<p>This thesis deals with ruthenium-catalyzed hydrogen transfer involving amines and imines and is divided into two parts. </p><p>In Part 1 a mechanistic study has been performed. The complexation of the imine to the catalyst and the decomplexation patterns of the formed ruthenium-amine complexes, isotope studies, and exchange studies show that the mechanism of the hydrogen transfer involving amines and imines is different from the hydrogen transfer involving alcohols and carbonyls.</p><p>In Part 2 synthetic applications of the hydrogen transfer is presented. First the rutheniumcatalyzed transfer hydrogenation of imines by 2-propanol in an unpolar solvent was investigated. The corresponding amines were isolated in good to excellent yields. Even imines bearing labile functional groups were smoothly transferred to amines with very low catalyst loadings and short reaction times employing microwave heating. Then the reverse reaction, transfer dehydrogenation of amines to imines, was investigated using either MnO₂ or oxygen as terminal oxidant. Important products such as aldimines, ketimines, and non benzylic anilines were prepared in the aerobic oxidation. We also demonstrated that the aerobic oxidation is compatible with proline-mediated organocatalysis, yielding amines in high yields and <i>ee</i>:s. Finally the racemization of chiral amines was investigated. A cumbersome side product formation was investigated and hampered by the use of a mild hydrogen donor, giving a mild and efficient racemization process for both primary and secondary amines.</p>

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

<p>In order to find suitable stable vaccine candidates against <i>Neisseria meningitidis</i> group A, several structures related to the capsular polysaccharide have been synthesised. The first part of the thesis describes the synthesis of C-phosphonate analogues starting from glucose. The key step is a Mitsunobu coupling of a methyl C-phosphonate monomer to the 6-hydroxyl group of a 2-acetamido mannose derivative. Contained within this work is a description of an improved synthesis of 2-azido-2-deoxy-D-mannopyranose. The second part outlines the synthesis of structural elements present in the native capsular polysaccharide of <i>Neisseria meningitidis</i> serotype A including different acetylation and phosphorylation patterns. The final chapter describes an improved synthesis of the Lewis b hexasaccharide needed for purification of and interaction studies with the <i>Helicobacter pylori</i> adhesin BabA.</p>

<p>The major part of this thesis describes the synthesis of enantiopure alcohols and diols by combining ruthenium-catalyzed racemization or epimerization and lipase-catalyzed asymmetric transformations. A minor part of this thesis is focused on ruthenium-catalyzed redox reactions for transfer hydrogenation of 1,3-cycloalkanediketones. </p><p>Kinetic resolution of racemic γ-hydroxy acid derivatives was performed via <i>Pseudomonas cepacia</i> lipase (PS-C)-catalyzed transesterification. γ-Hydroxy esters and γ-hydroxy amides were studied showing in higher selec-tivity and yields for the γ-hydroxy amides. The enzyme PS-C tolerates both variation in the chain length and different functionalities giving good to high enantioselectivity. Combining enzymatic kinetic resolution with a ruthenium-catalyzed racemization led to a dynamic kinetic resolution (DKR). The use of 2,4-dimethyl-3-pentanol as a hydrogen source to suppress ketone formation in the dynamic kinetic resolution increased the yields of the acetate product. The synthetic utility of this procedure was illustrated by the practical synthesis of the γ-lactone (R)-5-methyltetrahydrofuran-2-one.</p><p>A distereoselective transformation of <i>cis/trans</i>-1,3-cyclohexandiol using <i>Candida antarctica</i> lipase B (CALB)-catalyzed transesterification was of interest. Desymmetrization of <i>cis</i>-1,3-cyclohexanediol to the (<i>R</i>-monoacetate was successfully accomplished. Enantiopure (<i>R,R</i>)-diacetate was obtained from the (<i>R</i>)-monoacetate in a DYKAT process at room tem-perature. Metal- and enzyme-catalyzed transformation of <i>cis/trans</i>-1,3-cyclohexanediol using PS-C, gives a high diastereoselectivity for cis-diacetate. The (<i>S</i>)-mono-acetate was obtained from <i>cis</i>-diacetate by CALB-catalyzed hydrolysis. In addition, it was shown, by the use of deuterium-labeling that intramolecular acyl migration does not occur in the transformation of <i>cis</i>-monoacetate to the <i>cis</i>-diacetate. </p><p>Ruthenium-catalyzed transfer hydrogenation of 1,3-cyclohexanedione under microwave heating was developed as an efficient and fast method for the preparation of 1,3-cycloalkandiols.</p>

No description available.

