Dendritic cells (DC) are one of the major antigen presenting cells (APC) of the body. They, by capture of antigen and cross-presentation of these antigens, activate dormant T-cells and co-activate B-cells. As such they regulate the immune system toward either a more humoral type immune response or a more cellular type immune response. These properties have made them very studied over the past decade and many works have focus on the development of vaccine or therapeutic using DCs as a target. However, most of these actual studies have been done by injection of in vitro pre-activated DCs. The major drawback of this technique is the use of non-natural and non individual specific DCs (monocytes derived DCs and/or stem cells DCs). That is why therapeutic carrier targeting specifically DCs has to be developed. To achieve this goal, specific molecules present at the surface of DCs and involved in the activation of the immune system has to be targeted. Among them, DC-Specific ICAM-3 Grabbing Non-integrin CD209 (DC-SIGN) is very specifically expressed only on one subset of DCs called interstitial DCs. This lectin has been proven to be one of the first contacts of the DCs with T-cells and to induce one major interaction for cells proliferation of dormant T-cells. The goal of the project is to design a probe that can be used in vivo and post-mortem to target DCs via DC-SIGN. Therefore, we can use these particles as a proof of concept in vivo and in vitro, record the immune response obtained with them in vivo and in vitro and design probes that can be used to induce specific immune response for future therapy development. Lewis sugars have been shown to be quite specific to DC-SIGN. Their syntheses have been carried out in our lab with a cyanomethylthio linker at their anomeric position. This linker, once activated as a 2-imino-2-methoxyethyl moiety, has permitted the attachment of the oligosaccharides at the surface of dextran-coated iron oxide MRI nanoparticle. These particles have been chosen for their powerful properties and the advantage of the technique they are used for. Indeed, as particles their sizes mimic pathogens and DCs would interact with them, as they will with pathogen. Moreover, many copies of each oligosaccharide could be attached at their surface enhancing the interaction of the particles with the targeted lectin via a multivalent effect. As a technique, MRI has the advantage to be recorded over a long period of time (compare to ¹⁸F PET for example), with a relatively low signal/noise ratio (compare to fluorescence techniques) and without being harmful. FITC fluorescent Lewis X nanoparticles have been actually design and characterised (size by DLS, number of sugar by particles by ICP or fluorescamine fluorescence assay and binding affinity by ELISA with DC-SIGN-Fc). They have been first tested in vitro with models cells (Raji and monocytes derived DCs) for specific uptake assays, where they exhibit specific uptake and internalisation. Lewis-x nanoparticles have also been tested in vivo in a rat model and have been shown to be retained in Lymph nodes compared to control particles. Post mortem analysis appears to demonstrate that these particles were internalised by rat DCs and transported in the centre of the lymph node known as the T-cell region. Finally, cytokines and CD86 concentration measurement have shown that upon internalisation of the nanoparticles, DC maturated. In addition, an antigenic OVA peptide epitope was attached to the surface of the nanoparticles for future T-cell proliferation experiments. It will allow the determination of the immune response expected. In summary, we have developed an immunogenic MRI-active probe that can target specifically DC-SIGN via the interaction with Lewis antigens present at the surface of the probe and trigger DC maturation.

<strong>Introduction</strong> The introduction describes the importance of arylamine compounds to society and provides a brief overview of the methods available for their synthesis. The application of metathesis catalysis to the de novo synthesis of heteroaromatic compounds is also described. <strong>Results and discussion</strong> The first section describes efforts towards the de novo synthesis of arylamines using a cross metathesis/oxidation protocol to form a 1,5-unsaturated dicarbonyl followed by an amine mediated cyclisation. The scope with respect to the 1,5-unsaturated dicarbonyl and amine is covered as well as the utility of some of the products. The section concludes with a modification of the Bohlmann Rahtz pyridine synthesis to furnish arylamines. The next section describes the applications of our methodology to the synthesis of naphthylamines, specifically using the palladium catalysed &alpha;-arylation reaction. A discussion of the α-arylation reaction is included as well as our efforts to explore the scope of the reaction. The third section follows our efforts to apply this methodologyy to the synthesis of five benzo[c]phenanthridine alkaloids including the first reported synthesis of maclekarpine B and C. The final section concludes with a discussion of our efforts towards the de novo synthesis of furans bearing a benzylic stereocentre.

