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  • 1.
    Amirkhani, Ardeshir
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry, Analytical Chemistry.
    Development of Techniques and Methods for the Quantitative Analysis of Endogenous Substances by Microcolumn Liquid Chromatography Coupled to Mass Spectrometry2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Liquid chromatography-mass spectrometry (LC-MS) is a powerful technique for the analysis of endogenous compounds. The introduction of electrospray ionization (ESI) as an interface between LC and MS has contributed strongly to a trend towards miniaturization of LC, due to the possibility to perform ESI at low flow rates. In this thesis, several aspects regarding the design of miniaturized LC systems and electrospray emitters were investigated. In addition miniaturized LC-ESI-MS have been used for the qualitative and quantitative analysis of endogenous polar compounds, peptides and protein digests.

    The performance of miniaturized LC-MS was compared using different electrospray emitter configurations. The results indicated that the efficiency of the LC system is rather independent of the configuration of the emitter.

    The lifetime of gold-coated fused silica electrospray emitters based on vapor deposited adhesion layers of titanium were investigated. The long lifetime of the emitter facilitates the use in LC-MS experiments, exemplified LC-MS by analysis of neuropeptides.

    The ESI voltage is shown to interfere with liquid chromatographic separations performed in packed porous graphitic carbon capillary column. This interference is ascribed to the presence of an electric field over the conductive column in absence of a ground point between the column and the ESI emitter.

    The solid supported enhanced microdialysis for analysis of neuropeptides were compared with conventional microdialysis. The difference between the two methodologies were evaluated by LC-MS analysis of the microdialysates. The solid supported method gave in general higher relative recoveries.

    Finally, a method of standard addition was developed to determine total level of tryptophan and two of its metabolites in human plasma by capillary LC-ESI tandem mass spectrometry. The method was applied in a clinical study of multiple scleroses patients treated with cytokines (IFN Beta 1a, 1b). The results show that the intervention effects the tryptophan metabolism.

    List of papers
    1. Comparison between different sheathless electrospray emitter configurations regarding the performance of nanoscale liquid chromatography time-of-flight mass spectrometry analysis
    Open this publication in new window or tab >>Comparison between different sheathless electrospray emitter configurations regarding the performance of nanoscale liquid chromatography time-of-flight mass spectrometry analysis
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    2004 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1033, no 2, p. 257-266Article in journal (Refereed) Published
    Abstract [en]

    Four different sheathless electrospray ionization (ESI) configurations were investigated for a nano liquid chromatography (LC) system. The studied configurations were: a column with an integrated emitter, with the ESI potential applied before or after the column, and a column with separate emitter, with the ESI voltage applied at a union before the emitter or at the emitter tip. The results indicates that the efficiency of the LC system is rather independent of the configuration when using 95 μm i.d. columns, acetic mobile phase and standard peptides as a sample. Introduction of post column dead volume seems not to be a critical issue at least with flow rates down to 600 nl/min.

    Keywords
    Electrospray ionization, Band broadening, Principal component analysis, Instrumentation, Peptides
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-91889 (URN)10.1016/j.chroma.2004.01.063 (DOI)
    Available from: 2004-05-25 Created: 2004-05-25 Last updated: 2017-12-14Bibliographically approved
    2. Gold-coated fused-silica sheathless electrospray emitters based on vapor-deposited titanium adhesion layers
    Open this publication in new window or tab >>Gold-coated fused-silica sheathless electrospray emitters based on vapor-deposited titanium adhesion layers
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    2003 In: Rapid Communication Mass Spectrometry, Vol. 17, no 14, p. 1535-1540Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91337 (URN)
    Available from: 2004-01-30 Created: 2004-01-30Bibliographically approved
    3. Interference of the electrospray voltage on chromatographic separations using porous graphitic carbon columns
    Open this publication in new window or tab >>Interference of the electrospray voltage on chromatographic separations using porous graphitic carbon columns
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    2004 (English)In: Journal of Mass Spectrometry, ISSN 1076-5174, E-ISSN 1096-9888, Vol. 39, no 2, p. 216-222Article in journal (Refereed) Published
    Abstract [en]

    The electrospray ionization (ESI) voltage is shown to interfere with liquid chromatographic separations performed with packed porous graphitic carbon (PGC) capillary columns. This interference is ascribed to the presence of an electric field over the conductive column in the absence of an earth point between the column and the ESI emitter. The current evolved alters the chromatographic behavior of the catecholamine metabolite 3-O-methyl-DOPA significantly, as both peak splitting and a dramatic decrease in the retention time were observed. Furthermore, the response from the mass spectrometer was decreased by 33% at the same time. A related compound, tyrosine, exhibited decreased retention times but no peak splitting, whereas no shifts in the retention times (or peak splitting) were seen for the less retained dopamine and noradrenaline. When the current through the PGC column was eliminated by the use of an earth point between the column and the ESI emitter, the chromatographic behavior of the column was found to return slowly to normal after hours of equilibration with 60 : 40 (v/v) methanol-ammonium formate buffer of pH 2.9. The behavior of the PGC column with and without the earth point was found to be highly reproducible during a period of 1 month. We propose that the effect of the ESI voltage on the chromatographic behavior of the PGC column is due to associated redox reactions affecting both the PGC particles and the analytes. It is concluded that (for analytical reasons), care should be taken to ensure that no current is flowing through the chromatographic system when interfacing PGC columns, and conducting parts in general, to ESI mass spectrometry.

    Keywords
    catecholamine, dopamine, electrochemistry, porous graphitic carbon, electrospray, mass spectrometry, liquid chromatography
    National Category
    Inorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-91888 (URN)10.1002/jms.589 (DOI)
    Available from: 2004-05-25 Created: 2004-05-25 Last updated: 2017-12-14Bibliographically approved
    4. A feasibility study of solid supported enhanced microdialysis
    Open this publication in new window or tab >>A feasibility study of solid supported enhanced microdialysis
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    2004 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 76, no 6, p. 1678-1682Article in journal (Refereed) Published
    Abstract [en]

    For the first time, a solid supported enhanced microdialysis methodology for analysis of neuropeptides is described. The microdialysis samples were, in this study, subsequently collected in fractions, dissolved from the solid particles, dried, and resolved in a formic acid buffer in order to make them suitable for capillary liquid chromatography-mass spectrometry. Different microdialysis flow profiles were evaluated where air-gapped continuous flow was considered most suitable for the solid supported microdialysis mode. Six endogenous neuropeptides were initially used to investigate the feasibility of this enhanced microdialysis methodology. The improved relative recovery obtained from the solid supported enhanced microdialysis was varying from no effect to 10 times higher as compared to ordinary microdialysis. The most efficient enrichment was obtained for luteinizing hormone releasing hormone, which was the largest but also the most hydrophilic of the peptides. In contrast, no significant difference in recovery was observed for Leu-enkephalin being the smallest and the most hydrophobic peptide tested. These results indicate an increased flux and selective uptake of hydrophilic peptides across the membrane and enrichment on the particles in solid supported microdialysis.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-93181 (URN)10.1021/ac035305l (DOI)15018567 (PubMedID)
    Available from: 2005-05-10 Created: 2005-05-10 Last updated: 2017-12-14Bibliographically approved
    5. Quantitation of tryptophan, kynurenine and kynurenic acid in human plasma by capillary liquid chromatography - electrospray
    Open this publication in new window or tab >>Quantitation of tryptophan, kynurenine and kynurenic acid in human plasma by capillary liquid chromatography - electrospray
    2002 In: Journal of Chromatography B, Vol. 780, no 2, p. 381-387Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91340 (URN)
    Available from: 2004-01-30 Created: 2004-01-30 Last updated: 2011-03-21
    6. Beta-interferon effects the tryptophan metabolism in the plasma of multiple sclerosis patients
    Open this publication in new window or tab >>Beta-interferon effects the tryptophan metabolism in the plasma of multiple sclerosis patients
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    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-91341 (URN)
    Available from: 2004-01-30 Created: 2004-01-30 Last updated: 2011-03-21
  • 2.
    Bergström, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry, Analytical Chemistry.
    Integrated Micro-Analytical Tools for Life Science2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Advances in life science require knowledge of active molecules in complex biological systems. These molecules are often only present for a certain time and at limited concentrations. Integrated micro-analytical tools for sampling, separation and mass spectrometric (MS) detection would meet these requests and are therefore continuously gaining interest. An on-line coupling of analytical functions provides shorter analysis time and less manual sample handling. In this thesis, improved compatibility of microdialysis sampling and multidimensional separations coupled to MS detection are developed and discussed.

    Microdialysis was used in vitro for determination of the non-protein bound fraction of the drug ropivacaine. The sampling unit was coupled on-line to capillary column liquid chromatography (LC) followed by ultraviolet or MS detection. For MS detection, the system was extended with a desalting step and an addition of internal standard. A method for MS screening of microdialysates, collected in vivo, was also developed. The method involved sampling and measurements of the chemical pattern of molecules that generally are ignored in clinical investigations. Chemometric tools were used to extract the relevant information and to compare samples from stimulated and control tissues.

    Complex samples often require separation in more than one dimension. On-line interfaces for sample transfer between LC and capillary electrophoresis (CE) were developed in soft poly(dimethylsiloxane) (PDMS). MS detection in the LC-CE system was optimised on frequent sampling of the CE peak or on high resolution in mass spectra using time-of-flight (TOF)MS or Fourier transform ion cyclotron resonance (FTICR)MS, respectively. Aspects on electrode positioning in the LC-CE interface led to development of an on-column CE electrode. A successful method for deactivation of the PDMS surface using a polyamine polymer was also developed. The systems were evaluated using peptides and proteins, molecules that are gaining increased attention in bioscience, and consequently also in chemical analysis.

    List of papers
    1. Determination of the free concentration of ropivacaine in plasma by packed capillary liquid chromatography: A comparison of ultrafiltration and microdialysis as sample preparation methods
    Open this publication in new window or tab >>Determination of the free concentration of ropivacaine in plasma by packed capillary liquid chromatography: A comparison of ultrafiltration and microdialysis as sample preparation methods
    2001 (English)In: Journal of Microcolumn Separations, ISSN 1040-7685, E-ISSN 1520-667X, Vol. 13, no 5, p. 197-201Article in journal (Refereed) Published
    Abstract [en]

    In this study, ultrafiltration and microdialysis have been compared as sample preparation methods to separate the free fraction of ropivacaine from the protein bound in 150 μL plasma. A liquid chromatographic system with packed capillary columns (0.2 mm internal diameter) was used to enhance sensitivity when analyzing the small sample volumes obtained after the ultrafiltration and the microdialysis. The microdialysis was performed with probes of our own construction, and to save analysis time, the microdialysis sampling was coupled on-line to the liquid chromatographic system. The reduction of back pressure in the microdialysis outlet tube and in the injector was found to be essential. The free fraction obtained with each method was equivalent: both gave a free fraction of 6%.

    Keywords
    microdialysis, ultrafiltration, free fraction, ropivacaine, capillary liquid chromatography
    National Category
    Analytical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-93670 (URN)10.1002/mcs.1042 (DOI)
    Available from: 2005-10-28 Created: 2005-10-28 Last updated: 2017-12-14Bibliographically approved
    2. On-line coupling of microdialysis to packed capillary column liquid chromatography-tandem mass spectrometry demonstrated by measurement of free concentrations of ropivacaine and metabolite from spiked plasma samples
    Open this publication in new window or tab >>On-line coupling of microdialysis to packed capillary column liquid chromatography-tandem mass spectrometry demonstrated by measurement of free concentrations of ropivacaine and metabolite from spiked plasma samples
    2002 (English)In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 775, no 1, p. 79-87Article in journal (Refereed) Published
    Abstract [en]

    An on-line coupling of microdialysis to a packed capillary column switching liquid chromatographic system (0.2 mm I.D.) and mass spectrometric detection was developed. The microdialysates were collected in the loop of the first of three valves, coupled in direct series. A deuterated internal standard was added on-line by the middle valve and the third valve operated both a pre-column, for desalting of the physiological buffer used in the sampling procedure, and a separation column. The on-line system was used to study free concentrations of ropivacaine and its metabolite (PPX) in human plasma samples. The analytes were detected by electrospray ionization in a tandem mass spectrometer operating in multiple reaction monitoring mode. The free fractions of ropivacaine (200 nM total concentration) and PPX (20 nM total concentration) in spiked plasma samples were 12±3 and 47±5% (±standard deviation for day-to-day variations, n=3), respectively.

    National Category
    Analytical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-93671 (URN)10.1016/S1570-0232(02)00280-5 (DOI)
    Available from: 2005-10-28 Created: 2005-10-28 Last updated: 2017-12-14Bibliographically approved
    3. Screening of microdialysates using on-line desalting and mass spectrometric detection
    Open this publication in new window or tab >>Screening of microdialysates using on-line desalting and mass spectrometric detection
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    In: J. Chromatogr. AArticle in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-93672 (URN)
    Available from: 2005-10-28 Created: 2005-10-28Bibliographically approved
    4. On-column polymer-imbedded graphite inlet electrode for capillary electrophoresis coupled on-line with flow injection analysis in a poly(dimethylsiloxane) interface
    Open this publication in new window or tab >>On-column polymer-imbedded graphite inlet electrode for capillary electrophoresis coupled on-line with flow injection analysis in a poly(dimethylsiloxane) interface
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    2003 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 24, no 11, p. 1723-1729Article in journal (Refereed) Published
    Abstract [en]

    A method for coupling an electrophoretic driven separation to a liquid flow, using conventional fused-silica capillaries and a soft polymeric interface is presented. A novel design of the electrode providing high voltage to the electrophoretic separation was also developed. The electrode consisted of a conductive polyimide/graphite imbedded coating immobilized onto the capillary electrophoresis (CE) column inlet. This integrated electrode gave the same separation performance as a commonly used platinum electrode. The on-column electrode also showed good electrochemical stability in chronoamperometric experiments. In addition, with this electrode design, the electrode position relative to the inlet end of the CE column will always be constant and well defined. The on-line flow injection analysis (FIA)-CE system was used with electrospray ionization (ESI)-time of flight (TOF)-mass spectrometry detection. The preparation of the PDMS (poly(dimethylsiloxane)) interface for FIA-CE is described in detail and used for initial tests of the on-column polymer-imbedded graphite inlet electrode. In this interface, a pressure-driven liquid flow, a make up CE electrolyte and a CE column inlet meet in a two-level cross (95 μm ID) in the PDMS structure, enabling independent flow characterization.

