Iminosugars are polyhydroxylated alkaloids, and can be generally defined as sugar mimetics in which the endocyclic oxygen atom has been replaced with a basic nitrogen. A common affect of this atomic substitution is to bestow these compounds with the ability to inhibit various sugarprocessing enzymes; most significantly the glycosidases (glycoside hydrolases) which areintimately involved in a huge array of biological functions. Compounds which inhibit these enzymes concordantly possess much potential as medicinal agents for the treatment of a variety of diseases. Several iminosugars have already achieved market approval as drugs, and many more are promising candidates in the late stages of clinical development. As such there remains considerable interest in this class of compound, both in terms of the exploration of novel iminosugar structures, as well as the continual development of more efficient general methodology for their synthesis. The densely-packed functionality and stereochemical information present in iminosugars makes them challenging targets for asymmetric chemical synthesis, whereas carbohydrates are clearly very attractive as chiral-pool starting materials for this purpose. Indeed, the majority of the most successful syntheses of iminosugars use the latter approach, and such is the focus of this thesis. Chapter 1 presents a relatively brief introduction to iminosugars, including their types of structure, natural occurrence and biological mode of action. The rationale behind their use as therapeutic agents for the treatment of some significant disease targets is also discussed. Chapter 2 is concerned with the preparation of a number of novel polyhydroxylated azetidines, and their evaluation as glycosidase inhibitors. Such compounds represent an almost entirely neglected class of iminosugars within the literature. An overview of natural and synthetic products incorporating an azetidine motif is given, as well as a brief review of preparative methods and known azetidine iminosugars. A highly efficient and flexible method for the key azetidine ring formation is demonstrated by the cyclisations of 3,5-di-O-triflates of pentoses and hexoses, and of a 2,4-di-O-triflate of glucose, with various primary amines. In this manner, many azetidine triols and tetrols were prepared in good yield. Furthermore, this process is readily adaptable to the installation of added functionality to the azetidine scaffold, as demonstrated by the preparation of 1-acetamido analogues. The initial biological screening of these compounds showed a promising array of glycosidase inhibition, including that of selective inhibition of fungal enzymes. Chapter 3 describes a strategy with which to prepare all sixteen stereoisomers of a known piperidine iminosugar, alpha-homonojirimycin (alpha-HNJ), in a highly divergent manner from just four of the possible thirty-two 6-azidoheptitols using traditional chemical synthesis in tandem with biotechnological transformations. One half of the execution of this strategy is described in this thesis. Two 6-azidoheptitols were prepared from D-mannose, thereby providing access to four 6-azidoketoheptoses through a combination of microbial oxidation and enzymatic epimerisation. Catalytic hydrogenation of these 6-azidoketoheptoses furnished four diastereomeric mixtures of 2,6-iminoheptitols, with varying degrees of stereoselectivity. Purification of these mixtures allowed six 2,6-iminoheptitols to be isolated, two of which have never previously been tested for glycosidase inhibition. Significantly, one of them was found to be a potent and highly selectiveinhibitor of alpha-galactosidases, and may therefore be of interest in the treatment of Fabry disease.

This thesis describes the development of robust methodology to access cyclic alkenylsiloxanes, and their subsequent application in Hiyama-Denmark cross couplings. An early chapter shows the identification of Lindlar reduction conditions capable of generating cyclic alkenylsiloxanes from alkynylsiloxanes in high yields. The use of such species in Hiyama-Denmark cross coupling is then examined, with particular emphasis on the development of fluoride-free conditions, previously unreported for this class of organosilane. A ring-size dependent orthogonality is revealed, where 5-membered cyclic alkenylsiloxanes cross couple under basic conditions, while 6-membered analogues are inert. The origins of this effect are investigated experimentally and theoretically, leading to the proposal of detailed mechanisms for coupling. In the final chapter, the methodology that has been developed is applied to total synthesis. The great potential of the orthogonality uncovered is demonstrated with the highly convergent construction of anti-inflammatory natural product resolvin D3 by sequential, one-pot, orthogonal cross couplings.

