<p>This thesis contains seven papers dealing with iridium and ruthenium based catalytic asymmetric reductions, either of ketones into chiral alcohols, or olefins into chiral alkanes. The first part of the thesis describes how we have designed and evaluated new bicyclic ligands containing either <i>N</i>,<i>S</i> or <i>N</i>,<i>N</i> chelating atoms. The ligands have been evaluated in the asymmetric Ir-catalyzed transfer hydrogenation of acetophenone. The complexes evaluated induced good enentioselectivity of the product. Moreover we have also utilized a commercially available chiral diamine (QCD-amine) as a ligand in the Ru-catalyzed hydrogenation of prochiral ketones, with excellent enantioselectivity for some of the substrates used. As part of this work we investigated, both theoretically and experimentally, the mechanism of this hydrogenation. Based on these results we have proposed a new reaction mechanism for this type of hydrogenations which involves active participation of the solvent in the catalytic cycle. The last part of the thesis describes the design, synthesis and evaluation of <i>N</i>,<i>P</i> and <i>N</i>₂<i>C</i>-carbene,<i>N</i> ligands for the Ir-catalyzed hydrogenation of carbon-carbon double bonds. The selectivities obtained in these investigations are among the best reported so far for a broad variation of substrates. A selectivity model for this hydrogenation has been derived and used in the rationalization of the results. As a part of this work we have synthesized and evaluated a new class of substrates, vinyl silanes, and showed that the scope of the hydrogenation reaction can be expanded to this new substrate class.</p>

<p>This thesis is based on six research publications concerned with (i) study of the molecular structures and dynamics of modified nucleosides; (ii) investigation of the effect of incorporation of modified nucleosides on the structure of DNA; (iii) examination of the effect of the sugar modifications on the pseudo-aromatic properties (p<i>K</i>_a) of the nucleobases; (iv) analysis of the effect of the CH-π interactions on the relative stability of the DNA-RNA hybrid duplexes. The structural stability of the nucleic acids as well as their behavior in molecular recognition is dominated by hydrogen bonding and stacking interactions beside other non-covalent interactions. Naturally occurring nucleosides are found to have some specific functions. Modifications of nucleic acids, followed by studies of the resulting structural, chemical and functional changes, contribute to an understanding of their role in various biochemical processes, such as catalysis or gene silencing. In papers I-III, analysis of the structures of modified thymidine nucleosides with 1′,2′-(oxetane or azetidine) and 2′,4′-(LNA, 2′-amino LNA, ENA, and Aza-ENA) conformationally constrained sugar moieties, and dynamics of the modified nucleosides by NMR, ab initio, and molecular dynamics simulations are discussed. Based on whether the modification leads to 1′,2′- or 2′,4′- constrained sugar moieties, it is found that they fall into two distinct categories characterized by their respective internal dynamics of the glycosidic and backbone torsions as well as by their characteristic <i>NE</i>-type (P = 37° ± 27°, Φ_m = 25° ± 18°) for 1′,2′-constrained nucleosides, and <i>N</i>-type (P = 19° ± 8°, Φ_m = 48° ± 4°) for 2′,4′-constrained systems, respectively. Moreover, each group has different conformational hyperspace accessible. The effect of the incorporation of 1′,2′-oxetane locked thymidine nucleoside on the structure and dynamics of the Dickerson-Drew dodecamer, d(CGCGAATTCGCG)₂, determined by NMR, is discussed in the paper IV. It shows that the incorporation of oxetane locked T into the dodecamer has made local structural deformations and perturbation in base pairing, where the modification is included. The modulations of physico-chemical properties of the nucleobases in nucleotides by the C2′-modification of the sugar (paper V), 5′-phosphate group, and the effect of constrained pentofuranosyl moiety (sugar, paper III) have been studied. CH-π interactions between the methyl group of thymidine and the neighboring aromatic nucleobase are shown to increase the relative stability of the DNA-RNA hybrid duplexes over the isosequential RNA-DNA duplexes or vice versa (paper VI).</p>