    Keywords
    Capillary electrophoresis, Flow injection, Hyphenation, On-column electrode, Poly(dimethylsiloxane)
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-94267 (URN)10.1002/elps.200305362 (DOI)
    Available from: 2006-04-07 Created: 2006-04-07 Last updated: 2017-12-14Bibliographically approved
    5. Development of a poly(dimethylsiloxane) interface for on-line capillary column liquid chromatography-capillary electrophoresis coupled to sheathless electrospray ionization time-of-flight mass spectrometry
    Open this publication in new window or tab >>Development of a poly(dimethylsiloxane) interface for on-line capillary column liquid chromatography-capillary electrophoresis coupled to sheathless electrospray ionization time-of-flight mass spectrometry
    2003 In: Anal. Chem., ISSN 0003-2700, Vol. 75, no 20, p. 5461-5467Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93674 (URN)
    Available from: 2005-10-28 Created: 2005-10-28Bibliographically approved
    6. Polyamine deactivation of integrated poly(dimethylsiloxane) structures investigated by radionuclide imaging and capillary electrophoresis experiments
    Open this publication in new window or tab >>Polyamine deactivation of integrated poly(dimethylsiloxane) structures investigated by radionuclide imaging and capillary electrophoresis experiments
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    2005 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 77, no 3, p. 938-942Article in journal (Refereed) Published
    Abstract [en]

    The poly(dimethylsiloxane) (PDMS) material provides a number of advantageous features, such as flexibility, elasticity, and transparency, making it useful in integrated analytical systems. Hard fused-silica capillary structures and soft PDMS channels can easily be combined by a tight fit, which offers many alternatives for structure combinations. PDMS and fused silica are in different ways prone to adsorption of low levels of organic compounds. The need for modification of the inner wall surface of PDMS channels may often be necessary, and in this paper, we describe an easy and effective method using the amine-containing polymer PolyE-323 to deactivate both fused-silica and PDMS surfaces. The adsorption of selected peptides to untreated surfaces was compared to PolyE-323-modified surfaces, using both radionuclide imaging and capillary electrophoresis experiments. The polyamine modification displayed a substantially reduced adsorption of three hydrophobic test peptides compared to the native PDMS surface. Filling and storage of aqueous solution were also possible in PolyE-323-modified PDMS channels. In addition, hybrid microstructures of fused silica and PDMS could simultaneously be deactivated in one simple coating procedure.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-93675 (URN)10.1021/ac0492618 (DOI)
    Available from: 2005-10-28 Created: 2005-10-28 Last updated: 2017-12-14Bibliographically approved
    7. A simplified multidimensional approach for analysis of complex biological samples: on-line LC-CE-MS
    Open this publication in new window or tab >>A simplified multidimensional approach for analysis of complex biological samples: on-line LC-CE-MS
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    2006 (English)In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 131, no 7, p. 791-798Article in journal (Refereed) Published
    Abstract [en]

    Information on protein expression, disease biomarkers or surrogate markers and genetic disorders can nowadays be achieved from analysis of complex biological samples by liquid separation coupled to mass spectrometric (MS) detection. This paper describes fast multidimensional separation by on-line liquid chromatography (LC) and capillary electrophoresis (CE), followed by electrospray ionization (ESI) Fourier transform ion cyclotron resonance (FTICR) MS detection. This detector provides ultrahigh resolution of the detected ions, mass accuracy at the ppm-level and high sensitivity. Most of the challenge of this system lies in the development of a new interface for the on-line coupling of LC to CE. The interface developed in poly(dimethylsiloxane) provides a RSD for injection repeatability of <3.5% and surface control for unspecific binding by deactivation with a cationic polymer, PolyE-323. We have evaluated the interface, as well as the overall system, with respect to robustness and deconvolution ability. Sequence coverage for bovine serum albumin (BSA) of 93% showed a high recovery of sample in the different transfer steps through the system. The detection limit for identification is 277 ng mL−1 (or 280 nM) on average for peptides. In the future, we expect LC-CE-MS to be a novel strategy for elucidating the chemistry of biological matrices.

    National Category
    Analytical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-80932 (URN)10.1039/b601660j (DOI)
    Available from: 2006-06-29 Created: 2006-06-29 Last updated: 2017-12-14Bibliographically approved
    8. Poly(dimethylsiloxane)-Based Microchip for Two-Dimensional Solid-Phase Extraction-Capillary Electrophoresis with an Integrated Electrospray Emitter Tip
    Open this publication in new window or tab >>Poly(dimethylsiloxane)-Based Microchip for Two-Dimensional Solid-Phase Extraction-Capillary Electrophoresis with an Integrated Electrospray Emitter Tip
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    2005 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 77, no 16, p. 5356-5363Article in journal (Refereed) Published
    Abstract [en]

    A microchip in poly(dimethylsiloxane) (PDMS) for in-line solid-phase extraction-capillary electrophoresis-electrospray ionization-time-of-flight mass spectrometry (SPE-CE-ESI-TOF-MS) has been developed and evaluated. The chip was fabricated in a novel one-step procedure where mixed PDMS was cast over steel wires in a mold. The removed wires defined 50-um cylindrical channels. Fused-silica capillaries were inserted into the structure in a tight fit connection. The inner walls of the inserted fused-silica capillaries and the PDMS microchip channels were modified with a positively charged polymer, PolyE-323. The chip was fabricated in a two-level cross design. The channel at the lower level was packed with 5-um hyper-cross-linked polystyrene beads acting as a SPE medium used for desalting. The upper level channel acted as a CE channel and ended in an integrated emitter tip coated with conducting graphite powder to facilitate the electrical contact for sheathless ESI. An overpressure continuously provided fresh CE electrolyte independently of the flows in the different levels. Further studies were carried out in order to investigate the electrophoretic and flow rate properties of the chip. Finally, six-peptide mixtures, in different concentrations, dissolved in physiological salt solution was injected, desalted, separated, and sprayed into the mass spectrometer for analysis with a limit of detection in femtomole levels.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-74074 (URN)10.1021/ac050495g (DOI)16097780 (PubMedID)
    Available from: 2005-08-26 Created: 2005-08-26 Last updated: 2017-12-14Bibliographically approved
  • 3.
    Berlin, Stefan
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry.
    Construction of Five-Membered Heterocyclic Compounds via Radical Cyclization2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes how radical cyclization chemistry can be applied for the construction of heterocyclic compounds.

    In the first part, a series of electron deficient α-phenylselenenylalkenes were prepared via a PhSeCl-addition/HCl-elimination sequence. Allyl- and propargylamines readily underwent conjugate addition to these species to produce pyrrolidines or dihydropyrrol derivatives, after triethylborane initiated reductive radical cyclization in the presence of tris(trimethylsilyl)silane.

    The second part describes a convergent synthesis of the pineal hormone melatonin. The indole nucleus is secured via a tris(trimethylsilyl)silane mediated 5-exo radical cyclization. The protocol provides convenient and simple access to compounds useful for studies of biological activity and structure activity relationships.

    The third part describes construction of substituted tetrahydrofuran-3-ones and pyrrolidin-3-ones. Regioselective ring-opening of epoxides or aziridines with benzeneselenolate/tellurolate, followed by Michael addition to electron deficient alkynes afforded the corresponding O/N-vinylated compounds. The tetrahydrofuran-3-ones and pyrrolidin-3-ones were secured via radical carbonylation/reductive cyclization using pressurized carbon monoxide (80 atm).

    The fourth part is concerned with the effect of an N-protecting group on the cyclization of 2-substituted-3-aza-5-hexenyl radicals. Relative energies for reactants and transition states were determined using density functional calculations. Reactant and transition state conformers leading to cis-product were lower in energy than those leading to trans-product. The results can be explained by the unfavorable 1,2-strain present in chair-equatorial and boat-equatorial conformers.

    List of papers
    1. A Radical Cyclization Route to Pyrrolidines Based on Conjugate Addition to Electron Deficient Phenylselenenylalkenes
    Open this publication in new window or tab >>A Radical Cyclization Route to Pyrrolidines Based on Conjugate Addition to Electron Deficient Phenylselenenylalkenes
    2000 In: Tetrahedron Letters, Vol. 41, no 19, p. 3701-3704Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90418 (URN)
    Available from: 2003-05-12 Created: 2003-05-12Bibliographically approved
    2. Efficient Route to the Pineal Hormone Melatonin by Radical-Based Indole Synthesis
    Open this publication in new window or tab >>Efficient Route to the Pineal Hormone Melatonin by Radical-Based Indole Synthesis
    2003 (English)In: Synthetic Communications, ISSN 0039-7911, E-ISSN 1532-2432, Vol. 33, no 20, p. 3631-3641Article in journal (Refereed) Published
    Abstract [en]

    The hormone melatonin, which is known to have a range of important biological effects, has been prepared in a high-yielding route that features formation of the indole nucleus by radical cyclization. Mediation of the radical cyclization by tristrimethylsilylsilane (TTMSS) is more efficient than by N-ethylpiperidine hypophosphite.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-90419 (URN)10.1081/SCC-120024751 (DOI)
    Available from: 2003-05-12 Created: 2003-05-12 Last updated: 2017-12-14Bibliographically approved
    3. Construction of Tetrahydrofuran-3-ones from Readily Available Organochalcogen Precursors via Radical Carbonylation/Reductive Cyclization
    Open this publication in new window or tab >>Construction of Tetrahydrofuran-3-ones from Readily Available Organochalcogen Precursors via Radical Carbonylation/Reductive Cyclization
    2002 In: Organic Letters, Vol. 4, p. 3-6Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-90420 (URN)
    Available from: 2003-05-12 Created: 2003-05-12Bibliographically approved
    4. Radical Carbonylation/Reductive Cyclization for the Construction of Tetrahydrofuran-3-ones and Pyrrolidin3-0nes
    Open this publication in new window or tab >>Radical Carbonylation/Reductive Cyclization for the Construction of Tetrahydrofuran-3-ones and Pyrrolidin3-0nes
    In: Journal of Organic ChemistryArticle in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-90421 (URN)
    Available from: 2003-05-12 Created: 2003-05-12Bibliographically approved
    5. On the origin of cis selectivity in the cyclization of N-protected 2-substituted 3-aza-5-hexenyl radicals: a density functional study
    Open this publication in new window or tab >>On the origin of cis selectivity in the cyclization of N-protected 2-substituted 3-aza-5-hexenyl radicals: a density functional study
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    2004 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 69, no 5, p. 1487-1491Article in journal (Refereed) Published
    Abstract [en]

    Cyclization of the N-dimethylphosphinoyl-2-methyl-3-aza-5-hexenyl radical has been studied at the UB3LYP/6-31+G(d)//UB3LYP/6-31G(d) hybrid density functional level. The corresponding radical precursor has been synthesized and found to give cis/trans ratios of up to 10/1 in reductive radical cyclizations. The relative energies of reactant and transition state conformers were determined. In discord with the Beckwith-Houk model, it has been found that chair-axial transition states, which lead to cis products, are lowest in energy, rationalizing the observed experimental diastereoselectivity.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-90422 (URN)10.1021/jo030294h (DOI)14987001 (PubMedID)
    Available from: 2003-05-12 Created: 2003-05-12 Last updated: 2017-12-14Bibliographically approved
  • 4.
    Beşev, Magnus
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry, Organic Chemistry.
    Radical Cyclization Approaches to Pyrrolidines2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Five-membered rings are readily prepared by 5-exo-trig radical cyclization. This thesis is concerned with novel methodology for pyrrolidine synthesis. We have synthesised selenium containing radical precursors from aziridines and α-phenylseleno ketones, and cyclized them to 2,4- and 3,4-disubstituted pyrrolidines. A few examples of 5-exo-dig cyclization were also demonstrated. In another study we investigated the capacity of the nitrogen protecting group to direct diastereoselectivity in the formation of 2,4-disubstituted pyrrolidines. The diphenylphosphinoyl protecting group directed cyclization to occur in a highly cis-selective manner. When cyclizations were performed at 17 oC, cis/trans-ratios as high as 24/1 were obtained. In contrast, cyclization of the unprotected pyrrolidine precursor afforded the trans-diastereomer as the major product (cis/trans = 1/3.3 – 1/20). We also examined the use of a hydroxyl auxiliary for controlling diastereoselectivity in radical cyclization. The required selenium containing radical precursors were synthesised from 2-cyanoaziridines by addition of organometallic reagents, reduction of the resulting aziridine ketone, and benzeneselenol ring-opening of the aziridine. Cyclization at 17 oC produced 2,4-disubstituted pyrrolidines substantially enriched in the trans-isomer (cis/trans = 1/9 – 1/12). Novel radical cyclization approaches to thiazolines and pyrrolines were also tried.

    The thesis also describes attempts to improve the Hassner aziridine synthesis by employing stannous chloride as a functional group tolerant reducing agent.

