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  • 151.
    Nilsson, Johan
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Studies on Oxidative Couplings in H-Phosphonate Chemistry2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis oxidative coupling of H-phosphonate and H phosphonothioate diesters with different alcohols and amines are presented. Since the reactions with alcohols previously have been particularly unfavourable due to competing side reactions, a modified protocol leading to high coupling yields of structurally diverse hydroxylic components was developed. The phosphorylation reaction was studied using 31P NMR spectroscopy and for the first time the previously only postulated reactive intermediate involved in these reactions was observed.

    The use of iodine in combination with a bulky chlorosilane in pyridine was found to have a profound effect on both the suppression of side reactions and the rate of the oxidative couplings, and led to a clean formation of phosphorylated products in high yields. This synthetic protocol was then extended to include coupling reactions with bis-functional reagents containing hexamethylene linkers to provide handles for derivatisations of oligonucleotides.

    A synthetic protocol consisting of the stereospecific oxidative coupling of amines with H-phosphonate diesters to produce phosphoroamidates was designed in such a way that it permitted control of the stereochemical outcome of the reactions.

    Based on a silylation-mediated reaction utilising phenyl H phosphonothioate monoester as a thiophosphonyl transferring agent, a method was developed and used for the preparation of H-phosphonothioate building blocks for the synthesis of DNA analogues.

  • 152.
    Nordmark, Eva-Lisa
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Structural and Interaction Studies of Bacterial Polysaccharides by NMR Spectroscopy2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    An introduction to bacterial polysaccharides and the methods for structural determination are described in the first two parts of the thesis.

    In a structural elucidation of bacterial polysaccharides NMR experiments are important as is component analysis. A short description of immunochemical methods such as enzyme immunoassays is included. Two NMR techniques used for interaction studies, trNOE and STD NMR, are also discussed.

    The third part of the thesis discusses and summarizes the results from the included papers. The structures of the exopolysaccharides produced by two lactic acid bacteria are determined by one- and two dimensional NMR experiments. One is a heteropolysaccharide produced by Streptococcus thermophilus and the other a homopolysaccharide produced by Propionibacterium freudenreichii. The structure of an acidic polysaccharide from a marine bacterium with two serine residues in the repeating unit is also investigated. The structural and immunological relationship between two O-antigenic polysaccharides from Escherichia coli strain 180/C3 and O5 is discussed and investigated. Finally, interaction studies of an octasaccharide derived from the Salmonella enteritidis O-antigen and a bacteriophage are described which were performed with NMR experiments.

  • 153.
    Norinder, Jakob
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Asymmetric Synthesis and Mechanistic Studies on Copper(I)-Catalyzed Substitution of Allylic Substrates2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis deals with the copper-catalyzed substitution of allylic substrates.

    In the first part of this thesis, the synthesis of a series of metallocenethiolates is described. The thiolates were examined as ligands in the enantioselective copper(I)-catalyzed γ-substitution of allylic acetates.

    The second part describes a study on copper-catalyzed α-substitution of enantiomerically pure secondary allylic esters. It was observed that the degree of chirality transfer is strongly dependent on the reaction temperature. The loss of chiral information is consistent with an equilibration of the allylCu(III) intermediates prior to product formation, which is essential in order to realize a copper-catalyzed dynamic kinetic asymmetric transformation process.

    The third part describes a study on copper-catalyzed stereoselective α-substitution of enantiopure acyclic allylic esters. This method, when combined, with ruthenium and enzyme catalyzed dynamic kinetic resolution of allylic alcohols, provides a straightforward route to pharmaceutically important α-methyl carboxylic acids.

    The fourth part is a mechanistic study on the reaction of perfluoroallyl iodide with organocuprates. Experimental studies as well as theoretical calculations were used to explain the contrasting reactivity of perfluoroallyl iodide vs. allyl iodide in cuprate allylation reactions.

    In the fifth part, the development of a practical and useful method for the preparation of pentasubstituted acylferrocenes is presented.

  • 154.
    Närhi, Katja
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Studies on Palladium-Catalyzed Carbocyclizations of Allene-Substituted Olefins and 1,3-Dienes2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes the development and mechanistic studies of carbocyclization reactions of allene-substituted olefins and 1,3-dienes, catalyzed by palladium(0) and palladium(II). These reactions results in the formation of [n,3,0] bicyclic systems (n = 3-5) with high stereoselectivity and in good to excellent yields.

    The first carbocyclization presented is a novel palladium(0)-catalyzed cyclo- isomerization of allene-substituted olefins.

    Secondly an efficient aerobic biomimetic system has been developed for a Pd(II)-catalyzed allylic oxidative carbocyclization of allene-substituted olefins.

    Additionally, during the studies of palladium-catalyzed carbocyclizations of allene-substituted olefins, it was found that in the absence of palladium a mild thermal ene-reaction occurs. In this manner stereodefined, functionalized bicyclic compounds are obtained with good regioselectivity and in high yields.

    The third and fourth carbocyclization developed are a palladium(II)-catalyzed oxidation and a palladium(0)-catalyzed intramolecular telomerization of allene-substituted 1,3-dienes.

    A mechanistic study of the palladium(II)-catalyzed oxidation of allene-substituted 1,3-dienes was made, and reaction intermediates could be isolated. The stereochemistry of the reaction intermediates was assigned, and this made it possible to suggest a mechanism for the reaction. The presented mechanism is a trans carbopalladation of the 1,3-diene, where the allene act as the carbon nucleophile. Due to different stereochemical outcomes of the stoichiometric and catalytic reactions, this mechanism could only explain the stoichiometric reaction. Another mechanism for the catalytic reaction was suggested, which rationalizes both the regio- and stereochemistry of the products.

  • 155.
    Olofsson, Berit
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Fast, efficient and high-yielding routes to diaryliodonium salts2009In: European Symposium on Organic Chemistry (ESOC 16), Prague, Czech Republic, 2009, 2009Conference paper (Other academic)
  • 156.
    Olofsson, Berit
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Fast, efficient and high-yielding routes to diaryliodonium salts2009In: 44th EUCHEM Conference on Stereochemistry, Bürgenstock, Switzerland, May, 2009, 2009Conference paper (Other academic)
  • 157.
    Olofsson, Berit
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Fast, efficient and high-yielding routes to diaryliodonium salts2009In: XVIII EuCheMS Conference on Organometallic Chemistry, Gothenburg, Sweden, 2009, 2009Conference paper (Other academic)
  • 158.
    Olofsson, Berit
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Fast, efficient and high-yielding routes to diaryliodonium salts2009In: EUCHEMS Young Investigator Workshop, Liblice, Czech Republic, 2009, 2009Conference paper (Other academic)
  • 159.
    Olofsson, Berit
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Aggarwal, Varinder K.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Enantioselective alfa-Arylation of Ketones: Application to the Synthesis of (–)-Epibatidine2006In: Sterochemistry, Bürgenstock, Switzerland, 2006Conference paper (Other (popular science, discussion, etc.))
  • 160.
    Olofsson, Berit
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Aggarwal, Varinder K.
    Bristol University, UK.
    Enantioselective alfa-Arylation of Ketones: Application to the Synthesis of (–)-Epibatidine2006In: Organikerdagarna, Kalmar, Sweden, 2006, p. Le21, P47-Conference paper (Other (popular science, discussion, etc.))
    Abstract [en]

    The enantioselective introduction of electrophiles alfa to carbonyl compounds occupies a central position in asymmetric synthesis. Although asymmetric alkylations have been well developed, high enantioselectivity in α-arylation of ketones has only been achieved in a limited number of cases.

    We have developed a direct arylation reaction of cyclohexanones, employing diaryl iodonium(III) salts as electrophiles. The reaction was made enantioselective by the use of a chiral base, resulting in 2,4-substituted cyclohexanones in high yields and with high enantiomeric excesses and diastereoselectivities.

