This thesis describes the synthesis and biological evaluation of highly substituted, ring-fused 2-pyridones. The utility of the bicyclic 2-pyridones to gain fundamental insights into the disease processes of bacterial infections and Alzheimer’s disease has been investigated. The 2-pyridones have mainly been studied as a new class of anti-infective agents termed pilicides. The function of the pilicides has been explored using uropathogenic E. coli (UPEC) as a prototype pathogen and urinary tract infection as a model disease. The pilicides target the infectious ability of UPEC by inhibiting key proteins (chaperones) in the so-called chaperone-usher pathway, thus preventing the assembly of bacterial surface organelles (pili/fimbriae). Synthetic pathways to aminomethylate the 2-pyridones have been developed in order to increase their aqueous solubility while retaining biological activity. Also, the importance of a carboxylic acid has been demonstrated in studies with various carboxylate derivatives and by bioisosteric replacement. Moreover, synthetic procedures to extend the backbone of the rigid, dipeptide-mimicking 2-pyridones have been established. This rendered peptidomimetic building blocks and structures that alongside their potential use as pilicides are of more general interest in peptidomimetic-related research. The potential pilicides have been screened for chaperone affinity using relaxation-edited 1H-NMR spectroscopy. In addition, their ability to inhibit pilus biogenesis in E. coli has been demonstrated by assays of hemagglutination, biofilm formation and attachment to bladder cells, as well as with electron and atomic force microscopy. Moreover, it has been confirmed that pilicides regulate the expression of pili without affecting the biofunctional properties of the pilus rod. This was verified by measurements of individual P pili, on living bacteria, using force measuring optical tweezers. The pilicide binding site was investigated using NMR spectroscopy and X-ray crystallography of a pilicide-chaperone complex. Based on the results obtained, a mechanism whereby the pilicides may inhibit pilus assembly was proposed, which was subsequently experimentally supported by surface plasmon resonance assays and genetic analysis. Finally, based on the generic 2-pyridone scaffold, a new collection of substituted compounds has been synthesized and validated as inhibitors of Amyloid β (Aβ)-peptide aggregation, which has been suggested to be involved in Alzheimer’s disease.

The development of ligands derived from natural amino acids for asymmetric transfer hydrogenation (ATH) of prochiral ketones is described herein. In the first part, reductions performed in alcoholic media are examined, where it is found that amino acid-derived hydroxamic acids and thioamides, respectively, are simple and versatile ligands that in combination with [RhCp*Cl2]2 efficiently catalyze this particular transformation. Selectivities up to 97% ee of the corresponding secondary alcohols are obtained, and it is furthermore observed that the two different ligand classes, albeit based on the same amino acid scaffold, give rise to products of opposite configuration. The highly interesting enantioswitchable nature of the two abovementioned catalysts is studied in detail by mechanistic investigations. A structure/activity correlation analysis is performed, which reveals that the diverse behavior of the catalysts arise from different interactions between the ligands and the metal. Kinetic studies furthermore stress the catalyst divergence, since a difference in the rate determining step is established from initial rate measurements. In addition, rate constants are determined for each step of the overall reduction process. In the last part, catalyst development for ATH executed in water is discussed. The applicability of hydroxamic acid ligands is further extended, and catalysts based on these compounds are found to be efficient and compatible with aqueous conditions. The structurally even simpler amino acid amide is also evaluated as a ligand, and selectivities up to 90% ee are obtained in the reduction of a number of aryl alkyl ketones. The very challenging reduction of dialkyl ketones is moreover examined in the Rh-catalyzed aqueous ATH, where a modified surfactant-resembling sulfonylated diamine is used as ligand, and the reaction is carried out in the presence of SDS-micelles. A positive effect is to some extent found on the catalyst performance upon addition of phase-transfer components, especially regarding the catalytic activity in the reduction of more hydrophobic substrates. / At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: In press.