Using three complementary approaches, this work sought to tackle the widespread problem of antibiotic resistance. To circumvent the resistance mechanisms developed by bacteria, it is necessary to establish drug candidates that act on novel therapeutic targets, such as the ion channels used by bacteria to modulate homeostasis. Examples include the potassium efflux channel, Kef, and the mechanosensitive channel of small conductance, MscS, which are not found in humans. How these targets function must be well understood before drug candidates can be developed, as such, their identification and investigation is often accompanied by the evolution of the analytical techniques used to study them. Membrane protein mass spectrometry is one technique showing potential in the study of ion channels. However, spectra can be clouded by the detergents used to solubilise ion channels from their native membranes. Undertaken herein was the synthesis of some fluorescent glycolipid detergents, which it was hypothesised could be encouraged to dissociate from ion channels via laser-induced excitation within the gas phase of a mass spectrometer, thereby improving the clarity with which spectra can be obtained. For Kef, an unconfirmed mechanism of action had previously been proposed. To explore the suggestion that sterically-demanding central residues are important for channel activation, solid phase peptide synthesis was used to isolate three tripeptide analogues of N-ethylsuccinimido glutathione, a known activator with a high affinity for Kef. A competition fluorescence assay suggested these tripeptides bound to Kef with an affinity lower than predicted, allowing the conclusion that a more detailed assessment of the steric bulk required for activation was necessary before a mechanism of action could be confirmed. Lysophosphatidylcholine has been shown to activate MscS, although it is not known how. Affinity chromatography between MscS and lysophosphatidylcholine was proposed as a means by which specific binding interactions could be investigated. For this technique an amino-derivative of lysophosphatidylcholine was necessary and its challenging synthesis is also detailed herein.

Branched chain sugars display a varied and valuable range of biological activities. This thesis concerns the synthesis of 3,5-di-C-methyl-D-glucose, a potential inhibitor of glycogen phosphorylase (GP), and therefore a proposed therapeutic agent for type 2 diabetes. Chapter 1 looks at the occurrence of branched sugars in the natural world and current therapies for type 2 diabetes. Inhibition of GP is explored, and the molecular modelling studies which led to the design of the project target. Chapter 1 also looks into the development of new foodstuffs, the chemistry and biochemistry of imino sugars and branched hydroxy proline analogues. In Chapter 2, a range of different approaches to 3,5-di-C-methyl-D-glucose are investigated. Most of the initial investigations were carried out on the L-enantiomer, a readily available test system deriving from 2-C-methyl-D-ribono lactone. 2-C-Methyl-D-ribono lactone is synthesised rapidly from D-glucose in a one-pot reaction; as the key starting material for this work, the scalability of this process was investigated. One of the attempted syntheses of di-C-methyl glucose lead to the development of a route towards 3,5-di-C-methyl fructose, a novel dibranched ketose sugar. It was envisaged that through an enzymatic transformation, it might be possible to produce 3,5-di-C-methyl glucose stereoselectively. Synthesis of both enantiomers of 3,5-di-C-methyl glucose and mannose are reported, alongside results of GPb inhibition studies. Analysis of the preferred ring size of a range of di-C-methyl branched sugars and sugar lactones generated in this work is also presented. Chapter 3 explores the chemistry of 2,4-di-C-methyl-L-arabinono lactone, a key intermediate in the synthesis of 3,5-di-C-methyl-L-glucose. From this lactone a novel deoxy sugar, 2-deoxy-2,4-di-C-methyl-L-arabinono lactone, was generated. Routes towards a selection of imino sugars were explored, resulting in the synthesis of a methyl branched isofagomine analogue. A substituted aziridine was synthesised, from which a route to a di-C-methyl branched piperidine was proposed, and a pyrrolidine. Also presented is a synthesis of a dihydroxy di-C-methyl branched proline analogue. Detailed NMR analysis of several of the sugars generated in this work was carried out by Dr M. Wormald, of the University of Oxford Biochemistry department. The results of these investigations are presented in the Appendix. Throughout this work, the presence of quaternary centres has posed a problem with the assignment of relative configuration. As a result, this work has been greatly supported by X-ray crystallography, and the structures shown herein were wholly generated by me. Several other crystals were run during the course of this work, not all pertaining to these projects, and are provided in the CD appendix.

