Phosphines have number useful properties most notably its nucleophilicity and high oxophilicity which allows it to be an effective activator and reducing agent of oxygen containing compounds such as alcohols and carbonyls. These properties allow phosphine to participate in a number of widely used reactions such as the Wittig, Appel, Mitsunobu and Staudinger reactions. DMAP on the other hand has been used as an effective acylation catalyst and has been incorporated in to the widely utilised Steglich esterification. This thesis details the development of a new three component reagent system consisting of PPh3, I2 and DMAP. This new system takes advantage of both the initial activation properties of Ph3P-I2 adduct formed from the combination of phosphine and iodine, as well as the nucleophilic catalytic properties of DMAP. This was initially developed as a new method for the direct coupling of carboxylic acids with alcohols and amines. For this purpose the new reagent system was highly successful resulting in good-excellent yields of both esters and amides in an extremely rapid reaction. The mechanism of this acylation process consists of two distinct stages; the first involves initial activation of the carboxylic acid the second a DMAP catalytic cycle. This led to the development of a catalytic system in terms of the DMAP but still offered significantly faster reaction times compared to other common mild reaction condition methods. The reagent system was also applied to the activation and further reactivity of oximes with the intramolecular cyclisation of 2-hydroxy-benzaldehyde oximes resulting in rapid formation of the corresponding 1,2-benzisoxazoles. The activation of oximes also led to the formation of novel DMAP-hydrazones which could undergo further reactivity with methoxide anion to form imidates. Benzaldehyde oxime did not produce a stable DMAP-hydrazone and instead undergo elimination reaction straight to the benzonitrile. Finally, the reagent system was applied to the formation of phosphazenes. This produced a range of aryl-phosphazene in high yields and fast reaction times. A one-pot urea system was then developed producing both asymmetrical and symmetrical ureas in good yield and under mild reaction conditions.

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[For full abstract, with illustrations, see pdf file]. Part 1. Concise Synthesis of Highly Substituted Isoquinolin-1(2H)-ones via IMDA The primary goal of this DPhil research project was to further investigate the mechanism of a novel thermally activated cyclisation reaction discovered within the Parsons' research group. Through the synthesis and cyclisation of the substituted pyrrole rings 2.38a-c we have investigated the mechanism and increased the scope of the cyclisation reaction. We have also developed a robust route to advanced intermediate 2.10 in the synthesis of hymenialdisine 2.1. Part 2. Investigation and Development of a Novel Cascade Reaction The aim of this DPhil research project was to devise and execute a series of experiments to gain a better mechanistic understanding of the novel thermal cyclisation, discovered within the Parsons' research group. To further investigate the mechanism and scope of the cyclisation, the model system 2.1 was initially selected. Through extensive modification and manipulation of the cyclisation precursor 2.1, we have increased the scope of the cyclisation and postulated a reaction pathway. During these studies remarkable transformation of ketone 2.81 to alkyne 2.82 was also observed. The repeatability of the above reactions was also investigated by synthesising various analogues.

Organometallic complexes incorporating low-coordinate phosphorus have been synthesised with a view to better understanding the physical and electronic properties and reactivity of such compounds, along with synthetic methodologies to furnish them. Novel ruthenium complexes of the type [Ru(CO){κ3-N,C,P-P(PzR′R″)CH(R)}(PPh3)2] (Pz = pyrazolyl) have been synthesised via addition of pyrazolates to complexes of the type RuCl(CO)(PPh3)2(P=CHR). The general structure of the resultant products was elucidated, with a Ru–C–P three-membered ring and bridging pyrazolyl unit confirmed by heteronuclear NMR spectroscopy and X-ray diffraction studies. The nature of the R groups was found to affect the nature of the P–C bond, which lies between a typical single and double P–C bond. The formation of these complexes demonstrated for the first time the ambiphilic nature of the parent ruthenaphosphaalkenyl systems, which was explored by both DFT calculations and their reactivity upon addition of various nucleophiles and electrophiles. A range of extended π-systems have been sought for their potential utility in the synthesis of phosphapolyynyl fragments. Complexes of the type [Tp′M(CO)2(≡CC≡CR)] were pursued, (where R = CO2R') via a variety of synthetic protocols including traditional Sonogashira methodologies, in situ formation of the propargylidyne moiety (M≡C≡C–) and cross-coupling reactions between a terminal alkyne and Au(PPh3)-terminated propargylidynes. Additionally, a range of metal–alkynyl complexes were pursued via vinylidene/alkyne tautomerism reactions. In particular, the successful synthesis of a range of complexes of the type [RuCl(dppe)2(=CH=CR)][OTf] and [RuCl(dppe)2(C≡CR)] is discussed with characterization of the novel compounds by IR and heteronuclear NMR spectroscopies, mass spectrometry and X-ray diffraction studies. Finally, synthesis of a novel series of cyaphide-containing compounds is demonstrated. The physical and chemical properties of this elusive ligand are discussed and the electronic properties studied computationally. Attempts were also made to furnish complexes with η1-coordination of the phosphorus lone pair to a second metal centre, i.e. complexes of the type [(dppe)2(RC≡C)Ru–C≡P–MLn].

