The patellazoles are a family of marine polyketide natural products first isolated from Lissoclinum patella in 1988 by both the Moore and Ireland groups. They exhibit significant cytotoxicity against the HCT 116 human colon tumour cells. To date however, their full 3D stereostructure have yet to be elucidated, which has hindered their development as potential drugs, and hampered full investigation into their biological mechanism of action and has deterred total synthesis efforts. This thesis describes synthetic efforts towards Patellazole B, which exhibits the highest potency of the three main congeners. To fully elucidate the structure and renew interest in the patellazoles as anticancer compounds, we have developed a flexible and modular synthesis that aims to define the unknown stereocentres within the pertinent region and allow for rapid fragment union. Compound 36 has been chosen as an initial target for NMR comparison studies. The synthesis of all eight diastereomers of this macrocycle should aid determination of the four unknown stereocentres. Chapter 2 describes the synthesis of the C1–C12 fragment, focusing on the configuring of the C5 methyl stereocentre and the construction of the C7-C10 stereotetrad via a boron-mediated anti aldol with an in-situ reduction. In the third chapter, the synthesis of the C13-C19 fragment is outlined. A boron-mediated glycolate aldol has been used to install the C16-C17 anti stereochemistry and a substrate-controlled reduction at C15 delivered the hydroxyl with high diastereoselectivity. Studies into the C¬17¬ methylation are also described. Chapter 4 describes the synthesis of one possible diastereomer of the C20-C25 fragment, as a template for the preparation of the other 7 possible diastereomers. The route therefore employs only catalyst based control methods to install the three stereocentres, utilising a Sharpless asymmetric epoxidation and Evans aldol to construct the stereotriad. The 22R, 23S, 24S diastereomer has been initially chosen to investigate the later chemistry. Chapter 5 contains discussion of the ongoing work investigating fragment union and formation of the macrocycle. A Heck coupling reaction has been employed to construct the C19-C20 bond and a Suzuki coupling reaction has been developed to facilitate the C12-C13 bond formation. These two cross couplings have delivered the C1 - C25 fragment, 360, the final compound reported in this thesis, which is three steps away from the completed macrocycle and six from compound 36. The experimental procedures and spectroscopic characterisation of the synthesised intermediates can be found in Chapter 6 and the Appendix.

No description available.

Furanoeliangolidos são produtos naturais biologicamente ativos que contêm um esqueleto 11-oxabiciclo[6.2.1]undecano. Neste trabalho nós estudamos duas propostas sintéticas para síntese de um modelo simplificado do furanoeliangolido goiazensolido, através de uma reação de Diels-Alder seguida de clivagem da ligação central dos anéis. No desenvolvimento da primeira proposta nós preparamos o composto mesilato, porém as tentativas de efetuar a reação de eliminação resultaram em mistura complexa ou em produtos indesejados. Na proposta seguinte preparamos o éster, e testamos dois caminhos alternativos, entre várias possibilidades, para dar continuidade à síntese. No primeiro caminho o éster foi hidrolisado ao ácido, mas não foi possível obter a amida de Weinreb correspondente. No segundo caminho, o éster foi reduzido ao álcool, que foi oxidado ao aldeído; quando tratado com o ânion da hidrazona, o aldeído forneceu a hidrazona correspondente ao invés do esperado produto de adição de carbânion. Outras alternativas deverão ser investigadas no futuro. / Furanoheliangolides are biologically active natural products containing a 11-oxabicyclo[6.2.1]undecane skeleton. In this work we have investigated two different approaches to synthesize a model of the core structure of goyazensolide. Both approaches involve a Diels-Alder reaction and a bond breaking reaction to produce the polycyclic structure. In the first proposal we prepared mesylate compound. Attempts to effect an elimination reaction, however, resulted either in complex mixture or in undesired products. In the second proposal we prepared ester and investigated two alternative paths, out of several possibilities, to proceed the synthesis. In the first, ester was hydrolyzed to acid, but it was not possible to obtain the corresponding Weinreb amide. In the second path the ester was reduced to alcohol, that was oxidized to aldehyde; this, when treated with the anion from hydrazone, furnished hydrazone instead of the expected product of carbanion addition. Further studies should be developed in the future.

Furanoeliangolidos são produtos naturais biologicamente ativos que contêm um esqueleto 11-oxabiciclo[6.2.1]undecano. Neste trabalho nós estudamos duas propostas sintéticas para síntese de um modelo simplificado do furanoeliangolido goiazensolido, através de uma reação de Diels-Alder seguida de clivagem da ligação central dos anéis. No desenvolvimento da primeira proposta nós preparamos o composto mesilato, porém as tentativas de efetuar a reação de eliminação resultaram em mistura complexa ou em produtos indesejados. Na proposta seguinte preparamos o éster, e testamos dois caminhos alternativos, entre várias possibilidades, para dar continuidade à síntese. No primeiro caminho o éster foi hidrolisado ao ácido, mas não foi possível obter a amida de Weinreb correspondente. No segundo caminho, o éster foi reduzido ao álcool, que foi oxidado ao aldeído; quando tratado com o ânion da hidrazona, o aldeído forneceu a hidrazona correspondente ao invés do esperado produto de adição de carbânion. Outras alternativas deverão ser investigadas no futuro. / Furanoheliangolides are biologically active natural products containing a 11-oxabicyclo[6.2.1]undecane skeleton. In this work we have investigated two different approaches to synthesize a model of the core structure of goyazensolide. Both approaches involve a Diels-Alder reaction and a bond breaking reaction to produce the polycyclic structure. In the first proposal we prepared mesylate compound. Attempts to effect an elimination reaction, however, resulted either in complex mixture or in undesired products. In the second proposal we prepared ester and investigated two alternative paths, out of several possibilities, to proceed the synthesis. In the first, ester was hydrolyzed to acid, but it was not possible to obtain the corresponding Weinreb amide. In the second path the ester was reduced to alcohol, that was oxidized to aldehyde; this, when treated with the anion from hydrazone, furnished hydrazone instead of the expected product of carbanion addition. Further studies should be developed in the future.