    This methodology was applied in a short, enantioselective synthesis of (–)-Epibatidine, an alkaloid recently isolated from the Ecuadorian poison frog Epipedobates tricolor. The synthesis was accomplished in 6 steps and 31% overall yield, thus providing the shortest and most efficient asymmetric route to this important compound to date.

  • 161.
    Olofsson, Berit
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Aggarwal, Varinder K.
    Bristol University, UK.
    Synthesis of Novel Heteroaryl Iodonium Salts and Enantioselective a-Arylation of Cyclohexanones2006In: 2nd Int. Conference on Hypervalent Iodine, 2006Conference paper (Other academic)
    Abstract [en]

    We have developed a direct arylation reaction of cyclohexanones employing diaryl iodonium(Ill) salts as electrophiles. The

    reaction was made enantiosilective by the use of a chiral base, resultinginZ,4-disubstituted cyclohexanones in high yields and with high enantiomeric excesses and diastereoselectivities. Novel heteroaryl iodonium salts were subsequently synthesized and employed in the coupling to variously substituted cyclohexanones.

  • 162.
    Olsson, Ulrika
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Structural Studies of O-antigen polysaccharides, Synthesis of 13C-labelled Oligosaccharides and Conformational Analysis thereof, using NMR Spectroscopy2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In order to understand biological processes, to treat and diagnose diseases, find appropriate vaccines and to prevent the outbreak of epidemics, it is essential to obtain more knowledge about carbohydrate structures. This thesis deals with structure and conformation of carbohydrates, analysed by NMR spectroscopy and MD simulations.In the first two papers, the structures of O-antigen polysaccharides (PS) from two different E. coli bacteria were determined using NMR spectroscopy. The O-antigenic PS from E. coli O152 (paper I) consists of branched pentasaccharide repeating units, built up of three different carbohydrate residues and a phosphodiester, whilst the repeating unit of the O-antigen from E. coli O176 (paper II) is built up of a linear tetrasaccharide consisting of two different monosaccharides.

    In papers III and IV, the conformational analysis of different disaccharides is described. Conformational analysis was performed using NMR spectroscopy and MD simulations (paper IV). In paper III four different glucobiosides were studied using coupling constants and Karplus-type relationships. By use of specific 13C isotopically labelled derivatives, additional coupling constants were obtained and the number of possible torsion angles was reduced by half. In paper IV, we examine the conformations of two disaccharides that are part of an epitope of malignant cells. From NOE and T-ROE experiments, short proton-proton distances around the glycosidic linkage were estimated. Furthermore, interpretation of the extracted coupling constants using Kaplus relationships gave the values of the torsion angles. As in paper III, isotopically labelled compounds were synthesised in order to enhance the sensitivity of the analysis. Finally, MD simulations were performed and the results were compared with results from NMR data.

  • 163.
    Olsson, Vilhelm
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Development of New Synthetic Routes to Organoboronates by Catalytic Allylic Substitution and C-H bond Functionalization2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes the development of new catalytic methods for the synthesis and application of organometallic reagents, mainly focusing on allylboronic acid derivatives. Thus, palladium pincer-complex catalysis has been applied for extending the scope of palladiumcatalyzed borylation reactions in the synthesis of regio- and stereodefined functionalized allylboronic acid derivatives. These novel allylboronic acids were also employed as substrates in palladium catalyzed regioselective coupling reactions with iodobenzenes. We have also developed a new one-pot sequence based on preparation of allyl- and vinylboronates

    via catalytic carbon-hydrogen bond activation/borylation reactions. The synthetic scope of the reaction as well as mechanistic studies on the borylation process are presented. Finally, the synthesis of new chiral palladium pincer-complexes is described. These species were employed as catalysts in asymmetric electrophilic allyation of imines.

  • 164.
    Otero-Fraga, Jorge
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Montesinos-Magraner, Marc
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Mendoza, Abraham
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Perspectives on Intermolecular Azomethine Ylide [3+2] Cycloadditions with Non-Electrophilic Olefins2017In: Synthesis (Stuttgart), ISSN 0039-7881, E-ISSN 1437-210X, Vol. 49, no 4, p. 802-809Article, review/survey (Refereed)
    Abstract [en]

    Our interest in the synthesis of compact nitrogen heterocycles from abundant sources has motivated a critical analysis of the status in azomethine ylide chemistry. Despite the outstanding developments in catalytic enantioselective [3+2] cycloadditions, these are still limited to electron-poor olefins. Only a few examples can be found in the literature that report on cycloadditions using non-electrophilic alkenes and those are compiled herein. With this account we aim to extract lessons and challenges that will inspire future breakthroughs in this area.

  • 165.
    Pascanu, Vlad
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Bermejo Gómez, Antonio
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Ayats, Carles
    Platero-Prats, Ana E.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Carson, Fabian
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Su, Jie
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Yao, Qingxia
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Pericas, Miquel A.
    Zou, Xiaodong
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Martín-Matute, Belén
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Double-Supported Silica-Metal-Organic Framework Palladium Nanocatalyst for the Aerobic Oxidation of Alcohols under Batch and Continuous Flow Regimes2015In: ACS Catalysis, ISSN 2155-5435, E-ISSN 2155-5435, Vol. 5, no 2, p. 472-479Article in journal (Refereed)
    Abstract [en]

    Stable and easily synthesized metal-organic framework MIL-88B-NH2 represents an attractive support for catalysts employed in oxidation reactions, which are typically performed under relatively harsh conditions. However, MIL-88B-NH2, the thermodynamic polymorph of the more popular MIL-101-NH2, has been rarely employed in catalytic applications because of a difficult impregnation process caused by the flexible nature of the framework. We report herein a new catalyst denoted Pd@MIL-88B-NH2 (8 wt % Pd), the first example of metallic nanoparticles successfully impregnated in the pores of MIL-88B-NH2. Furthermore, by enclosing the MOF crystals in a tailored protective coating of SiO2 nanoparticles, an even more enduring material was developed and applied to the aerobic oxidation of benzylic alcohols. This doubly supported catalyst Pd@MIL-88B-NH2@nano-SiO2 displayed high activity and excellent performance in terms of endurance and leaching control. Under batch conditions, a very convenient and efficient recycling protocol is illustrated, using a teabag approach. Under continuous flow, the catalyst was capable of withstanding 7 days of continuous operation at 110 degrees C without deactivation. During this time, no leaching of metallic species was observed, and the material maintained its structural integrity.

  • 166.
    Pascanu, Vlad
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Carson, Fabian
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Vico Solano, Marta
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Su, Jie
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Zou, Xiaodong
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Johansson, Magnus J.
    Martín-Matute, Belén
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Selective Heterogeneous C−H Activation/Halogenation Reactions Catalyzed by Pd@MOF Nanocomposites2016In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 11, p. 3729-3737Article in journal (Refereed)
    Abstract [en]

    A directed heterogeneous C−H activation/halogenation reaction catalyzed by readily synthesized Pd@MOF nanocatalysts was developed. The heterogeneous Pd catalysts used were a novel and environmentally benign Fe-based metal–organic framework (MOF) (Pd@MIL-88B-NH2(Fe)) and the previously developed Pd@MIL-101-NH2(Cr). Very high conversions and selectivities were achieved under very mild reaction conditions and in short reaction times. A wide variety of directing groups, halogen sources, and substitution patterns were well tolerated, and valuable polyhalogenated compounds were synthesized in a controlled manner. The synthesis of the Pd-functionalized Fe-based MOF and the recyclability of the two catalysts are also presented.

