Chapter 1 gives an introduction to ribosomally synthesised and post-translationally modified peptides. The different classes of this group of natural products are described. Examples of linear azol(in)e-containing peptides and cyanobactins are given, along with more detail about these classes of peptides and examples of their chemical synthesis. Chapter 2 explains the importance of the natural product goadsporin 64, along with the retrosynthesis and a review of methods to synthese oxazoles, thiazoles and dehydroalanines. The first total synthesis of goadsporin 64 is then reported, demonstrating the use of rhodium catalysis to construct the four oxazole rings. Synthesis of the N-terminal fragment 78 validated methods for incorporating the sensitive enamide functionality, and removal of the necessary protecting group. These methods were then applied to the full structure to complete the total synthesis. Chapter 3 describes work carried out towards the total synthesis of the wewakazole natural products, again using rhodium catalysis methodology. The structures of wewakazole A 65 and wewakazole B 66 share a largely peptidic fragment 267, differing only by the bis-oxazole fragments 266 and 268, allowing the synthesis of two natural products via three main fragments. Reported herein is the synthesis of the bis-oxazole fragments 266 and 268 of wewakazole A 65 and B 66.

Many major advances in our fundamental chemical knowledge have emerged from novel metal-metal chemistry. Such complexes which exhibit metal-metal interactions, have provided excellent tools for developing our understanding of chemical structure and bonding, catalysis, metal surface chemistry and bioinorganic chemistry. However, whilst metal-metal bonding is now well understood in the p- and d- blocks and to some extent the s-block of the Periodic Table very little is known, in comparison, about that for the f-block and especially the actinide elements. Traditionally the chemistry of molecular f-element compounds has been dominated by the use of carbon, nitrogen, oxygen and halogen based ligands with the implementation of metal-based fragments as ligands considerably less developed. In recent years dinuclear species containing a metal-metal bond between two different transition metal centres bridged by a supporting ligand structure have rapidly been gaining interest, as they would be expected to exhibit different reactivity to those of monometallic or homobimetallic complexes. Early/late heterobimetallic complexes, featuring metal-metal interactions supported by a phosphinoamine ligand system, have received particular attention due to their two very different reaction sites, inherent bond polarity, and synergy between the two centres resulting in unique reactivity. A range of novel phosphinoamines, including MesN(H)PPh2, have been successfully synthesised to accompany the previously reported phosphinoamines DippN(H)PPh2 and MesN(H)PiPr2. All phosphinoamines were successfully deprotonated using nBuLi to afford the corresponding lithium salts as ligand transfer reagents. Reaction of uranium tetrachloride or thorium tetrachloride with three molar equivalents of either [Li(MesNPPh2)(Et2O)2] or [{LiNMes(PiPr2)(Et2O)}2] resulted in the respective tris(phosphinoamide) actinide(IV) chloride complexes [AnCl(MesNPPh2)3] and [AnCl(MesNPiPr2)3] (An = U, Th). Treatment of the tris(phosphinoamide) actinide(IV) halide complexes with Me3SiI afforded the corresponding tris(phosphinoamide) actinide(IV) iodide complexes. The installation of cobalt iodide into the coordination sphere of the uranium was achieved in the presence of zinc powder to afford the two uranium-cobalt complexes [UCl(MesNPPh2)3CoI] and [(MesNPiPr2)U(μ-X)(MesNPiPr2)2CoI] (X = 41% I, 59%Cl). [UCl(MesNPPh2)3CoI] adopts a paddle-wheel structure whereas [(MesNPiPr2)U(μ-X)(MesNPiPr2)2CoI] exhibits a structure with at best C2v symmetry and two bridging phosphinoamides and one bridging halide ligand. These structural differences confer very different magnetic behaviour. At low temperature [UCl(MesNPPh2)3CoI] can be formulated as an S = 1 spin system resulting from a combination of a magnetic singlet uranium(IV) and triplet cobalt(I). However, in contrast [(MesNPiPr2)U(μ-X)(MesNPiPr2)2CoI] is an S = 0 spin system at low temperature with antiferromagnetic exchange between uranium and cobalt proposed. Density functional theory calculations and topological bond analyses support the notion of formally dative Co → U bonds in both complexes. In an attempt to further support the claim of antiferromagnetic exchange between uranium and cobalt the thorium analogues were synthesised. To date, investigations into the respective electronic structures are still on going and conclusions about the exact nature of the cobalt centres cannot be drawn. There is however sufficient evidence which warrants further investigation that would be expected to be very detailed and that is thus unfortunately beyond the timeframe of this PhD. Reaction of the same four tris(phosphinoamide) actinide(IV) chlorides, that resulted in the synthesis of the actinide-cobalt complexes, with [Mo(MeCN)3(CO)3] in dichloromethane afforded the heterobimetallic uranium- and thorium-molybdenum complexes [AnCl(MesNPR2)2(MesNPR2{μ-NCMe})Mo(CO)3] (An = U, R = iPr; An = Th, R = iPr; An = U, R = Ph; An = Th, R = Ph). In contrast treatment of the tris(phosphinoamide) actinide(IV) iodides [IAn(MesNPiPr2)3] (An = Th, U) with [Mo(MeCN)3(CO)3] in toluene resulted in the formation of the complexes [(η2-MesNPiPr2)AnI(MesNPiPr2)({μ-NCMe}MesNPiPr2)Mo(CO)3 (An = U, Th). These compounds show unprecedented acetonitrile insertion as a bridging ligand between the actinide metal and Mo with structural analysis suggests an activation of the nitrile group. To synthesise the analogous actinide-molybdenum paddlewheel complexes to [UCl(MesNPPh2)3CoI], the appropriate tris(phosphinoamide) actinide(IV) halides were treated with [Mo(CO)3(NCMe)3] to afford the heterobimetallic uranium- and thorium-molybdenum complexes [M(X)(MesNPPh2)3Mo(CO)3] (M = U, X = Cl; M = U, X = I; M = Th, X = Cl; M = Th, X = I,). Orbital- and density-based quantum chemical calculations reveal dative MoM σ-interactions in all cases and so these complexes constitute unprecedented actinide-group 6 metal-metal bonds, where before heterobimetallic uranium-metal bonds were restricted to a few group 7-10 metals. With a synthetic route towards actinide-cobalt complexes established future work must look towards the reduction of these complexes to result in highly reactive and polarised early-late heterobimetallic compounds. The subsequent reaction of these compounds with small molecules such as CO, CO2 and H2 etc has the potential to result in novel and unusual chemistry which can help develop our fundamental understanding of the actinides. Although the actinide-molybdenum complexes were relatively straightforward to synthesise, surprisingly, the analogous chromium and tungsten complexes were not accessible by the same method, although it has been anticipated that photolysis could be an alternative synthetic route. Photolysis could also lead to the removal of one or more of the carbonyl groups situated on the group 6 metal and result in the targeted highly reactive and polarised early-late heterobimetallic compounds suitable for the activation of small molecules.

