  • 38.
    Engström, Karin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Enantioselective biotransformations using engineered lipases from Candida antarctica2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Enzymes are attractive catalysts in organic synthesis since they are efficient, selective and environmentally friendly. A large number of enzyme-catalyzed transformations have been described in the literature. If no natural enzyme can carry out a desirable reaction, one possibility is to modify an existing enzyme by protein engineering and thereby obtain a catalyst with the desired properties. In this thesis, the development of enantioselective enzymes and their use in synthetic applications is described. 

    In the first part of this thesis, enantioselective variants of Candida antarctica lipase A (CALA) towards α-substituted p-nitrophenyl esters were developed by directed evolution. A highly selective variant of CALA towards p-nitrophenyl 2-phenylpropanoate was developed by pairwise randomization of amino acid residues close to the active site. The E value of this variant was 276 compared to 3 for the wild type.

    An approach where nine residues were altered simultaneously was used to discover another highly enantioselective CALA variant (E = 100) towards an ibuprofen ester. The sterical demands of this substrate made it necessary to vary several residues at the same time in order to reach a variant with improved properties.

    In the second part of the thesis, a designed variant of Candida antarctica lipase B (CALB) was employed in kinetic resolution (KR) and dynamic kinetic resolution (DKR) of secondary alcohols. The designed CALB variant (W104A) accepts larger substrates compared to the wild type, and by the application of CALB W104A, the scope of these resolutions was extended.

    First, a DKR of phenylalkanols was developed using CALB W104A. An enzymatic resolution was combined with in situ racemization of the substrate, to yield the products in up to 97% ee. Secondly, the KR of diarylmethanols with CALB W104A was developed. By the use of diarylmethanols with two different aryl groups, highly enantioselective transformations were achieved.

  • 39.
    Engström, Olof
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Exploring the Molecular Behavior of Carbohydrates by NMR Spectroscopy: Shapes, motions and interactions2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Carbohydrates are essential biomolecules that decorate cell membranes and proteins in organisms. They are important both as structural elements and as identification markers. Many biological and pathogenic processes rely on the identification of carbohydrates by proteins, thereby making them attractive as molecular blueprints for drugs. This thesis describes how NMR spectroscopy can be utilized to study carbohydrates in solution at a molecular level. This versatile technique facilitates for investigations of (i) shapes, (ii) motions and (iii) interactions.

    A conformational study of an E. coli O-antigen was performed by calculating atomic distances from NMR NOESY experiments. The acquired data was utilized to validate MD simulations of the LPS embedded in a membrane. The agreement between experimental and calculated data was good and deviations were proven to arise from spin-diffusion. In another study presented herein, both the conformation and the dynamic behavior of amide side-chains linked to derivatives of D-Fucp3N, a sugar found in the O-antigen of bacteria, were investigated. J-couplings facilitated a conformational analysis and 13C saturation transfer NMR experiments were utilized to measure rate constants of amide cis-trans isomerizations.

    13C NMR relaxation and 1H PFG diffusion measurements were carried out to explore and describe the molecular motion of mannofullerenes. The dominating motions of the mannofullerene spectral density were found to be related to pulsating motions of the linkers rather than global rotational diffusion. The promising inhibition of Ebola viruses identified for a larger mannofullerene can thus be explained by an efficient rebinding mechanism that arises from the observed flexibility in the linker.

    Molecular interactions between sugars and caffeine in water were studied by monitoring chemical shift displacements in titrations. The magnitude of the chemical shift displacements indicate that the binding occurs by a face to face stacking of the aromatic plane of caffeine to the ring plane of the sugar, and that the interaction is at least partly driven by solvation effects. Also, the binding of a Shigella flexneri serotype Y octasaccharide to a bacteriophage Sf6 tail spike protein was investigated. This interaction was studied by 1H STD NMR and trNOESY experiments. A quantitative analysis of the STD data was performed employing a newly developed method, CORCEMA-ST-CSD, that is able to simulate STD data more accurately since the line broadening of protein resonances are accounted for in the calculations.

  • 40.
    Erbing, Elis
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Development of New Efficient Iridium-Catalyzed Methods for the Construction of Carbon-Heteroatom Bonds2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Today’s society has a large demand for biologically active chemicals that can be used for example as pharmaceuticals and in the agriculture. These are normally constructed by assembling together several smaller chemical molecules. In order to achieve this, we need that these small molecules contain certain reactive sites, or in other words, that they are functionalized with certain atoms. The work in this thesis investigates and develops new methods to create functionalities in molecules, which in turn can be used to construct larger compounds and other materials important for our society.