  • 5.
    Björkman, Margareta
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry.
    Palladium-promoted synthesis of compounds labelled with ¹¹C: Synthesis of ¹¹C-labelled prostacyclin and prostaglandin analogues2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Palladium-promoted reactions have been employed for the synthesis of compounds labelled with 11C (t½ = 20.3 min). The precursor [11C]methyl iodide was used in palladium-promoted cross-coupling reactions with organostannanes. With this method, large molecules with several functional groups, that is prostacyclin analogues, have been synthesised in up to 54 % decay-corrected radiochemical yield, calculated from [11C]methyl iodide. However, since this method did not afford reproducible yields, a second method where copper(I) was used as a co-catalyst with palladium, was developed. In the second method, a lower reaction temperature could be used and more reproducible yields were obtained. Employing this method, a prostaglandin analogue was synthesised in 34 % decay-corrected radiochemical yield calculated from [11C]methyl iodide. The total synthesis time was 30 min and the radiochemical purity was higher than 95 %. The specific radioactivity of the compounds obtained with these two methods was approximately 100 GBq/μmol.

    11C-Labelled aliphatic and aromatic alkenes were synthesised from [11C]methyl iodide in a Wittig olefination reaction using a published method. The 11C-labelled alkenes were reacted with five aromatic halidein Heck coupling reactions, producing five [11C]stilbene analogues in 34-40 % decay-corrected radiochemical yield. The radiochemical purity was higher than 95 % and the total synthesis timwas 40 min.

    11C-Labelled alkenes were also synthesised from 11C-labelled aldehydes. The 11C-labelled aldehydes were obtained from [11C]carbon monoxide in a palladium-mediated formylation of aryl iodides in 51-87 % radiochemical yield, determined by analytical LC and corrected for trappinefficiency. A range of palladium catalysts and hydride reagents were investigated. The labelled aldehydes were used in a subsequent Wittig olefination reaction where various Wittig salts were employed tsynthesise a variety of alkenes. The radiochemical yields were 30-76 %, determined by analytical LC.

  • 6.
    Bratt, Katharina
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry.
    Secondary plant metabolites as defence against herbivores and oxidative stress: Synthesis, isolation and biological evaluation2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In this thesis the isolation, synthesis and biological evaluation of natural defense compounds against herbivores or oxidative stress is discussed.

    The first part concerns the metabolites of platyphylloside ((5S)-5-hydroxy-1,7-bis-(4-hydroxyphenyl)-3-heptanone-5-O-β-D-glucopyranoside), a phenolic glucoside found in birch (Betula pendula) that possess digestibility inhibiting activity in herbivores. The structure-activity relationship of platyphylloside analogues were investigated regarding to stereochemistry and substitution pattern on the aromatic rings. The metabolites formed in vitro in rumen fluid were synthesized and the active metabolite determined as (R)-centrolobol (1,7-bis-(4-hydroxyphenyl)-3-heptanol). Treatment of mice and rats with rac-centrolobol did not effect either food intake or body weight. Effect of platyphylloside in moose was also investigated, and the results indicate that there was an in vivo digestibility reducing activity.

    The second part concerns naturally occurring antioxidants. Avenanthramides is a class of phenolic antioxidants found in oat (Avena sativa). Avenanthramides derived from either anthranilic acid or 5-hydroxyanthranilic acid were evaluated for their antioxidative capacity and quantified in oat extracts. Avenanthramides derived from 5-hydroxyanthranilic acid possessed higher activity than those from anthranilic acid. The order of reactivity depending on substitution pattern on the phenolic moiety was found to be 4-hydroxy < 4-hydroxy-3-methoxy < 3,5-dimethoxy-4-hydroxy and 3,4-dihydroxy. A synthesis towards antioxidative compounds such as 4-deoxycarbazomycin was developed.

    The third part concerns the isolation of compounds from Lodgepole pine (Pinus contorta) with antifeedant activity against pine weevil (Hylobius abietis). Two compounds possessing high activity were isolated and identified.

  • 7.
    Bylund, Dan
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry.
    Chemometric Tools for Enhanced Performance in Liquid Chromatography-Mass Spectrometry2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Liquid chromatography-mass spectrometry (LC-MS) has become an important analytical on-line technique, capable of producing large amounts of data with high selectivity and sensitivity. Optimal use of the sophisticated instrumentation can be attained if the analytical chemists are guided to perform the proper experiments and to extract the useful information from the acquired data. In this thesis, strategies and methods concerning these two issues are presented.

    LC-MS method development will benefit from fundamental understanding of the processes involved. An experimental procedure was designed to determine the coefficients in a model for the electrospray process. By relating these coefficients to the experimental conditions, the influence on signal level and sensitivity for presence of matrix compounds was studied.

    For the optimization of LC-MS methods, strategies based on empirical modelling were worked out. Comparisons were made between artificial neural network (ANN) modelling and linear modelling tools, and a genetic algorithm was implemented to explore the ANN models.

    Visual interpretation and multivariate analysis of LC-MS data is hampered by background signals and noise, and a digital filter for background suppression and signal-to-noise improvement was developed. It is also important to indicate the presence of overlapping peaks, and a strategy for the assessment of peak purity was therefore worked out. These methods and several established methods were implemented in an add-on program (LC-MS Toolbox 1.0) for information extraction of LC-MS data.

    Ultimately, the data produced with LC-MS can be separated into the mass spectra, the elution profiles and the concentrations of the analytes, e.g. with PARAFAC modelling. The trilinear data structure assumed may, however, be distorted by variations in the LC conditions causing retention time shifts. An improved algorithm for time warping that can compensate for some of these deviations was worked out, and its performance as a pre-processing tool for PARAFAC was examined.

  • 8.
    Bökman, C. Fredrik
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry, Analytical Chemistry.
    Analytical Aspects of Atmospheric Pressure Ionisation in Mass Spectrometry2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The actual signal recorded with an analytical instrument is not always a true reflection of the analysed sample. In this thesis a further insight of the atmospheric pressure ionisation processes electrospray (ESI) and atmospheric pressure chemical ionisation (APCI) has been endeavoured, to provide a deeper understanding of and ways to minimize this bias.

    A response model for ESI has been modified and used to study the influence of solvent composition on the observed mass spectrometric signal. The response model divides the response into an analyte partitioning coefficient and an instrumental response factor. A number of experimental parameters influencing the response were investigated including spray position relative to the orifice, spray potential, nebulizer and curtain gas flow rates, ionic strength and organic content of the sprayed solution. The history of the generated droplets turned out to be of significant importance to both the partitioning coefficients and the instrumental response factor. Furthermore, it was found that the total ionic strength and not only the electrolyte concentration will influence the instrumental response factor.

    In addition, based on the importance of hydrophobicity and electrophoretic mobility, a model was proposed for the ion distribution within the electrosprayed droplets.

    The coupling of an electrochemical (EC) cell to a mass spectrometric (MS) system has been evaluated. The coupling of the EC cell to the MS was made to decouple the cell from the high voltage circuit of the ESI. The feasibility for analyte ionisation, sample pre-concentration and solvent exchange as well as studying redox reaction products was shown.

  • 9.
    Dahlin, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry.
    Microscale Tools for Sample Preparation, Separation and Detection of Neuropeptides2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The analysis of low abundant biological molecules is often challenging due to their chemical properties, low concentration and limited sample volumes. Neuropeptides are one group of molecules that fits these criteria. Neuropeptides also play an important role in biological functions, which makes them extra interesting to analyze. A classic chemical analysis involves sampling, sample preparation, separation and detection. In this thesis, an enhanced solid supported microdialysis method was developed and used as a combined sampling- and preparation technique. In general, significantly increased extraction efficiency was obtained for all studied peptides. To be able to control the small sample volumes and to minimize the loss of neuropeptides because of unwanted adsorption onto surfaces, the subsequent analysis steps were miniaturized to a micro total analysis system (µ-TAS), which allowed sample pre-treatment, injection, separation, manipulation and detection.

    In order to incorporate these analysis functions to a microchip, a novel microfabrication protocol was developed. This method facilitated three-dimensional structures to be fabricated without the need of clean room facilities.

    The sample pre-treatment step was carried out by solid phase extraction from beads packed in the microchip. Femtomole levels of neuropeptides were detected from samples possessing the same properties as microdialysates. The developed injection system made it possible to conduct injections from a liquid chromatographic separation into a capillary electrophoresis channel, which facilitated for advanced multidimensional separations. An electrochemical sample manipulation system was also developed. In the last part, different electrospray emitter tip designs made directly from the edge of the microchip substrate were developed and evaluated. The emitters were proven to be comparable with conventional, capillary based emitters in stability, durability and dynamic flow range. Although additional developments remain, the analysis steps described in this thesis open a door to an integrated, on-line µ-TAS for neuropeptides analysis in complex biological samples.

    List of papers
    1. A feasibility study of solid supported enhanced microdialysis
    Open this publication in new window or tab >>A feasibility study of solid supported enhanced microdialysis
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    2004 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 76, no 6, p. 1678-1682Article in journal (Refereed) Published
    Abstract [en]

    For the first time, a solid supported enhanced microdialysis methodology for analysis of neuropeptides is described. The microdialysis samples were, in this study, subsequently collected in fractions, dissolved from the solid particles, dried, and resolved in a formic acid buffer in order to make them suitable for capillary liquid chromatography-mass spectrometry. Different microdialysis flow profiles were evaluated where air-gapped continuous flow was considered most suitable for the solid supported microdialysis mode. Six endogenous neuropeptides were initially used to investigate the feasibility of this enhanced microdialysis methodology. The improved relative recovery obtained from the solid supported enhanced microdialysis was varying from no effect to 10 times higher as compared to ordinary microdialysis. The most efficient enrichment was obtained for luteinizing hormone releasing hormone, which was the largest but also the most hydrophilic of the peptides. In contrast, no significant difference in recovery was observed for Leu-enkephalin being the smallest and the most hydrophobic peptide tested. These results indicate an increased flux and selective uptake of hydrophilic peptides across the membrane and enrichment on the particles in solid supported microdialysis.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-93181 (URN)10.1021/ac035305l (DOI)15018567 (PubMedID)
    Available from: 2005-05-10 Created: 2005-05-10 Last updated: 2017-12-14Bibliographically approved
    2. Poly(dimethylsiloxane)-Based Microchip for Two-Dimensional Solid-Phase Extraction-Capillary Electrophoresis with an Integrated Electrospray Emitter Tip
    Open this publication in new window or tab >>Poly(dimethylsiloxane)-Based Microchip for Two-Dimensional Solid-Phase Extraction-Capillary Electrophoresis with an Integrated Electrospray Emitter Tip
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    2005 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 77, no 16, p. 5356-5363Article in journal (Refereed) Published
    Abstract [en]

    A microchip in poly(dimethylsiloxane) (PDMS) for in-line solid-phase extraction-capillary electrophoresis-electrospray ionization-time-of-flight mass spectrometry (SPE-CE-ESI-TOF-MS) has been developed and evaluated. The chip was fabricated in a novel one-step procedure where mixed PDMS was cast over steel wires in a mold. The removed wires defined 50-um cylindrical channels. Fused-silica capillaries were inserted into the structure in a tight fit connection. The inner walls of the inserted fused-silica capillaries and the PDMS microchip channels were modified with a positively charged polymer, PolyE-323. The chip was fabricated in a two-level cross design. The channel at the lower level was packed with 5-um hyper-cross-linked polystyrene beads acting as a SPE medium used for desalting. The upper level channel acted as a CE channel and ended in an integrated emitter tip coated with conducting graphite powder to facilitate the electrical contact for sheathless ESI. An overpressure continuously provided fresh CE electrolyte independently of the flows in the different levels. Further studies were carried out in order to investigate the electrophoretic and flow rate properties of the chip. Finally, six-peptide mixtures, in different concentrations, dissolved in physiological salt solution was injected, desalted, separated, and sprayed into the mass spectrometer for analysis with a limit of detection in femtomole levels.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-74074 (URN)10.1021/ac050495g (DOI)16097780 (PubMedID)
    Available from: 2005-08-26 Created: 2005-08-26 Last updated: 2017-12-14Bibliographically approved
    3. A simplified multidimensional approach for analysis of complex biological samples: on-line LC-CE-MS
    Open this publication in new window or tab >>A simplified multidimensional approach for analysis of complex biological samples: on-line LC-CE-MS
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    2006 (English)In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 131, no 7, p. 791-798Article in journal (Refereed) Published
    Abstract [en]

    Information on protein expression, disease biomarkers or surrogate markers and genetic disorders can nowadays be achieved from analysis of complex biological samples by liquid separation coupled to mass spectrometric (MS) detection. This paper describes fast multidimensional separation by on-line liquid chromatography (LC) and capillary electrophoresis (CE), followed by electrospray ionization (ESI) Fourier transform ion cyclotron resonance (FTICR) MS detection. This detector provides ultrahigh resolution of the detected ions, mass accuracy at the ppm-level and high sensitivity. Most of the challenge of this system lies in the development of a new interface for the on-line coupling of LC to CE. The interface developed in poly(dimethylsiloxane) provides a RSD for injection repeatability of <3.5% and surface control for unspecific binding by deactivation with a cationic polymer, PolyE-323. We have evaluated the interface, as well as the overall system, with respect to robustness and deconvolution ability. Sequence coverage for bovine serum albumin (BSA) of 93% showed a high recovery of sample in the different transfer steps through the system. The detection limit for identification is 277 ng mL−1 (or 280 nM) on average for peptides. In the future, we expect LC-CE-MS to be a novel strategy for elucidating the chemistry of biological matrices.