Interactions between carbohydrates and proteins are increasingly being recognized as crucial in many biological processes, such as cellular adhesion and communication. In order to investigate the interactions of carbohydrates and proteins, the development of efficient analytic technologies, as well as novel strategies for the synthesis of carbohydrates, have to be explored. To date, several methods have been exploited to analyze interactions of carbohydrates and proteins, for example, biosensors, nuclear magnetic resonance (NMR); enzyme-linked immunosorbent assays (ELISA), X-ray crystallography and array technologies. This thesis describes the development of novel strategies for the synthesis of carbohydrates, as well as new efficient strategies to Quartz Crystal Microbalance- (QCM-) biosensors and carbohydrate microarrays technologies. These methodologies have been used to probe carbohydrate-lectin-interactions for a range of plant and animal lectins. / QC 20100915

This thesis deals mainly with two oxidation reactions: water oxidation and aerobic oxidation, both of which have been applied in a biomimetic fashion. In the former reaction molecular oxygen is generated whereas in the latter it was used as terminal oxidant in oxidation reactions. The first part of this thesis describes the synthesis of different ruthenium and manganese complexes that could potentially act as catalysts for water oxidation. This part includes a discussion of the stability and reactivity of a new manganese(III) amide-type complex, that has been used as a catalyst for both epoxidation of stilbene and alcohol oxidation. The second part of this thesis discusses the synthesis of two new hybrid catalysts consisting of hydroquinone linked cobalt(II) salophen and cobalt(II) salmdpt, which have been used as oxygen-activating catalysts in aerobic oxidation reactions. The former catalyst was applied to the Pd-catalyzed reactions such as 1,4-diacetoxylation of cyclohexadiene whereas the latter was applied to the Ru-catalyzed oxidation of secondary alcohols to ketones. Moreover, these two hybrid catalysts could be used in the Pd-catalyzed carbocyclization of enallenes. In all cases molecular oxygen was used as the stoichiometric oxidant.

According to the famous axiom known as Moore’s Law the number of transistors that can be etched on a given piece of silicon, and therefore the computing power, will double every 18 to 24 months. For the last 40 years Moore’s prediction has held true as computers have grown more and more powerful. However, around 2020 hardware manufac-turers will have reached the physical limits of silicon. A proposed solution to this dilemma is molecular electronics. Within this field researchers are attempting to develop individual organic molecules and metal complexes that can act as molecular equivalents of electronic components such as diodes, transistors and capacitors. By utilizing molecular electronics to construct the next generation of computers processors with 100,000 times as many components on the same surface area could potentially be created. We have synthesized a range of new pyridyl thienopyridine ligands and compared the electrochemical and photophysical properties of their corresponding Ru(II) complexes with that with the Ru(II) complexes of a variety of ligands based on 6-thiophen-2-yl-2,2´-bipyridine and 4-thiophen-2-yl-2,2´-bipyridine. While the electrochemistry of the Ru(II) complexes were similar to that of unsubstituted [Ru(bpy)3]2+, substantial differences in luminescence lifetimes were found. Our findings show that, due to steric interactions with the auxiliary bipy-ridyl ligands, luminescence is quenched in Ru(II) complexes that in-corporate the 6-thiophen-2-yl-2,2´-bipyridine motif, while it is on par with the luminescence of [Ru(bpy)3]2+ in the Ru(II) complexes of the pyridyl thienopyridine ligands. The luminescence of the Ru(II) com-plexes based on the 4-thiophen-2-yl-2,2´-bipyridine motif was en-hanced compared to [Ru(bpy)3]2+ which indicates that complexes of this category are the most favourable for energy/electron-transfer sys-tems. At the core of molecular electronics are the search for molecular ON/OFF switches. We have synthesized a reversible double cyclome-tallated switch based on the Ru(tpy) complex of 3,8-bis-(6-thiophen-2-yl-pyridin-2-yl)-[4,7]phenanthroline. Upon treatment with acid/base the complex can be switched between the cyclometallated and the S-bonded form. This prototype has potentially three different states which opens the path to systems based on ternary computer logic.

