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  • 151. Biswas, Srijit
    et al.
    Dahlstrand, Christian
    Watile, Rahul A.
    Kalek, Marcin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Samec, Joseph S. M.
    Atom-Efficient Gold(I)-Chloride-Catalyzed Synthesis of alpha-Sulfenylated Carbonyl Compounds from Propargylic Alcohols and Aryl Thiols: Substrate Scope and Experimental and Theoretical Mechanistic Investigation2013Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, nr 52, s. 17939-17950Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 152.
    Björklund, Catarina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Design and Synthesis of BACE-1 Inhibitors: Novel Compounds Targeting an Aspartic Protease Important in the Pathogenesis of Alzheimer’s Disease2009Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

  • 153.
    Björklund, Catarina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Jansson, Katarina
    Lindberg, Jimmy
    Vrang, Lotta
    Hallberg, Anders
    Rosenquist, Åsa
    Samuelsson, Bertil
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Discovery of Potent BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Exploration of P1’ Alkoxy Residues and an Aminoethylene (AE) Central Core2010Ingår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, nr 4, s. 1711-1723Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1’ methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1’ pocket by introducing a set of P1’ alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1’ positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1’ positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed IC50 values in the range of 4-45 nM, where the most potent compounds featured small P1’ groups. The cathepsin D selectivity which was high for the smallest P1’ sustituents (P1’=ethoxy, fold selectively >600) dropped for larger groups (P1’=benzyloxy, fold selectivity of 1.6). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.

  • 154.
    Björklund, Catarina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Oscarson, Stefan
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Benkestock, Kurt
    Borkakoti, Neera
    Jansson, Katarina
    Lindberg, Jimmy
    Vrang, Lotta
    Hallberg, Anders
    Rosenquist, Åsa
    Samuelsson, Bertil
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Design and synthesis of potent and selective BACE-1 inhibitors2010Ingår i: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, nr 4, s. 1458-1464Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Several highly potent BACE-1 protease inhibitors have been developed from an inhibitor series containing a novel hydroxyethylene (HE) core structure displaying aryloxymethyl or benzyloxymethyl P1 side chains and a methoxy P1’ side chain. The target molecules were readily synthesized from chiral carbohydrate starting materials, furnishing the inhibitor compounds in good overall yields. The inhibitors show both high BACE-1 potency and good selectivity against cathepsin D, where the most potent inhibitor furnish a BACE-1 IC50 value of 0.32 nM and displays > 3000 fold selectivity over cathepsin D.