  • 167.
    Pascanu, Vlad
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Hansen, Peter R.
    Bermejo Gomez, Antonio
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Ayats, Carles
    Platero-Prats, Ana E.
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Johansson, Magnus J.
    Pericas, Miquel A.
    Martín-Matute, Belén
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Highly Functionalized Biaryls via Suzuki-Miyaura Cross-Coupling Catalyzed by Pd@MOF under Batch and Continuous Flow Regimes2015In: ChemSusChem, ISSN 1864-5631, E-ISSN 1864-564X, Vol. 8, no 1, p. 123-130Article in journal (Refereed)
    Abstract [en]

    A diverse set of more than 40 highly functionalized biaryls was synthesized successfully through the Suzuki-Miyaura cross-coupling reaction catalyzed by Pd nanoparticles supported in a functionalized mesoporous MOF (8 wt% Pd@MIL-101(Cr)-NH2). This could be achieved under some of the mildest conditions reported to date and a strong control over the leaching of metallic species could be maintained, despite the presence of diverse functional groups and/or several heteroatoms. Some of the targeted molecules are important intermediates in the synthesis of pharmaceuticals and we clearly exemplify the versatility of this catalytic system, which affords better yields than currently existing commercial procedures. Most importantly, Pd@MIL-101-NH2 was packed in a micro-flow reactor, which represents the first report of metallic nanoparticles supported on MOFs employed in flow chemistry for catalytic applications. A small library of 11 isolated compounds was created in a continuous experiment without replacing the catalyst, demonstrating the potential of the catalyst for large-scale applications.

  • 168.
    Pascanu, Vlad
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Yao, Qingxia
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Bermejo Gomez, Antonio
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Gustafsson, Mikaela
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Yun, Yifeng
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Wan, Wei
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Samain, Louise
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Zou, Xiaodong
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Martin-Matute, Belen
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Sustainable Catalysis: Rational Pd Loading on MIL-101Cr-NH2 for More Efficient and Recyclable Suzuki-Miyaura Reactions2013In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, no 51, p. 17483-17493Article in journal (Refereed)
    Abstract [en]

    Palladium nanoparticles have been immobilized into an amino-functionalized metal-organic framework (MOF), MIL-101Cr-NH2, to form Pd@MIL-101Cr-NH2. Four materials with different loadings of palladium have been prepared (denoted as 4-, 8-, 12-, and 16wt%Pd@MIL-101Cr-NH2). The effects of catalyst loading and the size and distribution of the Pd nanoparticles on the catalytic performance have been studied. The catalysts were characterized by using scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier-transform infrared (FTIR) spectroscopy, powder X-ray diffraction (PXRD), N-2-sorption isotherms, elemental analysis, and thermogravimetric analysis (TGA). To better characterize the palladium nanoparticles and their distribution in MIL-101Cr-NH2, electron tomography was employed to reconstruct the 3D volume of 8wt%Pd@MIL-101Cr-NH2 particles. The pair distribution functions (PDFs) of the samples were extracted from total scattering experiments using high-energy X-rays (60keV). The catalytic activity of the four MOF materials with different loadings of palladium nanoparticles was studied in the Suzuki-Miyaura cross-coupling reaction. The best catalytic performance was obtained with the MOF that contained 8wt% palladium nanoparticles. The metallic palladium nanoparticles were homogeneously distributed, with an average size of 2.6nm. Excellent yields were obtained for a wide scope of substrates under remarkably mild conditions (water, aerobic conditions, room temperature, catalyst loading as low as 0.15mol%). The material can be recycled at least 10times without alteration of its catalytic properties.

  • 169. Patel, Dhilon S.
    et al.
    Pendrill, Robert
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Mallajosyula, Sairam S.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    MacKerell, Alexander D., Jr.
    Conformational Properties of alpha- or beta-(1 -> 6)-Linked Oligosaccharides: Hamiltonian Replica Exchange MD Simulations and NMR Experiments2014In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, no 11, p. 2851-2871Article in journal (Refereed)
    Abstract [en]

    Conformational sampling for a set of 10 alpha- or beta-(1 -> 6)-linked oligosaccharides has been studied using explicit solvent Hamiltonian replica exchange (HREX) simulations and NMR spectroscopy techniques. Validation of the force field and simulation methodology is done by comparing calculated transglycosidic J coupling constants and proton-proton distances with the corresponding NMR data. Initial calculations showed poor agreement, for example, with >3 Hz deviation of the calculated (3)J(H5,H6R) values from the experimental data, prompting optimization of the omega torsion angle parameters associated with (1 -> 6)-linkages. The resulting force field is in overall good agreement (i.e., within similar to 0.5 Hz deviation) from experimental (3)J(H5,H6R) values, although some small limitations are evident. Detailed hydrogen bonding analysis indicates that most of the compounds lack direct intramolecular H-bonds between the two monosaccharides; however, minor sampling of the O6 center dot center dot center dot HO2' hydrogen bond is present in three compounds. The results verify the role of the gauche effect between O5 and O6 atoms in gluco- and manno-configured pyranosides causing the omega torsion angle to sample an equilibrium between the gt and gg rotamers. Conversely, galacto-configured pyranosides sample a population distribution in equilibrium between gt and tg rotamers, while the gg rotamer populations are minor. Water radial distribution functions suggest decreased accessibility to the O6 atom in the (1 -> 6)-linkage as compared to the O6' atom in the nonreducing sugar. The role of bridging water molecules between two sugar moieties on the distributions of omega torsion angles in oligosaccharides is also explored.

  • 170.
    Pathi Pati, Stalin Reddy
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Development of new Catalytic Methods for the Selective Synthesis of Heterocycles2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In the field of organic chemistry, the development of new catalytic methods for the synthesis of complex molecules from simple precursors is a top priority. The main focus of this thesis concerns the diastereoselective synthesis of heterocyclic compounds using main group elements as Lewis acid catalysts.

    The first part of this thesis deals with an annulation reaction of nitrones with oxiranes, aziridines, and thiiranes using Al(III) or In(III) catalysts. From this protocol, 1,4,2-dioxazinanes, 1,2,4-oxadiazinanes, and 1,4,2-oxathiazinanes were obtained in moderate to high yields with excellent diastereoselectivity. The transformation was found to be stereospecific and proceed via an SN2-mechanism.

    The second and third parts concern the development of In(III)-catalyzed annulation of carbonyl compounds, amines, and alkynyl enones. InBr3 was found to be an efficient catalyst for the activation of alkynyl enones in a multicomponent reaction with aldehydes and amines. The method affords cyclopenta[c]furans in high yields and in good to excellent diastereomeric ratios. Bicyclo[3.n.1]alkenone derivatives were formed via a double Michael addition reaction of cyclic ketones, amines, and alkynyl enones, in the presence of InCl3. The utility of these protocols was also demonstrated by sequential transformations.

    In the fourth part, AgOTf and CuI were found to be efficient catalysts for the activation of pyridine-substituted enynes towards enamines, providing indolizine derivatives in high yield and good diastereomeric ratios.

    In the last part of the thesis, 1,2-aminoarylation of γ,δ-unsaturated oxime esters with arylboronic acids using Ni catalysis is discussed. The protocol demonstrates the potential of Ni-catalysts for the generation of iminyl radicals to furnish functionalized pyrroline derivatives. The utility of this protocol was exemplified by transforming the pyrroline products to the corresponding pyrrole and pyrrolidine derivatives. 

  • 171.
    Pathipati, Stalin R.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Eriksson, Lars
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Selander, Nicklas
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Stereoselective synthesis of bicyclo[3.n.1]alkenone frameworks by Lewis acid-catalysis2017In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 53, no 82, p. 11353-11356Article in journal (Refereed)
    Abstract [en]

    An intermolecular cyclization of alkynyl enones with cyclic ketones for the synthesis of bicyclo[3.n.1]alkenones is reported. This protocol exhibits a high functional group tolerance and provides access to a variety of bicyclic systems found as skeletons in many natural products.