Acid sulphate soils is a wide spread problem along the northern coast of Sweden. This is causing great damage through low pH and leaching of metals out into the streams. These soils are estimated to be found in several places in Sweden but also in many other areas in the world. One of these areas in Sweden that are believed to contain these sediments is Mälardalen. The purpose of this study is to evaluate the extension of the acid sulphate soils in this area. This has been accomplished through measurements of pH in the field as well as laboratorial work such as measuring the organic substance in the soil. The soils sulphur content was also analysed in a number of the samples. A total of 29 places has been visited in the area. The examination has been done as a pilot survey for the SGU. The study wanted to confirm if the acid sulphate soils are a problem in Mälardalen and if there is a connection between the soils that has a high organic matter and by what time they were deposited, and that those attributes would be a link to a low pH. The results is indicating that there is some correlation, mainly when it comes to soils with high organic content that has been deposited around 1000 years ago. With these quality’s the probability is going to be higher to find a soil that has a low pH. When examining diagrams showing these relations, we get an R-square value for the trend lines from both cases showing a correlation of 30%. This give us the indication that there are also other factors which will affect the pH. In this study the pH has been used as an indicator to where acid sulphate soils could be located. One cannot say that a high pH will exclude the possibility for a soil to become an acid sulphate soil, in the cases where the oxidized zone is small or absent. To ensure this fact, the soil will need to be oxidized as well as analysed to establish the sulphur content in the sample. This thesis has not shown any difference when it comes to the potential of acidification caused by these soils and the event of different kinds of sulphur compounds in Norrland and Mälardalen. According to our fulfilled literature studies the main difference are supposed to lay in the variation of the grain size in the different kinds of sediments. Air diffuse slower into a soil with a high content of clay compared to a soil with more silt. Clay may also have a bigger buffer system though high CaCo3 content or a high cation exchange capacity. The samples from the sites of Brantshammar, Kungsängen and Hova got time to oxidize as well as going through a sulphur analysis. Though these examinations as well as evaluations in the field, these sites could be confirmed to be acid sulphate soils. The number of parameters that was analysed for the other sites in this study are said to be too few, and gave inadequate results, and not the amount of information needed to be able to confirm the soils as acid sulphate soils. However, the correlation and the probability did increase with the number of consistent variables. The area would need another survey when there have been findings of acid sulphate soils as well as potential acid sulphate soils in this area. Further investigations can supplement the results from this current study and give a more apparent picture of the area, due to the fact that only a smaller amount of places could be reached within the time range of this survey. / Sura sulfatjordar är ett utbrett problem längs Sveriges nordligaste kust och orsakar skada genom låga pH och urlakning av metaller ut i vattendrag. Ett av dessa områden i Sverige tros vara Mälardalen och syftet med det här arbetet var att undersöka utbredningen utav sura sulfatjordar där. Genom att mäta pH på olika djup ute i fält, analysera organisk halt i labb samt svavelhalt i ett antal prover, så har 29 olika platser i området undersökts. Arbetet utfördes som en pilotstudie åt SGU. Målet var att se om sura sulfatjordar utgör ett problem i Mälardalen, och huruvida det finns ett samband mellan jordar med högt organiskt innehåll, vid vilken tidpunkt då avsättningen bildats och om dessa egenskaper sammanfaller med låga pH. Resultaten tyder på att ett visst samband finns, främst när det gäller högre organisk halt i jorden och områden som torrlagts genom landhöjning under de senaste 1000 åren. Sammanfaller dessa parametrar ökar sannolikheteten för att jorden kommer ha låga pH. I diagram över dessa samband visar R-kvadratvärdet för trendlinjen i båda fallen en korrelation på ca 30 % vilket antyder att det även finns andra faktorer som pH är beroende av. Det ska dock tilläggas att pH i den här undersökningen har använts som en indikator på om en jord kan klassificeras som en sur sulfatjord. På en del platser där pH i nuläget är högt skulle sura sulfatjordar kunna bildas om grundvattenytan sänktes. För att säkerställa detta skulle jorden behöva oxideras och pH mätas igen för att sedan analyseras för att ta reda på svavelhalten. Studien har inte visat någon skillnad gällande försurningspotential till följd av olika sulfidföreningar i Norrland gentemot Mälardalen. Enligt utförda litteraturstudier skall skillnaden i stället främst ligga i kornstorleken hos de olika jordarterna. Luft har svårare att tränga ned i en jord med hög lerhalt än i en siltigare jord. Lera kan också ofta ha en större buffrande effekt genom hög katjonutbyteskapacitet. Tidigare undersökningar visar även att Mälardalens gyttjeleror kan ha ett högre CaCO3- innehåll än normalt, vilket även verkar buffrande. Från platserna Brantshammar, Kungsängen och Hova togs prover som fick oxidera och genomgå svavelanalys. Genom dessa undersökningar, samt bedömning i fält, kunde jordarna med säkerhet fastställas som sura sulfatjordar. Antalet parametrar som analyserats på de övriga platserna i undersökning gav inte tillräckligt underlag för att kunna klassificera jordarna som sur sulfatjord, däremot ökade sannolikheten med antal överensstämmande parametrar. Området skulle behöva undersökas grundligare då det har hittats sura sulfatjordar med låga pH, samt områden som potentiellt skulle kunna bli det i framtiden. Vidare undersökningar kan komplettera resultaten från denna undersökning och ge en tydligare bild över området då endast en mindre mängd platser hann undersökas i denna studie.