  • 155.
    Blasco, Pilar
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Patel, Dhilon S.
    Engström, Olof
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Im, Wonpil
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Conformational Dynamics of the Lipopolysaccharide from Escherichia coli O91 Revealed by Nuclear Magnetic Resonance Spectroscopy and Molecular Simulations2017Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 56, nr 29, s. 3826-3839Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 156.
    Blomberg, Margareta R. A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Can Reduction of NO to N2O in Cytochrome c Dependent Nitric Oxide Reductase Proceed through a Trans-Mechanism?2017Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 56, nr 1, s. 120-131Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 157.
    Blomberg, Margareta R. A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    How Quantum Chemistry Can Solve Fundamental Problems in Bioenergetics2015Ingår i: International Journal of Quantum Chemistry, ISSN 0020-7608, E-ISSN 1097-461X, Vol. 115, nr 18, s. 1197-1201Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 158.
    Blomberg, Margareta R. A.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mechanism of Oxygen Reduction in Cytochrome c Oxidase and the Role of the Active Site Tyrosine2016Ingår i: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 55, nr 3, s. 489-500Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 159.
    Blomberg, Margareta R. A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Borowski, Tomasz
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Liao, Rong-Zhen
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Siegbahn, Per E. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Quantum Chemical Studies of Mechanisms for Metalloenzymes2014Ingår i: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 114, nr 7, s. 3601-3658Artikel, forskningsöversikt (Refereegranskat)
  • 160.
    Blomberg, Margareta R. A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Siegbahn, Per E. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    How cytochrome c oxidase can pump four protons per oxygen molecule at high electrochemical gradient2015Ingår i: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1847, nr 3, s. 364-376Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 161.
    Blomberg, Margareta R. A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Siegbahn, Per E. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Improved free energy profile for reduction of NO in cytochrome c dependent nitric oxide reductase (cNOR)2016Ingår i: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 37, nr 19, s. 1810-1818Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 162.
    Blomberg, Margareta R. A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Siegbahn, Per E. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Proton pumping in cytochrome c oxidase: Energetic requirements and the role of two proton channels2014Ingår i: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1837, nr 7, s. 1165-1177Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 163.
    Blomberg, Margareta R. A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Siegbahn, Per E. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Protonation of the binuclear active site in cytochrome c oxidase decreases the reduction potential of Cu-B2015Ingår i: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1847, nr 10, s. 1173-1180Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 164.
    Blomberg, Margareta R. A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Siegbahn, Per E. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Why is the reduction of NO in cytochrome c dependent nitric oxide reductase (cNOR) not electrogenic?2013Ingår i: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1827, nr 7, s. 826-833Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 165.
    Blomberg, Margareta R. A.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Ädelroth, Pia
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
    The mechanism for oxygen reduction in cytochrome c dependent nitric oxide reductase (cNOR) as obtained from a combination of theoretical and experimental results2017Ingår i: Biochimica et Biophysica Acta - Bioenergetics, ISSN 0005-2728, E-ISSN 1879-2650, Vol. 1858, nr 11, s. 884-894Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 166.
    Bogár, Krisztián
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Synthetic Transformations via Metal- and Enzyme-Catalyzed Dynamic Kinetic Resolution2007Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

  • 167.
    Bogár, Krisztián
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bäckvall, Jan-E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    High-yielding metalloenzymatic dynamic kinetic resolution of fluorinated aryl alcohols2007Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 48, nr 31, s. 5471-5474Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 168.
    Bogár, Krisztián
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Hoyos Vidal, Pilar
    Alcántara León, Andrés R.
    Bäckvall, Jan-E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Chemoenzymatic Dynamic Kinetic Resolution of Allylic Alcohols: A Highly Enantioselective Route to Acyloin Acetates2007Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 9, nr 17, s. 3401-3404Artikel i tidskrift (Refereegranskat)
    Abstract [en]

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

  • 169.
    Bogár, Krisztián
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Krumlinde, Patrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bacsik, Zoltán
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Hedin, Niklas
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Bäckvall, Jan E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Heterogenized Wilkinson's Catalyst for Transfer Hydrogenation of Carbonyl Compounds2011Ingår i: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, nr 23, s. 4409-4414Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Wilkinson’s catalyst [RhCl(PPh3)3] was heterogenized on common silica by the use of a grafting/anchoring technique. The immobilized catalyst showed high activity and selectivity in transfer hydrogenation reactions of a range of carbonyl compounds in 2-propanol. Reactions carried out in 2-propanol at reflux afforded the corresponding alcohols in high yields in short reaction times. The heterogeneous feature ofthe catalyst allows for easy recovery and efficient reuse in the same reaction up to 5 times without any detectible loss of catalytic activity.

  • 170. Bogár, Krisztián
    et al.
    Krumlinde, Patrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bäckvall, Jan-Erling
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Hydrogenized Wilkinson´s Catalyst for Transfer Hydrogenation of Carbonyl CompoundsManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Combining the advantages of homogeneous and heterogeneous catalysis is possible by heterogenization of homogeneous transition metal complexes based on a grafting/anchoring technique. Wilkinson’s catalyst ((RhCl(PPh3)3) immobilized on common silica showed high activity and selectivity in transfer hydrogenation reactions of different carbonyl compounds in isopropanol. Reactions conducted at reflux in isopropanol afforded the corresponding carbinols in high yields in short reaction times. The heterogeneous feature of the catalyst allows easy recovery and efficient reuse in the same reaction up to 5 times without loss of catalytic activity.