This thesis details the development of manganese(III) acetate-mediated oxidative radical cyclisation methodology. In particular, the use of radicals to form complex, highly sterically congested and strained carbo- and heterocycles in a stereocontrolled manner is described. Chapter 1 gives a summary of the literature regarding three key areas relevant to this work. Radical reaction mechanisms are introduced, including the use of transition metals and lanthanides in C-centred radical cyclisations. The formation of highly sterically congested vicinal all-carbon quaternary stereocentres is also discussed. Finally, the use of radical cyclisation methodology for the synthesis of complex cyclic structures and applications in natural product total synthesis is examined. Chapter 2 gives an account of the manganese(III) acetate-mediated cyclisation of 5-pentenyl malonates bearing a terminal aryl group. The effects of the aryl group are tested with a range of electronically varied substituents. The formation of bi- and tricyclic cyclopentane-lactones bearing adjacent quaternary-quaternary-tertiary stereocentres is demonstrated. Chapter 3 demonstrates the synthesis of highly strained tricyclic bis-lactones. The metal complexes manganese(III) acetate and cerium(IV) ammonium nitrate are shown to give complementary stereoselectivity across a range of cyclisation substrates. Possible synthetic applications of tricyclic bis-lactones are also investigated. Chapter 4 details an asymmetric formal synthesis of the proteasome inhibitor salinosporamide A. An oxidative radical cyclisation forms the key heterocycle in Danishefsky’s synthesis of this biologically important molecule, and showcases the use of the radical chemistry in natural product synthesis. Full experimental details, selected NMR spectra, and X-ray crystallographic data are also provided.

This thesis describes the development of synthetic strategies towards the densely functionalised pyrrolidinone core of the polyene &beta;-lactone-&gamma;-lactam antibiotic oxazolomycin A. <strong>Chapter 1 The oxazolomycins</strong> The oxazolomycins, a unique class of biologically active molecules containing a spiro-fused β-lactone-γ-lactam ring system are introduced. The isolation, structural elucidation and biological properties of the oxazolomycins as well as those of the structurally related inthomycins are reviewed. <strong>Chapter 2 Previous syntheses</strong> The two total syntheses of neooxazolomycin and the synthetic approaches to the pyrrolidinone core of oxazolomycin A and KSM-2690 B are evaluated. <strong>Chapter 3 Project aims</strong> An outline of the synthetic strategy employed in this project and details of the novel retrosynthesis of the pyrrolidinone core of oxazolomycin A are discussed. <strong>Chapter 4 Synthetic studies towards the pyrrolidinone core of oxazolomycin A</strong> The synthetic studies carried out towards the pyrrolidinone core of oxazolomycin A are described in detail. The preparation of an advanced intermediate containing the five chiral centres, four of which are contiguous, was achieved in twenty steps as a single diastereomer and as a single enantiomer. <strong>Chapter 5 Synthetic studies towards the middle fragment of oxazolomycin A</strong> A novel synthetic approach to the diene fragment contained in oxazolomycin A is reported. The formal synthesis of a dienyl iodide, in four fewer steps than previously reported was accomplished. <strong>Chapter 6 Conclusions and future work</strong> A summary of the synthetic work reported in this thesis and proposals for future study are presented. <strong>Chapter 7 Experimental</strong> Full experimental procedures and characterisation of compounds are reported. <strong>Chapter 8 References</strong> A complete list of citations employed in the previous seven chapters is provided.

Chapter 1 is a brief review on some of the recents developments in palladium-catalysed C-H functionalisation chemistry. The synthesis and functionalisation of heterocycles using these methodologies was particularly emphasised. Chapter 2 presents our efforts to identify a new catalytic system to promote the intramolecular coupling of vinyl bromides with unfunctionalised aryl C-H bonds for the formation of benzofurans. Dihydrobenzofurans were obtained efficiently under mild conditions in the presence of Pd(OAc)₂, X-Phos and K₂CO₃ in DMA at 80 °C and a subsequent one-pot isomerisation under acidic conditions afforded the desired benzofurans. A new strategy has also provided access to more complex benzofurans by functionalisation of the exocyclic alkene isomer in both a chiral and achiral manner. In Chapter 3, mechanistic studies were performed on the benzofuran formation reaction. The analysis of substituent effects on the aromatic ring is in accordance with an electrophilic aromatic substitution mechanism (SEAr); however, the existence of both intra and intermolecular kinetic isotope effects suggest a SE3 type pathway rather than a pure SEAr. In Chapter 4, the intramolecular coupling of vinyl bromides with unfunctionalised aryl C-H bonds was further extended to the synthesis of six-membered heterocycles by direct arylation of alkenyl bromide derivatives in the presence of Pd(OAc)₂, dppf and K₂CO₃ in DMA at 120 °C. The synthetic utility of this methodology was exemplified by the synthesis of substituted isoquinolines in six steps. Moreover, we have applied our methodology to the direct arylation of sulfonamides, leading to an interesting synthesis of widely used sultams. Both these new routes are currently being investigated and should provide access to a variety of differently substituted cyclic sulfonamides and isoquinolines. Finally, Chapter 5 presents a new strategy for the synthesis of benzo[b]furan was briefly investigated. It consists in consecutive Tsuji-Trost and C-H functionalisation reactions. This methodology requires simpler and more versatile substrates, allowing access to various heteroaromatics in a single step. We successfully proved the viability of this reaction through the synthesis of a range of benzofurans in modest yields. To our knowledge, this is the first example of a single palladium catalyst performing these different reactions in tandem in a simple procedure.