This thesis is concerned with the development of methodology for the asymmetric syntheses of the nakinadine family of marine alkaloids and through these synthetic endeavours, seeks to confirm the structure and assign the relative and absolute configurations of these alkaloids for the first time.

This thesis investigates a total synthesis of the incednine aglycon by utilising alkenylsilane reagents to assemble the pentaenyl and tetraenyl systems through cross-coupling reactions. The early chapters develop methodology to access both cyclic alkenylsiloxanes and functionalised (E)-alkenylsilanes by the controlled hydrogenation of alkynylsiloxanes and silylolefination of aldehydes, respectively, and culminate in the synthesis of a C6-C13 bis(alkenylsilane)incednine fragment (Scheme 1). The C1-C5 and C14-C23 coupling partners are synthesised in three and ten steps from propargyl alcohol and L-alanine methyl ester through phosphorous-based olefination strategies. In the final chapter we describe our first generation approach to incednine which entails orthogonal cross-couplings to construct the C5-C6 and C13-C14 bonds (Scheme 2).

The work presented in this thesis mainly describes the discovery and development of methodology for the synthesis of anthecularin and anthecotulides, a family of unusual sesquiterpene lactones. Firstly, two 1,3-dipolar cycloaddition approaches toward anthecularin have been evaluated, using either oxidopyrylium ylide chemistry (Path A) or carbonyl ylides, generated by rhodium-catalysed decomposition of diazo ketones (Path B). Synthesis of the key precursor for the diazo strategy was achieved but unfortunately no desired cycloadduct was isolated. Secondly, an experimentally straightforward method to stereoselectively synthesise β-hydroxymethyl-α-methylene-γ-butyrolactones was developed using chromium or zinc. The synthetic utility of this methodology was demonstrated in syntheses of (±)-methylenolactocin, (±)-hydroxymatairesinol and, ultimately, (±)-hydroxyanthecotulide using a gold-catalysed Meyer-Schuster rearrangement. Finally, the first asymmetric synthesis of (+)-anthecotulide has been achieved, in 6 steps from commercially available materials. During this synthesis the absolute configuration was established. Furthermore, a novel rhodium-catalysed enantioselective ene-yne cycloisomerisation was used to form the α-methylene-γ-butyrolactone core.

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.

This thesis firstly describes a synthesis of the natural product taurospongin A, a potent DNA polymerase beta inhibitor. Sharpless asymmetric dihydroxylation on olefin <b>E-1.60</b> followed by selective deoxygenation at C(2) via Barton‒McCombie reaction delivers the desired C(1)–C(10) carboxylic acid core. Subsequent esterification of the C(1)–C(10) fragment with C(1′)–C(25′) fatty acid furnishes the natural product in 13.5% yield. The structure of an unnamed natural product <b>2.14</b> isolated in 1974 is proven to be misassigned by previous studies within the Robertson group. As described in this thesis, two proposed structures A and B are obtained via total synthesis in order to reveal the identity of the natural product. A synthesis of key intermediate spirocycles <b>2.148</b> and <b>2.158</b> with desired trans- diol moiety is described by a dihydroxylation reaction on an electron deficient gamma-keto unsaturated acid with subsequent spirocyclisation reaction. Finally, methodology for generating high-value synthetic intermediates by an asymmetric, one-pot enzymatic di/polycarbonyl reduction is described. The concept of such methodology is first proven by the synthesis of (3R)-hydroxybutyl (3R)-hydroxybutanoate <b>3.20</b>. This thesis then describes substrate scope studies and corresponding stereochemical proof to provide more information about this methodology.

Manganese(III) acetate mediated radical cyclisations provide a mild and powerful tool in the construction of complex bicyclic systems. This thesis focuses on the formation of a number of alkenyl substituted [3.3.0]-bicyclic γ-lactones utilising a manganese(III) acetate/copper(II) triflate induced radical cyclisation. The methodology was then applied to a short catalytic and enantioselective synthesis of (+)-aphanamol I and related natural products. Chapter 1 presents a summary of the theories and methodology which will be utilised in this work. In particular, a key focus will revolve around oxidative radical cyclisations and how manganese(III) acetate has become a vital oxidant in such areas. Chapter 2 details a catalytic and asymmetric total synthesis of (+)-aphanamol I. Following an overview of the natural product and its previous total synthesis, a racemic and asymmetric total synthesis is presented which utilises a manganese(III) acetate mediated radical cyclisation and a Claisen ring expansion as key steps. Chapter 3 reports the synthesis and subsequent cyclisation of a wide range of dienyl malonate substrates. Variation of the γ-substituent is first explored, demonstrating the effect that substituent size has on the diastereoselectivity of the cyclisation. Following this, the synthesis of [2.3.0]-,[4.3.0]- and [5.3.0]- bicyclic γ-lactones are investigated. Chapter 4 describes studies towards the total synthesis of a dolabellane natural product. Investigations into substrate synthesis which can be used in a RCM will be presented. Full experimental details and spectral data, with select NMR spectra are also provided.