  • 171.
    Bogár, Krisztián
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Martín-Matute, B.
    Bäckvall, Jan-E.
    Large Scale Metalloenzymatic Dynamic Kinetic Resolution of (rac)-1-PhenylethanolManuskript (Övrigt vetenskapligt)
  • 172. Bogár, Krisztián
    et al.
    Martín-Matute, Belén
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bäckvall, Jan-Erling
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Large-scale ruthenium- and enzyme-catalyzed dynamic kinetic resolution of (rac)-1-phenylethanol2007Ingår i: Beilstein Journal of Organic Chemistry, ISSN 1860-5397, Vol. 3, s. artikel nr 50-Artikel i tidskrift (Refereegranskat)
  • 173.
    Bogár, Krisztián
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Olofsson, Berit
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Fransson, Ann-Britt L.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bäckvall, Jan-E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Asymmetric synthesis of 3,5-disubstituted piperidines by enzyme-metal combo catalysis2006Ingår i: Enzymatic Synthesis, Stockholm, Sweden, 2006Konferensbidrag (Övrig (populärvetenskap, debatt, mm))
  • 174. Bollmark, Martin
    et al.
    Kullberg, Martin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Stawinski, Jacek
    Nucleoside H-phosphonates. Part 19: Novel nucleotide analogues H-phosphonoselenoate mono- and diesters2002Ingår i: Tetrahedron Letters, ISSN 0040-4039, Vol. 43, nr 3, s. 515-518Artikel i tidskrift (Refereegranskat)
  • 175. Borgström, Magnus
    et al.
    Johansson, Olof
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Lomoth, Reiner
    Berglund-Baudin, Helena
    Wallin, Staffan
    Sun, Licheng
    Åkermark, Björn
    Hammarström, Leif
    Electron Donor-Acceptor Dyads and Triads Based on Tris(bipyridine)ruthenium(II) and Benzoquinone: Synthesis, Characterization, and Photoinduced Electron Transfer Reactions2003Ingår i: Inorganic Chemistry, ISSN 0020-1669, Vol. 42, nr 17, s. 5173-5184Artikel i tidskrift (Refereegranskat)
  • 176. Borgström, Magnus
    et al.
    Shaikh, Nizamuddin
    Johansson, Olof
    Anderlund, Magnus F.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Styring, Stenbjörn
    Åkermark, Björn
    Magnuson, Ann
    Hammarström, Leif
    Light Induced Magnanese Oxidation and Long-lived Charge Separation in a Mn2II,II-RuII-acceptor triadManuskript (Övrigt vetenskapligt)
  • 177.
    Bornschein, Christoph
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Universität Rostock, Germany.
    Gustafson, Karl P. J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Verho, Oscar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Beller, Matthias
    Bäckvall, Jan-E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Evaluation of Fe and Ru Pincer-Type Complexes as Catalysts for the Racemization of Secondary Benzylic Alcohols2016Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, nr 33, s. 11583-11586Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fe and Ru pincer-type catalysts are used for the racemization of benzylic alcohols. Racemization with the Fe catalyst was achieved within 30 minutes under mild reaction conditions, with a catalyst loading as low as 2 mol %. This reaction constitutes the first example of an iron-catalyzed racemization of an alcohol. The efficiency for racemization of the Fe catalyst and its Ru analogue was evaluated for a wide range of sec-benzylic alcohols. The commercially available Ru complex proved to be highly robust and even tolerated the presence of water in the reaction mixture.