Ces dernières années, différents épisodes d’intoxication ont touché les coquillages sur le littoral français et tout particulièrement les huîtres dans le Bassin d’Arcachon. Afin de venir en aide à la profession ostréicole, le Conseil Régional d’Aquitaine a mis en place un vaste projet de recherche. Au sein de ce programme, nous avons proposé d’étudier la faisabilité d’un immunocapteur, basé sur la reconnaissance anticorps/antigène, capable de détecter la présence de phycotoxines dans l’eau de mer. Les synthèses de molécules (haptènes), présentant une analogie structurale avec la partie commune des phycotoxines de la famille des ASP ont été réalisées à l'ISM. Après couplage de ces molécules à une protéine, des anticorps montrant une bonne reconnaissance des ASP ont été obtenus. La mise au point de l'immunocapteur a été effectuée en collaboration avec deux autres Unités de Recherche : le LIP (Univ. Bx II) pour l'immunologie et l'IMS (Univ. Bx I) pour la lecture et la transcription du signal sur le capteur. / In the last few years, oysters from the Arcachon Bay have been touched by several toxic episodes. To help oyster industry, an important research program was funded by the Conseil Régional d’Aquitaine. In this project, we proposed to study the feasibility of an immunosensor, based onantibody/antigen reaction, able to detect phycotoxins in seawater. Haptens showing astructural analogy with the common part of ASP toxins were synthesized at ISM. Aftercoupling of haptens with a protein carrier (BSA), antibodies showing a good ASP recognition were obtained. The transducer, a Love wave acoustic device, was developed by IMS (Univ.Bx I) and the antibodies used for specific biorecognition were characterized by LIP (Univ. BxII).

Total synthesis of the pyrrolizidine alkaloid NP25302: (+)-NP25302 is an unusual vinylogous urea containing pyrrolizidine alkaloid shown to exhibit cell adhesion inhibition. It was envisaged that this natural product could be accessed by a novel 5-endo-dig cyclisation to construct the pyrrolizidine core, and a Curtius rearrangement to install the vinylogous urea motif. This methodology was first tested on a model system, furnishing nor-NP25302 from L-proline in 12 steps and 9% overall yield. The total synthesis of (±)-NP25302 was completed in 9 steps and 26% overall yield from ethyl 2-nitropropionate using similar methodology. Studies into the stereospecificity of the Au(I)-catalysed cyclisation of monoallylic diols: During the synthesis of (+)-isoaltholactone in the Robertson group, the key Au(I)-catalysed cyclisation was observed to occur with some stereospecificity. Further investigations were therefore conducted into the stereochemical outcome of this reaction using stereodefined allylic alcohols, and from the combined results a mnemonic was proposed to predict the stereochemistry of the products of this reaction. Studies into the total synthesis of ascospiroketals A and B: Investigations were conducted into the total synthesis of the recently isolated natural products ascospiroketals A and B. A second generation synthesis was used to construct advanced intermediates 1 and 2.

A number of privileged starting materials based on aryl halide frameworks have emerged that allow access to a variety of different heterocyclic scaffolds through judicious choice of reaction conditions. This work describes efforts to develop and extend the utility of two of these general heterocycle precursors - ortho-(haloalkenyl)aryl halides A and α-(ortho-haloaryl) ketones B - in conjunction with cascade reactions involving the construction of key carbon-heteroatom bonds via palladium or copper catalysis. Chapter 1 entails an overview of the development of palladium- and copper-catalysed carbon-heteroatom bond forming processes. The application of these processes in heterocycle synthesis using ortho-(haloalkenyl)aryl halide and ortho-haloacetanilides/ α-(ortho-haloaryl) ketone precursors is also described. Chapter 2 focuses on the development of a two-step synthesis of cinnolines using ortho-(haloalkenyl)aryl halides via intermediate protected dihydrocinnoline derivatives C. Chapter 3 demonstrates how the inherent reactivity of protected dihydrocinnoline derivatives C can be harnessed to provide access to functionalised products. A brief target synthesis of a pharmaceutically-relevent cinnoline is also described. Chapter 4 details attempts to develop a novel synthesis of benzothiophenes D from both ortho-(haloalkenyl)aryl halide and α-(ortho-haloaryl) ketone precursors.

