This Thesis details the development of a series of rhodium catalysed asymmetric additions to activated aldimines to give enantioenriched protected secondary amines. A particular focus has been the choice of activating group to allow deprotection of the protected amines under mild conditions, which would tolerate a wide substrate scope. Initially methyl addition to give enantioenriched arylethanamines was studied, using diphenylphosphinoyl imines, dimethylzinc as the methyl source with rhodium catalysis in the presence of a bidentate phosphine ligand. Reduction of the starting material was identified as side reaction with a Meerwein˗Verley˗Ponndorf type mechanism for the reduction being proposed. Addition of the imine to the reaction mixture via a syringe pump was found to minimise this by-product. The imine scope was tested with yields ranging from 34-73% and enantiomeric excesses from 75-93%. Subsequently, aryl additions were concentrated on using aryl boroxines and boronic acids to give enantioenriched diarylmethylamine products. Bis˗sulfamyl aldimines were identified as an overlooked substrate class for asymmetric aryl additions, which gave addition products that could be converted to free amines using mild basic aqueous conditions. The rhodium catalysed aryl boroxine addition using a chiral diene ligand was optimised after which a study into the reaction’s scope was carried out. Yields ranged from 37˗76% with diastereomeric ratios of 91:9˗>99:1 and enantiomeric excesses of 90˗>99%. Unfortunately, the unwanted meso-diastereoisomer could not be removed, leading to a lowering of enantiomeric excess after deprotection, nevertheless the free diarylmethylamine were isolated in yields of 31-99% and enantiomeric excesses of 82-97%. Leading on from this work, a novel class of N-sulfamyl aldimines were developed which could be deprotected under the same mild conditions, and would avoid the problem of the undesired meso-diastereoisomer. A scalable synthesis of these substrates was developed. However, aryl addition proved more problematic with imine hydrolysis being a major side reaction. Eventually a set of conditions were settled on and the scope investigated briefly. The yields were found to depend on the electronic character of the substrates and the ligand employed. Finally, a brief investigation into the iridium catalysed reductive coupling of these activated aldimines and alkynes to give allylic amines was carried out. However, useful conversions were not achieved, with imine and alkyne hydrogenation being competing reactions.

Chapter One describes attempts at utilising ortho-quinodimethanes in the synthesis of polycyclic ring systems, where construction of the the 1,4-elimination precursor could not be achieved. Additionally, several attempts were made to utilise the diradical behaviour which ortho-quinodimethanes are thought to possess, in similar annulative reactions. Unsuccessful attempts at generating furanyl- ,benzofuranyl- and benzenoid- derived diradical species, however, brought these particular studies to an end. The remainder of this thesis is devoted to studies that were made into developing new uses for benzynes in organic synthesis. Their discovery, general history and subsequent application is divided for convenience into three chapters; Chapter Two covers the discovery of these classic species, and approaches to these species which have been improved from the highly impractical methods which were originally developed. Chapters Three and Four give an overall review of the past and recently reported applications of benzynes in organic synthesis; Chapter Three covers the use of benzynes in nucleophilic couplings, whilst Chapter Four covers their application in cycloaddition reactions. Chapter Five describes preliminary studies that were made into developing new routes to polycyclic ring systems via the intramolecular Diels-Alder trapping of benzynes. After unsuccessful attempts at utilising the anthranilic acid route to benzynes, the remainder of the studies were concentrated on utilising the 1-aminobenzotriazole route to benzynes, a mild, efficient, yet relatively underexploited route. An improved synthesis of 7-methyl-1-aminobenzotriazole is described, as is the functionalisation of the methyl substitutent in the BOC-derivative via the formation of the dianion. However, 1,3-diene incorporation via this route was unsuccessful, due to difficulties in preparing suitable l,3-dienes. Chapter Six describes attempts at applying the metallation chemistry of BOC-protected 7-methyl-l-aminobenzotriazole to the synthesis of 2-substituted dihydrobenzofurans (n = 0) and chromans (n = 1) via the intramolecular trapping of benzynes by flanking hydroxyl functions, which were incorporated via the condensation of the dianion with aldehydes and epoxides respectively. Using H-bromosuccinimide as the reagent for benzyne generation, benzo-fused heterocycles were successfully generated in moderate yields, with bromine incorporation also being achieved (X =Br). Using lead (1V) acetate, simple dihydrobenzofurans (X=H) were obtaine4 in better yields. Excellent yields, in some cases virtually quantitative, were obtained using N-iodosuccinimide as the reagent, with the iodine substituent (X = I) being incorporated. The additional bonus of having the iodine substituent was highlighted by utilising iododihydrobenzofurans and chromans in subsequent coupling reactions. Overall, this thesis describes the advances made in increasing the role of benzynes in synthetic organic chemistry, providing novel metalation chemistry on the aminobenzotriazole ring system, and a novel annulative approach to valuable synthetic and potentially active species such as dihydrobenzofurans and chromans. Above all, this work illustrates that under certain suitable conditions, benzynes can serve as extremely efficient reactive intermediates in heterocyclic annulations.