  • 178.
    Borén, Linnéa
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Enantioselective Synthesis of Sec-Alcohol Derivatives and Diols via Combined Ruthenium and Enzyme Catalysis2008Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

  • 179.
    Borén, Linnéa
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Leijondahl, Karin
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Bäckvall, Jan-Erling
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Dynamic Kinetic Asymmetric Transformation of 1,4-diols and Preparation of Trans-2,5-Disubstituted pyrrolidines2009Ingår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 50, nr 26, s. 3237-3240Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Dynamic kinetic asymmetric transformation (DYKAT) of a series of 1,4-diols is carried out with Candida antarctica lipase B (CALB), Pseudomonas cepacia lipase II (PS-C II), and a ruthenium catalyst. A β-chloro-substituted 1,4-diol is successfully transformed into an optically pure 1,4-diacetate, which is a highly useful synthetic intermediate. The usefulness of the optically pure 1,4-diacetates is demonstrated by the synthesis of enantiopure 2,5-disubstituted pyrrolidines.

  • 180.
    Borén, Linnéa
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Martín-Matute, Belén
    Xu, Yongmei
    Córdova, Armando
    Bäckvall, Jan-Erling
    (S)-Selective Kinetic Resolution and Chemoenzymatic Dynamic Kinetic Resolution of Secondary Alcohols2006Ingår i: Chemistry: a European Journal, ISSN 0947-6539, Vol. 12, nr 1, s. 225-232Artikel i tidskrift (Refereegranskat)
  • 181. Both, P.
    et al.
    Green, A. P.
    Gray, C. J.
    Sardzik, R.
    Voglmeir, J.
    Fontana, Carolina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Austeri, M.
    Rejzek, M.
    Richardson, D.
    Field, R. A.
    Widmalm, Göran
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Flitsch, S. L.
    Eyers, C. E.
    Discrimination of epimeric glycans and glycopeptides using IM-MS and its potential for carbohydrate sequencing2014Ingår i: Nature Chemistry, ISSN 1755-4330, E-ISSN 1755-4349, Vol. 6, nr 1, s. 65-74Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mass spectrometry is the primary analytical technique used to characterize the complex oligosaccharides that decorate cell surfaces. Monosaccharide building blocks are often simple epimers, which when combined produce diastereomeric glycoconjugates indistinguishable by mass spectrometry. Structure elucidation frequently relies on assumptions that biosynthetic pathways are highly conserved. Here, we show that biosynthetic enzymes can display unexpected promiscuity, with human glycosyltransferase pp-a-GanT2 able to utilize both uridine diphosphate N-acetylglucosamine and uridine diphosphate N-acetylgalactosamine, leading to the synthesis of epimeric glycopeptides in vitro. Ion-mobility mass spectrometry ( IM-MS) was used to separate these structures and, significantly, enabled characterization of the attached glycan based on the drift times of the monosaccharide product ions generated following collision-induced dissociation. Finally, ion-mobility mass spectrometry following fragmentation was used to determine the nature of both the reducing and non-reducing glycans of a series of epimeric disaccharides and the branched pentasaccharide Man3 glycan, demonstrating that this technique may prove useful for the sequencing of complex oligosaccharides.

  • 182.
    Bouma, M. J.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Olofsson, Berit
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    7.07 α-Oxygenation of Carbonyl Compounds2014Ingår i: Comprehensive Organic Synthesis II (Second Edition) / [ed] Paul Knochel and Gary A. Molander, Amsterdam: Oxford: Elsevier , 2014, 2nd, s. 213-241Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Abstract The chapter describes synthetically useful strategies for α-oxygenation of carbonyl compounds, with special emphasis on recent methods for catalytic and asymmetric reactions. The oxidation of enolates, enols, enol ethers, and α,β-unsaturated compounds is discussed in detail. Classical oxidation reagents like metal oxides, molecular oxygen, peroxides, and peracids are covered, with asymmetric dihydroxylation of enol ethers giving the highest enantioselectivities together with organocatalytic methods using peroxides. Oxaziridines, nitrosoarenes, and hypervalent iodine compounds are more recently developed α-oxygenation alternatives that allow metal-free oxidations under mild conditions. The combination of nitrosoarenes with organocatalysis is currently the best method for enantioselective α-oxygenations. The area of asymmetric α-oxygenations with hypervalent iodine compounds is currently under development, and high enantioselectivities have only been achieved in intramolecular reactions and epoxidations.