Stereochemistry plays an important role in nature because biologically important molecules such as amino acids, nucleotides and sugars, only exist in enantiomerically pure forms. Semiochemicals carry messages, between the same species (pheromones) and between different species (allelochemicals). Both pheromones and allelochemicals can be used as environmentally friendly pest management. Many semiochemicals, i.e. behaviour modifying chemicals, consist of pure or well-defined mixtures of stereoisomers, where some of the other stereoisomers can be repellent. It is therefore important to be able to separate them to produce a synthetic pheromone in a mixture that is attractive. Pine sawflies are a family of insects that in some cases can be severe defoliators of conifer trees. Diprion pini, Diprion similis and Neodiprion sertifer are severe pests for these trees and have got the most attention in pine sawfly pheromone studies. The pheromone precursors are stored in the female body as long-chain secondary alcohols, which, when released, are esterified to acetates or propionates. The alcohols are chiral, and normally one of the stereoisomer is the main pheromone component, sometimes possible together with other stereoisomers as essential minor components. Bicyclus is a genus of African butterflies, and especially Bicyclus anynana has become a popular model for the study of life history evolution, morphology, mating choice and genetics. The wing pattern of Bicyclus differs depending on the season, with large eyespots during the rain-season and small or absent spots during the dry season.  Euglossa is one of the genera among the orchid bees in the Neotropics that does not produce its own pheromone. Instead, the males collect fragrances from orchids and other sources and store them in a pocket in their hind legs. Both Bicyclus and Euglossa use semiochemicals similar to pine sawflies, and thus can be analysed by the same methods. Pheromones and other semiochemicals in insects are often present in low amounts in a complex matrix, and purification of the sample before chemical analysis is often required. A common method is gradient elution on a solid phase silica column. Separation of stereoisomers can be achieved either by using a column with a chiral stationary phase (CSP) or with pre-column derivatisation using a column with an achiral stationary phase (ASP) or a combination of both, with mass detection as the dominant detection method. The purpose of this work has been to improve the purification method, find suitable methods to separate the stereoisomers of secondary alcohols, and to apply this on extracts of insects. By selecting the right fractions to collect during gradient elution the purification method was optimised. To reduce plasticizer contamination from ordinary columns, solid phase columns of Teflon or glass were used. For pre-column derivatisation of different chiral alcohols various acid chlorides were tested. For the pine sawfly pheromone precursors enantiopure (2S)-2-acetoxypropionyl chloride was the best choice. To separate some of the stereoisomers achiral 2-naphthoyl chloride was used. For derivatisation of 6,10,14-trimethylpentadecan-2-ol (R)-trans-chrysanthemoyl chloride was the best choice. The derivatised alcohols were separated on different columns, both chiral and non-chiral. Varian FactorFour VF-23ms was chosen as a general-purpose column, the Agilent HP-88 column was the best column with an ASP of those tested, and the Chiraldex B-PA column (CSP) was the only one that could separate all eight stereoisomers of derivatised 3,7-dimethylundecan-2-ol, 3,7-dimethyldodecan-2-ol, and 3,7-dimethyltridecan-2-ol. To determine the stereoisomeric purity of standard solutions used in field experiments and extracts of different species of insects the optimised methods were applied. For extracts from B. anynana, Euglossa and Neodiprion lecontei this work describe the first determination of the stereochemistry of some of their semiochemicals. For the determination of the stereochemistry of chiral semiochemicals the methods for purification and separation presented herein have shown to be of great value. The results will hopefully contribute to a better understanding of the communication among insects, and ultimately to a more environmentally friendly pest control. / Många naturligt förekommande kemiska ämnen finns som två spegelbilder av varandra, ungefär som höger och vänster hand. Dessa kan ha helt olika egenskaper och det är därför viktigt att kunna separera dem. Insekter och andra djur använder olika doftämnen för att kommunicera med varandra, om det är inom samma art kallas de för feromoner. De kan bestå av ett ämne eller en blandning av flera. Dessa doftämnen kan man även använda för att på ett miljövänligt sätt bekämpa skadeinsekter. En fälla med syntetiskt feromon för en viss insekt lockar endast till sig den arten, medan alla andra är opåverkade. Eftersom dessa ämnen ofta finns som spegelbilder där kanske bara den ena är aktiv och den andra rent av frånstötande, måste man kunna separera dem för att framställa ett syntetiskt feromon som är attraktivt. Målet med detta arbete har varit att bestämma feromonet hos olika arter av tallsteklar som kan vara svåra skadedjur på tallskog. De metoder som tagits fram har även tillämpats på några arter av afrikanska fjärilar samt orkidébin från Centralamerika eftersom de använder snarlika doftämnen. Att få fram feromonet från en insekt är lite som att leta efter in nål i en höstack eftersom de ofta bara innehåller några miljarddels gram per individ. Provet behöver först renas, och en del av arbetet i det här projektet har gått ut på att ta fram en lämplig reningsmetod. Huvudfokus har dock varit på att ta fram metoder som kan separera och identifiera det eller de ämnen, och spegelbilder av dessa, som doftämnena består av. När lämpliga metoder tagits fram har extrakt av olika insektsarter analyserats. I några fall är det första gången som deras feromon bestämts i detalj. Resultaten kan förhoppningsvis bidra till en ökad kunskap om insekters sätt att kommunicera, och i slutändan till miljövänligare bekämpning av skadeinsekter.