2,6-Disubstituted spiro[3.3]heptanes were synthesized to investigate and develop synthetic methods for preparation of these compounds. Possibilities for introducing different functionalities like nitriles and sulfonamides were also investigated.   Synthetic routes presented describe successive [2+2] cycloadditions between dichloroketene and olefins to give the sought after spiro compounds with low to moderate yields throughout the multi-step synthesis. [2+2] Cycloadditions offered low turnovers and chromatography was required for purification.   A synthetic route with cyclisations through double substitution reactions between di-electrophiles and di-nucleophiles resulting in a 2,6-disubstituted spiro[3.3]heptane is also described. This multi-step synthesis offered higher turnover and yields and often there was no need for purification through chromatography.

Denna uppsats hade som övergripande syfte att undersöka hur asylsökande upplever asylprocessen. Vi valde följande frågeställningar som komplement till vår forskningsfråga: Hur upplever de asylsökande sin situation i väntan på beslut? Hur upplever de mottagandet i Sverige? Hur ser de på integration? Insamlingen av material har gjorts genom kvalitativa intervjuer med åtta utvalda personer.     Tidigare forskning visar att asylprocessen kan ha negativ inverkan på individers hälsa och bidra till en känsla av utanförskap. Asylprocessen är ofta en lång och utdragen process och genom att intervjua personer som upplevt hur det är att vänta på asyl har det framkommit gemensamma svårigheter kopplat till språk, sysselsättning och sociala nätverk. Vi har använt oss av Durkheims teorier om organisk solidaritet och menar att asylsökandes upplevelser av asylprocessen är ett klassiskt exempel på anomi.   Resultatet visade att intervjupersonerna hade en övergripande negativ upplevelse av asylprocessen. Alla intervjuer vittnade om en känsla av att stå utanför samhället, något som ofta var kopplat till att de under asylprocessen varken fick jobba eller studera på SFI. Många uttryckte en besvikelse över att samhället inte verkade möta dessa behov. Slutligen fann vi gemensamt för alla att språk, sysselsättning och ett starkt socialt kontaktnät är grunden till god integration i samhället samt att alla upplevde en stor frustration över att varken få komma in i arbetslivet eller få undervisning i språket innan beslut om uppehållstillstånd. Vi drar slutsatsen att det finns mycket som kan göras för att förbättra asylsökandes situation i väntan på uppehållstillstånd.