<p>The scope and limitations of nucleophilic substitutions of aryl halides have been studied using ethyl 3-mercaptopropionate as nucleophile and microwave heating. A diversity of aromatic compounds have been investigated according to different types of leaving groups, regio isomers and substituents. Experimental design has been used as a tool to optimize the reaction. An electron-withdrawing group in ortho or para position of the leaving group proved to be necessary for a positive outcome of the reaction. Fluorine was, without competition, the best leaving group. Some examples of how the synthesized aryl sulfanyl propionates can be used as starting material for producing aryl thio ethers, sulfoxides and unique benzothiophenes are described.</p>

No description available.

<p>Cyklosporin A (CsA) är en cyklisk polypeptid med molekylvikten är 1202.6 Da. Substansen har svampursprung (<em>Tolypocladium inflatum Gams)</em> och starka immunhämmande egenskaper. CsA används därför som immunsuppressivt läkemedel för att förhindra avstötning av transplanterade organ och benmärg, samt vid behandling av graft-versus-host-disease (transplantat-mot-värd-sjukdom). CsA har ett snävt terapeutiskt fönster, vilket betyder att skillnaden mellan effektivitet och toxicitet är liten. Biverkningarna av substansen är många och en del av dem allvarliga, såsom nedsatt njurfunktion och ökad risk för utvecklande av diabetes och maligna sjukdomar som exempelvis lymfom. Den inter- och intraindividuella variabiliteten i farmakokinetik och farmakodynamik är dessutom stor. Det är därför ytterst viktigt att följa behandlingen med koncentrationsbestämningar av CsA i helblod.</p><p>Det finns ett flertal olika analysmetoder för CsA tillgängliga, såsom immunoassays, vätskekromatografi (HPLC) och vätskekromatografi-tandem-massspektrometri (LC-MS/MS). Avdelningen för klinisk kemi vid Centralsjukhuset i Karlstad har sedan många år använt en radioimmunoassay, CYCLO-Trac SP^®, från DiaSorin för att bestämma CsA i helblod. Laboratoriets önskan är att ersätta denna metod, vilken använder radioaktiva isotoper, med en snabbare och mer selektiv LC-MS/MS-metod. </p><p>I detta arbete har en LC-MS/MS-metod för analys av cyklosporin A i helblod utvecklats och validerats. Metoden har snabb provupparbetning och kromatografi och använder positiv elektrospray som joniseringsteknik. Två procedurer för proteinfällning utvärderades som provupparbetningsförfarande under metodutvecklingen och två olika internstandarder testades; CsA analogen cyklosporin D och isotopmärkt CsA (d₁₂-CsA). </p><p>Efter den fullständiga valideringen infördes metoden i rutinarbetet 2009-11-01. Resultat från både LC-MS/MS och den radioimmunologiska metoden lämnas ut parallellt under minst fem månader.</p> / <p>Cyclosporine A (CsA) is a cyclic undecapolypeptide of fungal origin (<em>Tolypocladium inflatum Gams</em>). It has a molecular weight of 1202.6 Da and is used as an immunouppressive drug to prevent rejection of transplanted organs and bone marrow, and for the treatment of graft-versus-host disease. CsA exhibits a narrow therapeutic range between efficacy and toxicity. There are many side effects exerted by the drug and some of them are serious, such as renal dysfunction and increased risk of developing diabetes and malignant diseases such as lymphoma. In addition, the inter-individual and intra-individual pharmacokinetic and pharmacodynamic variability is large. Constant monitoring of the CsA-concentration is therefore mandatory. </p><p>There are several analytical methods available for the determination of CsA, such as immunoassays, liquid chromatography (HPLC) and tandem mass spectrometry (LC-MS/MS). The department of Clinical Chemistry at the Central Hospital in Karlstad has for many years used a radioimmunoassay, the CYCLO-Trac SP^® from DiaSorin, for CsA-determinations. The laboratory wants to replace this method, which uses radioactive isotopes, with a faster and more selective LC-MS/MS method. </p><p>In this work a LC-MS/MS method, utilizing positive electrospray, with a fast sample preparation and chromatography for the determination of CsA in whole blood has been developed and validated. Two protein precipitation procedures were evaluated for sample preparation during the method development and two different internal standards were tested; the CsA analog cyclosporine D (CsD) and an isotope labelled CsA (d₁₂-CsA). The LC-MS/MS assay was fully validated and implemented in the routine work at the laboratory on November 1 2009. Results from both the CYCLO-Trac SP^® method and the LC-MS/MS assay will be reported for at least five months.</p>