This work deals with radiochemistry and new approaches to develop novel PET tracers labelled with the radionuclide 11C. Two methods for the synthesis of 11C-labelled acrylamides have been explored. First, [1-11C]-acrylic acid was obtained from a palladium(0)-mediated 11C-carboxylation of acetylene with [11C]carbon monoxide; this could be converted to the corresponding acyl chloride and then combined with benzylamine to form N-benzyl[carbonyl-11C]acrylamide. In the second method, the palladium(0)-mediated carbonylation of vinyl halides with [11C]carbon monoxide was explored. This latter method, yielded labelled acrylamides in a single step with retention of configuration at the C=C double bond, and required less amine compared to the acetylene method. The vinyl halide method was used to synthesize a library of 11C-labelled EGFr-inhibitors in 7-61% decay corrected radiochemical yield via a combinatorial approach. The compounds were designed to target either the active or the inactive form of EGFr, following computational docking studies. The rhodium(I)-mediated carbonylative cross-coupling of an azide and an amine was shown to be a very general reaction and was used to synthesize a library of dual VEGFr-2/PDGFrβ inhibitors that were 11C-labelled at the urea position in 38-78% dc rcy. The angiotensin II AT1 receptor antagonist eprosartan was 11C-labelled at one of the carboxyl groups in one step using a palladium(0)-mediated carboxylation. Autoradiography shows specific binding in rat kidney, lung and adrenal cortex, and organ distribution shows a high accumulation in the intestines, kidneys and liver. Specific binding in frozen sections of human adrenal incidentalomas warrants further investigations of this tracer. Three angiotensin II AT2 ligands were 11C-labelled at the amide group in a palladium(0)-mediated aminocarbonylation in 16-36% dc rcy. One of the compounds was evaluated using in vitro using autoradiography, and in vivo using organ distribution and animal PET. The compound was metabolized fast and excreted via urine. High radioactivity was also found in the liver, meaning that more metabolically stable compounds are desirable for future development.