     The methods herein developed are based on the use of metal catalysts to construct carbon-halogen bonds. Examples of halogens include bromide and iodide. When a molecule contains one (or more) of these bonds, it can be transformed in a simple chemical step into other compounds. The number of possible chemical transformations becomes almost endless. Thus, by accessing these compounds, chemical libraries can be created easily.

    Throughout the work, sustainability has been prioritized by using, for the human health, friendly solvents whenever possible, by using versatile, stable and structurally simple but yet effective catalysts, and by minimizing the need to use unnecessary chemical activators.

    The full text will be freely available from 2019-12-10 09:00
  • 41.
    Fontana, Carolina
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    NMR spectroscopy in structural and conformational analysis of bacterial polysaccharides2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Carbohydrates constitute one of the three major classes of biomolecules found in all living cells and, unlike nucleic acids and proteins, their polymeric structures are not based on a template. The structural diversity of these molecules confers them an enormous capacity to encode information in biological systems, acting as efficient mediators in the interaction of the cell with the environment. In order to understand the roles of glycans in biological processes it is of key importance to have a detailed understanding of their structures and conformational preferences, and NMR spectroscopy is one of most powerful techniques for the study of these molecules in solution.

    This thesis is focused on the structural and conformational analysis of lipopolysaccharides from Gram-negative bacteria. In the first two projects (Chapter 2 and 3) the structural analyses of the biological repeating units of the O-antigen polysaccharides from E. coli O174ab and O115 are described; in both cases a combination of NMR spectroscopy and gas chromatography techniques were used. Special emphasis was made in the characterization of the O-acetylation patterns observed in the native O-antigen polysaccharide from E. coli O115. Chapter 4 describes the development of a new methodology for the determination of the absolute configuration of monosaccharide components of glycans. This methodology was used in the structural elucidation of the O-antigen PS of E. coli O155 (Chapter 5) that was carried out in a semi-automated manner using the program CASPER and unassigned NMR data. The conformational preferences of O-antigen PS of E. coli O5ac and O5ab are analyzed in Chapter 6, using a combination of NMR spectroscopy and molecular modeling methods. In Chapter 7 the structural analysis is focused on the core region of the LPS, and the structures of the deacylated lipooligosaccharides of three rough mutants of B. melitesis are reported. In several of the aforementioned chapters, the biosynthetic aspects behind the assembly of the respective PSs were examined on the bases of genetic information available in the NCBI and ECODAB databases.  Finally, in Chapter 8, different NMR pulse sequences available for the study of proteins and nucleic acids were evaluated and optimized for the structural analysis of 13C uniformly-labeled oligo- and polysaccharides.

  • 42.
    Fransson, Ann-Britt L.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Deracemization of Functionalized Alcohols via Combined Ruthenium and Enzyme Catalysis2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The major part of this thesis describes the synthesis of enantiopure alcohols and diols by combining ruthenium-catalyzed racemization or epimerization and lipase-catalyzed asymmetric transformations. A minor part of this thesis is focused on ruthenium-catalyzed redox reactions for transfer hydrogenation of 1,3-cycloalkanediketones.

    Kinetic resolution of racemic γ-hydroxy acid derivatives was performed via Pseudomonas cepacia lipase (PS-C)-catalyzed transesterification. γ-Hydroxy esters and γ-hydroxy amides were studied showing in higher selec-tivity and yields for the γ-hydroxy amides. The enzyme PS-C tolerates both variation in the chain length and different functionalities giving good to high enantioselectivity. Combining enzymatic kinetic resolution with a ruthenium-catalyzed racemization led to a dynamic kinetic resolution (DKR). The use of 2,4-dimethyl-3-pentanol as a hydrogen source to suppress ketone formation in the dynamic kinetic resolution increased the yields of the acetate product. The synthetic utility of this procedure was illustrated by the practical synthesis of the γ-lactone (R)-5-methyltetrahydrofuran-2-one.

    A distereoselective transformation of cis/trans-1,3-cyclohexandiol using Candida antarctica lipase B (CALB)-catalyzed transesterification was of interest. Desymmetrization of cis-1,3-cyclohexanediol to the (R-monoacetate was successfully accomplished. Enantiopure (R,R)-diacetate was obtained from the (R)-monoacetate in a DYKAT process at room tem-perature. Metal- and enzyme-catalyzed transformation of cis/trans-1,3-cyclohexanediol using PS-C, gives a high diastereoselectivity for cis-diacetate. The (S)-mono-acetate was obtained from cis-diacetate by CALB-catalyzed hydrolysis. In addition, it was shown, by the use of deuterium-labeling that intramolecular acyl migration does not occur in the transformation of cis-monoacetate to the cis-diacetate.

