Enantiopure α-alkyl-substituted aldehydes are widely recognised as important building blocks in synthesis. Despite this, methods to prepare such substrates are limited. Strategically, asymmetric intermolecular S_N2 α-alkylation represents a highly straightforward transformation, but still remains an elusive feat. This thesis describes efforts to address this challenge, with attempted access to enantioenriched α-alkyl aldehydes by way of C-alkylation of chiral, non-racemic, hindered aldenamines using simple alkyl halides. Enamines derived from four types of auxiliary (a tropane, an oxazolidine, a pyrrolidine and a homotropane) have been prepared, and their alkylation profile examined. While the desired levels of asymmetric induction were not attained, use of the tropane and homotropane auxiliaries, which differ only by a single methylene group, interestingly, gave complimentary diastereocontrol during alkylation with EtI. The observed stereoselectivity is supported by density functional studies performed for ethylation of both enamines. Additionally, in the course of preparing the homotropane a highly efficient asymmetric synthesis of a homotropinone bearing gem-α-substitution has been developed.

Systemic administration of adenovirus type 5 (Ad5) vectors for the treatment of cancer is limited by poor circulation kinetics and inefficient uptake from the bloodstream into tumours. This study reports a novel method for linkage of highly-PEGylated gold nanoparticles (AuPEG) to Ad5 by a single reduction cleavable bond. The resulting ‘dandelion’ structure provides very effective steric shielding with only minimal and reversible modification of the Ad5 capsid. This ablates in vitro cell infection, improves protection against the binding of antibodies, and enhances in vivo circulation kinetics. Focused ultrasound is a promising technology for the non-invasive, targeted treatment of cancer. In the context of drug delivery, cavitational energy generated upon exposure of ultrasound contrast agents to focused ultrasound can be used as a powerful stimulus to move therapeutics over distances of hundreds of microns away from blood vessels. In addition to providing a platform for effective stealthing, conjugation of AuPEG to Ad5 also increases the effective density of Ad5. This increase in density imparts a second major advantage on the strategy, observed for the first time in the present study: denser particles are transported significantly farther by cavitation-induced microstreaming than identically-sized particles of lower density. Specifically, in in vitro tests using a tumour-mimicking flow-channel phantom model and in in vivo experiments using tumour bearing mice, Ad5–AuPEG was delivered farther from vessels in response to ultrasound induced cavitation than either naked Ad5 or polymer-coated Ad5. The enhancements in stealthing and improvements in response to ultrasound provided by this strategy enabled up to 12% (S.D. 0.97) of the injected dose to be deposited in the tumour, compared to just 0.12% (S.D. 0.05) for Ad5 without ultrasound (p < 0.001). Consequently, in a survival study, mice treated with Ad5–AuPEG with focussed ultrasound had the slowest tumour growth and longest survival rate when compared to mice treated with Ad5 alone, Ad5–AuPEG alone, or Ad5 with focussed ultrasound. These results provide compelling evidence that the combination of focussed ultrasound with density-augmented stealthed Ad5 results in improved delivery to tumours and therapeutic efficacy. This combination of ultrasound with particle modification for optimal cavitation-mediated delivery has the potential to be applied to a broad range of anti-cancer nano-medicines and therapeutics to augment their bio-availability for improved cancer treatment.

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.

Benzylic fluorides are attractive target molecules for medicinal chemistry, agrochemicals and materials chemistry. The enantioselective synthesis of benzylic fluorides is challenging and few general methods exist. This thesis describes several approaches to the synthesis of benzylic fluoride targets, including enantioselective processes. Chapter 1: Reviews the properties, uses and synthetic approaches to fluorinated molecules, with a particular focus on benzylic fluorides and enantioselective syntheses. Chapter 2: Describes the fluorination cyclisation of prochiral indole precursors. The use of catalytic amounts of a bis-cinchona alkaloid gave good enantioselectivities for the cyclisation. Alcohol, tosylamine, amide and carbamate pendant nucleophiles all cyclised successfully to give quaternary benzylic fluorides in moderate yields and with enantioselectivities up to 92%. The substrate scope of the reaction is described, as well as methodology for deprotection of cyclised nitrogen nucleophiles. Chapter 3: Details an investigation of the Pd catalysed substitution of polycyclic benzylic fluorides by a range of nucleophiles and their relative reactivity in comparison to oxygen leaving groups. Modification of the methodology to enable reaction of monocyclic substrate substitution was enabled by the use of a protic solvent. Chemoselective reaction conditions were identified for selective reaction of Bn-F or Ar-Cl bonds and comparative reactivity studies were undertaken. The feasibility of Pd(0)/(II) catalysed nucleophilic C-F bond formation was examined. Chapter 4: The development of the defluorination methodology from Chapter 3 for secondary substrates is described. The stereochemical course of defluorination was probed, showing that displacement of fluoride is mechanistically similar to that of oxygen leaving groups. A kinetic resolution with a low selectivity was developed for access to enantioenriched benzylic fluorides.