    National Category
    Analytical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-80932 (URN)10.1039/b601660j (DOI)
    Available from: 2006-06-29 Created: 2006-06-29 Last updated: 2017-12-14Bibliographically approved
    4. On-line coupling of a microelectrode array equipped poly(dimethylsiloxane) microchip with an integrated graphite electrospray tip to electrospray mass spectrometry
    Open this publication in new window or tab >>On-line coupling of a microelectrode array equipped poly(dimethylsiloxane) microchip with an integrated graphite electrospray tip to electrospray mass spectrometry
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    In: Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-93184 (URN)
    Available from: 2005-05-10 Created: 2005-05-10 Last updated: 2011-03-21
    5. Sheathless electrospray from polymer microchips
    Open this publication in new window or tab >>Sheathless electrospray from polymer microchips
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    2003 In: Analytical Chemistry, Vol. 75, no 15, p. 3934-3940Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93185 (URN)
    Available from: 2005-05-10 Created: 2005-05-10 Last updated: 2011-03-21
    6. Capillary electrophoresis coupled to mass spectrometry from a polymer modified poly(dimethylsiloxane) microchip with an integrated graphite electrospray tip
    Open this publication in new window or tab >>Capillary electrophoresis coupled to mass spectrometry from a polymer modified poly(dimethylsiloxane) microchip with an integrated graphite electrospray tip
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    2005 (English)In: The Analyst, ISSN 0003-2654, E-ISSN 1364-5528, Vol. 130, no 2, p. 193-199Article in journal (Refereed) Published
    Abstract [en]

    Hybrid capillary-poly(dimethysiloxane) (PDMS) microchips with integrated electrospray ionization (ESI) tips were directly fabricated by casting PDMS in a mould. The shapes of the emitter tips were drilled into the mould, which produced highly reproducible three-dimensional tips. Due to the fabrication method of the microfluidic devices, no sealing was necessary and it was possible to produce a perfect channel modified by PolyE-323, an aliphatic polyamine coating agent. A variety of different coating procedures were also evaluated for the outside of the emitter tip. Dusting graphite on a thin unpolymerised PDMS layer followed by polymerisation was proven to be the most suitable procedure. The emitter tips showed excellent electrochemical properties and durabilities. The coating of the emitter was eventually passivated, but not lost, and could be regenerated by electrochemical means. The excellent electrochemical stability was further confirmed in long term electrospray experiments, in which the emitter sprayed continuously for more than 180 h. The PolyE-323 was found suitable for systems that integrate rigid fused silica and soft PDMS technology, since it simply could be applied successfully to both materials. The spray stability was confirmed from the recording of a total ion chromatogram in which the electrospray current exhibited a relative standard deviation of 3.9% for a 30 min run. CE-ESI-MS separations of peptides were carried out within 2 min using the hybrid PDMS chip resulting in similar efficiencies as for fused silica capillaries of the same length and thus with no measurable band broadening effects, originating from the PDMS emitter.

    National Category
    Analytical Chemistry Inorganic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-93084 (URN)10.1039/b414592e (DOI)15665973 (PubMedID)
    Available from: 2005-05-03 Created: 2005-05-03 Last updated: 2017-12-14Bibliographically approved
    7. Sample pretreatment on a microchip with an integrated electrospray emitter
    Open this publication in new window or tab >>Sample pretreatment on a microchip with an integrated electrospray emitter
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    2006 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 27, no 11, p. 2075-2082Article in journal (Refereed) Published
    Keywords
    Electrospray emitter, Microchip, PDMS, Sample pretreatment
    National Category
    Chemical Sciences Engineering and Technology
    Identifiers
    urn:nbn:se:uu:diva-95129 (URN)10.1002/elps.200500763 (DOI)
    Available from: 2006-11-17 Created: 2006-11-17 Last updated: 2017-12-14Bibliographically approved
  • 10.
    Diesen, Jarle Sidney
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry, Organic Chemistry.
    Asymmetric Hydrogenations of Imines, Vinyl Fluorides, Enol Phosphinates and Other Alkenes Using N,P-Ligated Iridium Complexes2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The research described in this thesis is directed toward the efficient, enantioselective synthesis of chiral products that have useful functionality. This goal was pursued through catalytic asymmetric hydrogenation, a reaction class that selectively introduces one or two stereocenters into a molecule in an atom-efficient step. This reaction uses a small amount (often <1 mol%) of a chiral catalyst to impart stereoselectivity to the product formed. Though catalytic asymmetric hydrogenation is not a new reaction type, there remain many substrate classes for which it is ineffective. The present thesis describes efforts to extend the reaction to some of these substrates classes. Some of the products synthesized in these studies may eventually find use as building blocks for the production of chiral pharmaceuticals, agrochemicals, or flavouring or colouring agents. However, the primary and immediate aim of this thesis was to develop and demonstrate new catalysts that are rapid and effective in the asymmetric hydrogenation of a broad range of compounds.

    Paper I describes the design and construction of two new, related chiral iridium compounds that are catalysts for asymmetric hydrogenation. They each contain an N,P-donating phosphinooxazoline ligand that is held together by a rigid bicyclic unit. One of these iridium compounds catalyzed the asymmetric hydrogenation of acyclic aryl imines, often with very good enantioselectivities. This is particularly notable because acyclic imines are difficult to reduce with useful enantioselectivity. The second catalyst was useful for the asymmetric hydrogenation of two aryl olefins. In Paper II, the class of catalysts introduced into Paper I is expanded to include many more related compounds, and these are also applied to the asymmetric hydrogenation of prochiral imines and olefins. By studying a range of related catalysts that differ in a single attribute, we were able to probe how different parts of the catalyst affect the yield and selectivity of the hydrogenation reactions.

    Whereas iridium catalysts had been applied to the asymmetric hydrogenation of imines and largely unfunctionalized olefins prior to this work (with varied degrees of success), they had not been used to reduce fluoroolefins. Their hydrogenation, which is discussed in Paper III, was complicated by concomitant defluorination to yield non-halogenated alkanes. To combat this problem, several iridium-based hydrogenation catalysts were applied to the reaction. Two catalysts stood out for their ability to produce chiral fluoroalkanes in good enantioselectivity while minimizing the defluorination reaction, and one of these bore a phosphinooxazoline ligand of the type described in Papers I and II.

    Enol phosphinates are another class of olefins that had not previously been subjected to iridium-catalyzed asymmetric hydrogenation. They do, however, constitute an attractive substrate class, because the product chiral alkyl phosphinates can be transformed into chiral alcohols or chiral phosphines with no erosion of enantiopurity. Iridium complexes of the phosphinooxazoline ligands described in Papers I and II were extremely effective catalysts for the asymmetric hydrogenation of enol phosphinates. They produced alkyl phosphinates from di- and trisubstituted enol phosphinate, β-ketoester-derived enol phosphinates, and even purely alkyl-substituted enol phopshinates, in very high yields and enantioselectivities.

    List of papers
    1. Application of Phosphine-Oxazoline Ligands in Ir-Catalyzed Asymmetric Hydrogenation of Acyclic Aromatic N-Arylimines
    Open this publication in new window or tab >>Application of Phosphine-Oxazoline Ligands in Ir-Catalyzed Asymmetric Hydrogenation of Acyclic Aromatic N-Arylimines
    2004 In: Organic Letters, Vol. 6, no 21, p. 3825-3827Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97350 (URN)
    Available from: 2008-05-13 Created: 2008-05-13Bibliographically approved
    2. Hydrogenation of Imines and Olefins Using Phosphine-Oxazoline Iridium Complexes as Catalysts
    Open this publication in new window or tab >>Hydrogenation of Imines and Olefins Using Phosphine-Oxazoline Iridium Complexes as Catalysts
    2006 In: Chemistry-A European Journal, Vol. 12, no 8, p. 2318-2328Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-97351 (URN)
    Available from: 2008-05-13 Created: 2008-05-13Bibliographically approved
    3. Iridium-Catalyzed Asymmetric Hydrogenation of Fluorinated Olefins Using N,P-Ligands: A struggle with hydrogenolysis and selectivity
    Open this publication in new window or tab >>Iridium-Catalyzed Asymmetric Hydrogenation of Fluorinated Olefins Using N,P-Ligands: A struggle with hydrogenolysis and selectivity
    2007 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 129, no 15, p. 4536-4537Article in journal (Refereed) Published
    Abstract [en]

    To broaden the substrate scope of asymmetric iridium-catalyzed hydrogenation, fluorine-functionalized olefins were synthesized and hydrogenated with iridium complexes. Preliminary results showed high levels of fluorine elimination together with low selectivity. The loss of vinylic fluorine at first seemed difficult to handle, but further studies revealed that a catalyst with an azanorbornyl scaffold in the ligand gave more promising results. With this in mind, a new ligand was developed. This gave among the best results published to date for fluorine asymmetric hydrogenation, yielding high conversion and very high ee's with very little fluorine elimination. Further increasing the selectivity, the trials also revealed that tetrasubstituted fluorine-containing olefins can be hydrogenated with high ee's, despite that this class of compounds has usually shown low reactivity in this reaction type.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-97352 (URN)10.1021/ja0686763 (DOI)000245739700016 ()17375924 (PubMedID)
    Available from: 2008-05-13 Created: 2008-05-13 Last updated: 2017-12-14Bibliographically approved
    4. Asymmetric Hydrogenation of Di and Trisubstituted Enol Phosphinates with N,P-Ligated Iridium Complexes
    Open this publication in new window or tab >>Asymmetric Hydrogenation of Di and Trisubstituted Enol Phosphinates with N,P-Ligated Iridium Complexes
    2008 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 130, no 16, p. 5595-5599Article in journal (Refereed) Published
    Abstract [en]

    The iridium-catalyzed asymmetric hydrogenation of various di- and trisubstituted enol phosphinates has been studied. Excellent enantioselectivities (up to >99% ee) and full conversion were observed for a range of substrates with both aromatic and aliphatic side chains. Enol phosphinates are structural analogues of enol acetates, and the hydrogenated alkyl phosphinate products can easily be transformed into the corresponding alcohols with conservation of stereochemistry. We have also hydrogenated, in excellent ee, several purely alkyl-substituted enol phosphinates, producing chiral alcohols that are difficult to obtain highly enantioselectively from ketone hydrogenations.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-97722 (URN)10.1021/ja711372c (DOI)000255041400050 ()
    Available from: 2008-11-11 Created: 2008-11-11 Last updated: 2017-12-14Bibliographically approved
  • 11.
    Eilers, Gerriet
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry.
    Molecular Approaches to Photochemical Solar Energy Conversion: Towards Synthetic Catalysts for Water Oxidation and Proton Reduction2007Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A molecular system capable of photoinduced water splitting is an attractive approach to solar energy conversion. This thesis deals with the functional characterization of molecular building blocks for the three principal functions of such a molecular system: Photoinduced accumulative charge separation, catalytic water oxidation, and catalytic proton reduction.

    Systems combining a ruthenium-trisbipyridine photosensitizer with multi-electron donors in form of dinuclear ruthenium or manganese complexes were investigated in view of the rate constants of electron transfer and excited state quenching. The kinetics were studied in the different oxidation states of the donor unit by combination of electrochemistry and time resolved spectroscopy. The rapid excited state quenching by the multi-electron donors points to the importance of redox intermediates for efficient accumulative photooxidation of the terminal donor.

    The redox behavior of manganese complexes as mimics of the water oxidizing catalyst in the natural photosynthetic reaction center was studied by electrochemical and spectroscopic methods. For a dinuclear manganese complex ligand exchange reactions were studied in view of their importance for the accumulative oxidation of the complex and its reactivity towards water. With the binding of substrate water, multiple oxidation in a narrow potential range and concomitant deprotonation of the bound water it was demonstrated that the manganese complex is capable of mimicking multiple aspects of photosynthetic water oxidation.

    A dinuclear iron complex was investigated as biomimetic proton reduction catalyst. The complex structurally mimics the active site of the iron-only hydrogenase enzyme and was designed to hold a proton on the bridging ligand and a hydride on the iron centers. Thermodynamics and kinetics of the protonation reactions and the electrochemical behavior of the different protonation states were studied in view of their potential catalytic performance.

    List of papers
    1. Iron hydrogenase active site mimic holding a proton and a hydride
    Open this publication in new window or tab >>Iron hydrogenase active site mimic holding a proton and a hydride
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    2006 (English)In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, no 5, p. 520-522Article in journal (Refereed) Published
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-95871 (URN)
    Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2017-12-14
    2. Ligand versus metal protonation of an iron hydrogenase active site mimic
    Open this publication in new window or tab >>Ligand versus metal protonation of an iron hydrogenase active site mimic
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    2007 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 13, no 25, p. 7075-7084Article in journal (Refereed) Published
    Abstract [en]

    The protonation behavior of the iron hydrogenase active-site mimic [Fe2(u-adt)(CO)4(PMe3)2] (1; adt=N-benzyl-azadithiolate) has been investigated by spectroscopic, electrochemical, and computational methods. The combination of an adt bridge and electron-donating phosphine ligands allows protonation of either the adt nitrogen to give [Fe2(μ-Hadt)(CO)4(PMe3)2]+ ([1H]+), the Fe-Fe bond to give [Fe2-(μ-adt)(μ-H)(CO)4(PMe3)2]+ ([1Hy]+), or both sites simultaneously to give [Fe2(μ-Hadt)(μ-H)(CO)4(PMe3)2]2+ ([1HHy]2+). Complex 1 and its protonation products have been characterized in acetonitrile solution by IR, 1H, and 31PNMR spectroscopy. The solution structures of all protonation states feature a basal/basal orientation of the phosphine ligands, which contrasts with the basal/apical structure of 1 in the solid state. Density functional calculations have been performed on all protonation states and a comparison between calculated and experimental spectra confirms the structural assignments. The ligand protonated complex [1H]+ (pKa =12) is the initial, metastable protonation product while the hydride [1Hy]+ (pKa=15) is the thermodynamically stable singly protonated form. Tautomerization of cation [1H]+ to [1Hy]+ does not occur spontaneously. However, it can be catalyzed by HCl (k=2.2M-1s-1), which results in the selective formation of cation [1Hy]+. The protonations of the two basic sites have strong mutual effects on their basicities such that the hydride (pKa=8) and the ammonium proton (pKa=5) of the doubly protonated cationic complex [1HHy]2+ are considerably more acidic than in the singly protonated analogues. The formation of dication [1HHy]2+ from cation [1H]+ is exceptionally slow with perchloric or trifluoromethanesulfonic acid (k= 0.15 M-1s-1), while the dication is formed substantially faster (k > 102 M-1 s-1) with hydrobromic acid. Electrochemically, 1 undergoes irreversible reduction at -2.2V versus ferrocene, and this potential shifts to -1.6, - 1.1, and -1.0 V for the cationic complexes [1H]+, [1Hy]+, and [1HHy]2+, respectively, upon protonation. The doubly protonated form [1HHy]2+ is reduced at less negative potential than all previously reported hydrogenase models, although catalytic proton reduction at this potential is characterized by slow turnover.