Chapter 1: Gives the reader a background on carbenes paying particular attention to N-heterocyclic carbenes (NHCs). The chapter describes NHC's electronic and structural properties and their behaviour as ligands. The recent usage of NHC-palladium complexes as catalysts for cross-coupling reactions is explored. Chapter 2: Provides a background on NHC-palladium complexes bearing N-donors as throwaway ligands, highlighting the importance of throw-away ligands on catalytic activity. The chapter describes the preparation of a number of novel NHC-palladium complexes bearing throw-away ligands and the activity of (IPr*)PdCl2(TEA) in Buchwald-Hartwig aminations is explored. Chapter 3: Provides a background on the Mizoroki Heck reaction, focusing on the importance of charged intermediates in the process. Then reviews the current development of anionic NHC-palladium complexes in the literature. An account of the discovery and preparation of novel [(NHC)PdCl3[TBA] complexes and the catalytic activity of [(SIPr)PdCl3[TBA] in Mizoroki-Heck coupling reactions is given. A plausible Amotore-Jutand type mechanism is proposed which is supported by DFT calculations provided by research collaborators. Chapter 4: Provides a background on C-H activation reactions catalysed by palladium compounds with particular focus on acetoxylation reactions. The chapter describes the synthesis of [(NHC)PdCl2X][Y] complexes including the development of [(IMes)PdCl2OAc][TBA] and its performance in acetoxylation reactions. A proposed mechanism for the reaction of [(IMes)PdCl2OAc][TBA] is discussed, using experimental observations.

The cyclooctane sesquiterpene lactone, asteriscanolide 1, has attracted considerable interest in the chemical literature since San Feliciano and colleagues first reported its isolation from Asteriscus aquaticus L. To date, no pharmaceutical applications have been found for 1. However, the challenge offered by the construction of its cyclooctanoid core represents an important target for the development of methods directed towards the preparation of other related eight-membered ring-containing terpenoids with more interesting biological properties. This thesis illustrates an investigation into the total synthesis of natural product asteriscanolide 1. Following up on the previous work established by Marsh,2 an approach to 1 was designed, seeking to build a suitable framework for an intramolecular [3 + 2] nitrile oxide-olefin cycloaddition (INOC) as the pivotal synthetic step to assemble the medium-sized ring. The INOC strategy was extensively investigated. As this remained unsuccessful, the investigation was extended to various other intramolecular strategies, including intramolecular [3 + 2] silyl nitronate-olefin cycloaddition (ISOC), samarium(II) iodide-mediated cyclisation, radical-mediated cyclisation, and nitronate anion-epoxide cyclisation, which identified certain limitations that would hinder further progress. To this end, a second generation towards 1 incorporating ring-closing metathesis (RCM) and intermolecular nitronate anion-epoxide addition was designed. A detail discussion of the results is contained within.

For genome integrity, adequate levels of deoxyribonucleotide (dNTPs) are essential to maintain faithful DNA replication and repair via the regulation of ribonucleotide reductase (RNR). In the fission yeast, RNR is composed of two subunits: Cdc22 and Suc22. The importance of Spd1 (RNR inhibitor) in Cdc22-Suc22 complex formation has been demonstrated by imaging of S. pombe containing fluorescent protein (FP) modified RNR subunit proteins in the presence of Spd1 and absence of Spd1 cells using confocal laser scanning microscopy. To investigate further the significant role of Spd1 in the regulation of RNR, 41 mutants created by Nestoras group. We used fluorescence resonance energy transfer (FRET) by acceptor photobleaching to investigate the RNR subunit interaction and provide evidence for a new model for the role of Spd1 in RNR regulation. Different treatments such as HU, 4NQO and heat shock have been used to investigate the effect of radical scavenging on the inhibition of RNR activity and induced DNA damage on S. pombe cell viability to elucidate further the role of Spd1 in the regulation of RNR. Finally a novel imaging technique, near-total internal reflection microscopy has been developed and applied with dual-view detection. The technique has been applied to image, simultaneously, the donor CFP and acceptor YFP channels of the FP-tagged RNR complex in the wild-type S. pombe cells and perform FRET measurements that are consistent with the confocal fluorescence results. In conclusion, a new hypothesis for the role of Spd1 has been drawn from the results, which is that the inhibitory role of Spd1 mediates the Suc22-Cdc22 (R1-R2) interaction to form a FRET competent but immature and inactive RNR complex, while with Spd1 deleted RNR is clearly active in a conformation that lacks FRET.