The work presented in this thesis describes several new and novel radical macrocyclisation-transannulation cascade reactions directed towards the single step construction of ring-D aromatic steroid ring systems. The introduction introduces the steroid class of natural products, their biosynthesis and previous literature strategies towards their construction. The ring-D aromatic steroids, together with their possible total synthesis via a novel freeradical cascade strategy, are then discussed. The results and discussion chapter summarises the radical cascade strategies towards ring-D aromatic steroid ring systems that have been investigated. It is divided into two sections: Part 1 describes the evolution of our current radical cascade approaches relating to the iododienynone precursors 117a-d (Schemes 26-29). We proposed that the precursors 117a-d would lead to the 6,6,6,6 ring-D aromatic steroid ring system (such as that found in the natural product nicandrenone 67), via a cascade of radical ring-forming reactions. However, the proposed radical cascade from the Z-iododienynones 117a,c halted at the macrocyclisation stage producing the macrocycles 137a,b, whilst a radical cascade from the E-iododienynones 117b,d instead led to the unusual bridged tricyclic structures 148a,b and 155 (depending on whether benzene or heptane was used as the solvent), rather than the anticipated linear tetracycles 116a,b. A rationale for these outcomes is given. Part 2 discusses an approach to 6,6,5,6 ring-D aromatic steroids via a macrocyclisation-transannulation radical cascade from the vinylcyclopropyl seleno ester precursor 193. A synthesis of the radical precursor 193 was first examined using a novel aryl-vinylcyclopropane Stille reaction coupling protocol (the development of which is discussed), as well as several alternative routes. A practical, albeit more lengthy, synthesis of the precursor 193, was then developed. The proposed radical cascade from the vinylcyclopropyl seleno ester 193 led to the desired ring-D aromatic steroid ring system 194a (with the correct trans, anti, trans stereochemistry) together with the methyl epimer 194b. Also isolated from the product mixture was the macrocycle 232, together with the products of reduction and decarbonylation of the acyl radical intermediate 235, i.e. 231 and 230, and the dioxolane 233. The experimental section describes all the procedures used to synthesise the precursor compounds 117a-d and 193 and the products of their radical mediated cascade cyclisations. Full NMR, and other spectroscopic data, alongside mass spectrometry data are also given. The appendices include some relevant X-ray and NMR spectroscopic details.

This thesis details the syntheses of catalysts and their applications in asymmetric reactions. Initially, the project focused on phase transfer catalysts; quaternary phosphonium salts derived from diethyl tartrate or from commercially available phosphorus compounds and their use primarily in the alkylation of N,N-diphenyl methylene glycine tert-butyl ester. Although some of the salts showed the ability to catalyse the alkylation reaction, all products obtained were racemic. The project then focused on bifunctional organocatalysis; catalysts derived from isoquinoline and BINOL were studied in Michael addition reactions between ethyl nitropropionate and MVK. Possible evidence for a bifunctional effect was observed, however, all Michael addition products obtained were racemic. Finally, an examination of proline-derived diamines as catalysts for aldol reactions is reported. Reversing the positions of the acid and base moieties of the catalyst results in the formation of the opposite enantiomer of the aldol product. In addition, these proline-derived diamines, along with two catalysts derived from a biarylazepine, were tested in a series of asymmetric reactions, with the best enantioselectivities (up to 90% ee) obtained in the conjugate addition between enones and nitro-containing compounds.