    Keywords
    density functional calculations, electrochemistry, enzyme models, hydride ligands, tautomerism
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-95872 (URN)10.1002/chem.200700019 (DOI)000249294300005 ()17566128 (PubMedID)
    Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2017-12-14Bibliographically approved
    3. Synthesis and characterization of dinuclear ruthenium complexes covalently linked to Ru(II) tris-bipyridine: an approach to mimics of the donor side of photosystem II
    Open this publication in new window or tab >>Synthesis and characterization of dinuclear ruthenium complexes covalently linked to Ru(II) tris-bipyridine: an approach to mimics of the donor side of photosystem II
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    2005 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 11, no 24, p. 7305-7314Article in journal (Refereed) Published
    Abstract [en]

    The structural rearrangements triggered by oxidation of the dinuclear Mn complex [Mn2(bpmp)(u-OAc)2]+ (bpmp = 2,6-bis[bis(2-pyridylmethyl)amino]methyl-4-methylphenol anion) in the presence of water have been studied by combinations of electrochemistry with IR spectroscopy and with electrospray ionization mass spectrometry (ESI-MS). The exchange of acetate bridges for water (D2O) derived ligands in different oxidation states could be monitored by mid-IR spectroscopy in CD3CN-D2O mixtures following the Vas(C-O) bands of bound acetate at 1594.4 cm-1 (II,II), 1592.0 cm-1 (II,III) and 1586.5 cm-1 (III,III). Substantial loss of bound acetate occurs at much lower water content (<0.5% v/v) in the III,III state than in the II,II and II,III states (>10%). The ligand-exchange reactions do not initially reduce the overall charge of the complex but facilitate further oxidation by proton-coupled electron transfer as the water-derived ligands are increasingly deprotonated in higher oxidation states. In the IR spectra deprotonation could be followed by the formation of acetic acid (DOAc, ~1725 cm-1, V(C-O)) from the released acetate (1573.6 cm-1, Vas(C-O)). By the on-line combination of an electrochemical flow cell with ESI-MS several product complexes could be identified. A di-u-oxo bridged III,IV dimer [Mn2(bpmp)(u-O)2]2+ (m/z 335.8) can be generated at potentials below the III,III/II,III couple of the di-u-acetato complex (0.61 V Vs. ferrocene). The ligand-exchange reactions allow for three metal-centered oxidation steps to occur from II,II to III,IV in a potential range of only 0.5 V, explaining the formation of a spin-coupled III,IV dimer by photo-oxidation with [Ru(bpy)3]3+ in previous EPR studies.

    Keywords
    electrochemistry, electron transfer, mixed-valent compounds, ruthenium cluster, sensitizers
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-95873 (URN)10.1002/chem.200500592 (DOI)16163754 (PubMedID)
    Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2017-12-14
    4. Ligand exchange upon oxidation of a dinuclear Mn complex - Detection of structural changes by FT-IR spectroscopy and ESI-MS.
    Open this publication in new window or tab >>Ligand exchange upon oxidation of a dinuclear Mn complex - Detection of structural changes by FT-IR spectroscopy and ESI-MS.
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    2005 (English)In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, no 6, p. 1033-1041Article in journal (Refereed) Published
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-95874 (URN)
    Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2017-12-14
    5. Synthesis and redox properties of a [meso-tris(4-nitrophenyl) corrolato]Mn(III) complex.
    Open this publication in new window or tab >>Synthesis and redox properties of a [meso-tris(4-nitrophenyl) corrolato]Mn(III) complex.
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    2005 (English)In: Journal of Porphyrins and Phthalocyanines, ISSN 1088-4246, E-ISSN 1099-1409, no 9(6), p. 379-386Article in journal (Refereed) Published
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-95875 (URN)
    Available from: 2007-05-04 Created: 2007-05-04 Last updated: 2017-12-14
  • 12.
    Erdélyi, Máté
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry, Organic Chemistry.
    Towards the Development of Photoswitchable β-Hairpin Mimetics2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Peptide secondary structure mimetics are important tools in medicinal chemistry, as they provide analogues of endogeneous peptides with new physicochemical and pharmacological properties. The β-hairpin motif has been shown to be involved in numerous physiological processes, among others in regulation of eucariotic gene transcription. This thesis addresses the design, synthesis and conformational analysis of photoswitchable β-hairpin mimetics.

    The developmental work included the establishment of an improved procedure for cross coupling of aryl halides with terminal alkynes. Microwave mediated Sonogashira couplings in closed vessels were optimized under homogeneous and solid-phase conditions furnishing excellent yields for a large variety of substrates within 5 – 25 minutes. In addition, microwave heating was shown not to have any non-conventional effect on the reaction rate.

    Furthermore, the most important factors affecting β-hairpin stability were evaluated. Studies of tetrapeptide and decapeptide analogues revealed the essential role of the β-turn in initiation of hairpin folding. Moreover, hydrogen bonding was shown to be the main interchain stabilizing force, whereas hydrophobic interactions were found to be relatively weak. Nevertheless, hydrophobic packing appears to provide an important contribution to the thermodynamic stability of β-hairpins.

    Photoswitchable peptidomimetics were prepared by incorporation of various stilbene moieties into tetra- and decapeptides. Synthesis, photochemical isomerisation and spectroscopic conformational analysis of the compounds were performed.

    List of papers
    1. Rapid Homogeneous-Phase Sonogashira Coupling Reactions Using Controlled Microwave Heating
    Open this publication in new window or tab >>Rapid Homogeneous-Phase Sonogashira Coupling Reactions Using Controlled Microwave Heating
    2001 In: Journal of Organic Chemistry, Vol. 66, no 12, p. 4165-4169Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91463 (URN)
    Available from: 2004-03-11 Created: 2004-03-11Bibliographically approved
    2. Rapid Microwave Promoted Sonogashira Coupling Reactions on Solid Phase
    Open this publication in new window or tab >>Rapid Microwave Promoted Sonogashira Coupling Reactions on Solid Phase
    2003 (English)In: Journal of Organic Chemistry, Vol. 68, no 16, p. 6431-6434Article in journal (Refereed) Published
    Abstract [en]

    A microwave-enhanced, rapid, and efficient solidphase version of the Sonogashira reaction is presented. It has been applied to the coupling of aryl iodides and bromides with various acetylene derivatives giving excellent yields in 15 to 25 min. The scopes of homogeneous, solventless, and solid-phase conditions for Sonogashira coupling of aryl halides are compared.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-91464 (URN)10.1021/jo034284s (DOI)
    Available from: 2004-03-11 Created: 2004-03-11 Last updated: 2011-01-05
    3. Insight into β-Hairpin Stability: A Structural and Thermodynamic Study of Diastereomeric β-Hairpin Mimetics
    Open this publication in new window or tab >>Insight into β-Hairpin Stability: A Structural and Thermodynamic Study of Diastereomeric β-Hairpin Mimetics
    2002 In: New Journal of Chemistry, Vol. 26, p. 834-843Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91465 (URN)
    Available from: 2004-03-11 Created: 2004-03-11Bibliographically approved
    4. Synthesis and Conformational Analysis of Novel Stibene-type Peptidomimetics
    Open this publication in new window or tab >>Synthesis and Conformational Analysis of Novel Stibene-type Peptidomimetics
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    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-91466 (URN)
    Available from: 2004-03-11 Created: 2004-03-11Bibliographically approved
    5. Synthesis and Conformational Analysis of Novel β-Hairpin mimetics. Factors Affecting Stability and Incorporation of a Photoswitchable Dipeptide Mimic
    Open this publication in new window or tab >>Synthesis and Conformational Analysis of Novel β-Hairpin mimetics. Factors Affecting Stability and Incorporation of a Photoswitchable Dipeptide Mimic
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-91467 (URN)
    Available from: 2004-03-11 Created: 2004-03-11Bibliographically approved
  • 13.
    Ericsson, Cecilia
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry, Organic Chemistry.
    Synthesis of Tetrahydrofuran and Pyrrolidine Derivatives Utilising Radical Reactions: Organochalcogenides in Reductive, Carbonylative and Group-Transfer Cyclisation2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes free-radical reactions for the construction of tetrahydrofuran and pyrrolidine derivatives. The studies are concerned with (i) diastereoselectivity in radical cyclisation, (ii) construction of tetrahydrofuran-3-ones and pyrrolidin-3-ones via radical carbonylation/cyclisation and (iii) synthesis of tetrahydrofuran derivatives via group-transfer cyclisation of organochalcogen compounds.

    (i) Diastereoselectivity in the synthesis of tetrahydrofuran derivatives via radical cyclisation was controlled by addition of Lewis acids. In the synthesis of 2,4-disubstitued tetrahydrofurans, the trans-isomer was formed as the major product in the unperturbed reaction. Upon addition of trialkylalumiums the diastereoselectivity was reversed. In a similar fashion, exo/endo-diastereoselectivity in the synthesis of bicyclic 2,3,4-trisubstituted tetrahydrofurans could also be controlled.

    (ii) Procedures for construction of tetrahydrofuran-3-ones and pyrrolidin-3-ones were presented. Epoxides were ring-opened with benzeneselenolate or benzenetellurolate and the resulting β-hydroxyalkyl phenyl chalcogenides were vinylated using ethyl propiolate/NMM or E-1,2-bis(phenylsulfonyl)ethylene/NaH. The corresponding nitrogen analogues were accessed by N-vinylation of aziridines followed by benzeneselenolate ring-opening. The two types of organochalcogen radical precursors were then treated with TTMSS/AIBN under an atmosphere of carbon monoxide (80 atm) to afford tetrahydrofuran-3-ones and pyrrolidin-3-ones, respectively, in high yields.

    (iii) Microwaves were found to induce group-transfer cyclisation of β-allyloxyalkyl aryl chalcogenides. Short time heating (3-10 min) at 250 oC in ethylene glycol was required to obtain tetrahydrofuran derivatives in 60-91% yield.

    List of papers
    1. Diastereocontrol by Trialkylaluminums in the Synthesis of Tetrahydrofurans via Radical Cyclisation
    Open this publication in new window or tab >>Diastereocontrol by Trialkylaluminums in the Synthesis of Tetrahydrofurans via Radical Cyclisation
    2001 In: Organic Letters, Vol. 3, p. 3459-Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91437 (URN)
    Available from: 2004-02-26 Created: 2004-02-26Bibliographically approved
    2. Construction of Tetrahydrofuran-3-ones from Readily Available Organochalcogen Precursors via Radical Carbonylation/Reductive Cyclization
    Open this publication in new window or tab >>Construction of Tetrahydrofuran-3-ones from Readily Available Organochalcogen Precursors via Radical Carbonylation/Reductive Cyclization
    2002 In: Organic Letters, Vol. 4, p. 3-Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91438 (URN)
    Available from: 2004-02-26 Created: 2004-02-26Bibliographically approved
    3. Radical Carbonylation/Reductive Cyclization for the Construction of Tetrahydrofuran-3-ones and Pyrrolidin-3-ones
    Open this publication in new window or tab >>Radical Carbonylation/Reductive Cyclization for the Construction of Tetrahydrofuran-3-ones and Pyrrolidin-3-ones
    2003 In: Journal of Organic Chemistry, Vol. 68, p. 8386-Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-91439 (URN)
    Available from: 2004-02-26 Created: 2004-02-26Bibliographically approved
    4. Microwave-Assisted Group-Transfer Cyclisation of Organotellurium Compounds
    Open this publication in new window or tab >>Microwave-Assisted Group-Transfer Cyclisation of Organotellurium Compounds
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-91440 (URN)
    Available from: 2004-02-26 Created: 2004-02-26Bibliographically approved
  • 14.
    Eriksson, Alf
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry.
    Voltammetric properties of olsalazine sodium and some related compounds2001Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The voltammetric properties of Olsalazine sodium, seven other azosalicylic acids and the azoxy analogue of Olsalazine sodium have been studied in aqueous solutions mainly by cyclic voltammetry and constant potential coulometry. It was found that these compounds can all be both reduced and oxidised at a glassy carbon electrode. The reduction and oxidation potentials of the compounds were dependent on the pH and the structure of the compounds. All compounds, except 4,4'-azobis-(2-hydroxybenzoic acid), were reduced to the corresponding amino salicylic acids in a 4 e-, 4 H+ reaction, as shown by spectrophotometric and voltammetric investigations of the reduced solutions. A further electrochemical characterisation of the formed reduction products 3-, 4- and 5-aminosalicylic acid was also carried out.

    It was found that the oxidation of the investigated azo compounds occurs according to two different pathways. Compounds with, at the most one hydroxyl group in the 2- or 4- position were shown to be irreversibly oxidised while Olsalazine sodium, its azoxy analogue and 2-hydroxy-5-[(3'-carboxy-2'-hydroxyphenyl)azo]benzoic acid disodium salt were oxidised in a reversible 2e-, 2H+ reaction. The oxidation product of Olsalazine sodium was characterised by UV/VIS and NMR spectroscopic methods and a structure for the oxidation product was proposed. The oxidative properties of Olsalazine sodium were also utilised to determine nM concentrations of this compound by liquid chromatography with electrochemical detection (LCEC).

  • 15.
    Eriksson, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry, Organic Chemistry.
    Synthesis of 11C-labelled Alkyl Iodides: Using Non-thermal Plasma and Palladium-mediated Carbonylation Methods2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Compounds labelled with 11C (β+, t1/2 = 20.4 min) are used in positron emission tomography (PET), which is a quantitative non-invasive molecular imaging technique. It utilizes computerized reconstruction methods to produce time-resolved images of the radioactivity distribution in living subjects.

