Four new synthetic methods employing an oxidative dearomatization - rearomatization strategy are presented. In Chapter 2, a new oxidative dearomatization - radical cyclization - rearomatization approach to form fused oxygen-containing heterocycles is presented. Origins, design, reaction, and optimizations are discussed. In Chapter 3, meta-selective alkylation of catechol mono-ethers is described employing an oxidative dearomatization - radical addition - rearomatization approach using trialkylboranes as source of alkyl radicals. In Chapter 4, a metal-free method to synthesize fluorinated indoles from aniline starting materials is described. Chapter 5 lays the groundwork for para-selective functionalization of catechol mono-ethers. Chapters 6 and 7 highlight the work related to pharmaceutical drug analyses. Chapter 6 presents the FDA approved drugs organized in Disease Focused Posters. Chapter 7.1 and 7.2 present the drug analysis of Sulfur- and Fluorine-Containing Drugs, and Nitrogen-Heterocycle Containing Drugs, respectively.

A collection of twenty three selectively mono-protected di- and triamines, masked with the Boc, Fmoc or Ddiv protecting groups, were synthesised via continuous flow synthesis in a self-assembled meso-scale PTFE flow reactor. The continuous flow strategy offered direct access to the mono-protected compounds in good yields, especially in the case of the Fmoc carbamates which circumvented the use of another sacrificial protecting group. Two of the mono-Boc-protected carbamates were used as starting materials to generate N-alkylglycine monomers; synthesised via tandem mono-alkylation and Fmoc carbamation, linked by an in-line scavenging protocol using a silica-based trisamine scavenger resin. The final step of the monomer synthesis employed catalytic transfer hydrogenolysis using 20% Pd(OH)2/C and 1,4- cyclohexadiene. The three-step flow procedure gave access to two monomers, with one of them being a novel N-alkylglycine unit bearing a triethylene glycol bridge. The monomers were used as building blocks to assemble new oligo-N-alkylglycines (peptoids) via microwave-assisted solid phase synthesis. Three different types of peptoids were synthesised: (i) oligo-N-(6-aminohexyl)glycines (“standard” peptoids), (ii) oligo-N-{2-[2-(2-aminoethoxy)ethoxy]ethyl}glycines (“triethylene glycol” [TEG] peptoids) and (iii) hetero-oligomers of alternating “standard” and “TEG” monomers (“hybrid” peptoids). The peptoids were evaluated for their cellular permeability and cytotoxicity with HeLa, HEK-293 and CHO cells. All the peptoids were shown to be non-cytotoxic at 10 μM based on cell proliferation assays. In general, it was found that the cellular uptake of the hybrid peptoids outperformed their standard and TEG analogues. Flow cytometry and confocal microscopy results revealed that the hybrid nonamer had the highest cellular uptake efficiency of all the peptoids synthesised. At a concentration of 1 μM, it outperformed the second best molecular transporter (standard nonamer) by a factor of seven.

Chitooligosaccharides are composed of linear β-(1→4)-linked 2-acetamido-2-deoxy-β-D-glucopyranose (GlcNAc) and/or 2-amino-2-deoxy-β-D-glucopyranose (GlcN). They are of interest due to their remarkable biological properties including antibacterial, antitumor, antifungal and elicitor activities. They can be obtained from the aminoglucan chitosan by chemical or enzymatic degradation which obviously affords rather heterogenous mixtures. On the other hand, chemical synthesis provides pure compounds with defined sequences of GlcNAc and GlcN monomers. The synthesis of homo- and hetero-chitobioses and hetero-chitotetraoses is described in this thesis. Dimethylmaleoyl and phthaloyl groups were used for protection of the amines. The donor was activated as the trichloroacetimidate in order to form the β-linkages. Glycosylation in the presence of trimethylsilyl trifluoromethanesulfonate, followed by N- and O-deprotection furnished chitobioses and chitotetraoses in good yields. / Chitooligosacchride bestehen aus linear β-(1→4)-verknüpften 2-acetamido-2-deoxy-β-D-glucopyranose (GlcNAc) and/or 2-amino-2-deoxy-β-D-glucopyranose (GlcN) Einheiten. Sie beanspruchen aufgrund ihrer bemerkenswerten biologischen Eigenschaften – u.a. antibakterielle, antitumor, antimykotische und Elicitor Aktivität - grosses Interesse. Sie sind durch chemischen oder enzymatischen Abbau von Chitosan zugänglich, wobei diese Methoden unausweichlich zu komplexen, sehr heterogenen Mischungen von Chiooligosacchariden führen. Chemische Synthesen von Chitooligosacchariden mit definierter Sequenz von GlcNAc und GlcN Einheiten sind daher von erheblichem Interesse. In der vorliegenden Arbeit werden Synthesen von partiell acetylierten Chitobiosen und –tetraosen beschrieben. Die Aminogruppen wurden als N-Dimethylmaleoyl- bzw. Phthaloylimide geschützt. Die Donoren wurden als Trichloacetimidate aktiviert, wobei aufgrund von Nachbargruppeneffekten ausschliesslich die β-Glycoside entstehen. Die Trimethylsilyltrifluoromethansulfonat-promovierte Glycosidierung geeigneter Akzeptoren lieferte schliesslich die Chitobiosen und die Chitotetraosen in guten Ausbeuten.