  • 172.
    Pathipati, Stalin R.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Singh, Vipender
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Eriksson, Lars
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Selander, Nicklas
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Lewis Acid Catalyzed Annulation of Nitrones with Oxiranes, Aziridines, and Thiiranes2015In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 17, no 18, p. 4506-4509Article in journal (Refereed)
    Abstract [en]

    A highly selective Lewis acid catalyzed annulation of three-membered heterocycles with nitrones has been developed. Oxiranes, aziridines, and thiiranes were used as substrates for the synthesis of various six-membered heterocycles using Al or In catalysts. This catalytic protocol demonstrates a broad substrate scope and provides access to new structural motifs in high yields and in excellent selectivity under mild reaction conditions.

  • 173.
    Pathipati, Stalin R.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    van der Werf, Angela
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Eriksson, Lars
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Selander, Nicklas
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Diastereoselective Synthesis of Cyclopenta[c]furans by a Catalytic Multicomponent Reaction2016In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 55, no 39, p. 11863-11866Article in journal (Refereed)
    Abstract [en]

    A diastereoselective three-component reaction between alkynyl enones, aldehydes and secondary amines is reported. With the aid of a benign indium catalyst, a range of highly substituted cyclopenta[c]furan derivatives can be obtained in a single-step procedure. The formation of the stereodefined heterocyclic motifs takes place via in situ generation of enamines followed by two sequential cyclization steps.

  • 174.
    Pendrill, Robert
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Conformations of Flexible Oligosaccharides: Molecular Simulations and NMR spectroscopy2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The conformational preferences of several oligosaccharides are investigated herein using a combination of NMR spectroscopy and molecular dynamics (MD) simulations, focusing on the torsion angles associated with the glycosidic linkages.

    Strategies for obtaining usable J-HMBC spectra for carbons with an adjacent 13C label are described. By employing a selective pulse or a constant time modification, spectra free from interferences are obtained for site-specifically 13C labeled oligosaccharides.

    Intermolecular hydrogen bonding in sucrose is investigated using MD simulations performed at different concentrations. One of the most frequent intermolecular hydrogen bonds in the simulations, O3f∙∙∙HO3g, was detected using the HSQC-TOCSY NMR experiment.

    Based on MD simulations and NMR spectroscopy, the conformational ensemble for a trisaccharide segment of the LeaLex hexasaccharide is proposed to feature conformational exchange between conformations with positive and negative values for the ψ3 torsion angle in the β-D-GlcpNAc-(1→3)-β-D-Galp linkage.

    Using MD simulations, the conformation of the N-acetyl group is shown to influence the glycosidic conformation at a nearby linkage in two oligosaccharides.

    Short (1→6)-linked oligosaccharides are shown to exhibit conformational exchange at the ω and ψ torsion angles. Notably, the former torsion angle populates states with ψ ≈ ±90°. Conformationally sensitive homo- and heteronuclear coupling constants are determined using various NMR experiments. The experimental data, including effective distances from NOESY obtained for two of the compounds, is used to improve the representation of the ω torsion angle in the CHARMM36 force field.

  • 175.
    Pendrill, Robert
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Eriksson, Lars
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Methyl 4-O-benzyl-alpha-l-rhamno-pyrano-side2014In: Acta Crystallographica Section E: Structure Reports Online, ISSN 1600-5368, E-ISSN 1600-5368, Vol. 70, p. o561-o562Article in journal (Refereed)
  • 176.
    Pendrill, Robert
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Jonsson, K. Hanna M.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Glycan synthesis, structure, and dynamics: A selection2013In: Pure and Applied Chemistry, ISSN 0033-4545, E-ISSN 1365-3075, Vol. 85, no 9, p. 1759-1770Article in journal (Refereed)
    Abstract [en]

    Glycan structural information is a prerequisite for elucidation of carbohydrate function in biological systems. To this end we employ a tripod approach for investigation of carbo hydrate 3D structure and dynamics based on organic synthesis; different experimental spectroscopy techniques, NMR being of prime importance; and molecular simulations using, in particular, molecular dynamics (MD) simulations. The synthesis of oligosaccharides in the form of glucosyl fluorides is described, and their use as substrates for the Lam16A E115S glucosyl synthase is exemplified as well as a conformational analysis of a cyclic beta-(1 -> 3)-heptaglucan based on molecular simulations. The flexibility of the N-acetyl group of aminosugars is by MD simulations indicated to function as a gatekeeper for transitions of glycosidic torsion angles to other regions of conformational space. A novel approach to visualize glycoprotein (GP) structures is presented in which the protein is shown by, for example, ribbons, but instead of stick or space-filling models for the carbohydrate portion it is visualized by the colored geometrical figures known as CFG representation in a 3D way, which we denote 3D-CFG, thereby effectively highlighting the sugar residues of the glycan part of the GP and the position(s) on the protein.

  • 177.
    Pendrill, Robert
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Säwén, Elin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Conformation and Dynamics at a Flexible Glycosidic Linkage Revealed by NMR Spectroscopy and Molecular Dynamics Simulations: Analysis of β-ʟ-Fucp-(1→6)-α-ᴅ-Glcp-OMe in Water Solution2013In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 117, no 47, p. 14709-14722Article in journal (Refereed)
    Abstract [en]

    The intrinsic flexibility of carbohydrates facilitates different 3D structures in response to altered environments. At glycosidic (1 -> 46)-linkages, three torsion angles are variable, and herein the conformation and dynamics of beta-1.-Fucp-(1 -> 6)-alpha-D-Glcp-OMe are investigated using a combination of NMR spectroscopy and molecular dynamics (MD) simulations. The disaccharide shows evidence of conformational averaging for the psi and co torsion angles, best explained by a four-state conformational distribution. Notably, there is a significant population of conformations having psi = 85 degrees (clinal) in addition to those having psi = 180 degrees (anfiperiplanar). Moderate differences in C-13 R-1 relaxation rates are found to be best explained by axially symmetric tumbling in combination with minor differences in librational motion for the two residues, whereas the isomerization motions are occurring too slowly to significantly to the observed relaxation rates. The MD simulation was found to give a reasonably good agreement with experiment, especially with respect to diffusive properties, among which the rotational anisotropy, D parallel to/D parallel to, is found to be 2.35. The force field employed showed too narrow omega torsion angles in the gauche trans and gauche gauche states as well as overestimating the population of the gauche trans conformer. This information can subsequently be used in directing parameter developments and emphasizes the need for refinement of force fields for (1 -> 6)-linked carbohydrates.

  • 178.
    Pendrill, Robert
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Sørensen, Ole W.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Suppressing one-bond homonuclear 13C,13C scalar couplings in the J-HMBC NMR experiment: application to 13C site-specifically labeled oligosaccharides2014In: Magnetic Resonance in Chemistry, ISSN 0749-1581, E-ISSN 1097-458X, Vol. 52, no 3, p. 82-86Article in journal (Refereed)
    Abstract [en]

    Site-specific C-13 isotope labeling is a useful approach that allows for the measurement of homonuclear C-13,C-13 coupling constants. For three site-specifically labeled oligosaccharides, it is demonstrated that using the J-HMBC experiment for measuring heteronuclear long-range coupling constants is problematical for the carbons adjacent to the spin label. By incorporating either a selective inversion pulse or a constant-time element in the pulse sequence, the interference from one-bond C-13,C-13 scalar couplings is suppressed, allowing the coupling constants of interest to be measured without complications. Experimental spectra are compared with spectra of a nonlabeled compound as well as with simulated spectra. The work extends the use of the J-HMBC experiments to site-specifically labeled molecules, thereby increasing the number of coupling constants that can be obtained from a single preparation of a molecule.