This thesis details work towards the efficient production of low oxidation state taxanes either by synthetic biology or synthetic chemistry. With over 400 natural taxanes isolated to date, many low oxidation state taxanes have been eclipsed by the intense interest in Taxol®. Some of these low oxidation state taxanes have important medicinal properties, many are currently unexplored. Chapter I introduces the taxane family of natural products, their biosynthesis and biological activity. Chapter II documents our efforts to utilise synthetic biology to rapidly access low oxidation state taxanes. In this chapter we describe the semi-synthesis of a novel oxa-cyclotaxane (OCT2) and 5α-hydroxytaxadiene, both low oxidation state taxanes. Here we also report that taxadiene, extracted from genetically modified tomato fruit, can undergo epoxidation and rearrangement with a reduced iron porphyrin to form the same products encountered when taxadiene 5α-hydroxylase is expressed in foreign organisms. We conclude that the established free radical mechanism, based heavily on speculation, is most probably incorrect in favour of an epoxidation/ rearrangement mechanism. Chapter III describes our chemical synthesis of low oxidation state taxanes utilising carbon building blocks from renewable sources. We make use of the well-established Diels-Alder approach to construct the A and B taxane rings simultaneously, culminating in the synthesis of the natural product 5α-hydroxytaxadiene. This chapter then goes on to present both our work towards an asymmetric synthesis of taxanes utilising Yamamoto’s chiral BrØnsted acid catalyst and our efforts in the manipulation of taxane oxidation both by reduction and C-H oxidation.