HTML clipboardKinetics on molecular excited states is a challenging subject in the field of theoretical chemistry. This thesis pays attention to theoretical studies on kinetics of photo-induced processes, including photo-chemical reactions, radiative and non-radiative transitions (intersystem crossing and internal conversion) in molecular and bio-related systems. One- or multi- dimensional potential energy surfaces (PESs) not only provide qualitative mechanistic explanation for excited state decay, but also make it possible to perform kinetic simulations. We have constructed several types of PESs by using computational methods of high-accuracy for a variety of systems of interest. In particular, density functional theory (DFT) and couple cluster singles and doubles (CCSD) method are employed to build PESs of the ground and lowest triple states. For medium-sized molecules, the complete active space self-consistent (CASSCF) method is used for constructing the PESs of excited states. Various kinetic theories for the decay processes of excite states are briefly introduced, in particularly adiabatic and nonadiabatic Rice–Ramsperger–Kassel -Marcus (RRKM) approaches for the kinetics of nonradiative decay of excited 2-aminopridine molecule. Special attention has been devoted to Monte Carlo transition state theory which can provide an efficient way to predict the rate of nonradiative transitions of polyatomic molecules on multi-dimensional PESs. Examples of Monte Carlo simulations on the intersystem crossing of isocyanic acid and a model molecule of hexacoordinate heme, as well as internal conversion process for 2-amininopyridine dimer and the adenine-thymine base pair are presented. / QC20100720

Different theoretical approaches have been presented in this thesis to study the Raman scattering effect. The first one is response theory applied up to third order of polarization, where the determination of α, β and γ is used to calculate linear Raman scattering (resonance Raman scattering (RRS) and normal Raman scattering (NRS)), hyper Raman scattering (HRS) and coherent anti-Stokes Raman scattering (CARS), respectively. The response theory refers to adiabatic time-dependent density functional theory in the complex domain with applications on RRS and NRS, and to a recently developed methodology (Thorvaldsen et al. [105, 106]) for the analytic calculation of frequency-dependentpolarizability gradients of arbitrary order, here with applications on CARSand HRS. Various systems have been studied with the response theory, such as explosive substances (DNT, TNT, RDX and H2O2), optical power limiting materials (platinum(II) acetylide molecules), DNA bases (methylguanine-methylcytosine) and other systems (Trans-1,3,5-hexatriene and Pyridine). We have explored the dependency of the calculated spectra on parametrization in terms of exchange-correlation functionals and basis sets, and on geometrica loptimization. The second approach refers to time-dependent wave packet methodology for RRS and its time-independent counterpart in the Kramers-Heisenberg equation for the scattering cross section, which reduces the calculation of the RRS amplitude to computation of matrix elements of transition dipole moments between vibrational wave functions. The time-dependent theory has been used to examine RRS as a dynamical process where particular attention is paid to the notion of fast scattering in which the choice of photon frequency controls the scattering time and the nuclear dynamics. It is shown that a detuning from resonance causes a depletion of the RRS spectrum from overtones and combination bands, a situation which is verified in experimental spectra. The cross section of NRS has been predicted for the studied molecules to be in the order of 10−30 cm2/sr. A further increase in sensitivity with a signal enhancement up to 104 to 105 is predicted for the RRS technique, while CARS conditions imply an overall increase of the intensity by several orders of magnitude over NRS. In contrast to RRS and CARS, the HRS intensity is predicted to be considerably weaker than NRS, by about four orders of magnitude. However, silent modes in NRS can be detected by HRS which in turncan provide essential spectroscopic information and become complementary to NRS scattering. With the above mention methodological development for NRS, RRS, CARS and HRS, we have at our disposal a powerful set of modelling tools for the four different Raman techniques. They have complementary merits and limitations which facilitate the use of these spectroscopes in applications of Raman scattering for practical applications, for instance stand-off detection of foreign substances. / QC 20110112