  • 183.
    Bouma, Marinus J.
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Olofsson, Berit
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    General One-Pot Synthesis of Alkynyliodonium Salts and Alkynyl Benziodoxolones from Aryl Iodides2012Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 18, nr 45, s. 14242-14245Artikel i tidskrift (Refereegranskat)
  • 184. Bratt, Emma
    et al.
    Verho, Oscar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Johansson, Magnus J.
    Bäckvall, Jan-Erling
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    A General Suzuki Cross-Coupling Reaction of Heteroaromatics Catalyzed by Nanopalladium on Amino-Functionalized Siliceous Mesocellular Foam2014Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 79, nr 9, s. 3946-3954Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Suzuki-Miyaura cross-coupling reactions of heteroaromatics catalyzed by palladium supported in the cavities of amino-functionalized siliceous mesocellular foam are presented. The nanopalladium catalyst effectively couples not only heteroaryl halides with boronic acids but also heteroaryl halides with boronate esters, potassium trifluoroborates, MIDA boronates, and triolborates, producing a wide range of heterobiaryls in good to excellent yields. Furthermore, the heterogeneous palladium nanocatalyst can easily be removed from the reaction mixture by filtration and recycled several times with minimal loss in activity. This catalyst provides an alternative, environmentally friendly, low-leaching process for the preparation of heterobiaryls.

  • 185.
    Brea, Oriana
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Mó, Otilia
    Yáñez, Manuel
    Merced Montero-Campillo, M.
    Alkorta, Ibon
    Elguero, José
    Are beryllium-containing biphenyl derivatives efficient anion sponges?2018Ingår i: Journal of Molecular Modeling, ISSN 1610-2940, E-ISSN 0948-5023, Vol. 24, nr 1, artikel-id 16Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The structures and stabilities of 2,2'-diBeX-1,1'-biphenyl (X = H, F, Cl, CN) derivatives and their affinities for F-, Cl-, and CN- were theoretically investigated using a B3LYP/6-311 + G(3df, 2p)//B3LYP/6-31 + G(d,p) model. The results obtained show that the 2,2'-diBeX-1,1'-biphenyl derivatives (X = H, F, Cl, CN) exhibit very high F-, Cl-, and CN- affinities, albeit lower than those reported before for their 1,8-diBeX-naphthalene analogs, in spite of the fact that the biphenyl derivatives are more flexible than their naphthalene counterparts. Nevertheless, some of the biphenyl derivatives investigated are predicted to have anion affinities larger than those measured for SbF5, which is considered one of the strongest anion capturers. Therefore, although weaker than their naphthalene analogs, the 2,2'-diBeX-1,1'-biphenyl derivatives can still be considered powerful anion sponges. This study supports the idea that compounds containing -BeX groups in chelating positions behave as anion sponges due to the electron-deficient nature and consequently high intrinsic Lewis acidity of these groups.

  • 186. Breistein, Palle
    et al.
    Johansson, Jonas
    Ibrahem, Ismail
    Lin, Shuangzheng
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Deiana, Luca
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Sun, Junliang
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK), Avdelningen för oorganisk kemi och strukturkemi.
    Cordova, Armando
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK), Avdelningen för oorganisk kemi och strukturkemi.
    One-Step Catalytic Enantioselective a-Quaternary 5-Hydroxyproline Synthesis: An Asymmetric Entry to Highly Functionalized a-Quaternary Proline Derivatives2012Ingår i: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 354, nr 6, s. 1156-1162Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The highly enantioselective cascade reaction between N-protected a-cyanoglycine esters and a,beta-unsaturated aldehydes is disclosed. The reaction represents a one-step entry to polysubstituted 5-hydroxyproline derivatives having a quaternary a-stereocenter generally in high yields with up to >95:5 dr and 99:1 er. It is also a direct catalytic two-step entry to functionalized a-quaternary proline derivatives.