The use of single-walled carbon nanotubes (SWNTs) as test tubes for the encapsulation of metallic nanoparticles (MNPs) and the formation of inorganic nanomaterials has been advanced. A methodology to encapsulate the group 10 and 11 metals inside SWNTs to investigate their properties has been optimised. Each metal interacts with carbon differently at the atomic level, as shown by aberration-corrected high resolution transmission electron microscopy (AC-HRTEM), leading to the promotion of a plethora of different processes stimulated by MNPs under the electron beam. Additionally, interactions between SWNTs and small clusters of the group 10 metals have been examined, revealing marked differences between metal-carbon bonding for each metal. This has allowed for a useful insight into metal-carbon interactions on the atomic level which could have profound implications on the future development of new catalysts or nanoscale devices. Following on from this, a series of chemical reactions with platinum compounds were carried out within SWNTs which have shown SWNTs to be both a very effective reaction vessel and template for the formation of low-dimensional PtX2 (X = I, S) nanocrystals, materials that are difficult to create by traditional synthetic methods. The stepwise synthesis within SWNTs has enabled the formation of the platinum compounds to be monitored at each reaction stage by AC-HRTEM, verifying the atomic structures of the products and intermediates, and also by an innovative combination of fluorescence-detected X-ray absorption spectroscopy (FD-XAS) and Raman spectroscopy, monitoring the oxidation states of the platinum guest compounds within the nanotube and the vibrational properties of the host SWNT respectively. The stepwise synthesis has appeared to offer only limited preparative potential because of the lack of stoichiometric control in the resultant inorganic nanomaterials. A new approach for nanoscale synthesis in nanotubes developed in this study utilises the versatile coordination chemistry of platinum which has enabled the insertion of the required chemical elements (e.g. metal, and halogens or chalcogens) into the nanoreactor in the correct proportions for the controlled formation of PtI¬2 and PtS2 with the exact stoichiometry and structure. FD-XAS has also been used to probe the transformations of Pt(acac)2@SWNT to Pt@SWNT, and Cu(acac)2@SWNT to Cu2Ox@SWNT (where x > 1). It was shown that the temperature of both transformations was significantly lower than required for the same reactions in the bulk, which demonstrates the ability of SWNTs to lower the activation energy by polarising encapsulated molecules. Finally, a variety of novel MNPs and MO¬x¬ (M = Pt, Pd, Ni) materials were encapsulated within hollow graphitised carbon nanofibres (GNFs) and evaluated for the sensing of glucose. MOx@GNFs were revealed to be more active sensors than their corresponding MNPs which can be attributed to the increase in Lewis acidity of the metal centres upon oxide formation. Furthermore, the effectiveness of each metal and their corresponding oxides for glucose detection was found to increase in the order Pt > Pd > Ni which can be attributed to both physical and chemical properties of the respective metals. Overall, this thesis demonstrates that nanotubes can be used effectively to not only investigate chemical transformations on the atomic level, but also act as nano-sized test tubes and templates for the formation of novel, low-dimensional inorganic materials with bespoke structure and composition.

This thesis describes a variety of high resolution synchrotron powder diffraction studies of guest-loaded metal-organic frameworks (MOFs). These studies have been used to provide insight into the binding mechanisms of the guest molecules. Chapter 1 contains an introduction to MOFs, highlighting some potential applications that were investigated in this work. A description of the powder diffraction analysis techniques is also included. Chapter 2 describes the design and implementation of a remote control gas dosing system for use on the powder diffraction beamline (I11) at Diamond Light Source. To assess the precision of this system, and to gain an insight into the high CO2/N2 selectivity of the V(III) MOF, MFM-300(V), an in situ powder diffraction experiment was performed, firstly using pure CO2 and then with an equimolar mixture of CO2/N2. Two CO2 sites were found in all cases, with CO2-A forming a dipole-dipole interaction with the framework’s hydroxyl group, and CO2-B interacting with CO2-A via further dipole-dipole interaction. In the presence of N2, particularly at low loadings, the positions of the CO2 molecules vary quite significantly due to the presence of disordered N2 within the pore. Further to this investigation, the long term SO2 adsorption stability of the Al(III) MOF, MFM-300(Al), was studied by powder diffraction. The SO2-loaded MOF was found to remain stable over a period of 37 weeks. In Chapter 3, an investigation into the C8 hydrocarbon vapour adsorption and liquid phase separation properties of MFM-300(M) (M=Al, V, In) is described, with supporting structural information obtained from high resolution powder diffraction. In the vapour phase, MFM-300(Al) was the only MOF of the three studied to show any discrimination between the 4 isomers, whereas in the liquid phase, it showed no significant separation. Conversely, MFM-300(In) showed the highest degree of separation of m-xylene from ethylbenzene and o-, and p-xylene, however this was accompanied by poor separation of ethylbenzene and o-xylene. MFM-300(V) showed a lesser degree of separation of m-xylene from ethylbenzene and o-, and pxylene, but with a much better separation of ethylbenzene and o-xylene. The structural studies revealed π-π stacking interactions between the C8 hydrocarbons and the phenyl ring of the framework, and in the case of MFM-300(In)(p-xylene), tetragonal I4122 → orthorhombic I212121 phase change was observed. To further investigate the apparent flexible nature of MFM-300(In), high pressure powder diffraction was used, and a similar phase change was observed at 0.584 GPa. Chapter 4 describes the synthesis and characterisation of a Zr(IV) MOF, MFM-450. The CO2 and N2 adsorption properties of this MOF were investigated, and it was found to adsorb 2.32 mmol/g CO2 at 273 K, followed by 1.97 mmol/g CO2 at 283 K, and 1.48 mmol/g CO2 at 298 K. The N2 adsorption at these temperatures was negligible, resulting in high selectivities. To investigate the nature of CO2 binding in MFM-450, in situ powder diffraction was used. Two CO2 adsorption sites were found. The site in cage A was found to interact with the phenyl ring of the framework via π-π interactions, and the site in cage B interacts with the carboxylate group of the phenyl ring via a dipole-dipole interaction.