Porous graphitic carbon has been developed as a high-performance liquid chromatography stationary phase over the past 30 years. The evolution of PGC as a stationary phase was motivated by the desire to find a substitute for reversed-phase silica gel based materials in areas where these materials are inadequate (e.g. extremes of pH). However, PGC possesses a number of chromatographic properties which are thus far largely unexplained and differ from traditional silica-based reversed-phase supports. The retention mechanisms of mono-substituted benzenes and biphenyls on porous graphitic carbon stationary phase were investigated using chromatographic and computational methods. The studies on a range of n-alkylbenzene analytes demonstrated that retention on PGC was found to be greatly influenced by hydrophobic parameters such as Hansch-Fujita and log P and that PGC has superior selectivity for isomers of amylbenzene in terms of its chromatographic retention properties when compared to octadecyl-silica (ODS). Molecular modelling of the alkylbenzene analytes indicated that the interaction between toluene and ethylbenzene and PGC was in a cofacial geometry whereas that between the longer chain alkylbenzene was of a face-edge (perpendicular) nature. This was confirmed by the relatively poor retention of highly branched amylbenzenes. Benzene derivatives demonstrated retention properties on PGC such that the logarithm of the retention factor (log kw) was found to be closely correlated with a combination of the Hansch-Fujita parameter and Lowest Unoccupied Molecular Orbital Energy (ELUMO) of the analytes. This was augmented by similar correlations between log kw and Hansch-Fujita, ELUMO and mean polarisability. Chromatographic studies of the benzene derivatives on PGC gave enhanced retention for polar and charged analytes and reduced retention for the alkyl substituted benzenes used in this study when compared with ODS. Preliminary semi-empirical calculations of the interaction between the analyte and the PGC stationary phase for benzene derivatives showed qualitative relationships between the energy of interaction and log kw for closely related benzene derivatives. The retention of mono-substituted biphenyl compounds was found to be greater on PGC than on ODS stationary phase, with the strongest retention found for highly conjugated species (such as 4-phenylcinnamic acid and 4-vinylbiphenyl). This observation supports the hypothesis that the presence of a planar moiety in a molecule imparts an increased retention when using PGC as the stationary phase. PGC was found to be more retentive for the separation of both polar and non-polar biphenyl derivatives. Semi-empirical calculations suggested that the ease with which an analyte could attain a planar geometry was an important factor influencing the retention of biphenyl derivatives on PGC.

This thesis describes the development of a novel route for preparation of hyperbranched polymers. The aim is to produce hyperbranched polymers via enhanced deactivation ATRP without crosslinking even at high conversion. Our strategy will be to use excess Cu(I1) to control gelation, so called enhanced deactivation ATRP. Chapter I provides a general introduction to the basic concepts of living polymerisation and dendritic polymers. Chapter 2 covers the hyperbranched homopolymer prepared by enhanced deactivation ATRP. The hyperbranched poly(divinylbenzene) and poly(ethylene glycol dimethacrylate) are synthesised by enhanced deactivation ATRP in a concentrated system. Chapter 3 focuses on the synthesis of hyperbranched copolymer via the enhanced deactivation ATRP. Also. the interesting potential applications, for example dye encapsulation and viscosity control are explored in this chapter. Chapter 4 demonstrates two routes to prepare novel core-shell polymers. First, the hyperbranched polyDYB was used as a core to produce hyperbranched core-shell polymers. Second, a novel hyperbranched polymer which combines ring open polymerisation and RAFT technique was developed. Chapter 5 summarises all the research presented in this thesis. Moreover, some possible research routes for the investigation in the future are listed in this part.

In Chapter one a review of the l-aza-Diels-Alder reaction is presented. The hetero Diels-Alder reaction of l-aza-l,3-butadienes with both alkene and alkyne dienophiles has been shown to be an efficient and versatile method for the preparation of a large range of nitrogen-containing six-membered heterocycles. The use of electron-rich 1- azadienes in the normal electron-demand Diels-Alder reaction is primarily examined, followed by a brief look at the synthetic applications of the inverse electron-demand process. In Chapter two the intermolecular hetero-Diels-Alder cyc1oadditions of 3-siloxy-1aza-1,3-butadienes with electron-deficient dienophiles is presented as an efficient route to tri- and tetra-substituted pyridine core of the thiopeptide antibiotic nosiheptide. A series of alpha, beta-unsaturated oximes and hydrazones were prepared and subsequently shown to participate readily in the hetero-Diels-Alder reaction with dimethyl acetylenedicarboxylate. In Chapter three, the intramolecular Diels-Alder reaction is presented as a versatile method for the preparation of chromeno[ c ]pyridines. First a series of model systems was prepared and shown to undergo thermally induced intramolecular cyc1oaddition. This methodology was then utilised in the rapid preparation of the penta-substituted pyridine core of the anti tumour antibiotic streptonigrin. Chapter four contains experimental procedures for all of the work detailed above.

The aim of this work was to analyse the surface of biomedically relevant polymers with a range of surface sensitive techniques both in the interest of improving our knowledge of such polymeric delivery systems and the techniques used. Specifically time of flight- secondary ion mass spectrometry (ToF-SIMS) was a focus of this work complemented by a range of supportive surface and bulk analytical techniques. The new technique of X-ray photoelectron spectroscopy (XPS) depth profiling of organics was scrutinised through its application to a thin film blend of poly(l-lactic acid) (PLA) and the analgesic codeine in Chapter 3. Surface depletion of drug was observed in these films and was quantified for the first time with XPS. A multilayer model was created containing alternating layers of the codeine/PLA blend and biodegradable hydroxypropyl methylcellulose (HPMC) to test the application of SIMS to such formulations described in Chapter 4. Codeine was found to diffuse into a HPMC layer below it but not above due to a solubilisation of the bottom HPMC layer by the chloroform allowing small mobile codeine molecules to penetrate the layer below where the larger PLA chains were unable to. Interface widths observed when casting HPMC above a codeine/PLA layer was far broader than those observed when reversing layer order. This observation suggests HPMC is more sensitive to ion beam induced damage effects than PLA. The detailed characterisation of protein drug loaded polymeric microspheres was undertaken described in Chapter 5 revealing the discontinuous presence of surfactant at the surface and allowed for inferences to be made as to how the production process could be amended to tailor desired attributes. The work describes the thorough characterisation of biomedically relevant polymers with an array of surface sensitive techniques in the interest of improving the future description of such increasingly important formulations.