    Ruthenium-catalyzed transfer hydrogenation of 1,3-cyclohexanedione under microwave heating was developed as an efficient and fast method for the preparation of 1,3-cycloalkandiols.

  • 43.
    Franzén, Johan
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Palladium-Catalyzed Carbocyclizations of Allenes with Unsaturated Hydrocarbons2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Palladium-catalyzed reactions of unsaturated hydrocarbons are important processes in organic chemistry especially for the generation of ring systems. This thesis describes the development and mechanistic studies of carbocyclization reactions of allenes with olefins, allyls or 1,3-dienes catalyzed by palladium(0)- and palladium(II)-complexes. These reactions generally exhibit high stereo- and regioselectivity and give rise to stereodefined [n,3,0] bicyclic systems (n=3,4,5,6) in good to excellent yields. The mechanisms for these reactions were investigated with special attention directed to the intramolecular reaction of (π-allyl)palladium(II)-complexes and (π-1,3-diene)palladium(II)-complexes with allenes. It was demonstrated that the carbon-carbon bond formation occurred by nucleophilic attack of the middle carbon atom of the allene on the face of the allyl or 1,3-diene opposite to that of the palladium atom. Further, two new types of oxidative palladium(II)-catalyzed reactions between allenes and olefins or 1,3-dienes have been developed. These cyclizations constitute a new type of carbon-carbon bond forming reaction and there are support for a palladium(II)-catalyzed C-H activation at the allenic moiety rendering a vinylidienepalladium-intermediate followed by carbon-carbon bond formation via insertion of the olefin or 1,3-diene.

  • 44.
    Frigell, Jens
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Synthesis of O-linked Carbasugar Analogues of Galactofuranosides and N-linked Neodisaccharides2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, carbohydrate mimicry is investigated through the syntheses of carbohydrate analogues and evaluation of their inhibitory effects on carbohydrate-processing enzymes.

    Galactofuranosides are interesting structures because they are common motifs in pathogenic microorganisms but not found in mammals. M.tuberculosis, responsible for the disease tuberculosis, has a cell wall containing a repeating unit of alternating (1→5)- and (1→6)-linked β-D-galactofuranosyl residues. Synthetic inhibitors of the enzymes involved in the biosynthesis of the cell wall could find great therapeutic use.

    The first part of this thesis describes the first synthesis of the hydrolytically stable carbasugar analogue of galactofuranose, 4a-carba-β-D-Galf, and the synthetic work of synthesising β-linked pseudodisaccharides containing carba-Galf, which were tested for glycosyltransferease inhibitory activity. The pseudodisaccharide carba-Galf-(β1→5)-carba-Galf was found to be a moderate inhibitor of the glycosyltransferase GlfT2 of M.tuberculosis. The thesis also describes how a general method towards biologically relevant α-linked carba-Galf ethers was developed.

    The final part of this thesis is focussed on the formation of nitrogen-linked monosaccharides without the participation of the anomeric centre. Such a mode of coupling is called tail-to-tail neodisaccharide formation. The couplings of carbohydrate derivatives via the Mitsunobu reaction are successfully reported herein. The method describes the key introduction of an allylic alcohol in the electrophile and the subsequent functionalisation of the alkene to obtain the neodisaccharide. Two synthesised neodisaccharides presented in this thesis have been sent to be tested for glycosidase inhibitory activity.

  • 45.
    Gemma, Emiliano
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Synthesis of Oligosaccharides for Interaction Studies with Various Lectins2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, the syntheses of oligosaccharides for interaction studies with various lectins are described. The first section reports the syntheses of tetra, tri- and disaccharides corresponding to truncated versions of the glucosylated arm of Glc1Man9(GlcNAc)2, found in the biosynthesis of N-glycans. The thermodynamic parameters of their interaction with calreticulin, a lectin assisting and promoting the correct folding of newly synthesised glycoproteins, were established by isothermal titration calorimetry. In the second section, a new synthetic pathway leading to the same tetra- and trisaccharides is discussed. Adoption of a convergent strategy and of a different protecting group pattern resulted in significantly increased yields of the target structures. The third section describes the syntheses of a number of monodeoxy-trisaccharides related to the above trisaccharide Glc-α-(1→3)-Man-α-(1→2)-Man-α-OMe. Differentsynthetic approaches were explored and the choice of early introduction of the deoxy functionality proved the most beneficial. In the last section, the synthesis of spacer-linked LacNAc dimers as substrates for the lectins galectin-1 and -3 is presented. This synthesis was realized by glycosidation of a number diols with peracetylated LacNAc-oxazoline. Pyridinium triflate was tested as a new promoter, affording the target dimers in high yields. This promoter in combination with microwave irradiation gave even higher yields and also shortened the reaction times.

