Diss. (sammanfattning) Uppsala : Univ., 2005. / Härtill 3 uppsatser.

<p>In this thesis, mechanistic and synthetic studies on transformations of H-phosphonates into DNA analogues containing P-S or P-C bonds are described. </p><p>Configurational stability of dinucleoside H-phosphonates and the stereochemical course of their sulfurisation in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were investigated. In light of these studies, the reported stereoselective sulfurisation of dinucleoside H-phosphonates and benzoylphosphonates in the presence of DBU was proved to be incorrect.</p><p>Efficient protocols for the synthesis of new nucleotide analogues with non-ionic C-phosphonate internucleotide linkages were developed. The synthesis of dinucleoside 2-pyridylphosphonates was successfully performed by a DBU-promoted reaction of H-phosphonate diesters with <i>N</i>-methoxypyridinium salts. The thio analogues, 2-pyridyl- and 4-pyridyl phosphono<i>thio</i>ate diesters, could be obtained by modifying the reactions developed for their oxo counterparts. Dinucleoside 3-pyridylphosphonates were prepared <i>via</i> a palladium(0)-catalysed cross coupling strategy that could be extended also to the synthesis of nucleotide analogues with metal-complexing properties, <i>i.e</i>. terpyridyl- and bipyridylphosphonate derivatives.</p><p>Oligonucleotides modified with pyridylphosphonate internucleotide linkages have been prepared and preliminary studies on their hybridisation properties and resistance towards enzymatic degradation were performed.</p><p>Finally, nucleotidic units for the incorporation of pyridylphosphonate groups at the 5’-terminus of oligonucleotides were designed. Condensations of such units with a suitably protected nucleoside afforded after oxidation the expected dinucleoside (3’-5’)-phosphates with pyridylphosphonate monoester functions at the 5’-ends.</p>

In this thesis, mechanistic and synthetic studies on transformations of H-phosphonates into DNA analogues containing P-S or P-C bonds are described. Configurational stability of dinucleoside H-phosphonates and the stereochemical course of their sulfurisation in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were investigated. In light of these studies, the reported stereoselective sulfurisation of dinucleoside H-phosphonates and benzoylphosphonates in the presence of DBU was proved to be incorrect. Efficient protocols for the synthesis of new nucleotide analogues with non-ionic C-phosphonate internucleotide linkages were developed. The synthesis of dinucleoside 2-pyridylphosphonates was successfully performed by a DBU-promoted reaction of H-phosphonate diesters with N-methoxypyridinium salts. The thio analogues, 2-pyridyl- and 4-pyridyl phosphonothioate diesters, could be obtained by modifying the reactions developed for their oxo counterparts. Dinucleoside 3-pyridylphosphonates were prepared via a palladium(0)-catalysed cross coupling strategy that could be extended also to the synthesis of nucleotide analogues with metal-complexing properties, i.e. terpyridyl- and bipyridylphosphonate derivatives. Oligonucleotides modified with pyridylphosphonate internucleotide linkages have been prepared and preliminary studies on their hybridisation properties and resistance towards enzymatic degradation were performed. Finally, nucleotidic units for the incorporation of pyridylphosphonate groups at the 5’-terminus of oligonucleotides were designed. Condensations of such units with a suitably protected nucleoside afforded after oxidation the expected dinucleoside (3’-5’)-phosphates with pyridylphosphonate monoester functions at the 5’-ends.

<p>The positron emitting 68Ga radionuclide (T1/2 = 68 min) has the potential of practical interest for clinical PET. The metallic cation, 68Ga3+, is suitable for complexation reactions with chelators either naked or conjugated with macromolecules such as peptides and oligonucleotides. Such labeling procedures require pure and concentrated radiometal preparations, which cannot be sufficiently fulfilled by the presently available 68Ge/68Ga generator eluate. This thesis presents a method to increase the concentration and purity of 68Ga obtained from a commercial 68Ge/68Ga generator. DOTATOC (DOTA = 1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid, TOC = D-Phe1-Tyr3–Octreotide) was used as a test molecule for comparing the labeling properties of different 68Ga preparations. In addition, DOTA-RDG (RGD = Cys2-6; c[CH2CO-Lys(DOTA)-Cys-Arg-Gly-Asp-Cys-Phe-Cys]-CCX6-NH2) and NODAGATATE (NODAGA = 1,4,7-triazacyclononane-1,4,7-triacetic, TATE = Tyr3 - Octreotate) were used to prove the concept. The use of the concentrated and purified 68Ga eluate along with microwave activation allowed quantitative 68Ga-labelling of peptide conjugates of ≤1 nanomolar quantities within 10 min. The specific radioactivity of the radiolabelled peptides was improved by a factor of >100 compared to previously applied techniques using non-treated generator eluate and conventional heating. A commercial 68Ge/68Ga generator in combination with this method for purification, concentration and microwave activated labeling resulted in a kit technology for 68Ga-tracer production.Four 17-mer oligonucleotides modified and functionalised with an hexylamine group in the 3'- or 5'- position were conjugated with DOTA and labelled with 68Ga using microwave activation. Chemical modification of the oligonucleotide backbone or sugar moiety did not influence the labelling nor the hybridisation ability of the oligonucleotides. However, the radioactivity organ biodistribution in rats differed dependent on the oligonucleotide structure. This indicated that metabolism and non-specific binding were affected by the backbone and sugar moiety structure.</p>

<p>Carbohydrates are a complex group of biomolecules with a high structural diversity. Their almost omnipresent occurrence has generated a broad field of research in both biology and chemistry. This thesis focuses on three different aspects of carbohydrate chemistry, synthesis, structure elucidation and the conformational analysis of carbohydrates.</p><p>The first paper describes the synthesis of a penta- and a tetrasaccharide related to the highly branched capsular polysaccharide from <i>Streptococcus pneumoniae </i>type 37. In the second paper, the structure of the O-antigenic repeating unit from the lipopolysaccharide of <i>E. coli </i>396/C1 was determined along with indications of the structure of the biological repeating unit. In addition, its structural and immunological relationship with <i>E. coli</i> O126 is discussed. In the third paper, partially protected galactopyranosides were examined to clarify the origin of an intriguing ⁴<i>J</i>_HO,H coupling, where a <i>W</i>-mediated coupling pathway was found to operate. In the fourth paper, the conformation of methyl a-cellobioside is studied with a combination of molecular dynamics simulations and NMR spectroscopy. In addition to the expected syn-conformation, detection and quantification of anti-<i>ø </i>and anti-<i>ψ</i> conformers was also possible.</p>

No description available.

<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>