    The feasibility of preparing [11C]methyl iodide from [11C]methane and iodine via a single pass through a non-thermal plasma reactor was explored. [11C]Methyl iodide with a specific radioactivity of 412 ± 32 GBq/µmol was obtained in 13 ± 3% decay-corrected radiochemical yield within 6 min via catalytic hydrogenation of [11C]carbon dioxide (24 GBq) and subsequent iodination, induced by electron impact.

    Labelled ethyl-, propyl- and butyl iodide was synthesized, within 15 min, via palladium-mediated carbonylation using [11C]carbon monoxide. The carbonylation products, labelled carboxylic acids, esters and aldehydes, were reduced to their corresponding alcohols and converted to alkyl iodides. [1-11C]Ethyl iodide was obtained via palladium-mediated carbonylation of methyl iodide with a decay-corrected radiochemical yield of 55 ± 5%. [1-11C]Propyl iodide and [1-11C]butyl iodide were synthesized via the hydroformylation of ethene and propene with decay-corrected radiochemical yields of 58 ± 4% and 34 ± 2%, respectively. [1-11C]Ethyl iodide was obtained with a specific radioactivity of 84 GBq/mmol from 10 GBq of [11C]carbon monoxide. [1-11C]Propyl iodide was synthesized with a specific radioactivity of 270 GBq/mmol from 12 GBq and [1-11C]butyl iodide with 146 GBq/mmol from 8 GBq.

    Palladium-mediated hydroxycarbonylation of acetylene was used in the synthesis of [1-11C]acrylic acid. The labelled carboxylic acid was converted to its acid chloride and subsequently treated with amine to yield N-[carbonyl-11C]benzylacrylamide. In an alternative method, [carbonyl-11C]acrylamides were synthesized in decay-corrected radiochemical yields up to 81% via palladium-mediated carbonylative cross-coupling of vinyl halides and amines. Starting from 10 ± 0.5 GBq of [11C]carbon monoxide, N-[carbonyl-11C]benzylacrylamide was obtained in 4 min with a specific radioactivity of 330 ± 4 GBq/µmol.

    List of papers
    1. [C-11]methyl iodide from [C-11]methane and iodine using a non-thermal plasma method
    Open this publication in new window or tab >>[C-11]methyl iodide from [C-11]methane and iodine using a non-thermal plasma method
    2006 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 49, no 13, p. 1177-1186Article in journal (Refereed) Published
    Abstract [en]

    A method and an apparatus for preparing [C-11]methyl iodide from [C-11]methane and iodine in a single pass through a non-thermal plasma reactor has been developed. The plasma was created by applying high voltage (400 V/31 kHz) to electrodes in a stream of helium gas at reduced pressure. The [C-11]methane used in the experiments was produced from [C-11]carbon dioxide via reduction with hydrogen over nickel. [C-11]methyl iodide was obtained with a specific radioactivity of 412 +/- 32 GBq/mu mol within 6 min from approximately 24 GBq of [C-11]carbon dioxide. The decay corrected radiochemical yield was 13 +/- 3% based on [C-11]carbon dioxide at start of synthesis. [C-11]Flumazenil was synthesized via a N-alkylation with the prepared [C-11]methyl iodide.

    Keywords
    [C-11]methyl iodide, [C-11]methane, non-thermal plasma, specific radioactivity
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-94929 (URN)10.1002/jlcr.1135 (DOI)000242796700006 ()
    Available from: 2006-10-05 Created: 2006-10-05 Last updated: 2017-12-14Bibliographically approved
    2. Synthesis of [1-11C]ethyl iodide from carbon monoxide and its application in alkylation reactions
    Open this publication in new window or tab >>Synthesis of [1-11C]ethyl iodide from carbon monoxide and its application in alkylation reactions
    2004 (English)In: Journal of Labelled Compounds and Radiopharmaceuticals, ISSN 0362-4803, Vol. 47, no 11, p. 723-731Article in journal (Refereed) Published
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-94930 (URN)
    Available from: 2006-10-05 Created: 2006-10-05 Last updated: 2015-09-24
    3. Synthesis of [1-C-11]propyl and [1-C-11]butyl iodide from [C-11]carbon monoxide and their use in alkylation reactions
    Open this publication in new window or tab >>Synthesis of [1-C-11]propyl and [1-C-11]butyl iodide from [C-11]carbon monoxide and their use in alkylation reactions
    2006 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 49, no 12, p. 1105-1116Article in journal (Refereed) Published
    Abstract [en]

    A method to prepare [1-C-11]propyl iodide and [1-C-11]butyl iodide from [C-11]carbon monoxide via a three step reaction sequence is presented. Palladium mediated formylation of ethene with [C-11]carbon monoxide and hydrogen gave [1-C-11]propionaldehyde and [1-C-11]propionic acid. The carbonylation products were reduced and subsequently converted to [1-C-11]propyl iodide. Labelled propyl iodide was obtained in 58 +/- 4% decay corrected radiochemical yield and with a specific radioactivity of 270 +/- 33 GBq/mu mol within 15 min from approximately 12 GBq of [C-11]carbon monoxide. The position of the label was confirmed by C-13-labelling and C-13-NMR analysis. [1-C-11]Butyl iodide was obtained correspondingly from propene and approximately 8 GBq of [C-11]carbon monoxide, in 34 +/- 2% decay corrected radiochemical yield and with a specific radioactivity of 146 +/- 20 GBq/mu mol. The alkyl iodides were used in model reactions to synthesize [O-propyl-1-C-11]propyl and [O-butyl-1-C-11]butyl benzoate. Propyl and butyl analogues of etomidate, a (beta-11-hydroxylase inhibitor, were also synthesized.

    Keywords
    [C-11]carbon monoxide, [1-C-11]propyl iodide, [1-C-11]butyl iodide, carbonylation, formylation, alkylation
    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-94931 (URN)10.1002/jlcr.1119 (DOI)000242335900009 ()
    Available from: 2006-10-05 Created: 2006-10-05 Last updated: 2017-12-14Bibliographically approved
    4. Synthesis of [11C]/[13C]acrylamides by palladium-mediated carbonylation
    Open this publication in new window or tab >>Synthesis of [11C]/[13C]acrylamides by palladium-mediated carbonylation
    2007 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, no 3, p. 455-461Article in journal (Refereed) Published
    Abstract [en]

    Two methods are presented for the synthesis of acrylamides labelled with C-11 (beta(+), t(1/2) = 20.4 min) and C-11 in the carbonyl position. In the first method, [1-C-11]acrylic acid is synthesised from [C-11]carbon monoxide by palladium-mediated hydroxy-carbonylation of acetylene. The labelled carboxylic acid is converted into the acyl chloride and subsequently treated with amine to yield N-benzyl[carbonyl(11)C]acrylamide, The second method utilizes [C-11]carbon monoxide in a palladium-mediated carbonylative cross-coupling of vinyl halides and amines. A higher radiochemical yield is achieved with the latter method and the amount of amine needed is decreased to 1/20. The C-11-labelled acrylamides were isolated in up to 81 % decay-corrected radiochemical yield. Starting from 10 +/- 0.5GBq of [C-11]carbon monoxide, N-benzyl[carbonyl-C-11]acrylamide was obtained in 4 min with a specific radioactivity of 330 +/- 4 GBq mu mol-(1). Co-labelling with C-11 and C-13 enabled confirmation of the labelled position by C-13 NMR spectroscopy.

    Keywords
    Carbonylation, Amides, Carbon monoxide, Isotopic labelling, Carbon-11, 11C, PET
    National Category
    Chemical Sciences
    Research subject
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-98592 (URN)10.1002/ejoc.200600700 (DOI)000243600100007 ()
    Available from: 2009-02-27 Created: 2009-02-27 Last updated: 2017-12-13Bibliographically approved
    5. [1-11C]Ethyl iodide and [1-11C]propyl iodide in the synthesis of two potential NK1-receptor ligands and initial PET-imaging
    Open this publication in new window or tab >>[1-11C]Ethyl iodide and [1-11C]propyl iodide in the synthesis of two potential NK1-receptor ligands and initial PET-imaging
    Show others...
    (English)Manuscript (Other academic)
    National Category
    Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-94933 (URN)
    Available from: 2006-10-05 Created: 2006-10-05 Last updated: 2018-01-13
  • 16.
    Eriksson, Ludvig
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry, Organic Chemistry.
    Transition Metal Mediated Transformations of Carboranes2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes the use of copper and palladium to mediate transformations of carboranes, especially p-carborane.

    1-(1-p-carboranyl)-N-methyl-N-(2-butyl)-3-isoquinolinecarboxamide, a carborane containing analogue of the peripheral benzodiazepine receptor (PBR) ligand PK11195, has been synthesised. A key step in the reaction is the copper (I) mediated coupling of p-carborane with ethyl 1-bromo-isoquinoline-3-carboxylate.

    p-Carborane has been arylated on the 2-B-atom in high yields, using the Suzuki–Miyaura reaction. Thus the reaction between 2-I-p-carborane and various arylboronic acids [1-naphthyl-, phenyl-, 4-MeO-C6H4-, 3-CH3CONH-C6H4-, 4-NC-C6H4-, 3-NO2-C6H4-], gave the corresponding 2-aryl-p-carboranes in DME solution when reacted in the presence of cesium fluoride and the catalytic Pd2(dba)3–dppb system. Under the same conditions, the boron-boron bond forming reaction of two p-carboranylboronic esters (2-[(pinacolato)boron]-p-carborane and 2-[(neopentyl glycolato)boron]-p-carborane) was also shown feasible.

    p-Carborane has been vinylated on the 2-B-atom in high yields by use of the Heck reaction. The coupling between 2-I-p-carborane and various styrenes [4-H-, 4-C6H4-, 4-Cl , 4-Br-, 4-NO2-, 4-CH3O- and 4 CH3 ] resulted in the formation of the correspondingtrans-β-(2-B-p-carboranyl) styrene in DMF solution when reacted in the presence of silver phosphate and the palladacycle Herrmann´s catalyst. The reaction was shown to proceed at higher rate with electron rich than with electron deficient olefins.

    The feasibility of palladium-catalysed isotopic exchange of an iodinated closo-carborane with a radioisotope of iodine has been studied. 2-I-p-carborane was selected as a model compound. It was shown, that such isotopic exchange is possible and provides a high yield (83 ± 4.2 %) during 40 min long reaction. The reaction conditions were optimised, and it was demonstrated that presence of the tetra n-butylammonium hydrogensulphate is important in order to stabilise catalyst and provide reproducibility of labelling. In this work we have modified the methodology and extended the application to a wider range of iodinated carboranes. By the use of Herrmann’s catalyst in toluene at 100 °C this [125I]-iodide labelling could be improved and extended. 2-I-p- 9-I-m-, 9-I-o-, 3-I-o-carborane, 1-phenyl-3-I-o-carborane and 1,2-diphenyl-3-I-o-carborane could be [125I]-iodide labelled in high to excellent yields within 5 minutes.This reported palladium catalyzed radio-iodination of the uncharged closo-carboranes might find use in pharmacokinetic studies of carborane derivatives.

  • 17.
    Gayet, Arnaud
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry, Organic Chemistry.
    Development of New Chiral Bicyclic Ligands: Applications in Catalytic Asymmetric Transfer Hydrogenation, Epoxidations, and Epoxide Rearrangements2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes the synthesis and application of new chiral bicyclic ligands and their application in asymmetric catalysis. The studies involved: [i] The development of novel chiral bicyclic amino sulfur ligands and their use in transfer hydrogenation. [ii] The development of the kinetic resolution of racemic epoxide through the use of chiral lithium amides. [iii] The synthesis and application of chiral bicyclic amine in the organocatalysed epoxidation of alkenes. [iv] Development and application of new chiral diamine ligands in the rearrangement of epoxides into allylic alcohols.

    [i] The preparation of two-series of amino thiol ligands based on the structure of camphor is described, together with their application in the iridium-catalysed asymmetric transfer hydrogenation of acetophenone using isopropanol as the hydrogen source. Excellent activity and good enantioselectivity have been achieved using 2 mol% of chiral ligand in combination with [IrCl(COD)]2.

    [ii] The chiral diamines (1S,3R,4R)-3-(pyrrolidine-1-ylmethyl)-2-aza-bicyclo[2.2.1]heptane and its (2R,5R)-dimethylpyrrolidine derivative were applied to the kinetic resolution of a variety of racemic 5-7 membered cycloalkene oxides with lithium diisopropylamide (LDA) as the bulk base. Using 5 mol% of the chiral diamines, both unreacted epoxides and allylic alcohols could be produced in enantiomeric excess up to 99%.

    [iii] The synthesis of chiral bicyclic amines and their use in the organocatalysed epoxidation of alkene has been described. Using a substoichiometric amount of the chiral amines and aldehydes as ligands precursors, with Oxone® as oxidant, a good activity but moderate enantioselectivity was observed for the epoxidation of trans-stilbene.

    [iv] The preparation of 6-substituted-7-bromo-aza-bicyclo[2.2.1]heptanes via nucleophilic addition of organocopper reagents to 3-bromo-1-azoniatricyclo[2.2.1.0]heptyle bromide has been described. These compounds have been utilised as chiral building blocks in the preparation of novel chiral diamine ligands, which have been successfully applied to the catalysed asymmetric rearrangement of epoxide into the corresponding allylic alcohol.