This thesis describes the studies towards the synthesis of β-amino acids found in the microsclerodermins, a family of complex macrocyclic hexapeptides. These β-amino acids have four or five contiguous stereocentres and an aliphatic side-chain. The synthetic route utilised an aminohydroxylation reaction to install the most challenging moiety in the structure - the 1,2- amino alcohol. The work aimed to construct the core structure (five contiguous stereocentres) of the β-amino acids and install the side-chain later to enable the synthesis of multiple members (A, B, F, G, H and I) of the microsclerodermin family. The synthesis started with Roche ester, which contained the first methyl stereocentre. It was converted to the diene precursor in four high yielding steps. The next two stereocentres were installed via a Sharpless asymmetric dihydroxylation. With the appropriate protecting groups in place, the remaining two stereocentres were to be installed via a Sharpless asymmetric aminohydroxylation. Various reported reagents and conditions were used to effect the transformation, but the attempts were unsuccessful. This forced us to alter our synthetic plans, and the revised synthetic route involved the use of the tethered aminohydroxylation (TA) reaction developed by the Donohoe group. After the development of an efficient protocol to prepare the TA-precursor, the alkene, with three stereocentres already in place, was successfully converted to the desired stereopentad via the TA-reaction (10 steps, 11% overall yield). With the stereopentad in hand, installation of the side-chain of the β-amino acids through an alkenyl or alkyl linkage was investigated. For alkenyl-linked side-chains, the appropriate aldehyde was synthesised, but attempts to effect the transformation via a Horner-Wadsworth- Emmons reaction or a Witting reaction failed. With lessons learnt from those, we then focused our efforts on installing an alkyl-linked side-chain. In this case, we were able to install a side- chain via a copper-mediated displacement reaction, which gave us a protected form of the precursor of the β-amino acid of microsclerodermin B. Finally, various efforts to study the reactivity of the stereopentad and the investigations into finding the most effective set of protecting groups have been used to propose a synthetic route for the incorporation of the β- amino acid into the macrocycle.

The work presented in this thesis mainly describes the development of new reactions of &beta;-lithiooxyphosphonium ylides to access stereodefined substituted alkenes in a highly convergent fashion. Firstly, &beta;-lithiooxy ylides prepared from aldehydes and phosphonium ylides were shown to react with halogen electrophiles to provide a highly stereoselective route to E-alkenyl bromides and iodides. This methodology was successfully applied to the first total synthesis of naturally occurring (5E,9Z)-6-bromohexadeca-5,9-dienoic acid. Secondly, an experimentally straightforward method was developed for the stereocontrolled formation of trisubstituted Z-allylic esters by in situ trapping of &beta;-lithiooxyphosphonium ylides with readily available halomethyl esters. The synthetic utility of this methodology was demonstrated with the synthesis of plaunotol [(2Z,6E)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-6-methylocta-2,6-diene-1,8-diol] and the first asymmetric synthesis of the naturally occurring geranylgeraniol-derived diterpene (6S,7R,Z)-7-hydroxy-2-((E)-6-hydroxy-4-methylhex-4-enylidene)-6,10-dimethylundec-9-enyl acetate. Furthermore, the chemistry of &beta;-lithiooxyphosphonium ylides was expanded to access synthetically useful disubstituted Z-allylic esters. The synthetic utility of Z-allylic esters was also demonstrated in a versatile and diastereoselective Ireland-Claisen rearrangement to access &gamma;,&delta;-unsaturated acids. Finally, the synthesis of the side-chain of the 6,7-dideoxysqualestatin H5 was also investigated. It was demonstrated that the side-chain of 6,7-dideoxysqualestatin H5 could be accessed by a convergent and stereoselective organozinc-based strategy.