The use of enzymes as catalysts in organic synthesis constitutes an attractive alternative to conventional chemical catalysis. Enzymes are non-toxic and biodegradable and they can operate under mild reaction conditions. Furthermore, they often display high chemo-, regio- and stereoselectivity, enabling specific reactions with single product outcome. By the use of protein engineering, enzymes can be altered for the specific needs of the researcher. The major part of this thesis describes engineering of lipase A from Candida antarctica (CalA), for improved enantioselectivity in organic synthetic transformations. The first part of the thesis describes a highly combinatorial method for the introduction of mutation sites in an enzyme library. By the simultaneous introduction of nine mutations, we found an enzyme variant with five out of the nine possible mutations. This quintuple variant had an enlarged active site pocket and was enantioselective and active for our model substrate, an ibuprofen ester. This is a bulky substrate for which the wild-type enzyme shows no enantioselectivity and very poor activity. In the second part of the thesis, we continued our approach of combinatorial, focused enzyme libraries. This time we aimed at decreasing the alcohol pocket of CalA, in order to increase the enantioselectivity for small and medium-sized secondary alcohols. The enzyme library was bound on microtiter plates and screened by a transacylation reaction in organic solvent. This library yielded an enzyme variant with high enantioselectivity for the model substrate 1-phenyl ethanol, and high to excellent selectivity for other alcohols tested. Screening in organic solvent is advantageous since a potential hit is more synthetically useful. In the third part of the thesis, we used manipulated beads of controlled porosity glass (EziG™) for enzyme immobilization, and demonstrated the generality of this carrier for several enzyme classes. EziG™ allowed fast enzyme immobilization with simultaneous purification and yielded active biocatalysts in all cases. The last project describes the function of the proposed active site flap in CalA. In our study, we removed this motif. The engineered variant was compared to the wild-type enzyme by testing the amount of interfacial activation and the selectivity for certain alcohols. We showed that the motif is indeed controlling the entrance to the active site and that the flap is not part of the enantioselectivity determining machinery. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.</p>

This thesis focuses on the development of methods for the activation of the hydroxyl group in non-derivatized alcohols in substitution reactions. The thesis is divided into two parts, describing three different catalytic systems. The first part of the thesis (Chapter 2) describes nucleophilic allylation of amines with allylic alcohols, using a palladium catalyst to generate unsymmetrical diallylated amines. The corresponding amines were further transformed by a one-pot ring-closing metathesis and aromatization reaction to afford β-substituted pyrroles with linear and branched alkyl, benzyl, and aryl groups in overall moderate to good yields. The second part (Chapters 3 and 4) describes the direct intramolecular stereospecific nucleophilic substitution of the hydroxyl group in enantioenriched alcohols by Lewis acid and Brønsted acid/base catalysis. In Chapter 3, the direct intramolecular substitution of non-derivatized alcohols has been developed using Fe(OTf)3 as catalyst. The hydroxyl groups of aryl, allyl, and alkyl alcohols were substituted by the attack of O- and N-centered nucleophiles, to provide five- and six-membered heterocycles in up to excellent yields with high enantiospecificities. Experimental studies showed that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile of the substrate. Competition and catalyst-substrate interaction experiments demonstrated that this transformation proceeds via an SN2-type reaction pathway. In Chapter 4, a Brønsted acid/base catalyzed intramolecular substitution of non-derivatized alcohols was developed. The direct intramolecular and stereospecific substitution of different alcohols was successfully catalyzed by phosphinic acid (H3PO2). The hydroxyl groups of aryl, allyl, propargyl, and alkyl alcohols were substituted by O-, N-, and S-centered nucleophiles to generate five- and six-membered heterocycles in good to excellent yields with high enantiospecificities. Mechanistic studies (both experiments and density functional theory calculations) have been performed on the reaction forming five-membered heterocyclic compounds. Experimental studies showed that phosphinic acid does not promote SN1 reactivity. Rate-order determination indicated that the reaction follows first-order dependence with respect to the catalyst, the internal nucleophile, and the internal electrophile. DFT calculations corroborated with a reaction pathway in which the phosphinic acid has a dual activation mode and operates as a bifunctional Brønsted acid/Brønsted base to simultaneously activate both the nucleophile and nucleofuge, resulting in a unique bridging transition state in an SN2-type reaction mechanism. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript.</p>