  • 187. Brown, Michael
    et al.
    Delorme, Marion
    Malmedy, Florence
    Malmgren, Joel
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Olofsson, Berit
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Wirth, Thomas
    Synthesis of New Chiral Diaryliodonium Salts2015Ingår i: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 26, nr 11, s. 1573-1577Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A structurally diverse range of chiral diaryliodonium salts have been synthesised which have potential application in metal-free stereoselective arylation reactions.

  • 188.
    Bruneau, Alexandre
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Gustafson, Karl P. J.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Yuan, Ning
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK). Swedish University of Agricultural Sciences, Sweden.
    Tai, Cheuk-Wai
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Persson, Ingmar
    Zou, Xiaodong
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Bäckvall, Jan-E.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för material- och miljökemi (MMK).
    Synthesis of Benzofurans and Indoles from Terminal Alkynes and Iodoaromatics Catalyzed by Recyclable Palladium Nanoparticles Immobilized on Siliceous Mesocellular Foam2017Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, nr 52, s. 12886-12891Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Herein, we report on the utilization of a heterogeneous catalyst, consisting of Pd nanoparticles supported on a siliceous mesocellular foam (Pd-0-AmP-MCF), for the synthesis of heterocycles. Reaction of o-iodophenols and protected o-iodoanilines with acetylenes in the presence of a Pd nanocatalyst produced 2-substituted benzofurans and indoles, respectively. In general, the catalytic protocol afforded the desired products in good to excellent yields under mild reaction conditions without the addition of ligands. Moreover, the structure of the reported Pd nanocatalyst was further elucidated with extended X-ray absorption fine-structure spectroscopy, and it was proven that the catalyst could be recycled multiple times without significant loss of activity.

  • 189.
    Buitrago, Elina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Transition metal catalyzed reduction of ketones2010Licentiatavhandling, sammanläggning (Övrigt vetenskapligt)
  • 190.
    Buitrago, Elina
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Transition metal-catalyzed reduction of carbonyl compounds: Fe, Ru and Rh complexes as powerful hydride mediators2012Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

  • 191.
    Buitrago, Elina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Lundberg, Helena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Andersson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Ryberg, Per
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    High Throughput Screening of a Catalyst Library for the Asymmetric Transfer Hydrogenation of Heteroaromatic Ketones: Formal Syntheses of (R)-Fluoxetine and (S)-Duloxetine2012Ingår i: ChemCatChem, ISSN 1867-3880, E-ISSN 1867-3899, Vol. 4, nr 12, s. 2082-2089Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A total of 21 amino acid based ligands including hydroxy amide, thioamide, and hydroxamic acid functionalities, respectively, were combined with [Ru(p-cymene)Cl2]2 and [RhCp*Cl2]2, and used as catalysts for the asymmetric transfer hydrogenation of four different heteroaromatic ketones in 2-propanol. The reactions were performed on a Chemspeed automated high-throughput screening robotic platform. Optimal catalysts were identified for the individual heterocyclic substrate classes. Based on these results, the formal syntheses of the antidepressant drugs (R)-fluoxetine and (S)-duloxetine were conducted by using the found catalysts in the key reaction step, which results in high isolated yields (94?%) and excellent product enantioselectivities (>99?% ee) of the formed 1,3-amino alcohols.

  • 192.
    Buitrago, Elina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Lundberg, Helena
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Andersson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Ryberg, Per
    Aztra Zeneca, Global Process R&D, Södertälje, Sweden.
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Selective reduction of heteroaromatic ketones: A combinatorial approach2011Konferensbidrag (Övrigt vetenskapligt)
    Abstract [en]

    The enantioselective reduction of prochiral ketones is a most productiveway towards enantio enriched secondary alcohols used in the preparation of biologically active compounds. There are numerous transition metal catalyzed methods for this transformation, particularly based on Ru(II)-and Rh(I)-complexes, but there is a demand for a larger substrate scope. Heteroaromatic ketones are traditionally more challenging substrates. Normally a catalyst is developed for one benchmark substrate, and asubstrate screen is made with the best performing catalyst. Using this methodology, there is a high probability that for different substrates, another catalyst could outperform the one used. We have executed a multiple screen, containing a variety of different ligands together with both Ru and Rh, and heteroaromatic ketones to fine-tune, and find the optimum catalyst depending on the substrate. The acquired information was used to synthesize known, biologically active compounds, where the key reduction steps were performed with high enantioselectivities and yields.