In recent years, photoredox catalysis emerged as a privileged tool for small molecules activation via single-electron transfer mechanisms. Despite their ubiquity as reagents in organic synthesis, the use of boronic acid derivatives to generate carbon-centred radicals remains elusive. This dissertation explores the utilisation of photoredox catalysis to generate carbon radicals from boronic acid derivatives and subsequently engage them in C–C cross-coupling reactions. In the first chapter, an introduction to photoredox catalysis and organoboron reagents is provided, as well as a discussion on the key mechanistic aspects of photoredox catalysed C–C cross-coupling reactions. The second chapter presents our initial coupling strategy and how it evolved in understanding that pinacol boronic ester species can be used as a source of carbon radicals via single-electron oxidation from a photoredox catalyst. Coordination of the boronic esters with Lewis basic species was identified as a fundamental activating interaction. The synthetic utility of this discovery was highlighted by performing a wide range of photoredox catalysed arylations of pinacol boronic esters. The third chapter builds on our mechanistic understanding to identify a set of Lewis base catalysts that conveniently activates boronic esters and acids towards single-electron oxidation. The usefulness of this improved set of conditions was demonstrated by alkylating a wide range of boronic acid derivatives. The fourth chapter describes the application of this methodology in synthesising four active pharmaceutical ingredients from the GABA family. An emphasis was made on developing an efficient flow process and “transition metal free” conditions to survey the attractiveness of the method for the pharmaceutical industry. Finally, the fifth chapter describes the experimental procedures relevant to the results described in chapters 2 to 4.

No description available.

Bien que la synthèse peptidique en phase solide (SPPS) soit maintenant une technique mature et très largement popularisée pour des peptides simples, certaines séquences restent encore compliquées à produire, comme les peptides riches en ponts disulfure (DRPs). Ces produits naturels, ligands sélectifs d’un grand nombre de cibles thérapeutiques, sont des outils pharmacologiques de premier ordre et sont considérés comme de bons candidats médicaments. La proportion importante de cystéines dans leur séquence (plus de 10%) leur confère des propriétés remarquables, mais limite aussi leur synthèse,conduisant à des purifications HPLC délicates, associées à des rendements faibles et une pureté médiocre.Dans l’optique de simplifier la production de DRPs par voie chimique, notre but est de proposer une méthode de purification non-chromatographique. Pour cela, nous avons développé un bras N-terminal conçu pour être complètement compatible avec les peptides riches en cystéines: Boc-Cys(Trt)-1-{6-[1,3-diméthyl-2,4,6(1H,3H,5H)trioxopyrimidine-5-ylidène]hexyle}. A la fin de l’élongation sur support solide, ce bras est introduit sélectivement à l'extrémité N-terminale du peptide cible, sans réagir avec les peptides tronqués acétylés qui constituent les principales impuretés de la SPPS. Après coupure de la résine SPPS, le peptide cible est immobilisé sur un second support solide par le biais d’une réaction de ligation chimique native(NCL). Les peptides tronqués sont alors éliminés par simple filtration, puis le peptide cible est relargué en solution par coupure du bras N-terminal. Ayant comme objectif d’élargir par la suite notre stratégie à la synthèse de très longs DRPs via l’assemblage de multiples segments peptidiques par NCLs successives enphase solide, nous avons étudié en détail la stabilité et les conditions de coupure du bras.La méthode a été appliquée à la purification de deux séquences naturelles riches en cystéines et biologiquement pertinentes : AvBD2 (36 AA), un peptide antimicrobien appartenant à la famille des β défensines aviaires et Bv8 (77 AA) un peptide d’amphibien de la famille des prokinéticines. / Although solid phase peptide synthesis (SPPS) is a mature and widely popularized technique for simple peptides, some sequences are still complicated to produce, such as disulfide-rich peptides (DRPs). These natural products are able to selectively bind a wide number of therapeutically relevant targets, hence they are considered as promising drug candidates and pharmacological tools. The large proportion of cysteines in their sequence (more than 10%) confers them remarkable properties, but also limits their synthesis, lead ingto delicate HPLC purifications associated with low yields and poor purity.With the aim to simplify the chemical production of DRPs, we have developed an N-terminal linker: Boc-Cys(Trt)-1-{6-[1,3-dimethyl-2,4,6(1H,3H,5H)trioxopyrimidine-5-ylidene]hexyl}, which can be used for non chromatographiccatch-and-release purifications. It has been designed to be completely compatible with unprotected cysteine-containing peptides. Following solid phase elongation, this linker is selective lyintroduced at the N-terminus of the target peptide, leaving unreacted truncated acetylated peptides which are the main co-products of SPPS. After cleavage from the SPPS resin, the target peptide is immobilized on a second solid support through native chemical ligation (NCL). The truncated peptides are then removed by simple filtration. Cleavage of the linker finally releases the purified peptide into solution.Having in mind the future extension our strategy to the synthesis of very long DRPs through successive solid-supported NCLs of multiple peptide segments, we have studied in detail the stability and cleavage conditions of the N-terminal linker.To explore the scope and limitations of the method, it has been applied to the purification of two biologically-relevant cysteine-rich peptide sequences: chicken AvBD2 (36 AA), a β defensin antimicrobial peptide, and Bv8 (77 AA), a prokineticin-like peptide from yellow-bellied toad.