  • 179. Perepelov, Andrei V.
    et al.
    Shashkov, Alexander S.
    Guo, Xi
    Filatov, Andrei V.
    Weintraub, Andrej
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Knirel, Yuriy A.
    Structure and genetics of the O-antigen of Escherichia coli O169 related to the O-antigen of Shigella boydii type 62015In: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 414, p. 46-50Article in journal (Refereed)
    Abstract [en]

    The O-polysaccharide (O-antigen) of Escherichia coli O169 was studied by sugar analysis along with 1D and 2D H-1 and C-13 NMR spectroscopy. The following structure of the branched hexasaccharide repeating unit was established: [GRAPHICS] The O-polysaccharide of E. coli O169 differs from that of Shigella boydii type 6 only in the presence of a side-chain glucose residue. A comparison of the O-antigen biosynthesis gene clusters between the galF to gnd genes in the genomes of the two bacteria revealed their close relationship. The glycosyltransferase gene responsible for the formation of the beta-D-Glcp-(1 -> 6)-alpha-D-Galp linkage in the O-antigen was identified in the gene cluster.

  • 180. Perepelov, Andrei V.
    et al.
    Wang, Quan
    Filatov, Andrei V.
    Xia, Xianghong
    Shashkov, Alexander S.
    Weintraub, Andrej
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Wang, Lei
    Knirel, Yuriy A.
    Structures and gene clusters of the closely related O-antigens of Escherichia coli O46 and O134, both containing D-glucuronoyl-D-allothreonine2015In: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 409, p. 20-24Article in journal (Refereed)
    Abstract [en]

    The O-polysaccharides (O-antigens) were isolated by mild acid degradation of the lipopolysaccharide (LPS) of Escherichia coli O46 and O134. The structures of their linear tetrasaccharide repeating units were established by sugar analysis along with 1D and 2D H-1 and C-13 NMR spectroscopy: [GRAPHICS] where D-aThr indicates D-allothreonine and R indicates O-acetyl substitution (similar to 70% on aThr and similar to 15% on GalNAc) in E. coli O46 whereas the O-acetylation is absent in E. coli O134. Functions of genes in the essentially identical O-antigen gene clusters of E. coli O46 and O134 were tentatively assigned by a comparison with sequences in available databases and found to be in agreement with the O-polysaccharide structures established.

  • 181.
    Persson, Andreas K. Å.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Palladium(II)-Catalyzed Oxidative Cyclization Strategies: Selective Formation of New C-C and C-N Bonds2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The main focus of this thesis has been directed towards preparation and oxidative carbocyclization of en-, dien- and aza-enallenes.

    In the first part of this thesis, a stereoselective oxidative carbocyclization of dienallenes was realized. By employing cheap and readily available palladium trifluoroacetate we were able to efficiently cyclize a variety of dienallenes into hydroxylated carbocycles in high yield and high selectivity. This oxidative process was compatible with two different reoxidation protocols: one relying on p-benzoquinone (BQ) as the oxidant and the other employing molecular oxygen as the oxidant.

    In the second part of the thesis the carbocyclization methodology was extended to include carbocyclization of aza-enallenes. This was achieved in two distinct steps. First, a copper-catalyzed coupling of allylic sulfonamides with bromoallenes was developed, giving access to the corresponding aza-enallenes. Subjecting these substrates to catalytic amounts of palladium acetate, along with BQ as the oxidant, rendered N-heterocycles in good yield. The reactivity of these N-heterocycles towards activated dienophiles was later exploited in a tandem (aerobic) oxidative carbocyclization/Diels-Alder reaction.

    The third topic involves efficient oxidative arylative/borylative carbocyclization of enallenes. These reactions, catalyzed by palladium acetate, relies on transmetallation of a (σ-alkyl)palladium(II) intermediate with diboranes or arylboronic acids. With this novel methodology we were able to obtain an array of arylated or borylated carbocycles, as single diastereomers, in high yield.

    Finally, we developed a palladium(II)-catalyzed cyclization of allylic carbamates. This mild, operationally simple, and scalable catalytic reaction opens up access to an array of oxazolidinones in high yield and excellent diastereoselectivity.

  • 182.
    Peters, Byron
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Iridium Catalysed Asymmetric Hydrogenation of Olefins and Isomerisation of Allylic Alcohols2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The work described in this thesis is focused on exploring the efficacy of asymmetric iridium catalysis in the hydrogenation of challenging substrates, including precursors to chiral sulfones and chiral cyclohexanes. Furthermore, iridium catalysis was used to isomerise allylic alcohols to aldehydes, and in a formal total synthesis of Aliskiren (a renin inhibitor). A large variety of unsaturated sulfones (cyclic, acyclic, vinylic, allylic and homoallylic) were prepared and screened in the iridium catalysed hydrogenation reaction using a series of previously developed N,P-ligated Ir-catalysts. The outcome was a highly enantioselective (>90% ee) protocol to prepare sulfones bearing chiral carbon scaffolds, sometimes having purely aliphatic substituents at the stereogenic centre. Furthermore, performing the Ramberg-Bäcklund reaction on the chiral products, under optimised conditions, produced cyclic and acyclic unsaturated derivatives without erosion of enantiomeric excess. This hydrogenation protocol was also successful in the hydrogenation of a number of cyclohexene-containing compounds. Minimally functionalised, functionalised and heterocycle-containing cyclohexenes were hydrogenated in up to 99% ee. Hitherto, both chiral sulfones and chiral cyclohexanes have been challenging targets for most catalytic asymmetric methodologies. Although the preparation of aldehydes and ketones by isomerisation of the corresponding allylic alcohol is well established, there has been limited success in the development of good enantioselective protocols. For the isomerisation of a number γ,γ-allylic alcohols to the corresponding chiral aldehydes, high enantioselectivities (up to >99% ee) and modest yields were achieved using an N,P-iridium catalyst. Noteworthy is the high selectivity obtained for isomerisation of and dialkyl γ,γ-allylic alcohols, which prior to this study had been difficult to isomerise in high enantioselectivity. Preparation of a key intermediate used in the synthesis of Aliskiren, a renin inhibitor drug was also accomplished. Using a convergent synthesis strategy, two allylic alcohol fragments were hydrogenated with high enantiomeric excess (>92% ee). These fragments were then joined using a Julia-Kocienski reaction, providing >95% geometry around the C=C bond, which was crucial for the subsequent steps in the synthesis.

  • 183.
    Peters, Byron K.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Liu, Jianguo
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Margarita, Cristiana
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Rabten, Wangchuk
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Kerdphon, Sutthichat
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Orebom, Alexander
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Morsch, Thomas
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Andersson, Pher G.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Enantio- and Regioselective Ir-Catalyzed Hydrogenation of Di- and Trisubstituted Cycloalkenes2016In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, no 36, p. 11930-11935Article in journal (Refereed)
    Abstract [en]

    A number of cyclic olefins Were prepared and evaluated for the asymmetric hydrogenation reaction using novel N,P-ligated iridium imidazote-based Catalysts (Crabtree type). The diversity of these cyclic olefins spanned those having little functionality to others bearing strongly coordinating substituents and heterocycles. Excellent enantioselectivities were observed both for substrates having little functionality (up to >99% ee) and for substrates possessing functional groups several carbons away from the olefin. Substrates having functionalities such as carboxyl groups, alcohols, or heterocycles in the vicinity of the C=C bond were hydrogenated in high enantiomeric excess (up to >99% ee). The hydrogenation was also found to be regioselective, and by controlling the reaction conditions, selective hydrogenation of one of two trisubstituted olefins can be achieved: Furthermore, trisubstituted olefins can be selectively hydrogenated in the presence of tetrasubstituted olefins.