Two photon absorption (TPA) is the near simultaneous absorption of two photons of light to achieve an electronically excited state. It has led to huge advances in microscopy and microfabrication due to its quadratic dependence on the local light intensity. This thesis describes the design, synthesis and application of dyes with strong TPA properties, and as such is divided into three chapters. The first introduces the theory and measurement of TPA as well as structure-property relationships known to maximise the efficiency of TPA. The subsequent chapters present explorations of the application of these dyes in biological applications; namely two-photon uncaging and two-photon photodynamic therapy. A recurring theme in my research is the discussion and evaluation of strategies for improving the compatibility of organic macromolecules with biological systems. Uncaging is the use of photolysis to achieve a rapid increase in the local concentration of a physiologically active species via a photoremovable protecting groups. Photoremovable protecting groups are covalently attached to the physiologically active species, thus rendering it inactive. At the desired time and location, a light dose releases the molecule in its active form. There are many compounds known to uncage following photoexcitation, but there are few examples of caging groups which exhibit both strong two-photon absorption properties and highly efficient uncaging. Chapter 2 discusses the rational design of such groups through the development of a new mechanism for uncaging, in which a photoinduced electron transfer (PeT) between a two-photon-excited electron donor and an electron acceptor/release group drives the uncaging event. Photodynamic therapy (PDT) is a treatment for neoplastic disorders such as cancer in which localised cell death is induced through photoexcitation of a sensitiser. Following light absorption, the photosensitiser enters a relatively long-lived excited state which reacts with cellular oxygen to produce its highly cytotoxic singlet form. The main challenges of the field are to achieve deep penetration of light into tissue and to reduce coincident damage to unaffected tissue by light scattering during irradiation. In 2008, the Anderson group reported the development of PDT photosensitisers with highly efficient two-photon absorption as well as high singlet oxygen quantum yields. Chapter 3 discusses strategies for improving the pharmacokinetics and defining the sub-cellular localisation of these photosensitisers.

The development of organic-inorganic hybrid materials is of great interest in thermoelectrics for its potential to combine the desirable characteristics of both classes of materials. Thermoelectric materials must combine low thermal conductivity with high electrical conductivity, but in most materials, thermal and electrical conductivity are closely related and positively correlated. By combining the low thermal conductivity, flexibility, facile processing, and low cost of organic components with the high electrical conductivity and stability of inorganic components, materials with beneficial thermoelectric properties may be realized. Here, we describe the synthesis and characterization of anthracene-containing organic-inorganic hybrid materials for thermoelectric purposes. Specifically, POSS-ANT was synthesized when aminopropylisobutyl-POSS was functionalized with a single anthracene unit via DCC-mediated amide formation. Acrylate-POSS was functionalized with multiple anthracene units in a Heck coupling reaction to synthesize System 1. System 2 was developed through a two-step synthetic process. In the first reaction, (3- acryloxypropyl)methyl dimethyoxy silane was functionalized with anthracene at the 9- position through a Heck coupling reaction. The second reaction was a base-catalyzed solgel process to form polymeric nanoparticles. Finally, System 3 was synthesized through a similar process to System 2, though polymers formed in the initial step. The System 3 precursor was to be developed through a potassium carbonate-catalyzed ether synthesis from 3-(bromopropyl)trimethoxysilane and 9-anthracene methanol, followed by a basecatalyzed sol-gel process to form nanoparticles. The precursor was never isolated because of premature polymerization during the precursor synthesis step, and polymeric nanoparticles were obtained for System 3 during the sol-gel process. These materials were characterized by TEM to reveal the nanostructures that formed upon evaporation from solution. Future work will focus on the characterization of thermoelectric parameters and incorporation into thermoelectric devices.