This thesis describes the development and study of catalysts for redox reactions, which either utilize oxygen or hydrogen peroxide for the purpose of selectively oxidizing organic substrates, or produce oxygen as the necessary byproduct in the production of hydrogen by artificial photosynthesis. The first chapter gives a general introduction about the use of environmentally friendly oxidants in the field of organic synthesis, and about the field of artificial photosynthesis. The second chapter describes a computational study of the mechanism of palladium-catalyzed oxidative carbohydroxylation of allene-substituted conjugated dienes. The proposed mechanism, which was supported by DFT calculations, involves an unusual water attack on a (π-allyl)palladium complex. The third chapter describes a computational study of the oxidation of unfunctionalized hydrocarbons, ethers and alcohols with hydrogen peroxide, catalyzed by methyltrioxorhenium (MTO). The mechanism was found to proceed via rate-limiting hydride abstraction followed by hydroxide transfer in a single concerted, but highly asynchronous, step as shown by intrinsic reaction coordinate (IRC) scans. The fourth chapter describes the use of a new hybrid (hydroquinone-Schiff base)cobalt catalyst as electron transfer mediator (ETM) in the palladium-catalyzed aerobic carbocyclization of enallenes. Covalently linking the two ETMs gave a fivefold rate increase compared to the use of separate components. The fifth chapter describes an improved synthetic route to the (hydroquinone-Schiff base)cobalt catalysts. Preparation of the key intermediate 5-(2,5-hydroxyphenyl)salicylaldehyde was improved by optimization of the key Suzuki coupling and change of protecting groups from methyl ethers to easily cleaved THP groups. The catalysts could thus be prepared in good overall yield from inexpensive starting materials. Finally, the sixth chapter describes the preparation and study of two catalysts for water oxidation, both based on ligands containing imidazole groups, analogous to the histidine residues present in the oxygen evolving complex (OEC) and in many other metalloenzymes. The first, ruthenium-based, catalyst was found to catalyze highly efficient water oxidation induced by visible light. The second catalyst is, to the best of our knowledge, the first homogeneous manganese complex to catalyze light-driven water oxidation. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 5: Accepted. Paper 6: Submitted.</p>

This thesis describes the design, synthesis and structure-activity relationships analysis of potential inhibitors targeting the hepatitis C virus (HCV) NS3 protease. Also discussed is the disease caused by HCV infection and the class of enzymes known as proteases. Furthermore are explained why such enzymes can be considered to be suitable targets for developing drugs to combat diseases in general and in particular HCV, focusing on the NS3 protease. Moreover, some strategies used to design protease inhibitors and the desired properties of potential drug candidates are briefly examined. Synthesis of linear and macrocyclic NS3 protease inhibitors comprising a designed trisubstituted cyclopentane moiety as an N-acyl-(4R)-hydroxyproline bioisostere is also addressed, and several very potent and promising compounds are evaluated. / Report code: LIU-TEK-LIC-2006:46.

This thesis deals with the development of catalytic oxidation reactions utilizing hydrogen peroxide as terminal oxidant. The main focus has been to find flavin catalysts that are easy to handle and stable to store but still able to perform the desired reaction. A variety of dihydroflavins were prepared and the electrochemical oxidation potentials were measured and compared with their catalytic activity. A flavin catalyst was applied in the sulfoxidation of allylic and vinylic sulfides by H2O2. This transformation was highly chemoselective and the sulfoxides were obtained without formation of other oxidation products. The scope of the reaction was demonstrated by applying the method on substrates with a wide range of functional groups such as a tertiary amine. Another flavin catalyst was immobilized in the ionic liquid [BMIm]PF6 and used for sulfoxidations by H2O2. The chemoselectivity was maintained in this system and the catalyst-ionic liquid system could be recycled several times. Finally two bimetallic catalyst systems for the dihydroxylation of alkenes by H2O2 were immobilized in the ionic liquid. These systems employed either vanadium acetylacetonate VO(acac)2 or methyl trioxorhenium (MTO) as co-catalysts together with the substrate-selective osmium catalyst. Good to excellent yields of the diols were obtained.

In this thesis, the chemistry of compounds containing P-Se bonds has been studied. As a new addition to this class of compounds, H-phosphonoselenoate monoesters, have been introduced and two synthetic pathways for their preparation have been developed. The reactivity of H-phosphonoselenoate monoesters towards a variety of condensing agents has been studied. From these, efficient conditions for the synthesis of H-phosphonoselenoate diesters have been developed. The produced diesters have subsequently been used in oxidative transformations, which gave access to the corresponding P(V) compounds, e.g. dinucleoside phosphoroselenoates or dinucleoside phosphoroselenothioates. Furthermore, a new selenizing agent, triphenyl phosphoroselenoate, has been developed for selenization of P(III) compounds. This reagent has high solubility in organic solvents and was found to convert phosphite triesters and H-phosphonate diesters efficiently into the corresponding phosphoroselenoate derivatives. The selenization of P(III) compounds with triphenyl phosphoroselenoate proceeds through a selenium transfer reaction. A computational study was performed to gain insight into a mechanism for this reaction. The results indicate that the transfer of selenium or sulfur from P(V) to P(III) compounds proceeds most likely via an X-philic attack of the P(III) nucleophile on the chalcogen of the P(V) species. For the transfer of oxygen, the reaction may also proceed via an edge attack on the P=O bond.