  • 184.
    Platero-Prats, Ana E.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK). Argonne National Laboratory, USA.
    Bermejo Gómez, Antonio
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Chapman, Karena W.
    Martin-Matute, Belén
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Zou, Xiaodong
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Functionalising metal-organic frameworks with metal complexes: the role of structural dynamics2015In: CrystEngComm, ISSN 1466-8033, E-ISSN 1466-8033, Vol. 17, no 40, p. 7632-7635Article in journal (Refereed)
    Abstract [en]

    A series of iridium-functionalised UiO-67 metal-organic frameworks (MOFs) were synthesised under conditions that simulate kinetically- and thermodynamically-controlled regimes. The degree of functionalisation depends on the reaction time and relative acidity of the native- and metallo-linkers, and can be optimised by controlling the reaction time.

  • 185.
    Platero-Prats, Ana E.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry. Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Bermejo Gómez, Antonio
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Samain, Louise
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Zou, Xiaodong
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Martin-Matute, Belén
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    The First One-Pot Synthesis of Metal-Organic Frameworks Functionalised with Two Transition-Metal Complexes2015In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 2, p. 861-866Article in journal (Refereed)
    Abstract [en]

    The synthesis of a metal-organic framework (UiO-67) functionalised simultaneously with two different transition metal complexes (Ir and Pd or Rh) through a one-pot procedure is reported for the first time. This has been achieved by an iterative modification of the synthesis parameters combined with characterisation of the resulting materials using different techniques, including X-ray absorption spectroscopy (XAS). The method also allows the first synthesis of UiO-67 with a very wide range of loadings (from 4 to 43 mol%) of an iridium complex ([IrCp*(bpydc)(Cl)Cl](2-); bpydc=2,2'-bipyridine-5,5'-dicarboxylate, Cp* = pentamethylcyclopentadienyl) through a pre-functionalisation methodology.

  • 186.
    Pu, Maoping
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Molecular Motion in Frustrated Lewis Pair Chemistry: insights from modelling2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Mechanisms of reactions of the frustrated Lewis pairs (FLPs) with carbon dioxide (CO2) and hydrogen (H2) are studied by using quantum chemical modelling. FLPs are relatively novel chemical systems in which steric effects prevent a Lewis base (LB) from donating its electron pair to a Lewis acid (LA). From the main group of the periodic table, a variety of the electron pair donors and acceptors can create an FLP and the scope of the FLP chemistry is rapidly expanding at present. Representative intermolecular FLPs are phosphines and boranes with bulky electron-donating groups on phosphorus and bulky electron-withdrawing groups on boron – e.g., the tBu3P/B(C6F5)3 pair. The intramolecular FLPs feature linked LB and LA centers in one molecule.

    Investigations of the FLP reaction mechanisms were carried out using the transition state (TS) and the potential energy surface (PES) calculations plus the Born-Oppenheimer molecular dynamics (BOMD) as an efficient and robust implementation of general ab initio molecular dynamics scheme. In BOMD simulations, quantum and classical mechanics are combined. The electronic structure calculations are fully quantum via the density functional theory (DFT). Molecular motion at finite (non-zero) temperature is explicitly accounted for at non-quantized level via Newton’s equations. Due to recent advancements of computers and algorithms, one can treat fairly large macromolecular systems with BOMD and even include significant portion of the first solvation shell surrounding a large reacting complex in the molecular model.

    Main results are as follows. It is shown that dynamics is significant for understanding of FLP chemistry. The multiscale nature of motion – i.e., light molecules such as CO2 or H2 versus a pair of heavy LB and LA molecules – affects the evolution of interactions in the reacting complex. Motion which is perpendicular to the reaction coordinate was found to play a role in the transit of the activated complex through the TS-region. Regarding the heterolytic cleavage of H2 by tBu3P/B(C6F5)3 FLP simulated in gas phase and with explicit solvent, it was found that (i) the reaction path includes shallow quasi-minima “imbedded” in the TS-region, and (ii) tBu3P/B(C6F5)3 are almost stationary while proton- and hydride-like fragments of H2 move toward phosphorous and boron respectively. For binding of CO2 by tBu3P/B(C6F5)3 FLP, it was found that (i) the reacting complex can “wander” along the “potential energy wall” that temporarily blocks the path to the product, and (ii) the mechanism can combine the concerted and two-step reaction paths in solution. The discovered two-step binding of CO2 by tBu3P/B(C6F5)3 FLP involves solvent-stabilized phosphorus-carbon interactions (dative bonding). These and other presented results are corroborated and explained using TS and PES calculations. With computations of observable characteristics of reactions, it is pointed out how it could be possible to attain experimental proof of the results.

  • 187.
    Quan, Xu
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Hydrogenation, Transfer Hydrogenation and Hydrogen Transfer Reactions Catalyzed by Iridium Complexes2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The work described in this thesis is focused on the development of new bidentate iridium complexes and their applications in the asymmetric reduction of olefins, ketones and imines. Three new types of iridium complexes were synthesized, which included pyridine derived chiral N,P-iridium complexes, achiral NHC complexes and chiral NHC-phosphine complexes. A study of their catalytic applications demonstrated a high efficiency of the N,P-iridium complexes for asymmetric hydrogenation of olefins, with good enantioselectivity. The carbene complexes were found to be very efficient hydrogen transfer mediators capable of abstracting hydrogen from alcohols and subsequently transfer it to other unsaturated bonds. This hydrogen transferring property of the carbene complexes was used in the development of C–C and C–N bond formation reactions via the hydrogen borrowing process. The complexes displayed high catalytic reactivity using 0.5–1.0 mol% of the catalyst and mild reaction conditions. Finally chiral carbene complexes were found to be activated by hydrogen gas. Their corresponding iridium hydride species were able to reduce ketones and imines with high efficiency and enantioselectivity without any additives, base or acid.

  • 188.
    Quan, Xu
    et al.
    Uppsala University, Sweden.
    Parihar, Vijay Singh
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Bera, Milan
    University of KwaZulu-Natal, South Africa.
    Andersson, Pher G.
    Stockholm University, Faculty of Science, Department of Organic Chemistry. University of KwaZulu-Natal, South Africa.
    Iridium Catalysts with Chiral Bicyclic Pyridine-Phosphane Ligands for the Asymmetric Hydrogenation of Olefins2014In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 2014, no 1, p. 140-146Article in journal (Refereed)
    Abstract [en]

    New bicyclic pyridine-phosphane ligands were prepared, and their iridium complexes were evaluated in asymmetric hydrogenation of trisubstituted olefins with non-coordinating and weakly coordinating substituents. The iridium catalysts showed high reactivity and enantioselectivity for both types of olefins.

  • 189.
    Rabten, Wangchuk
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    The Use of N,P-Iridium and N,P-Palladium Complexes in Asymmetric Synthesis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The work presented in this thesis concerns asymmetric catalysis using chiral N,P-ligands and iridium or palladium transition metals. The first part  (Chapters 2 and 3) highlights the N,P-iridium catalyzed asymmetric hydrogenation of 1,4-cyclohexadienes having functionalized or unfunctionalized substituents, including allylsilane side chains. A series of N,P-iridium catalysts were synthesized and screened on a number of cyclohexadienes. The developed N,P-iridium catalysts have provided excellent chemo-, regio- and enantioselectivity for most of the products obtained. For substrates having an allylsilane sidechain, the chiral cyclic allylsilane products were used to induce stereocontrol in a subsequent Hosomi-Sakurai reaction using TiCl4 as Lewis acid and aldehydes as electrophiles. The corresponding homoallylic alcohols were obtained in good to excellent diastereoselectivity. 

    The second part (Chapter 4) describes the N,P-iridium catalyzed asymmetric hydrogenation of various vinyl fluorides. A number of tri- and tetrasubstituted vinyl fluorides were synthesized and evaluated for the asymmetric hydrogenation. The corresponding saturated chiral fluoro compounds were obtained in very high enantioselectivity (up to 99% ee). The defluorination, usually known to occur under the catalytic hydrogenation conditions, were not observed for the majority of the substrates. 