L’acide γ-aminobutyrique ou GABA est le principal neurotransmetteur inhibiteur présent dans le système nerveux central (CNS). Afin d’obtenir un nouveau dérivé cyclobutanique du GABA, le cis-3,4CB-GABA, sous forme énantiomériquement pure, deux stratégies de synthèses efficaces et reproductibles ont été mises au point. Ces deux voies de synthèse impliquent toutes les deux une étape-clé de photocycloaddition [2+2] qui permet de créer le cycle à 4 chaînons. La première consiste en une homologation de l’acide cis-2-aminocyclobutanique (cis-ACBC), et la deuxième est une synthèse multi-étape qui utilise le caprolactame comme composé de départ.D’autre part, grâce à une synthèse stéréosélective du (1R,2S)-cis-2,3CB-GABA, quelques oligomères C- et N-protégés – di, tri, et tétra-peptides – de cet aminoacide ont été préparés. Ceux-ci ont été caractérisés par les techniques de RMN 1D et 2D, IR, RX. Les analyses ont montré qu’il n’existe pas d’interactions non-covalentes (liaisons hydrogène) inter-résidu au sein de ces structures moléculaires. En revanche, la propriété de gélification de ces oligomères dans différents solvants organiques a été mise en évidence. Des solutions et des gels formés à partir de ces peptides ont été analysés par microscope électronique à balayage et des clichés ont été obtenus montrant une organisation du dipeptide et du tetrapeptide en fibrilles. Le tripeptide lui n’a présenté aucun assemblage intermoléculaire régulier. / The γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). In order to obtain new enantiomerically pure cyclobutanic derivative of GABA, the cis-3,4CB-GABA, two efficient synthetic strategies have been established. Both synthetic routes employed a photocycloaddition [2 +2] protocol, which provided the cyclobutanic ring. The first route involved the homolgation of the cis-2-aminocyclobutanecarboxylic acid (cis-ACBC), whereas the second route is a multi-step synthesis using caprolactam as starting material.On the other hand, the (1R,2S)-cis-GABA-2,3CB was synthetized, and a series of N- and C-protected oligomers of di, tri, and tetrapeptides of this amino acid were prepared. These oligomers were characterized by NMR (1D and 2D) techniques, IR, and X-ray. The analyses have shown that there are no non-covalent interactions (hydrogen bonds) between the residues of each oligomers. However, the gelation property of these oligomers in various organic solvents was demonstrated. Solutions and gels formed from these peptides were analyzed by scanning electron microscopy, and the obtained images showed a fibrous organization of the di- and tetrapeptide, while the tripeptide showed no regular intermolecular assembly.