  • 193.
    Buitrago, Elina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Tinnis, Fredrik
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Efficient and Selective Hydrosilylation of Carbonyls Catalyzed by Iron Acetate and N-Hydroxyethylimidazolium Salts2012Ingår i: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 354, nr 1, s. 217-222Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aromatic aldehydes, along with aryl alkyl, heteroaryl alkyl, and dialkyl ketones were efficiently reduced to their corresponding primary and secondary alcohols, respectively, in high yields, using the commercially available and inexpensive polymeric silane, polymethylhydrosiloxane (PMHS), as reducing agent. The reaction is catalyzed by in situ generated iron complexes containing hydroxyethyl-functionalized NHC ligands. Turnover frequencies up to 600 h−1 were obtained

  • 194.
    Buitrago, Elina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Zani, Lorenzo
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Fe/NHC-catalyzed hydrosilylation of aromatic ketones2009Ingår i: Abstracts of Papers, 238th ACS National Meeting, Washington, DC, United States, August 16-20, 2009, Washington, DC: American Chemical Society , 2009Konferensbidrag (Övrigt vetenskapligt)
  • 195.
    Buitrago, Elina
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Zani, Lorenzo
    Adolfsson, Hans
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Selective hydrosilylation of ketones catalyzed by in situ-generated iron NHC complexes2011Ingår i: Applied organometallic chemistry, ISSN 0268-2605, E-ISSN 1099-0739, Vol. 25, nr 10, s. 748-752Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aryl alkyl-, heteroaryl alkyl- and dialkyl ketones were readily reduced to their corresponding secondary alcohols in high yields, using the commercially available and inexpensive polymeric silane polymethylhydrosiloxane (PMHS), as reducing agent. The reaction is catalyzed by an in situ-generated iron complex, conveniently generated from iron(II) acetate and the commercially available N-heterocyclic carbene (NHC) precursor IPr·HCl.

  • 196.
    Bunrit, Anon
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Stockholm University.
    Direct Catalytic Nucleophilic Substitution of Non-Derivatized Alcohols2017Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    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.

  • 197. Bunrit, Anon
    et al.
    Dahlstrand, Christian
    Olsson, Sandra K.
    Srifa, Pemikar
    Huang, Genping
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Orthaber, Andreas
    Sjöberg, Per J. R.
    Biswas, Srijit
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Samec, Joseph S. M.
    Brønsted Acid-Catalyzed Intramolecular Nucleophilic Substitution of the Hydroxyl Group in Stereogenic Alcohols with Chirality Transfer2015Ingår i: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 137, nr 14, s. 4646-4649Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The hydroxyl group of enantioenriched benzyl, propargyl, allyl, and alkyl alcohols has been intramolecularly displaced by uncharged O-, N-, and S-centered nucleophiles to yield enantioenriched tetrahydrofuran, pyrrolidine, and tetrahydrothiophene derivatives with phosphinic acid catalysis. The five-membered heterocyclic products are generated in good to excellent yields, with high degree of chirality transfer, and water as the only side-product. Racemization experiments show that phosphinic acid does not promote S(N)1 reactivity. Density functional theory calculations corroborate a reaction pathway where the phosphinic acid operates as a bifunctional catalyst in the intramolecular substitution reaction. In this mechanism, the acidic proton of the phosphinic acid protonates the hydroxyl group, enhancing the leaving group ability. Simultaneously, the oxo group of phosphinic acid operates as a base abstracting the nucleophilic proton and thus enhancing the nucleophilicity. This reaction will open up new atom efficient techniques that enable alcohols to be used as nucleofuges in substitution reactions in the future.