  • 46.
    González Miera, Greco
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Homogeneous and heterogeneous Cp*Ir(III) catalytic systems: Mechanistic studies of redox processes catalyzed by bifunctional iridium complexes, and synthesis of iridium-functionalized MOFs2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The purpose of this doctoral thesis is to investigate and develop catalytic processes mediated by iridium(III) complexes. By understanding the mechanisms, the weaknesses of the designed catalysts can be identified and be overcome in the following generation.

    The thesis is composed of two general sections dedicated to the synthesis and applications of homogeneous catalysts and to the preparation of heterogeneous catalysts based on metal-organic frameworks (MOFs). After a general introduction (Chapter 1), the first part of the thesis (Chapters 2-4, and Appendix 1) covers the use of several homogeneous bifunctional [Cp*Ir(III)] catalysts in a variety of chemical transformations, as well as mechanistic studies.

    Chapter 2 summarizes the studies on the N-alkylation of anilines with benzyl alcohols catalyzed by bifunctional Ir(III) complexes. Mechanistic investigations when the reactions were catalyzed by Ir(III) complexes with a hydroxy-functionalized N-heterocyclic carbene (NHC) ligand are discussed, followed by the design of a new generation of catalysts. The chapter finishes presenting the improved catalytic performance of these new complexes.   

    A family of these NHC-iridium complexes was evaluated in the acceptorless dehydrogenation of alcohols, as shown in Chapter 3. The beneficial effect of a co-solvent was investigated too. Under these base-free conditions, a wide scope of alcohols was efficiently dehydrogenated in excellent yields. The unexpected higher activity of the hydroxy-containing bifunctional NHC-Ir(III) catalysts, in comparison to that of the amino-functionalized one, was investigated experimentally.

    In the fourth chapter, the catalytic process presented in Chapter 3 was further explored on 1,4- and 1,5-diols, which were transformed into their corresponding tetrahydrofurans and dihydropyrans, respectively. Mechanistic investigations are also discussed.

    In the second part of the thesis (Chapter 5), a Cp*Ir(III) complex was immobilized into a MOF. The heterogenization of the metal complex was achieved efficiently, reaching high ratios of functionalization. However, a change in the topology of the MOF was observed. In this chapter, the use of advanced characterization techniques such as X-ray absorption spectroscopy (XAS) and pair distribution function (PDF) analyses enabled to study a phase transformation in these materials.

  • 47.
    Gustafson, Karl P. J.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Studies on Metalloenzymatic Dynamic Kinetic Resolutions and Iron-Catalyzed Reactions of Allenes2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The main focus of this thesis lies in the development of new transition metal-catalyzed chemoenzymatic dynamic kinetic resolutions (DKR) of both alcohols and amines. The first part of the thesis deals with the development of new heterogeneous systems for the DKR of amines. The racemization catalysts in these different systems are all composed of palladium nanoparticles supported on either mesoporous silica or incorporated in a biocomposite that is composed of a bioactive cross-linked enzyme aggregate. 

    The second part of the thesis deals with the development of a homogeneous iron catalyst in the racemization of sec-alcohols for the implementation in a chemoenzymatic DKR. Two protocols for the racemization of sec-alcohols are reported. The first one could not be combined with a chemoenzymatic kinetic resolution, although this was overcome in the second iron based protocol. 

    Following the successful iron catalyzed chemoenzymatic DKR of sec-alcohols, the iron catalyst was used in the cyclization of α-allenic alcohols and N-protected amines to furnish 2,3-dihydrofurans and 2,3-dihydropyrroles, respectively. The cyclization is proceeding in a diastereoselective manner.

    The last part of the thesis deals with attempts to further elucidate the mechanism of activation of a known ruthenium racemization catalyst. X-ray absorption spectroscopy using synchrotron radiation was used for this purpose.