This thesis contains seven papers dealing with iridium and ruthenium based catalytic asymmetric reductions, either of ketones into chiral alcohols, or olefins into chiral alkanes. The first part of the thesis describes how we have designed and evaluated new bicyclic ligands containing either N,S or N,N chelating atoms. The ligands have been evaluated in the asymmetric Ir-catalyzed transfer hydrogenation of acetophenone. The complexes evaluated induced good enentioselectivity of the product. Moreover we have also utilized a commercially available chiral diamine (QCD-amine) as a ligand in the Ru-catalyzed hydrogenation of prochiral ketones, with excellent enantioselectivity for some of the substrates used. As part of this work we investigated, both theoretically and experimentally, the mechanism of this hydrogenation. Based on these results we have proposed a new reaction mechanism for this type of hydrogenations which involves active participation of the solvent in the catalytic cycle. The last part of the thesis describes the design, synthesis and evaluation of N,P and N2C-carbene,N ligands for the Ir-catalyzed hydrogenation of carbon-carbon double bonds. The selectivities obtained in these investigations are among the best reported so far for a broad variation of substrates. A selectivity model for this hydrogenation has been derived and used in the rationalization of the results. As a part of this work we have synthesized and evaluated a new class of substrates, vinyl silanes, and showed that the scope of the hydrogenation reaction can be expanded to this new substrate class.

This thesis is based on six research publications concerned with (i) study of the molecular structures and dynamics of modified nucleosides; (ii) investigation of the effect of incorporation of modified nucleosides on the structure of DNA; (iii) examination of the effect of the sugar modifications on the pseudo-aromatic properties (pKa) of the nucleobases; (iv) analysis of the effect of the CH-π interactions on the relative stability of the DNA-RNA hybrid duplexes. The structural stability of the nucleic acids as well as their behavior in molecular recognition is dominated by hydrogen bonding and stacking interactions beside other non-covalent interactions. Naturally occurring nucleosides are found to have some specific functions. Modifications of nucleic acids, followed by studies of the resulting structural, chemical and functional changes, contribute to an understanding of their role in various biochemical processes, such as catalysis or gene silencing. In papers I-III, analysis of the structures of modified thymidine nucleosides with 1′,2′-(oxetane or azetidine) and 2′,4′-(LNA, 2′-amino LNA, ENA, and Aza-ENA) conformationally constrained sugar moieties, and dynamics of the modified nucleosides by NMR, ab initio, and molecular dynamics simulations are discussed. Based on whether the modification leads to 1′,2′- or 2′,4′- constrained sugar moieties, it is found that they fall into two distinct categories characterized by their respective internal dynamics of the glycosidic and backbone torsions as well as by their characteristic NE-type (P = 37° ± 27°, Φm = 25° ± 18°) for 1′,2′-constrained nucleosides, and N-type (P = 19° ± 8°, Φm = 48° ± 4°) for 2′,4′-constrained systems, respectively. Moreover, each group has different conformational hyperspace accessible. The effect of the incorporation of 1′,2′-oxetane locked thymidine nucleoside on the structure and dynamics of the Dickerson-Drew dodecamer, d(CGCGAATTCGCG)2, determined by NMR, is discussed in the paper IV. It shows that the incorporation of oxetane locked T into the dodecamer has made local structural deformations and perturbation in base pairing, where the modification is included. The modulations of physico-chemical properties of the nucleobases in nucleotides by the C2′-modification of the sugar (paper V), 5′-phosphate group, and the effect of constrained pentofuranosyl moiety (sugar, paper III) have been studied. CH-π interactions between the methyl group of thymidine and the neighboring aromatic nucleobase are shown to increase the relative stability of the DNA-RNA hybrid duplexes over the isosequential RNA-DNA duplexes or vice versa (paper VI).