    List of papers
    1. Novel Catalytic Kinetic Resolution Of Racemic Epoxides to Allylic alcohols
    Open this publication in new window or tab >>Novel Catalytic Kinetic Resolution Of Racemic Epoxides to Allylic alcohols
    2002 In: Organic Letters, ISSN 1523-7060, Vol. 4, no 22, p. 3777-3779Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92519 (URN)
    Available from: 2005-01-10 Created: 2005-01-10Bibliographically approved
    2. Development of new camphor based N,S chiral ligands and their application in transfer hydrogenation
    Open this publication in new window or tab >>Development of new camphor based N,S chiral ligands and their application in transfer hydrogenation
    2004 In: Organic & Biomolecular Chemistry, ISSN 1477-0520, Vol. 2, no 13, p. 1887-1893Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92520 (URN)
    Available from: 2005-01-10 Created: 2005-01-10Bibliographically approved
    3. Synthesis of 6-Substituted 7-Bomoazabicyclo[2.2.1]heptanes via Nucleophilic Addition to 3-Bromo-1-azoniatricyclo[2.2.1.0]-heptane Bromide
    Open this publication in new window or tab >>Synthesis of 6-Substituted 7-Bomoazabicyclo[2.2.1]heptanes via Nucleophilic Addition to 3-Bromo-1-azoniatricyclo[2.2.1.0]-heptane Bromide
    2005 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 347, no 9, p. 1242-1246Article in journal (Refereed) Published
    Abstract [en]

    We describe herein an efficient method for the preparation of a functionalised bicyclic framework (6-substituted 7-bromo-aza-bicyclo[2.2.1]heptane) through the selective opening of the aziridium 2 with organocuprates in up to 90% yield. These interesting chiral building blocks were then utilised as novel ligands in the rearrangement of epoxides to afford chiral allylic alcohols.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-92521 (URN)10.1002/adsc.200404322 (DOI)
    Available from: 2005-01-10 Created: 2005-01-10 Last updated: 2017-12-14Bibliographically approved
  • 18.
    Ghirmai, Senait
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry.
    Synthesis of Organic Compounds for Nuclide Therapy: Derivatives of Carboranes, 9-Aminoacridine and Anthracyclines2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis addresses the synthesis of organic compounds, some of them are derivatives of compounds with DNA binding properties, for potential use in targeted nuclide therapy. The compounds synthesized therefore also need to contain potent nuclides. Here the nuclides considered are the radionuclide 125I, and the stable isotope 10B, which becomes radioactive upon neutron activation. 125I is an Auger-electron emitter, which emits particles that can travel only about 1-2 µm through human tissue and hence has to be delivered to the cancer cell nucleus to cause DNA damage. Neutron activated 10B emits highly cell killing α-particles and 7Li3+ ions, the application of which in Boron Nuclide Capture Therapy (BNCT) has proven very promising.

    The thesis can be divided into three parts:

    i) A nido-carborate, 7-(3´-ammoniopropyl)-7,8-dicarba-nido-undecaborate(-1), has been synthesized and radioiodinated for use as a pendant group for attachment of 125I to tumor-seeking macromolecules. Radiolabeling was achieved in greater than 95% yield.

    ii) Both enantiomers of m-carboranylalanine, a carborane analogue of phenylalanine, have been prepared in high enantiomeric excess, and are of potential interest in BNCT. The synthesis involved amination of the N-acyl derivative formed from [3-(1,7-dicarba-closo-dodecarborane(12)-1-yl)-2-propanoic acid and Oppolzer’s camphor sultam.

    iii) Derivatives of the DNA intercalating compounds 9-aminoacridine, daunorubicin and doxorubicin have been synthesized and labeled with 125I. The 9-aminoacridines were synthesised with a variety of functional groups such as carboxyl, amino and hydroxyl. The anthracylines daunorubicin and doxorubicin are efficient chemotherapeutic agents; the synthesis routes of ester, amide and amine derivatives of these compounds are presented.

    The Chloramine T method was used for the radioiodinations, and the radioiodination precursors of both the acridine and the anthracycline derivatives, were made to contain either a trimethylstannyl group or a phenolic substituent. In the former case the trimethylstannyl group was replaced by 125I, and in the latter case, the compounds were radiolabeled directly at the o- position to the phenolic hydroxyl group. Both methods gave high radiolabeling yields.

    List of papers
    1. Synthesis and Radioiodination of 7-(3´-Ammoniopropyl)-7,8-dicarba-nido-undecaborate(-1), (ANC)
    Open this publication in new window or tab >>Synthesis and Radioiodination of 7-(3´-Ammoniopropyl)-7,8-dicarba-nido-undecaborate(-1), (ANC)
    Show others...
    2004 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 47, no 9, p. 557-569Article in journal (Refereed) Published
    Abstract [en]

    Derivatives of nido-carborate have potential use in tumour targeting as hydrophilic boron-rich compounds for boron neutron capture therapy (BNCT) and as pendant groups for attachment of radiohalogens to tumour-seeking molecules. For this purpose, functionalized derivatives of nido-carborates that can be conjugated to biomolecules should be synthesized and evaluated. In this study, racemic 1, 7-(3′-ammoniopropyl)-7,8-dicarba-nido-undecaborate(-1) (acronym ANC) was obtained by degradation of the corresponding aminopropyl-o-carborane, which was synthesized in three steps from 1-tert-butyldimethylsilyl-2-(3-bromopropyl)-o-carborane, with sodium hydroxide in absolute ethanol. The racemate 1 was radioiodinated (125I) using the Chloramine-T method. Radio-TLC results showed that radiolabelling with 125I was achieved in a yield greater than 95%.

    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-91769 (URN)10.1002/jlcr.840 (DOI)
    Available from: 2004-04-22 Created: 2004-04-22 Last updated: 2017-12-14Bibliographically approved
    2. Enantioselective Synthesis of m-Carboranylalanine a Boron-rich Analogue of Phenylalanine
    Open this publication in new window or tab >>Enantioselective Synthesis of m-Carboranylalanine a Boron-rich Analogue of Phenylalanine
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-91770 (URN)
    Available from: 2004-04-22 Created: 2004-04-22Bibliographically approved
    3. Synthesis and Radioiodination of Some 9-Aminoacridine Derivatives
    Open this publication in new window or tab >>Synthesis and Radioiodination of Some 9-Aminoacridine Derivatives
    Show others...
    2004 (English)In: European Journal of Organic Chemistry, ISSN 1434-193X, E-ISSN 1099-0690, Vol. 17, p. 3719-3725Article in journal (Refereed) Published
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-69939 (URN)10.1002/ejoc.200400296 (DOI)
    Available from: 2006-05-17 Created: 2006-05-17 Last updated: 2017-11-21Bibliographically approved
    4. Synthesis and radioiodination of some 9-aminoacridine derivatives for potential use in radionuclide therapy
    Open this publication in new window or tab >>Synthesis and radioiodination of some 9-aminoacridine derivatives for potential use in radionuclide therapy
    Show others...
    2005 (English)In: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 48, no 12, p. 855-871Article in journal (Refereed) Published
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-83610 (URN)10.1002/jlcr.960 (DOI)
    Available from: 2006-11-07 Created: 2006-11-07 Last updated: 2017-12-14Bibliographically approved
    5. Synthesis and radioiodination of some daunorubicin and doxorubicin derivatives
    Open this publication in new window or tab >>Synthesis and radioiodination of some daunorubicin and doxorubicin derivatives
    2005 (English)In: Carbohydrate Research, ISSN 0008-6215, E-ISSN 1873-426X, Vol. 340, no 1, p. 15-24Article in journal (Refereed) Published
    Abstract [en]

    Daunorubicin and doxorubicin are efficient agents for cancer treatment. Their clinical efficacy is, however, hampered by their indiscriminant toxicity. This problem may be circumvented by encapsulating the drugs in liposomes and selectively targeting the tumor cells using tumor targeting agents. Furthermore, the antitumor effect could be enhanced by attaching the Auger electron emitter, 125I, to daunorubicin an ddoxorubicin derivatives. In this context a number of ester, amide, and amine derivatives of daunorubicin an ddoxorubicin were synthesized. Benzoic acid ester derivatives of daunorubicin were synthesized by nucleophilic esterification of the 14-bromodaunorubicin with the potassium salt of the corresponding benzoic acid, resulting in good yields. Nicotinic acids and benzoic acids, activated with a succinimidyl group, were coupled to the amino group of daunorubicien to give the corresponding amide derivatives. Amine derivatives were obtained by the reductive amination of aromatic aldehydes with daunorubicin hydrochloride. The stannylated ester and amide derivatives were uses as precursors for radioiodination. Radiolabeling with 125I was performed using chloroamine-T as an oxidant. The optimized labeling resulted in high radiolabeling yields (85-95%) of the radioiodinated daunorubicin and doxorubicin derivatives. Radioiodination of the amines was conducted at the ortho position of the activated phenyl rings providing moderate radiochemical yields (55-75%).

    Keywords
    Daunorubicin, Doxorubicin, Radioiodination, 125I, Chloramine-T
    National Category
    Organic Chemistry
    Identifiers
    urn:nbn:se:uu:diva-70001 (URN)doi:10.1016/j.carres.2004.10.014 (DOI)15620662 (PubMedID)
    Available from: 2006-06-29 Created: 2006-06-29 Last updated: 2017-11-21Bibliographically approved
  • 19.
    Guliashvili, Tamaz
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry, Organic Chemistry.
    Synthesis and Reactivity Studies of Zwitterionic Silenes and 2-Silenolates2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes synthesis and reactivity studies of 2-amino-2-siloxysilenes and 2-silenolates, species that are strongly influenced by reversed Si=C bond polarization, i.e. an Siδ-=Cδ+ polarization as compared to the natural Siδ+=Cδ- polarization. Because of the reversed polarization, the 2-amino-2-siloxysilenes are zwitterions and the 2-silenolates are predominantly described by the resonance structure with the negative charge at Si.

    Transient zwitterionic 2-amino-2-siloxysilenes are formed thermolytically from carbamylpolysilanes (tris(trimethylsilyl)silylamides) and trapped with 1,3-dienes in nearly quantitative yields. These silenes have structure and reactivity characteristics that differ from earlier studied Si=C bonded compounds. They are thermodynamically stable toward dimerization and react with 1,3-dienes to give exclusively [4+2] cycloadducts. Their reactions with 1,3-dienes proceed in accordance with inverse electron demand (IED) Diels-Alder reactions which is explained by the electron-rich nature of these silenes. The 2-amino-2-siloxysilenes are also less reactive toward alcohols than earlier silenes. Hence, alcohols do not react with 2-amino-2-siloxysilenes but with the silene precursor, the carbamylpolysilanes, leading to alkoxysilanes in high yields. The latter reaction represents a novel base-free synthetic protocol for protection of primary and secondary alcohols with the fluoride resistant but photolabile tris(trimethylsilyl)silyl group.

    Another class of formally Si=C bonded compounds, metal 2-silenolates, has been formed in high yields using a novel facile method. Reaction of acyl- and carbamylpolysilanes with potassium tert-butoxide in tetrahydrofurane gives potassium 2-silenolates. The potassium 2-silenolates are stable at room temperature, in contrast to earlier lithium 2-silenolates that degrade rapidly at ambient temperature. The first crystallisable complex of a 2-silenolate was formed and characterized by X-ray crystallography. This 2-silenolate has a pyramidal central Si (ΣSi = 317.8°), and an Si-C single rather than Si=C double bond (r(SiC) = 1.926 Å). The potassium 2-silenolates give exclusively Si alkylated products with alkyl halides and only [4+2] cycloadducts with 1,3-dienes.

    List of papers
    1. Evidence for Formation of Silenes Strongly Influenced by Reversed Si=C Bond Polarity
    Open this publication in new window or tab >>Evidence for Formation of Silenes Strongly Influenced by Reversed Si=C Bond Polarity
    Show others...
    2002 In: Organic Letters, ISSN 1523-7060, Vol. 4, no 11, p. 1915-1918Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92331 (URN)
    Available from: 2004-11-03 Created: 2004-11-03Bibliographically approved
    2. Formation of Transient Zwitterionic Silenes and Their Diels-Alder Reactions with 1,3-Dienes: Mechanism and Stereoselectivity
    Open this publication in new window or tab >>Formation of Transient Zwitterionic Silenes and Their Diels-Alder Reactions with 1,3-Dienes: Mechanism and Stereoselectivity
    Show others...
    In: Journal of Americal Chemical Society, ISSN 0002-7863Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-92332 (URN)
    Available from: 2004-11-03 Created: 2004-11-03Bibliographically approved
    3. The First Unsuccesful attempt to Add Alcohols to a Silene
    Open this publication in new window or tab >>The First Unsuccesful attempt to Add Alcohols to a Silene
    In: Organometallics, ISSN 0276-7333Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-92333 (URN)
    Available from: 2004-11-03 Created: 2004-11-03Bibliographically approved
    4. The First Isolable 2-Silenolate
    Open this publication in new window or tab >>The First Isolable 2-Silenolate
    2003 In: Angewandte Chemie International Eddition, ISSN 1433-7851, Vol. 42, no 14, p. 1640-1642Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92334 (URN)
    Available from: 2004-11-03 Created: 2004-11-03Bibliographically approved
    5. Potassium 1-N,N-Dialkylamino-2,2-bis(trimethylsilyl)-2-Silenolates: Heavy Enolates with Remarkable Stability
    Open this publication in new window or tab >>Potassium 1-N,N-Dialkylamino-2,2-bis(trimethylsilyl)-2-Silenolates: Heavy Enolates with Remarkable Stability
    Show others...
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-92335 (URN)
    Available from: 2004-11-03 Created: 2004-11-03 Last updated: 2010-01-13Bibliographically approved
  • 20.
    Hedberg, Christian
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry.
    Design, Synthesis, Mechanistic Rationalization and Application of Asymmetric Transition-Metal Catalysts2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis describes mechanistic studies, rational ligand design, and synthesis of asymmetric transition metal catalysts. The topics addressed concerned [Papers I-VII]:

    [I] The asymmetric addition of diethyl zinc to N-(diphenylphosphinoyl)benzalimine catalyzed by bicyclic 2-azanorbornyl-3-methanols was studied. An efficient route to both diastereomers of new bicyclic 2-azanorbornyl-3-methanols with an additional chiral center was developed, in the best case 97% ee was obtained with these ligands. The experimental results were rationalized by a computational DFT-study.