  • 48.
    Görbe, Tamás
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Heterogeneous catalysis in racemization and kinetic resolution along a journey in protein engineering2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The first part of my thesis concerns the use of heterogeneous acidic resins for racemization of tert-alcohols without any side-product formation. The focus was to develop a system which can be further extended to a DKR protocol consisting of an enzymatic KR reaction. Based on our knowledge of the resins, an unexpected migratory DKR protocol turned out to be an efficient method for the synthesis of carbocyclic allylic carbinols.

    The development of enzyme and metal catalyst hybrids was already an ongoing theme in our group. A supporter-free biohybrid catalyst was developed which can be used in several different types of reactions. The Pd(0)-CalB CLEA catalyst was applied in a two-step-cascade transformation and in the DKR of benzylic primary amines. The catalyst was characterized by different analytical techniques, to understand its composition and structure.

    The enzymes have always been the main focus of the studies and therefore wild type enzymes were initially utilized. However, these natural biocatalysts are associated with certain limitations. In contrast, protein engineering allows for enzymes to be modified and optimized. We have used the technique to create a subtilisin Carlsberg mutant, which was studied both by modeling and in vitro. The mutant was found to catalyze the (S)-selective transesterification of sec-alcohols containing long aliphatic carbon chains, and it also exhibited higher performance in organic solvent.

    The last project concerned the protein engineering of CalA enzyme towards tert-alcohols. The kinetic resolution of tert-alcohols with this enzyme is very slow but it occurs with good enantioselectivity. The aim was therefore to improve the activity of CalA via protein engineering. Seven amino acids were mutated close to the active site and a library was created based on our prediction. Throughout the screening, a few variants showed higher activity, which were sequenced and further analyzed in the transesterification of tert-alcohols.

  • 49.
    Hamark, Christoffer
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    The sweet side of molecular structure: NMR spectroscopic studies of glycans and their interactions with proteins2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis, within the topic of bioorganic chemistry, the molecular structure of carbohydrates has been studied. Carbohydrates, or glycans, are ubiquitous biomolecules exhibiting a wide range of biological roles. The specific functions of these molecules are largely determined by their interactions with proteins and molecular structure ultimately governs such specialized recognition events.

    Glycan-binding proteins, such as lectins or enzymes, often interact with their sweet ligands in a transient fashion and nuclear magnetic resonance spectroscopy (NMR) is a viable technique to probe these complexes. In particular, ligand-based NMR techniques have been employed, typically in combination with other biophysical as well as biochemical and computational methods. The aim of this work has been to gain new insights about specific biological systems, to develop methods and to devise protocols for their studies.

    The first two papers cover NMR-interaction studies of native ligands as well as inhibitor glycans with the enzyme hen egg-white lysozyme and the lectin botulinum neurotoxin type A. Screening experiments were performed to investigate ligand affinities and selectivities. Solution models in combination with X-ray crystal structures were compared in order to evaluate their agreement and the details of interactions.

    A method for application in carbohydrate ligand NMR-screening was developed in paper three. The heteronucleus selenium was exploited as a reporter of selenoglycosides binding to lectins. 77Se NMR spectroscopy proved sensitive to binding events and the presented approach should be useful in large screenings of glycomimetic inhibitors.  In order to obtain sufficient amounts of glycans for bioorganic studies their production often relies on chemical synthesis. In the last paper, the structure of some conformationally highly activated glycosyl donors was thoroughly investigated and related to their reactivity in synthetic glycosylation reactions.  

  • 50.
    Hansson, Jonas
    Stockholm University.
    Synthesis of phosphate-containing oligosaccharides corresponding to capsular antigen structures from Haemophilus influenzae2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes the synthesis of spacer-equipped di- and trimeric oligosaccharide structures corresponding to fragments of the capsular polysaccharides of Haemophilus influenzae types c and f. Both of these polysaccharides are of the teichoic acid type, built up by disaccharide repeating units linked via interglycosidic phosphodiester bonds. Introduction of the phosphodiester linkages was accomplished employing the glycosyl H-phosphonate method. The syntheses are designed in such a way as to allow the formation of even larger structures, as well as conjugation to a carrier protein. The first section of this thesis presents a general overview of the biological significance and structural features of anomeric phosphodiesters and synthetic approaches towards these structures, including a literature survey of research in this area during the past decade. In the second part, a new approach to the synthesis of anomeric phosphodiester linkages, utilizing non-anomeric glycosyl H-phosphonate acceptors and various galactosyl donors in glycosylation reactions, is described. Finally, synthesis of the capsular polysaccharide fragments of H. influenzae types c and f is discussed.

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