Bromodomains (BRDs) are protein modules which bind to acetylated lysines on histones and transcriptional regulating proteins. BRD-containing proteins are involved in a large variety of critical cellular processes and their misregulation, or mutation of the genes encoding for them, has been linked to pathogenesis in humans. The generation of chemical probes (potent, selective and cell permeable small molecules) in cellular experiments to investigate the biological role of the BRDs is thus desirable. A chemical probe for the CREB (cyclic-AMP response element binding protein) binding-protein (CBP) and E1A binding protein (p300) BRDs was developed, starting from a low molecular weight, weak and non-selective dimethylisoxazole benzimidazole compound. Parallel synthesis was used to optimise the initial hit into a weak, but selective CBP inhibitor. Further modification of the two N-1 and C-2 moieties of the benzimidazole scaffold, led to highly potent and selective CBP inhibitors. Structure-guided design was then applied to optimise the selectivity of the series for CBP over the first domain of bromodomain-containing protein 4 BRD4(1). A strategy to reduce the flexibility of the N-1 and C-2 ethylene linker groups through the incorporation of conformational constraints led to inhibitors with increased selectivity. The optimal compound was highly potent for the CBP and p300 BRDs (K_d 21 nM and 32 nM, respectively) and selective over BRD4(1) (40-fold and 27-fold, respectively). On-target cellular activity was observed in a fluorescence recovery after photobleaching (FRAP) assay (0.1 μM), a p53 reporter gene assay (IC₅₀ 1.5 μM) and a Förster resonance energy transfer (FRET) assay (5 μM). A weak indolizine bromodomain-containing protein 9 (BRD9) inhibitor was used as the starting point for the development of a BRD9/BRD7 chemical probe. Analogues were synthesised via [3+2] cycloadditions. An optimised compound was found to be highly potent (68 nM) and selective over BRD4(1) (34-fold). On-target cellular activity was observed in a FRAP assay (5 μM). Efforts were made to improve the cellular activity through the introduction of an ionisable centre to aid solubility. A selection of piperazine analogues were shown to be potent and selective, and these compounds warrant further investigation of their selectivity and cellular activity. Overall, the work has led to the first potent and selective inhibitors of the CBP/p300 and BRD9 BRDs. It also highlights the role of structural analysis in the development of inhibitors that modulate protein-protein interactions.

Chapter 1 is an overview of the key developments in rhodium-catalysed hydroacylation. The main focus of this chapter is the use of various chelation strategies for the stabilisation of key rhodium-acyl intermediates. In addition, the more recent emergence of regioselective hydroacylation processes has been highlighted. Chapter 2 discloses the branched-selective intermolecular hydroacylation of 1,3-dienes and S-chelating aldehydes to afford synthetically useful 1,5-dione products. The evaluation of a number of different phosphine ligands for this process identifies a correlation between ligand bite angle and reaction regioselectivity. Chapter 3 discusses the development of a linear-selective hydroacylation process for previously challenging alkyne substrates. This, in combination with a complementary branched-selective process, provides a ligand-controlled regioselectivity switch between the branched and linear pathways. Finally, Chapter 4 details efforts towards the development of multicomponent, tandem processes through exploitation of our synthetically useful branched hydroacylation adducts.

The aim of this project was to develop new catalytic methods to control asymmetry in electrocyclic reactions, and to apply these methods to generate complex molecules. Initial efforts were directed towards the catalysis of anionic 8π electrocyclizations (Chapter 2 and Figure i). 8π electrocyclization was not achieved due to issues with alkene geometry and anion stability. Our efforts were then directed towards using phase-transfer catalysis to generate complex polycyclic compounds via a cascade electrocyclization-1,4-addition (Chapter 3 and Figure ii). Pyrrolidines and indolizidines were generated in excellent yield from simple starting-materials with high levels of stereocontrol. Finally, we investigated the catalysis of a 6π [1,6] electrocyclization to generate dihydroquinolones (Chapter 4 and Figure iii). A novel BINOL-derived copper(II) catalyst was developed, and afforded dihydroquinolones directly from their amine and aldehyde precursors with good yields and enantioselectivities.