This thesis is concerned with the synthesis of allenic compounds and their gold-catalyzed isomerization reactions. Its general aim is the development of new reaction methodologies within these topics and the work has been published in two separate articles. After an introductory chapter (covering relevant literature upto 2010) three separate projects are discussed: 1. Development of tandem enzyme/gold-catalyzed reaction where lipase-catalyzed kinetic resolution of alpha-allenic acetates [R1 2CCCH(CHR2OAc)] (R1,R2 = alkyl) leads to the formation of alpha-hydroxyallenes with 86-99% ee and this transformation is followed by the cycloisomerization of the alpha-hydroxyallenes to the corresponding 2,5-dihydrofurans in a one-pot reaction. It is found that the two transformations work well in one pot except in the case where R2 is branched, which are not hydrolysed. 2. A new approach is developed for the synthesis of allenyl acetates [Ar(R1)CCCH(O2CR2)] (R1 = alkyl, R2 = Me, Ph, t-Bu) using cuprate-mediated SN2’nucleophilic substitution to propargylic dicarboxylates. The reaction was successfull with a range of substrates (11 examples). Investigation on a catalytic variant for the synthesis of the above allenyl acetates. Nickel-catalyzed SN2’ nucleophilic substitution to propargylic dicarboxylates gives the highest selectivity of the desired allenic products but the transformation is not very high-yielding. Attempts towards an asymmetric reaction are thwarted by low enantioselectivities (<22% ee). 3. Comparing the reactivity of propargylic acetates and allenyl acetates (prepared in Sections 2-3) in the gold-catalyzed synthesis of indenes. It was discovered that the allenyl acetates prepared earlier yield indenes with up to quantitative yields and high chemoselectivity, whereas propargylic acetates with terminal a alkyne group only yielded a mixture of cyclization and elimination products.

This thesis details the synthesis of highly C02-soluble hydrocarbon stabilisers using reversible addition fragmentation chain transfer (RAFT) polymerisation techniques, and their application in the dispersion polymerisation of N-vinyl pyrrolidone (NVP) in supercritical carbon dioxide (scC02). Chapter 1 outlines the key themes explored throughout the thesis. This introductory chapter focuses on the RAFT polymerisation process, the use of scC02 as an alternative solvent for polymerisation, and the process of dispersion polymerisation, including the types of stabilisers employed in such reactions. In Chapter 2, the equipment and characterisation techniques are detailed. The high pressure vessels used extensively throughout the thesis are described, including the high pressure variable volume view cell and the 60 ml clamp-sealed autoclave. Polymer characterisation techniques such as scanning electron microscopy (SEM), nuclear magnetic resonance (NMR) and gel permeation chromatography (OPC) are also considered. Chapter 3 is the first of three research chapters, and investigates the synthesis of hydrocarbon stabilisers composed of the monomers of vinyl acetate (V Ac) and vinyl pivalate (VPi) using xanthate-mediated RAFT polymerisation. The phase behaviour of a range of stabilisers in scC02 is determined through cloud point measurements using a high pressure variable volume view cell. The impact of adjustments to parameters such as polymer composition and molecular weight on CO2-solubility are considered. Chapter 4 details the application of the homopolymers and statistical copolymers of V Ac and VPi synthesised in the previous chapter. The polymers are employed as stabilisers in the dispersion polymerisation of NVP in SCC02. A range of stabilisers are considered and the resulting poly(vinyl pyrrolidone) (PNVP) products compared using NMR and SEM to gauge the effect on particle morphology. Chapter 5 describes the extension of the research to consider the impact of changes to the hydrocarbon stabiliser architecture. A series of block copolymer structures are prepared, and the phase behaviour and stabilising ability of these materials in scC02 is considered. Additionally, modification of the alpha- and omega-end of the RAFT-terminated polymers is considered through use of a different xanthate-based RAFT agent, and modification of the polymer post-polymerisation via radical-induced reduction. Chapter 6 describes the overall conclusions obtained from the work presented in the thesis, and also details possible avenues for further research in this area.