The involvement of hetero Diels-Alder dimerisations in the biosynthesis of natural products has been a source of debate for many years. Hypoestoxide and dihypoestoxide are two verticillane-type diterpenoids with closely related structures. Both were isolated from the same extracts of Hypoestes rosea in Nigeria. These two natural products constitute another example of a potential hetero Diels-Alder dimerisation in biosynthesis. Therefore, this thesis reports the work towards the diterpene hypoestoxide in order to study the hetero Diels-Alder dimerisation. The introduction emphasises the different biological properties of hypoestoxide and the isolation of dihypoestoxide. The biosynthesis of terpenes, the only previous synthesis of an isomer of hypoestoxide reported to date and the hetero Diels-Alder dimerisation in biosynthesis are described. Former Hayes group work about the stereochemical assignment of dihypoestoxide is also detailed in this part. The results and discussion suggests a synthetic route to hypoestoxide starting from geraniol, which constitutes a sustainable source of starting material for this synthesis. Different approaches towards the formation of the exocyclic enone moiety of hypoestoxide at a later stage in the synthesis would be discussed. Challenges to remove the additional carbon at C12 position would be detailed in this part. A brief conclusion and future work in this regard are given. Experimental procedures and full characterisation data of the different intermediates synthesised by this route are detailed.

This thesis describes the use of cinchona derived squaramide catalyst 27 in the asymmetric intramolecular N-conjugate addition of nitrogen nucleophiles with a,B-unsaturated carbonyls. The first chapter describes investigation of intramolecular N-conjugate addition reactions of sulfonamides with aromatic ketones, esters, thioesters and amides generating chiral 2-substituted piperidines, morpholines and oxazinanes. The squaramide catalyst 27 was found to efficiently catalyse the reaction, good yields of cyclic products were obtained with excellent enantioselectivities. Further modification of these products towards natural and drug targets is outlined. A possible mechanism based on observed stereochemistry and in silico modelling of transition states is proposed. The second chapter describes investigation of altered substrates formed by varying functionality linking the a,B-unsaturated carbonyl to the nitrogen nucleophile. For example, 4-Substitued 3,4-dihydro-2H-benzo[e][1,3]oxazin-2-ones and cyclic sulfamates were synthesised this way, but unfortunately enantioselectivity was poor in this case. Finally the influence of chiral substrates on asymmetric cyclisation was investigated during the synthesis of 2,4-disubstituted pyrrolidines. It was found that the intrinsic diastereoselectivity of the cyclisation is difficult to overcome using asymmetric organocatalysis.