FLUORINATED ARENE, IMIDE AND LACTAM-FUNCTIONALIZED DONOR ACCEPTOR CONJUGATED POLYMERS: SYNTHESIS, STRUCTURE-PROPERTY AND DEVICE STUDIES After the discovery of doped polyacetylene, organic semiconductor materials are widely studied as high impending active components in consumer electronics. They have received substantial consideration due to their potential for structural tailoring, low cost, large area and mechanically flexible alternatives to common inorganic semiconductors. To acquire maximum use of these materials, it is essential to get a strong idea about their chemical and physical nature. Material chemist has an enormous role to play in this novel area, including development of efficient synthetic methodologies and control the molecular self-assembly and (opto)-electronic properties. The body of this thesis mainly focuses on the substituent effects: how different substituent’s affect the (opto)-electronic properties of the donor-acceptor (D-A) conjugated polymers. The main priority goes to understand, how different alkyl substituent effect to the polymer solubility, crystallinity, thermal properties (eg: glass transition temperature) and morphological order. Three classes of D-A systems were extensively studied in this work. The second chapter mainly focuses on the synthesis and structure-property study of fluorinated arene (TFB) base polymers. Here we used commercially available 1,4-dibromo-2,3,5,6-tetrafluorobenzene (TFB) as the acceptor material and prepare several polymers using 3,3’-dialkyl(3,3’-R2T2) or 3,3’-dialkoxy bithiophene (3,3’-RO2T2) units as electron donors. A detail study was done using 3,3’-bithiophene donor units incorporating branched alkoxy-functionalities by systematic variation of branching position and chain length. The study allowed disentangling the branching effects on (i) aggregation tendency, intermolecular arrangement, (iii) solid state optical energy gaps, and (iv) electronic properties in an overall consistent picture, which might guide future polymer synthesis towards optimized materials for opto-electronic applications. The third chapter mainly focused on the structure-property study of imide functionalized D-A polymers. Here we used thiophene-imide (TPD) as the acceptor moiety and prepare several D-A polymers by varying the donor units. When selecting the donor units, more priority goes to the fused ring systems. One main reason to use imide functionality is due to the, open position of the imide nitrogen, which provides an attaching position to alkyl substituent. Through this we can easily manipulate solubility and solid state packing arrangement. Also these imide acceptors have low-lying LUMOs due to their electron deficient nature and this will allow tuning the optical energy gap by careful choice of donor materials with different electron donating ability. The fourth chapter mainly contribute to the synthesis and structure property study of a completely novel electron acceptor moiety consist of a unsaturated pyrrolidinone unit known as Pechmann dye (PD) core. Pechmann dyes are closely related to the Indigo family. This can refer as 3-butenolide dimer connected via an alkene bridge, containing a benzene ring at the 5 and 5’ positions of the lactone rings. We have prepared several D-A polymers using this PD system with benzodithiophene (BDT) as the donor unit. Different to common D-A polymers the HOMO and LUMO of the PD acceptor moiety are energetically located within the gap of the BDT, so that the electronic and optical properties (HOMO-LUMO transition) are dictated by the PD properties. The promising electronic properties, band gaps, high absorption coefficients and broad absorption suggest this new D-A polymers as an interesting donor material for organic solar cell (OSC) applications.

The study of the biosynthetic logic of natural products has established itself to be one of the more exciting areas of research and have become an important part of modern drug discovery and development efforts. Therefore, understanding the pathway and the chemical mechanism of the biosynthesis of natural products is important in that knowledge on these processes can be applied for combinatorial biosynthesis to generate new natural product derivatives with enhanced biological activities. In addition to the practical value, a lot of unprecedented chemical mechanisms can be found in the enzymes involved therein, which will significantly advance our understanding of enzyme catalysis. The works described in this dissertation focus on elucidating the chemical mechanism of a number of enzymes involved in natural product biosynthesis by utilizing the versatility of synthetic chemistry to prepare enzyme substrates and mechanistic probes. First, SpnF and SpnL responsible for constructing the tetracyclic architecture of spinosyn A have been investigated. In vitro assay revealed the importance of the highly conjugated system for the [4+2]cycloaddition catalyzed by SpnF. Biochemical studies strongly suggest that SpnL employs the Rauhut-Currier mechanism for the second cyclization step in the biosynthesis of spinosyn A. It was also demonstrated that SpnL requires SAM for its activity. Second, a radical SAM enzyme DesII involved in the desosamine pathway has been investigated. It has been demonstrated that DesII can catalyze the dehydrogenation of TDP-D-quinovose as well as the deamination of the natural substrate, which makes DesII unique among radical SAM enzymes. In vitro assays revealed that DesII requires stoichiometric amount of SAM, which. EPR study firmly established the intermediacy of a C-3 radical in the DesII-catalyzed dehydrogenation of TDP-D-quinovose. Finally, the chemical mechanism of AXS responsible for the biosynthesis of UDP-apiose has been investigated. In vitro activity assay using UDP-2F-glucuronic acid showed that the analog is a competitive inhibitor of AXS. A coupled assay strategy was also developed to investigate the chemical mechanism of AXS in the reverse direction. In addition, the stereospecificity of two separate hydride transfer steps of AXS reaction has been firmly established. / text

In this work, a new methodology for the synthesis of a number of silylated bicyclic dienes has been reported. These bicyclic dienes allowed access to a variety of enones and phenols in 2 further steps. The stabilities and reactivities of different dialkylisopropoxy silanes have been evaluated,revealing relative instability of the dimethylisopropoxy silyl group towards chromatography. When using the analogous diethylisopropoxy silyl group instead, the products showed greater stability towards chromatography, however a higher temperature was necessary to oxidise the more sterically hindered silyl group to the desired hydroxyl moiety. A powerful cascade cyclisation for the synthesis of the CDE-core of rubriflordilactone A was then demonstrated and was successfully used for the synthesis of two systems, 284 and 333. The phenolic oxygen has been successfully installed by oxidation of a dialkylisopropoxy silane. The synthesis of these ring systems provides a solid foundation for the completion of the total synthesis of rubriflordilactone A. Finally the synthesis of suitable diynes 405 for the synthesis of the acyclic precursor of the cyclisation has been achieved. The stabilities of theses silanes towards a range of reaction have been demonstrated.

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.