    Finally, Chapter 5 describes the application of N,P-ligands in the asymmetric cycloisomerization of 1,6-enynes using a palladium precatalyst. The enantioselectivities for the products were found to depend both on the substrate as well as the hydrogen source. These developed catalytic reactions provide attractive methods to create multiple stereogenic centers in a molecule in relatively few steps from readily available starting materials.

  • 190.
    Rabten, Wangchuk
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Margarita, Margarita
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Eriksson, Lars
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK).
    Andersson, Pher G.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Ir-Catalyzed Asymmetric and Regioselective Hydrogenation of Cyclic Allylsilanes and Generation of Quaternary Stereocenters via the Hosomi-Sakurai Allylation2018In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, no 7, p. 1681-1685Article in journal (Refereed)
    Abstract [en]

    A number of cyclic dienes containing the allylsilane moiety were prepared via Birch reduction and subjected to iridium-catalyzed regioselective and asymmetric hydrogenation, which provided chiral allylsilanes in high conversion and enantiomeric excess (up to 99 % ee). The compounds were successively used in the Hosomi-Sakurai allylation with various aldehydes employing TiCl4 as Lewis acid, providing adducts with two additional stereogenic centers in excellent diastereoselectivity.

  • 191.
    Ramstadius, Clinton
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Synthesis of Carbohydrate Mimics and Development of a Carbohydrate Epimerisation Method2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis the synthesis of several hydrolytically stable carbohydrate mimics with the potential to function as glycosidase or lectin inhibitors are described. This work is presented in Chapters 2-5.

    Chapters 2 and 3 describe synthetic efforts for producing carbasugars, and include the first synthesis of 1,2-bis-epi-valienamine and the preparation of two previously known aminocarbasugars. All three compounds were synthesised starting from D-mannose, using ring-closing metathesis as the key step. 1,2-Bis-epi-valienamine was found to inhibit Cellulomonas fimi β-mannosidase with a Ki value of 140 mM. Also included is the development of a novel synthetic route from cheap D-fructose to three mannose-mimicking carbasugars using a ring-closing metathesis strategy. Two of the compounds are potential inhibitors of the FimH adhesin.

    In Chapters 4 and 5 the synthesis of a number of pseudodisaccharides are presented; valienamine- and epi-valienamine-containing pseudodisaccharides and a small library of S-linked pseudodisaccharides were prepared. Various synthetic strategies were explored, including an alkylation strategy, Mitsunobu couplings, and sulfonate displacements. This is the first report on the synthesis of a valienamine pseudodisaccharide with β-lyxo-configuration. Two of the S-linked pseudodisaccharides were found to bind to Concanavalin A with high affinity.

    The final chapter (Chapter 6) of this thesis focuses on the development of a carbohydrate epimerisation method using transition metal catalysis. Two equilibrium constants involving gluco/manno- and gluco/allo-alcohols were determined via this method.

  • 192.
    Reitti, Marcus
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Villo, Piret
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Olofsson, Berit
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    One-Pot C-H Functionalization of Arenes by Diaryliodonium Salts2016In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 55, no 31, p. 8928-8932Article in journal (Refereed)
    Abstract [en]

    A transition-metal-free, mild, and highly regioselective synthesis of nitroarenes from arenes has been developed. The products are obtained in a sequential one-pot reaction by nitration of iodine(III) reagents with two carbon ligands, which are formed in situ from iodine(I). This novel concept has been extended to formation of aryl azides, and constitutes an important step towards catalytic reactions with these hypervalent iodine reagents. An efficient nitration of isolated diaryl-iodonium salts has also been developed, and the mechanism is proposed to proceed by a [2,2] ligand coupling pathway.

  • 193. Rojas-Macias, Miguel A.
    et al.
    Ståhle, Jonas
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Luetteke, Thomas
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Development of the ECODAB into a relational database for Escherichia coli O-antigens and other bacterial polysaccharides2015In: Glycobiology, ISSN 0959-6658, E-ISSN 1460-2423, Vol. 25, no 3, p. 341-347Article in journal (Refereed)
    Abstract [en]

    Escherichia coli O-antigen database (ECODAB) is aweb-based application to support the collection of E. coli O-antigen structures, polymerase and flippase amino acid sequences, NMR chemical shift data of O-antigens as well as information on glycosyltransferases (GTs) involved in the assembly of O-antigen polysaccharides. The database content has been compiled from scientific literature. Furthermore, the system has evolved from being a repository to one that can be used for generating novel data on its own. GT specificity is suggested through sequence comparison with GTs whose function is known. The migration of ECODAB to a relational database has allowed the automation of all processes to update, retrieve and present information, thereby, endowing the system with greater flexibility and improved overall performance. ECODAB is freely available at http://www.casper.organ.su.se/ECODAB/. Currently, data on 169 E. coli unique O-antigen entries and 338 GTs is covered. Moreover, the scope of the database has been extended so that polysaccharide structure and related information from other bacteria subsequently can be added, for example, from Streptococcus pneumoniae.

  • 194.
    Rönnols, Jerk
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Structure, dynamics and reactivity of carbohydrates: NMR spectroscopic studies2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The main focus of this thesis is on the ring conformations of carbohydrate molecules; how the conformational equilibria and the rates of the associated interconversions are affected by the molecular constitution and their surroundings.

    The conformational equilibria of a group of amine linked pseudodisaccharides, designed as potential glycosidase inhibitors, comprising α-D-altrosides are described in Chapter 3. The OS2 conformation was largely populated, and the ring conformation was found to depend on the charge of the amine functionality.

    The conformations of β-D-xylopyranoside derivatives with naphthyl-based aglycones, which are potential anti-cancer agents, are described in chapter 4. Solvent dependent flexibility was observed. Intramolecular hydrogen bonds were concluded to be involved in the stabilization of 1C4 conformers in non-hydrogen bonding solvents of low polarity.

    Chapter 5 describes the first measurements of the conformational exchange rates of mannuronic acid ester derivatives between the 4C1 and 1C4 conformations, through DNMR measurements. The relative reactivity of glycosyl triflates as electrophiles in glycosylation reactions were investigated with NMR-based competition experiments.

    In Chapter 6, investigations of ruthenium-catalyzed epimerizations of the allylic alcohols of glycal derivatives, and stereoselective synthesis of esters through a DYKAT protocol, are described. The kinetics of the epimerizations were elaborated through different NMR-spectroscopic methods.

    Chapter 7 describes additions of NMR chemical shift data of mono- and oligosaccharides to database of the computer program CASPER, and applications thereof.

  • 195.
    Rönnols, Jerk
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Manner, Sophie
    Ellervik, Ulf
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Conformational effects due to stereochemistry and C3-substituents in xylopyranoside derivatives as studied by NMR spectroscopy2014In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 12, no 40, p. 8031-8035Article in journal (Refereed)
    Abstract [en]

    Glycosaminoglycans contain a beta-D-xylopyranose residue at its reducing end, which links the polysaccharide to the protein in proteoglycans. 2-Naphthyl beta-D-xylopyranosides have shown inhibition of tumor growth and we herein investigate conformation and dynamics of compounds structurally and stereochemically modified at the C3 position as well as the influence of solvent. The 3-deoxygenated compound, the 3-C-methyl-substituted beta-D-xylopyranoside, beta-D-ribopyranoside, the 3-C-methyl-substituted beta-D-ribopyranoside as well as 2-naphthyl beta-D-xylopyranoside were analyzed by NMR spectroscopy. Conformational equilibria were dependent on the solvent of choice, either methanol-d(4) or chloroform-d, with mainly C-4(1) and C-1(4) conformations present but also skew conformations to some extent. Intramolecular hydrogen bonding was concluded to be important for the 3-C-methyl-substituted beta-D-xylopyranosides in the non-polar solvent. Dynamic NMR (DNMR) spectroscopy was carried out for the 3-deoxygenated compound, which at 25 degrees C in methanol-d(4) exists with equally populated states of the C-4(1) and the C-1(4) conformations, but at -100 degrees C only a few percent is present of the latter. Using C-13 NMR detection for DNMR, resonance lines were shown to broaden at -40 degrees C and to sharpen again below -90 degrees C, without the emergence of a second set of NMR resonances, a typical behavior for an unequally populated equilibrium. The enthalpy and entropy activation barriers were calculated and resulted in Delta H-double dagger = 47.3 kJ mol(-1) and Delta S-double dagger = 54 J mol(-1) K-1.