Bohlmann et al. reported the oxidative spirocyclisation of 2-(ω-hydroxyalkyl)furans under Clauson-Kaas conditions to furnish 1,6-dioxaspiro[4.5]dec-3-enes, thereafter termed the “Bohlmann cyclisation.” This thesis describes the development of an analogous aza-Bohlmann cyclisation. Treatment of 2-(ω-aminoalkyl)furans with m-CPBA or singlet oxygen generates hydroxy- or methoxybutenolides, respectively, which undergo spirocyclisation upon treatment with H₂SO₄ to generate [4.4]- and [4.5]-spiroaminoacetals. The axial/equatorial preferences of N-sulfonylspiroaminoacetals featuring a 3-O-isovaleryl or 3-O-benzyl substituent are described. Acid-catalysed equilibration revealed that in acetonitrile the axial isomer is thermodynamically favoured for both substrates. The first total synthesis of the spiroaminoacetal alkaloid pandamarilactone-1 is discussed, via an aza-Bohlmann cyclisation, in 13 steps and 3% overall yield from 4-pentyn-1-ol.

In the following thesis, new methodologies towards the synthesis of a range of sulfonyl (-SO₂-) containing functional groups are documented. These methods utilise easy-to-handle sulfur dioxide surrogates, such as DABSO (vide infra), and exploit palladium catalysis as a new mechanistic protocol for the incorporation of the -SO2- unit. <b>Chapter 1</b> is a literature review surveying sulfur dioxide in organic synthesis, the established uses of SO₂ surrogates and the importance of the sulfonyl moiety in chemistry. Palladium-catalysed (carbonylative) cross-couplings are also broadly discussed as they provide inspiration for, and mechanistic similarities with, the proposed chemistry. <b>Chapter 2</b> describes a de novo synthesis of the sulfonamide functional group; a three-component and convergent methodology coupling (hetero)aryl and alkenyl halides with sulfur dioxide (provided by easy-to-handle surrogates such as DABSO) and hydrazine nucleophiles, is documented. This is achieved through the action of a readily available palladium catalytic system and is the first example of a metal-catalysed sulfonylative cross-coupling of halide based electrophiles. <b>Chapter 3</b> presents a new method of generating (hetero)aryl and alkenyl sulfones. The ability of organometallic reagents to add to sulfur dioxide (supplied via DABSO) is applied to deliver the corresponding metal sulfinate salt. This in situ derived sulfinate is coupled with an (hetero)aryl or alkenyl (pseudo)halide using palladium catalysis to form the desired sulfone. An electronically modified XantPhos-type ligand was designed for the reaction in order to suppress unwanted aryl-aryl exchange. <b>Chapter 4</b> documents the generation of (hetero)aryl and alkenyl sulfinates from the corresponding halide and DABSO through a palladium-catalysed sulfination protocol, obviating the need for organometallic reagents. A mild set of conditions using IPA as both a solvent and reductant together with a low loading of palladium catalyst offers an attractive route to sulfonyl compounds thanks to the in situ derived sulfinates being converted into a broad variety of functional groups via established onwards reactivity. <b>Chapter 5</b> discusses the conclusion of the research and the potential for future work. <b>Chapter 6</b> presents the experimental data.

The cobalt-catalysed oxidative cyclisation of 5-hydroxy alkenes has been demonstrated to be a powerful synthetic tool for the formation of trans-THFs with excellent diastereoselectivity. This thesis describes the utilisation of this methodology in the synthesis of the FG fragment of pectenotoxin-4, allowing the scope of the reaction to be further explored. Introduction: This section introduces the pectenotoxins, a family of structurally complex closed-chain polyether macrolides with promising biological activities. The isolation, structural elucidation, and biological properties of the pectenotoxins are reviewed, along with a summary of previous syntheses towards the FG fragment of pectenotoxin-4. In addition, the cobalt-catalysed oxidative cyclisation of 5-hydroxy alkenes and its application in synthesis is discussed. Results and Discussion: An outline of the synthetic strategy employed in this project and details of the novel retrosynthesis of the C31-C40 fragment of pectenotoxin-4 is described. The synthetic studies carried out towards the synthesis of the FG fragment of pectenotoxin-4 are discussed in detail, with the exploitation of a cobalt-catalysed oxidative cyclisation as the key step to form the trans-THF F-ring. Overall, the FG fragment, which contains six stereogenic centres, was achieved in 18 total synthetic steps (13 longest linear sequence).