    [II] An aza-Diels-Alder reaction of cyclopentadiene with chiral heterocyclic imines derived from (S)-1-phenylethylamine and different heteroaromatic aldehydes was developed. The cycloaddition proved to be highly diastereoselective and offers a very rapid access to possible biologically active compounds and interesting precursors for chiral (P,N)-ligands.

    [III] A convenient and high-yielding method for the preparation of (R)-tolterodine, utilizing a catalytic asymmetric Me-CBS reduction was developed. Highly enantio-enriched (R)-6-methyl-4-phenyl-3,4-dihydrochromen-2-one (94% ee) was recrystallized to yield practically enantiopure material (ee >99%) and converted to (R)-tolterodine in a four-step procedure.

    [IV] The reaction mechanism of the iridium-phosphanooxazoline-catalyzed hydrogenation of unfunctionalized olefins has been studied by means of DFT-calculations (B3LYP) and kinetic experiments. The calculations suggest that the reaction involves an unexpected IrIII-IrV catalytic cycle facilitated by coordination of a second equivalent of dihydrogen. On the basis of the proposed catalytic cycle, calculations were performed on a full system with 88 atoms. These calculations were also used to explain the enantioselectivity displayed by the catalyst.

    [V and VI] A new class of chiral (P,N)-ligands for the Ir-catalyzed asymmetric hydrogenation of aryl alkenes was developed. These new ligands proved to be highly efficient and tolerate a broad range of substrates. The enantiomeric excesses are, so far, the best reported and can be rationalized using the proposed selectivity model.

    [VII] The complex formed between the quincorine-amine, containing both a primary and a quinuclidine amino function, and [Cp*RuCl]4 catalyzes the hydrogenation of aromatic and aliphatic ketones in up to 90% ee approx. 24-times faster than previously reported Ru-diamine complexes. The reason for the lower but opposite stereoselectivity seen with the quincoridine-amine, as compared to the quincorine-amine, was rationalized by a kinetic and computational study of the mechanism. The theoretical calculations also revealed a significantly lower activation barrier for the alcohol mediated split of dihydrogen, as compared to the non-alchol mediated process. A finding of importance also for the diphosphine/diamine mediated enantioselective hydrogenation of ketones.

    List of papers
    1. A Theoretical and Experimental Study of the Asymmetric Addition of Dialkylzinc to N-(diphenylphosphinoyl)benzalimine
    Open this publication in new window or tab >>A Theoretical and Experimental Study of the Asymmetric Addition of Dialkylzinc to N-(diphenylphosphinoyl)benzalimine
    Show others...
    1999 In: Chemistry-A European Journal, ISSN 0947-6539, Vol. 5, no 6, p. 1692-1699Article in journal (Refereed) Published
    Abstract
    Identifiers
    urn:nbn:se:uu:diva-92875 (URN)
    Available from: 2005-04-07 Created: 2005-04-07 Last updated: 2016-08-17Bibliographically approved
    2. Diels-Alder Reaction of Heterocyclic Imine Dienophiles
    Open this publication in new window or tab >>Diels-Alder Reaction of Heterocyclic Imine Dienophiles
    2000 In: Journal of Organic Chemistry, ISSN 0022-3263, Vol. 65, no 9, p. 2810-2812Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-92876 (URN)
    Available from: 2005-04-07 Created: 2005-04-07Bibliographically approved
    3. Catalytic Asymmetric Total Synthesis of Muscarinic Receptor Antagonist (R)-Tolterodine
    Open this publication in new window or tab >>Catalytic Asymmetric Total Synthesis of Muscarinic Receptor Antagonist (R)-Tolterodine
    2005 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 347, no 5, p. 662-666Article in journal (Refereed) Published
    Abstract [en]

    A convenient and high yielding method for the preparation of (R)-tolterodine, utilizing a catalytic asymmetric Me-CBS reduction was developed. Highly enantioenriched (R)-6-methyl-4-phenyl-3,4-dihydrochromen-2-one (94% ee) was recrystallized to yield practically enantiopure material (ee >99%) and converted to (R)-tolterodine in a four-step procedure. The configuration of the crucial stereocenter was preserved during the synthesis and the obtained product was identified by chiral HPLC to be the (R)-tolterodine enantiomer.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-92877 (URN)10.1002/adsc.200404234 (DOI)
    Available from: 2005-04-07 Created: 2005-04-07 Last updated: 2017-12-14Bibliographically approved
    4. New Mechanistic Insights into the Iridium-Phosphanooxazoline Catalyzed Hydrogenation of Unfunctionalized Olefins: A DFT and Kinetic Study
    Open this publication in new window or tab >>New Mechanistic Insights into the Iridium-Phosphanooxazoline Catalyzed Hydrogenation of Unfunctionalized Olefins: A DFT and Kinetic Study
    2003 In: Chemistry-A European Journal, ISSN 0022-3263, Vol. 9, no 1, p. 339-347Article in journal (Refereed) Published
    Abstract
    Identifiers
    urn:nbn:se:uu:diva-92878 (URN)
    Available from: 2005-04-07 Created: 2005-04-07 Last updated: 2016-08-17Bibliographically approved
    5. Rationally Designed Ligands for Asymmetric Iridium-Catalyzed Hydrogenation of Olefins
    Open this publication in new window or tab >>Rationally Designed Ligands for Asymmetric Iridium-Catalyzed Hydrogenation of Olefins
    Show others...
    2004 In: Journal of the American Chemical Society, ISSN 0002-7863, Vol. 126, no 44, p. 14308-14309Article in journal (Refereed) Published
    Abstract
    Identifiers
    urn:nbn:se:uu:diva-92879 (URN)
    Available from: 2005-04-07 Created: 2005-04-07 Last updated: 2016-08-17Bibliographically approved
    6. Origin of Enantioselectivity in Ir-Catalyzed Asymmetric Hydrogenation of Tri-Substituted Olefins
    Open this publication in new window or tab >>Origin of Enantioselectivity in Ir-Catalyzed Asymmetric Hydrogenation of Tri-Substituted Olefins
    Show others...
    Manuscript (Other academic)
    Abstract
    Identifiers
    urn:nbn:se:uu:diva-92880 (URN)
    Available from: 2005-04-07 Created: 2005-04-07 Last updated: 2016-08-17Bibliographically approved
    7. Mechanistic Insights into the Phosphine free RuCp*-Diamine Catalyzed Hydrogenation of Arylketones: An Experimental and Theoretical Study
    Open this publication in new window or tab >>Mechanistic Insights into the Phosphine free RuCp*-Diamine Catalyzed Hydrogenation of Arylketones: An Experimental and Theoretical Study
    Show others...
    In: Journal of the American Chemical Society, ISSN 0002-7863Article in journal (Refereed) Submitted
    Abstract
    Identifiers
    urn:nbn:se:uu:diva-92881 (URN)
    Available from: 2005-04-07 Created: 2005-04-07 Last updated: 2016-08-17Bibliographically approved
  • 21.
    Hyllbrant Forngren, Benita
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry.
    Liquid chromatography-mass spectrometry in the analysis of radiolabelled compounds for positron emission tomography2000Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Methods for liquid chromatography-mass spectrometry (LC/MS) with electrospray ionization (ESI) have been developed for the determination of specific radioactivity and for metabolic studies of radiolabelled compounds used in positron emission tomography (PET). These compounds often provide an analytical challenge mainly due to their low concentrations in complex sample matrices.

    The effect on sensitivity using different mobile phase additives, such as trifluoroacetic acid and formic acid, was investigated. The ESI-MS response shows higher stability and sensitivity when volatile additives are used. For reversed phase ion-pair chromatography separations, however, non-volatile counter-ions are used that destabilize the detector response and reduce the sensitivity. A method was therefore developed for on-line removal of the ion-pairing reagents prior to detection.

    Packed capillary columns and on-column focusing were used to improve mass sensitivity when analysing limited sample amounts. A commercial interface was modified to assist electrospray ionization at the low flow-rates (1 μl/min) required by columns with an inner diameter of 200 µm.

    LC-MS methods were developed for determination of specific radioactivity of compounds labelled with short-lived radionuclides (i.e. 11C with T½=20.3 min and 76Br T½=16.2 h). In comparison with UV absorption detection, ESI-MS showed equal or improved sensitivity for all compounds investigated. The sensitivity of the developed methods allowed for detection of the radiolabelled isotope directly by mass spectrometry.

    A packed capillary LC/MS method was developed for determination of raclopride in plasma samples taken from patients during PET studies after intravenous injection of nanomolar doses. The validated assay exhibited satisfactory accuracy and precision over the concentration range 0.2-15 nM.

  • 22.
    Ikegami, Hidetsugu
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry. Analytisk kemi.
    Pettersson, Roland
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry. Analytisk kemi.
    Evidence of Enhanced Nonthermal Nuclear Fusion2002Report (Other academic)
  • 23.
    Isaac, Giorgis
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry, Analytical Chemistry.
    Development of Enhanced Analytical Methodology for Lipid Analysis from Sampling to Detection: A Targeted Lipidomics Approach2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis covers a wide range of analytical method development for lipid analysis in complex biological samples; from sample preparation using pressurized fluid extraction (PFE) and separation with reversed phase capillary liquid chromatography (RP-LC) to detection by electrospray ionization mass spectrometry (ESI/MS) and tandem MS.

    The requirements for fast, reliable and selective extraction methods with minimal usage of solvents have accelerated the development of new extraction techniques. PFE is one of the new automated, fast and efficient liquid extraction techniques which use elevated temperature and pressure with standard liquid solvents. In this thesis the reliability and efficiency of the PFE technique was investigated for the extraction of total lipid content from cod, herring muscle and human brain tissue as well as for pesticides from fatty foodstuffs. Improved or comparable efficiencies were achieved with reduced time and solvent consumption as compared to traditional methods.

    A RP-LC coupled online to ESI/MS for the analysis of phosphatidylcholine (PC) and sphingomyelin (SM) molecular species was developed and used for the analysis of brain lipids from eight groups of mice treated with vehicle and various neuroleptics. The effect of postnatal iron administration in lipid composition and behavior was investigated. Whether or not these effects could be altered by subchronic administration of the neuroleptics (clozapine and haloperidol) were examined. The results support the hypothesis that an association between psychiatric disorders, behavior abnormalities and lipid membrane constitution in the brain exists.

    Finally, a tandem MS precursor ion scan was used to analyze the developmental profile of brain sulfatide accumulation in arylsulfatase A (ASA) deficient (ASA -/-) as compared to wild type control (ASA +/+) mice. The ASA -/- mice were developed as a model of the monogenic disease metachromatic leukodystrophy with an established deficiency of the lysosomal enzyme ASA. The results showed that an alteration in the composition of sulfatide molecular species was observed between the ASA -/- and ASA +/+ mice.

    This thesis shows that modern analytical methods can provide new insights in the extraction and analysis of lipids from complex biological samples.

    List of papers
    1. Total Lipid Extraction of Homogenized and Intact Lean Fish Muscles Using Pressurized Fluid Extraction and Batch Extraction Technique
    Open this publication in new window or tab >>Total Lipid Extraction of Homogenized and Intact Lean Fish Muscles Using Pressurized Fluid Extraction and Batch Extraction Technique
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    2005 (English)In: Journal of Agricultural and Food Chemistry, ISSN 0021-8561, E-ISSN 1520-5118, Vol. 53, no 14, p. 5506-5512Article in journal (Refereed) Published
    Abstract [en]

    The reliability and efficiency of pressurized fluid extraction (PFE) technique for the extraction of total lipid content from cod and the effect of sample treatment on the extraction efficiency have been evaluated. The results were compared with two liquid-liquid extraction methods, traditional and modified methods according to Jensen. Optimum conditions were found to be with 2-propanol/n-hexane (65:35, v/v) as a first and n-hexane/diethyl ether (90:10, v/v) as a second solvent, 115 oC, and 10 min of static time. PFE extracts were cleaned up using the same procedure as in the methods according to Jensen. When total lipid yields obtained from homogenized cod muscle using PFE were compared yields obtained with original and modified Jensen methods, PFE gave significantly higher yields, ~10% higher (t test, P < 0.05). Infrared and NMR spectroscopy suggested that the additional material that inflates the gravimetric results is rather homogeneus and is primarily consists of phospholipid with headgroups of inositidic and/or glycosidic nature. The comparative study demonstrated that PFE is an alternative suitable technique to extract total lipid content from homogenized cod (lean fish) and herring (fat fish) muscle showing a precision comparable to that obtained with the traditional and modified Jensen methods. Despite the necessary cleanup step, PFE showed important advantages in the solvent consumption was cut by ~50% and automated extraction was possible.

    Keywords
    Lean fish, phospholipids, pressurized fluid extraction, PFE, total lipid content
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-93095 (URN)10.1021/jf0501286 (DOI)15998106 (PubMedID)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2017-12-14Bibliographically approved
    2. Pressurized Fluid Extraction (PFE) as an Alternative General Method for the Determination of Pesticide Residues in Rape Seed
    Open this publication in new window or tab >>Pressurized Fluid Extraction (PFE) as an Alternative General Method for the Determination of Pesticide Residues in Rape Seed
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    2002 In: The Analyst, ISSN 0003-2654, Vol. 127, no 4, p. 554-559Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93096 (URN)
    Available from: 2005-04-29 Created: 2005-04-29Bibliographically approved
    3. Analysis of Phosphatidylcholine and Sphingomyelin Molecular Species From Brain Extracts Using Capillary Liquid Chromatography Electrospray Ionization Mass Spectrometry
    Open this publication in new window or tab >>Analysis of Phosphatidylcholine and Sphingomyelin Molecular Species From Brain Extracts Using Capillary Liquid Chromatography Electrospray Ionization Mass Spectrometry
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    2003 In: Journal of Neuroscience Methods, ISSN 0165-0270, Vol. 128, no 1-2, p. 111-119Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93097 (URN)
    Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2011-03-21