  • 196.
    Rönnols, Jerk
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Pendrill, Robert
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Fontana, Carolina
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Hamark, Christoffer
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Angles d'Ortoli, Thibault
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Engström, Olof
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Ståhle, Jonas
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Zaccheus, Mona V.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Säwén, Elin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Hahn, Liljan E.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Iqbal, Shahzad
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Widmalm, Göran
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Complete H-1 and C-13 NMR chemical shift assignments of mono- to tetrasaccharides as basis for NMR chemical shift predictions of oligosaccharides using the computer program CASPER2013In: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 380, p. 156-166Article in journal (Refereed)
    Abstract [en]

    H-1 and C-13 NMR chemical shift data are used by the computer program CASPER to predict chemical shifts of oligo- and polysaccharides. Three types of data are used, namely, those from monosaccharides, disaccharides, and trisaccharides. To improve the accuracy of these predictions we have assigned the H-1 and C-13 NMR chemical shifts of eleven monosaccharides, eleven disaccharides, twenty trisaccharides, and one tetrasaccharide; in total 43 compounds. Five of the oligosaccharides gave two distinct sets of NMR resonances due to the alpha- and beta-anomeric forms resulting in 48 H-1 and C-13 NMR chemical shift data sets. In addition, the pyranose ring forms of Neu5Ac were assigned at two temperatures, due to chemical shift displacements as a function of temperature. The H-1 NMR chemical shifts were refined using total line-shape analysis with the PERCH NMR software. H-1 and C-13 NMR chemical shift predictions were subsequently carried out by the CASPER program (http://www.casper.organ.su.se/casper/) for three branched oligosaccharides having different functional groups at their reducing ends, namely, a mannose-containing pentasaccharide, and two fucose-containing heptasaccharides having N-acetyllactosamine residues in the backbone of their structures. Good to excellent agreement was observed between predicted and experimental H-1 and C-13 NMR chemical shifts showing the utility of the method for structural determination or confirmation of synthesized oligosaccharides.

  • 197.
    Sahoo, Suman
    et al.
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Inorganic and Structural Chemistry.
    Lundberg, Helena
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Edén, Mattias
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Physical Chemistry.
    Ahlsten, Nanna
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Wan, Wei
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Inorganic and Structural Chemistry.
    Zou, Xiaodong
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Inorganic and Structural Chemistry.
    Martín-Matute, Belén
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Single Site Supported Cationic Rhodium(I) Complexes for the Selective Redox Isomerization of Allylic Alcohols2012In: ChemCatChem, ISSN 1867-3880, E-ISSN 1867-3899, Vol. 4, no 2, p. 243-250Article in journal (Refereed)
    Abstract [en]

    The isomerization of allylic alcohols to carbonyl compounds by a heterogeneous rhodium complex is reported. Different silica material supports and catalyst/ligand systems were evaluated. The most efficient catalyst in terms of catalytic activity and stability was found to be a cationic rhodium(I) complex with sulfonated phosphine ligands anchored on a mesoporous aluminosilica AlSBA-15. The heterogeneous complex catalyzed the isomerization of a variety of allylic alcohols in excellent yields with very low catalyst loadings (0.5 mol %). The catalyst could be recycled without significant loss of activity or selectivity. The optimized catalyst was characterized by N2 sorption, powder X-ray diffraction, transmission electron microscopy, as well as solution and solid-state nuclear magnetic resonance, and Fourier Transform infrared spectroscopies.

  • 198.
    Samec, Joseph S M
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Ruthenium-catalyzed hydrogen transfer involving amines and imines: Mechanistic studies and synthetic applications2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis deals with ruthenium-catalyzed hydrogen transfer involving amines and imines and is divided into two parts.

    In Part 1 a mechanistic study has been performed. The complexation of the imine to the catalyst and the decomplexation patterns of the formed ruthenium-amine complexes, isotope studies, and exchange studies show that the mechanism of the hydrogen transfer involving amines and imines is different from the hydrogen transfer involving alcohols and carbonyls.

    In Part 2 synthetic applications of the hydrogen transfer is presented. First the rutheniumcatalyzed transfer hydrogenation of imines by 2-propanol in an unpolar solvent was investigated. The corresponding amines were isolated in good to excellent yields. Even imines bearing labile functional groups were smoothly transferred to amines with very low catalyst loadings and short reaction times employing microwave heating. Then the reverse reaction, transfer dehydrogenation of amines to imines, was investigated using either MnO2 or oxygen as terminal oxidant. Important products such as aldimines, ketimines, and non benzylic anilines were prepared in the aerobic oxidation. We also demonstrated that the aerobic oxidation is compatible with proline-mediated organocatalysis, yielding amines in high yields and ee:s. Finally the racemization of chiral amines was investigated. A cumbersome side product formation was investigated and hampered by the use of a mild hydrogen donor, giving a mild and efficient racemization process for both primary and secondary amines.

  • 199.
    Sandström, Anders G.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Protein Engineering of Candida antarctica Lipase A: Enhancing Enzyme Properties by Evolutionary and Semi-Rational Methods2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Enzymes are gaining increasing importance as catalysts for selective transformations in organic synthetic chemistry. The engineering and design of enzymes is a developing, growing research field that is employed in biocatalysis. In the present thesis, combinatorial protein engineering methods are applied for the development of Candida antarctica lipase A (CALA) variants with broader substrate scope and increased enantioselectivity. Initially, the structure of CALA was deduced by manual modelling and later the structure was established by X-ray crystallography. The elucidation of the structure of CALA revealed several biocatalytically interesting features. With the knowledge derived from the enzyme structure, enzyme variants were produced via iterative saturation mutagenesis (ISM), a powerful protein engineering approach. Several of these variants were highly active and enantioselective towards bulky esters. Furthermore, an extensively combinatorial protein engineering approach was developed and investigated. A CALA variant with a spacious substrate binding pocket that can accommodate an unusually bulky substrate, an ester derivate of the non-steroidal anti-inflammatory drug (S)-ibuprofen, was obtained with this approach.

  • 200.
    Sandström, Anders G.
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Wikmark, Ylva
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Engström, Karin
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Nyhlén, Jonas
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Bäckvall, Jan-E.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Combinatorial reshaping of the Candida antarctica lipase A substrate pocket for enantioselectivity using an extremely condensed library2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 1, p. 78-83Article in journal (Refereed)
    Abstract [en]

    A highly combinatorial structure-based protein engineering method for obtaining enantioselectivity is reported that results in a thorough modification of the substrate binding pocket of Candida antarctica lipase A (CALA). Nine amino acid residues surrounding the entire pocket were simultaneously mutated, contributing to a reshaping of the substrate pocket to give increased enantioselectivity and activity for a sterically demanding substrate. This approach seems to be powerful for developing enantioselectivity when a complete reshaping of the active site is required. Screening toward ibuprofen ester 1, a substrate for which previously used methods had failed, gave variants with a significantly increased enantioselectivity and activity. Wild-type CALA has a moderate activity with an E value of only 3.4 toward this substrate. The best variant had an E value of 100 and it also displayed a high activity. The variation at each mutated position was highly reduced, comprising only the wild type and an alternative residue, preferably a smaller one with similar properties. These minimal binary variations allow for an extremely condensed protein library. With this highly combinatorial method synergistic effects are accounted for and the protein fitness landscape is explored efficiently.

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