  • 198. Bunrit, Anon
    et al.
    Dahlstrand, Christian
    Srifa, Pemikar
    Olsson, Sandra K.
    Huang, Genping
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Tianjin University, China.
    Biswas, Srijit
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Samec, Joseph S. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Uppsala University, Sweden.
    Nucleophilic Substitution of the Hydroxyl Group in Stereogenic Alcohols with Chirality Transfer2016Ingår i: Synlett: Accounts and Rapid Communications in Synthetic Organic Chemistry, ISSN 0936-5214, E-ISSN 1437-2096, Vol. 27, nr 2, s. 173-176Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A brief overview of the development of direct substitution of the hydroxyl (OH) group of alcohols in our research group is presented. By applying a BrOnsted acid, an intramolecular substitution of the OH group in stereogenic alcohols with chirality transfer was achieved. Noteworthy, the intramolecular substitution has a wide scope in respect to both the nucleophile and also the nucleofuge. A mechanistic study by both experiments and DFT calculations revealed a unique reaction pathway in which the BrOnsted acid operates in a bifunctional manner to promote an S(N)2-type reaction mechanism.

  • 199.
    Bunrit, Anon
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Uppsala University, Sweden.
    Sawadjoon, Supaporn
    Tšupova, Svetlana
    Sjöberg, Per J. R.
    Samec, Joseph S. M.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi. Uppsala University, Sweden.
    A General Route to beta-Substituted Pyrroles by Transition-Metal Catalysis2016Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, nr 4, s. 1450-1460Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    An atom-efficient route to pyrroles substituted in the beta-position has been achieved in four high yielding steps by a combination of Pd, Ru, and Fe catalysis with only water and ethene as side-products. The reaction is general and gives pyrroles substituted in the beta-position with linear and branched alkyl, benzyl, or aryl groups in overall good yields. The synthetic route includes a Pd-catalyzed monoallylation step of amines with substituted allylic alcohols that proceeds to yield the monoallylated products in moderate to excellent yields. In a second step, unsymmetrical diallylated aromatic amines are generated from the reaction of a second allylic alcohol with high selectivity in moderate to good yields by control of the reaction temperature. Ru-catalyzed ring-closing metathesis performed on the diallylated aromatic amines yields the pyrrolines substituted in the beta-position in excellent yields. By addition of ferric chloride to the reaction mixture, a selective aromatization to yield the corresponding pyrroles substituted in the beta-position was achieved. A reaction mechanism involving a palladium hydride, generated from insertion of palladium to O-H of an allyl alcohol, that is responsible for the C-O bond cleavage to generate the pi-allyl intermediate is proposed.

  • 200.
    Bunrit, Anon
    et al.
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Srifa, Pemikar
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Dahlstrand, Christian
    Huang, Genping
    Biswas, Srijit
    Himo, Fahmi
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Watile, Rahul
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    Samec, Joseph
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för organisk kemi.
    H3PO2-Catalyzed Intramolecular Stereospecific Substitution of the Hydroxyl Group in Stereogenic Secondary Alcohols by N-, O-, and S-centered Nucleophiles to Generate HeterocyclesManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    The direct intramolecular stereospecific substitution of the hydroxyl group in stereogenic secondary alcohols was successfully accomplished by phosphinic acid catalysis. The hydroxyl group was displaced by O-, S-, and N-centered nucleophiles to provide enantioenriched five- and six-membered heterocycles in good to excellent yields and high enantiospecificity with water as the only by product. Mechanistic studies using both experiments and calculations have been performed. Rate order determination shows first-order dependences in catalyst, internal nucleophile, and electrophile concentrations, however, independence on external nucleophile and electrophile. Furthermore, phosphinic acid does not promote SN1 reactivity. Computational studies support a bifunctional role of the phosphinic acid in which activations of both nucleofuge and nucleophile occur in a bridging SN2-type transition state. 

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