This thesis details the discovery and development of several novel gold-catalysed reactions for the synthesis of nitrogen containing carbo- and heterocyclic frameworks from carbon-carbon triple bonds. The realisation of a 1,1-carboalkoxylation strategy to generate gold carbenes from ynamides is described. This novel skeletal rearrangement proceeds with a previously unreported nitrogen migration onto a gold carbene for the synthesis of highly functionalised indenes. The mechanism has been investigated using isotopic labelling which confirms the predicted mode of cyclisation, enforced by the electronic properties of ynamides. This work led to the discovery of a gold-catalysed polycyclisation reaction to generate complex three-dimensional tetracyclic products. The scope and limitations of this method are described, and the mechanism has been probed using isotopic labelling. A novel copper-catalysed cascade reaction has also been demonstrated towards the synthesis of valuable nitrogen heterocycles. Finally a gold-catalysed rearrangement of electron deficient alkynes under oxidative conditions is detailed along with the reaction optimisation and difficulties encountered.

The coordination chemistry of the rigid, aliphatic triamino ligand \(cis,trans\)-1,3,5-triaminocyclohexane (\(trans\)-tach) is investigated. With closed shell transition metals, \(trans\)-tach forms 1-D {Ag(OTf), ZnCl\(_2\)} networks and a 3-D {AgNO\(_3\)} coordination polymer with unprecedented topology. Coordination to the open shell transition metals {NiCl\(_2\), Ni(NO\(_3\))\(_2\), Cu(NO\(_3\))\(_2\), CuBr\(_2\), CuCl\(_2\), CuF\(_2\), CuSO\(_4\)} leads to discrete diligand complexes. Protonation of the copper(II) complexes predominantly forms monoligand species, which can aggregate into higher nuclearity clusters. Protonated Cu(NO\(_3\))\(_2\) and CuBr\(_2\) complexes (HNO\(_3\) and HBr, respectively) remain mononuclear. CuCl\(_2\) and CuBr\(_2\) complexes protonated with HCl, however, form trinuclear species comprising trigonal planar \(\mu_3\)-chloro ligands that aggregate into 1-D trinuclear copper(II) chains via hydrogen-bonded interactions. Protonated CuF\(_2\) forms a tetranuclear cubane type structure that aggregates into a 3-D nanoporous network via hydrogen-bonded interactions. Protonation of the CuSO\(_4\) diligand complex maintains the diligand coordination, forming a 1-D nanoporous network through hydrogen-bonded interactions. Coordination to square planar palladium(II) ions forms all possible coordination motifs (‘Tail’ = monodentate, ‘Head’ = bidentate coordination). ‘Head-to-Head’ coordination results in diligand complexes, ‘Head-to-Tail’ coordination forms cyclic hexanuclear structures and ‘Tail-to-Tail’ coordination leads to a trinuclear species. Extension of \(trans\)-tach via Schiff base formation with pyridine-2-carboxaldehyde results in a hexadonor ligand suitable for metal coordination. Depending on the stoichiometry of the metal, mono- or polynuclear complexes are formed.

The prenylated indole alkaloids are a large family of natural products that have been isolated from various marine and terrestrial strains of Penicillium, Aspergillus and Malbranchea fungi. These compounds possess complex polycyclic structures including a characteristic bicyclo[2.2.2]diazaoctane core and have displayed wide-ranging biological activities. Chapter 1 gives an introduction to the prenylated indole alkaloids and important synthetic strategies to the key bicyclic core and an overview of previous work from our research group in this area. Recent work showed that triketopiperazines will undergo highly enantioselective Michael-additions and Michael addition–ring-closure reactions, efficiently generating compounds possessing the bicyclo[2.2.2]diazaoctane core found in the natural products. Chapter 2 discusses the extension of previous methodology towards a bicyclic triketopiperazine derived from proline including its synthesis and successful implementation in asymmetric Michael additions. Chapter 3 then explores the Michael addition–ring-closure of the proline derived triketopiperazine which was found to give highly enantioselective and high yielding access to hydroxy diketopiperazines possessing the key bicyclo[2.2.2]diazaoctane. The chapter also contains further transformations towards the natural product scaffold including a radical Barton-McCombie deoxygenation. Chapter 4 focusses on a novel Michael–Michael cascade strategy for the synthesis of molecules possessing the bicyclo[2.2.2]diazaoctane core of the prenylated indole alkaloids.