Graphite is widely used in modern industry, particularly in nuclear power generation in the UK. Understanding its formation is important for economical and safety reasons. The process to turn carbon materials into graphite by heat treatment is called the graphitisation process. It is the transformation of amorphous carbon, through a 2D turbostratic carbon intermediate, into 3D ordered layers of graphite. While many manufacturing processes have been established and many authors have contributed to understanding the important stages of graphitisation, the chemistry involved is not fully understood. It appears that impurities found in precursors can have a direct impact on the final graphite obtained. The following work is an investigation of the role played by these heteroatoms during the graphitisation process. Using density functional theory (DFT), calculations on possible mechanisms involved in the graphitisation process are investigated. However, the initial stages contain complex and poorly defined chemistry, so we have chosen to avoid this area, even though factors such as the C:H:O ratios are clearly important. Instead, this work is focussed on the latter stages of graphitisation in order to better understand the ordering processes to obtain graphite (and their inverse disordering, insofar as it is relevant to radiation damage). In this way it is still possible to invoke standard concepts in the physics and chemistry of defects in crystals. If there is too much disorder, and the system is close to amorphous in nature, complexity would overwhelm the project. The descriptions of an amorphous material with a little extra order would be much more difficult than the descriptions of a crystal with some disorder. For this reason, we have focussed on the heteroatoms which endure until the later stages of graphitisation, boron and sulphur, and also on turbostratic graphite, where calculations of interlayer separation as a function of relative rotation of a layer and of its neighbours are described. We find for sulphur that it can open up folds in graphite, forming very stable sulphur decorated edges. In dislocation terms, this could be the beginning of the dissociation of a perfect prismatic edge dislocation. An edge dislocation is described as an added half plane. If the plane is a bilayer graphene terminating in a fold, the dislocation is perfect. If the plane is a single graphene the dislocation is ‘partial'. Importantly two partial dislocations have lower elastic energy than the perfect, so dissociation is important in stabilising the structure. For boron, we show how it can pin twist boundaries, preventing slip and suggest that radiation damage can achieve the same effect through vacancies. The mechanism does not appear to involve cross-linking bonds and provides a good explanation for the variations in C44 between different graphites and different methods of measurement. Furthermore, we show that B can aid in the removal of twist boundaries by pushing up their formation energy with respect to AB graphite.

Metal-catalysed reactions are highly attractive processes due to their atom economy and open opportunities in the development of new transformations. In the introduction, the theoretical aspects of gold(I) catalysis with examples of gold(I) complexes and their transformations are described with emphasis on enantioselective synthesis. The results and discussion chapter begins with the investigations of a chirally active counterion moiety. The triflic amide moiety was found to be an efficient new counterion and provide opportunity to introduce chiral bidentate ligand on gold(I) complexes. In conclusion, a series of chiral bidentate gold(I) catalysts were synthesised and their catalytic activity demonstrated on model transformations. A number of strategies improve a bidentate ligand for gold(I) catalysts.

The discovery of the novel thermal cyclization of enediyne molecules within the Parsons group during studies directed towards the total synthesis of lactonamycin has stimulated an intense research into the cyclization of the enediynes. In this research different functionalised enediynes were synthesised to investigate:- (i) the scope and limitations of the thermal cyclization reactions, (ii) the proposed biradical mechanism for the cyclization reactions, (iii) the intermolecular trappings of the proposed biradical, and (iv) the effect of sterically demanding groups on the rate of cyclization. In the process of testing these objectives, we have been able to synthesize highly functionalised heterocyclic rings by simple thermal cyclization reactions without using any metal catalyst. We have discovered that the cyclizations may have involved free radical mechanism or an ene reaction, followed by a Diels – Alder cycloaddition reactions. Interestingly the cyclised compound 2.1 shows two stereogenic centres at C2 and C4 with an absolute configuration of R and S respectively. An in-depth exploration of the stereochemistry of these reactions may increase their application in controlling the stereochemistry of ring systems through simple metal free thermal cyclization reactions. Confirmation of the specific mechanism constitutes an ongoing research within the Parsons group. Conclusively cyclization of highly functionalised enediynes had been proved to be a versatile route to the synthesis of diverse heterocyclic compounds. The ease of cyclizations of a majority of the enediynes in this study has shown that functionalisation and diversification of the core enediyne systems could be utilized in the synthesis of pharmaceutically important antitumour drugs.