This thesis describes advances in novel (3+2) dipolar cycloadditions of pyridinium ylides, their reactions with electrophilic alkenes afford tetrahydroindolizines which can possess alkaloid-like scaffolds. Pyridinium ylides have been shown to be highly reactive intermediates that are able to rapidly generate molecular complexity with excellent regio and diastereoselectivity. Chapter one reports an introduction on the chemistry of pyridinium ylides and introduces spirocyclic indolizidine containing natural products which could conceivably be synthesised through (3+2) dipolar cycloadditions. The results and discussion section is divided into three chapters: Chapter two describes the synthesis of indoxyl dipolarophiles including a novel approach towards the synthesis of 2-alkenylindol-3-ones. Details of the reactions of these dipolarophiles with pyridinium ylides to afford spirocyclic indoxyl cycloadducts follow. Subsequent modification of the 1,2-dihydropyridine moiety in the resulting cycloadducts is also demonstrated; Chapter three describes the investigation towards an asymmetric (3+2) dipolar cycloaddition, using pyridinium ylides generated by the in situ decomposition of diazo compounds with transition metal catalysts; Finally, chapter four describes attempts to synthesise spirocyclic indoxyl compounds which are structurally related to the opioid mitragynine pseudoindoxyl. Initially this is investigated via the methodology developed in chapter two, then subsequently using a magnesium iodide promoted ring expansion of a cyclopropane.

Metal Organic Frameworks (MOFs) are an interesting class of porous materials, for potential commercial applications such as storage and separation of gases. However, the industrial use of MOFs would require their synthesis on a much larger scale, necessitating the development of scalable synthesis techniques that are both greener and faster than those currently employed. This Thesis describes the recent progress towards the clean and scalable synthesis of MOF materials via the use of high temperature water (HTW) and related solvents. Supercritical ethanol extraction is also presented as a greener alternative for the removal of impurities, such as unreacted ligand, from within the pores of MOFs. Chapter 1 introduces the concepts explored during this work, such as green chemistry, and includes a brief overview of MOF materials, covering their properties, applications and synthesis, as well as the challenges facing their industrial implementation. The properties of HTW and supercritical ethanol, in relation to their use as cleaner solvents for MOF processing, are summarised and the aims of this project stated. The high pressure equipment and analysis techniques used during this work are then described in Chapter 2. Detailed descriptions and standard operating procedures for the following equipment are included: high pressure mini autoclaves; a continuous flow HTW reactor for the synthesis of MOF materials; and a supercritical ethanol extraction set up, for the removal of impurities from within MOF samples. (Information regarding a new continuous flow rig developed during this project can be found in Chapter 6). The use of supercritical ethanol as a cleaner alternative method for the removal of uncoordinated ligand from within the pores of MOF materials is explored in Chapter 3, where MIL 53(Al), an archetypal aluminium MOF, was used as an example throughout. The impact of this technique on the properties of the resulting MOF samples are also considered within this chapter. Chapter 4 illustrates the broad applicability of HTW to MOF materials, demonstrating the synthesis of a wide range of MOFs, primarily as fast batch reactions. Unlike typical MOF syntheses which require several days, reaction times of just 10 minutes were used during this investigation. This highlights the fact that the synthesis of MOFs in HTW is both faster and cleaner than many previous methods. The variety of MOFs synthesised in this chapter contain different metal centres and ligands, confirming that HTW synthesis is not limited to a small sub set of MOF materials. MOFs successfully synthesised in this manner include: MIL 96(Al); NOTT 300(Al); NOTT-300(In); scandium terephthalate, plus amine and nitro group containing analogues; and MOF 74(Ni). The synthesis of a larger (10 g) sample of one of these MOFs, NOTT 300(Al), is the subject of Chapter 5, which can be viewed as a case study into the challenges facing the scalable synthesis of MOF materials in both batch and continuous flow. Building on experience gained during this investigation, a new continuous flow HTW MOF synthesis reactor was designed and constructed, the development and testing of which forms the basis of Chapter 6. This new reactor was then implemented in Chapter 7, which describes the HTW synthesis of a range of functionalised aluminium MOFs, based on the MIL 53(Al) structure, containing additional amine or nitro groups, in both batch and flow. These MOFs were the first examples of the synthesis of functionalised MOF materials in HTW, demonstrating the flexibility of this technique and suggesting that it may be successfully applied to a much wider range of MOFs in the future. Finally, Chapter 8 revisits the aims set out in Chapter 1, providing a summary of the progress made towards meeting each aim and highlighting possible future directions.

Chapter one describes two efficient synthesis methods for the preparation of functionalised phosphonium salts. The first method utilises aryl radicals generated by a photo-induced decomposition of diaryliodonium salts, with the second method generating aryl radicals from arylboronic acids and manganese acetate. In both cases a broad substrate scope is demonstrated with respect to both the phosphorus and arylating species. Chapter two describes approaches to the total synthesis of plant sesqui-neolignans. The synthesis of macranthol was achieved in 5 steps from commercially available 4-allylanisole in 7% yield. As well as the first synthesis of the core [4.3.0] ring structure of the fargenin/fargenone family of natural products.