Läsinlärning är en stor del av undervisningen i ett visst stadium. Lärare arbetar med olika läsinlärningsmetoder i undervisningen för att skapa möjlighet för elever att lära sig läsa. Syftet med denna studie är att ta reda på lärares uppfattningar om syntetiska och analytiska metoder för elever i förskoleklass och årskurs 1. Syftet besvaras genom följande frågeställningar: Vilka syntetiska och analytiska metoder använder lärare för att utveckla tidig läsinlärning i förskoleklass och årskurs 1? Hur använder lärare syntetiska och analytiska metoder för att utveckla elevernas tidiga läsinlärning? Hur uppfattar lärare att syntetiska och analytiska metoder kan bidra till en utveckling av elevernas läsinlärning? Studien genomfördes med en kvalitativ metod där data samlades in genom semistrukturerade intervjuer med sex lärare. Teorin som studien har utgått ifrån är sociokulturellt perspektiv. Resultatet redovisas under fem rubriker som är kopplade till studiens syfte: Lärarnas arbete med läsinlärning, den tidiga läsundervisningen, det fortsatta arbetet med läsinlärning, elevers synliga utveckling och elevers motivation och engagemang mot läsutveckling. Resultatet visar att lärarna uppskattar metoderna för elevernas läsinlärning. Lärarna använder modellerna Bornholm, Fonomix, ASL och dialogisk högläsning för att utveckla elevernas läsinlärning och hur de används redogörs i resultatet. Resultatet visar även att eleverna synligt utvecklas i sin läsinlärning och att lärarna uppfattar att motivation behövs för att elever ska komma vidare i sin läsinlärning. / The learning to read process is a major part of the education at a certain stage. Teachers work with different methods to teach students to read, and to create opportunities for reading development. The purpose with this study is to answer which perceptions teachers’ have on synthetic and analytical methods for students in preschool and grade 1. The purpose is answered through the following questions: Which synthetic and analytical methods do teachers use to develop early learning to read in preschool and grade 1? How do teachers use synthetic and analytical methods to develop students early reading? How do the teachers’ perceptions of synthetic and analytical methods contribute to students’ development in the learning to read process? The data was collected through semi-structured interviews with six teachers. The study is based on the sociocultural perspective. The result is reported through five headings that are linked to the purpose of this study: Teachers work with learning to read, the early reading instruction, the following work with learning to read, students’ visible development and students’ motivation and commitment to reading development. The results show that the teachers approve of the methods for students’ development for learning to read. The teachers use the models Bornholm, Fonomix, ASL and dialogical reading to develop students learning to read and how they use them is explained in the results. The results shows that teachers perceptions are that motivation also is needed for students’ development to read.

Att lära sig läsa är en väsentlig del i dagens skola och samhälle. Därför läggs mycket fokus på just läsundervisning i de tidiga åren. Lärares kunskap och didaktik har stor betydelse för att främja elevernas läsinlärning. Det krävs en förståelse för läsprocessens komplexitet och vilka förmågor hos eleverna som är viktiga att utveckla. Följaktligen är studiens syfte att undersöka hur sex lärare på tre olika skolor uppfattar att en god läsundervisning etableras. Undersökningen vill belysa lärarens syn på vilka förmågor som är viktiga att utveckla i den tidiga läsundervisningen, vilka läsinlärningsmetoder som används och hur. Studien tar ansats i den sociokulturella teorin, där den proximala utvecklingszonen stöttar inlärning. Läraren behöver ha läsinlärningskunskaper för att kunna ta reda på var eleven befinner sig i sin utveckling och för att stötta hen vidare till en högre nivå i kunskapstrappan. Undersökningen genomförs med individuella semistrukturerade intervjuer med samtliga lärare. De semistrukturerade intervjuerna används för att samtalet ska vara någorlunda öppet men ändå följa en struktur. Resultatet visade att läsmotivation, avkodning och språkförståelse behövs för en effektiv läsinlärning. I studien framträder flera läsinlärningsmetoder, tre syntetiska och en analytisk. De tre syntetiska metoderna fokuserar mer på avkodning medan den analytiska metoden börjar i förståelsen. Undersökningen visar att det är givande att arbeta med flera metoder eftersom man dels kan anpassa undervisningen på olika nivåer, dels för att de olika metoderna passar olika elever. Genom varierande arbetssätt och läsinlärningsmetoder gynnas fler elever av läsundervisningen, vilket möjliggör att fler barn lär sig läsa. / Learning to read is an essential part of today`s school and society. Therefore, a lot of focus is placed on reading teaching in the early years. Teachers´ knowledge and didactics are great importance in promoting students´ learning to read. It requires an understanding of the complexity of the reading process and which abilities of the student are important to develop. Consequently, the aim of the study is to investigate how six teachers at three different schools perceive that good reading teaching is established. The survey wants to shed light om the teacher`s view of which abilities are important for pupils to develop in early reading teaching, which reading learning methods are used and how. The study takes an approach in the sociocultural theory, where the proximal development zone supports learning. The teacher needs to have reading learning skills to be able to find out where the student is in his development and support him further to a higher level on the knowledge ladder. The survey is carried out with individual semi-structured interviews with all teachers. The semi-structured interviews are used so that the conversation is reasonably open but still follows a structure. The results showed that reading motivation, decoding and language comprehension are needed for effective reading learning. Several reading learning methods appear in the study, three synthetic and one analytic. The three synthetic methods focus more on decoding while the analytical one begins in understanding. The survey shows that it is rewarding to work with several methods, partly because you can adapt the teaching at different levels, partly because the different methods suit different students. By using more varied working methods and reading learning methods, the teaching of reading benefits more students, which enables more children to learn to read.

No description available.