[FeFe]-hydrogenase plays an important role in the microbial energy metabolism, catalysing the reduction of protons into molecular hydrogen. Herein the synthesis and the spectroscopic analysis (NMR, IR, UV/vis) of [FeFe]-complexes based on the naphtho[1,8-cd][1,2]dithiole, naphtho[1,8-cd][1,2]diselenole and naphtho[1,8-cd][1,2]thiaselenole backbone, which incorporate substituents in position 2 of the naphthalene ring (OMe, tBu) are described. Additionally, dichalcogenide-based [FeFe]-complexes, containing the rigid aromatic phenanthrene and fluorene backbones are discussed. Cyclic voltammetry was applied in order to investigate the electrochemical properties of these new [FeFe]-hydrogenase synthetic analogues. Titration with pTsOH was monitored by cyclic voltammetry and showed that these [FeFe]-complexes are catalysts for proton reduction. After having studied these promising systems for proton reduction catalysis, the functionalization of naphthalene-1,8-dithiolate and diselenolate-based [FeFe]-complexes by insertion of aromatic and alkyl amino and imino groups is described. Spectroscopic and electrochemical techniques were applied to confirm protonation of the nitrogen, upon acid addition, and the effect on proton reduction catalysis, which was remarkably improved. Following these results, the synthesis of a molecular dyad containing zinc tetraphenylporphyrin, covalently linked to naphthalene-1,8-dithiolate-based [FeFe]-complex, via amino group, is reported. The initial investigations (UV/vis and emission spectroscopy) showed catalytic photo-induced hydrogen production, which was monitored by gas chromatography.

In this work, reactions of either LiBH\(_4\), ZnCl\(_2\) or Zn\(_3\)N\(_2\) with LiNH\(_2\) have been studied. The presence of CoO significantly affected the products and hydrogen release on heating mixtures of χLiBH\(_4\)-γLiNH\(_2\). The ratios of the l4\(_1\)/amd and the P2\(_1\)/c polymorphs of Li\(_3\)BN\(_2\) in the products have been changed under different conditions studied. On addition of CoO, the temperature of hydrogen release from the χLiBH\(_4\)-γLiNH\(_2\) systems was greatly reduced, starting from 100°C and peaking around 250°C, much lower than 240°C and 330°C without catalyst. Ball-milling helped to improve the amounts of hydrogen desorbed from 3–4 wt% up to ≥10 wt%. In the reactions of ZnCl\(_2\) + nLiNH\(_2\) (where \(\textit n\) = 2–6), main products were LiCl, Zn\(_3\)N\(_2\), and LiZnN. NH\(_3\) was the main gas released from these reactions and the addition of LiH changed NH\(_3\) into H\(_2\), which was released around 90°C, much lower than in the absence of LiH. A mixture of LiZnN and LiCl obtained from this reaction was partly rehydrogenated to form Li\(_2\)NH and Zn. The reaction of Zn\(_3\)N\(_2\) and LiNH\(_2\) was found to produce pure LiZnN without LiCl. Neither pure LiZnN nor Zn\(_3\)N\(_2\) could be hydrogenated under the conditions tried, but a mixture resulting from the reaction could react with H\(_2\) to form LiNH\(_2\) and Zn. The cyclability of the Li–Zn–N system showed an ability to release and take up gases under different pressure conditions. Mg-doping in LiZnN was examined to improve reversibility of the Li–Zn–N system but was not successful.

Despite the privileged position of Hamilton’s barbiturate binding system in supramolecular chemistry, this motif has never been used in generating interlocked structures, such as rotaxanes or catenanes. This thesis demonstrates the feasibility of such structures. A series of Hamilton-like receptors has been synthesised. Their conversion from “open” to “closed” forms by metathesis and their binding with barbital was studied, demonstrating the importance of the macrocycle size. Barbiturates disubstituted with flexible chains terminated either by reacting groups (anthracenes, olefins) or stoppers (trityl) were also synthesised. The fluorescence properties of anthracene-tagged barbiturates and their kinetics of intramolecular anthracene photodimerisation and thermal return were studied, demonstrating remarkable differences depending on the chain length. Binding studies of these barbiturates with the receptors were then undertaken, revealing smaller binding constants compared with barbital. A series of ring-closing experiments involving the barbiturate complexes was then undertaken, either by anthracene photodimerisation or olefin metathesis. In one metathesis experiment, indirect evidence for the formation of a low amount of catenane was obtained by mass spectrometry, where the smallest ring is formed by a chain of only 19 carbon atoms, which is unprecedented. Finally, different synthetic pathways for the synthesis of barbiturates substituted with large rigid substituents were investigated. Models of their complexes with the receptors and IR studies are presented that suggest that their structure would facilitate the formation of interlocked complexes.

Metal-organic framework materials have been the subject of great interest in recent years as their enormous chemical and structural diversity offers opportunities for potential applications. We have developed synthetic routes to a series of new zinc organophosphonate materials, exemplified by the zinc carboxyethylphosphonate (NH\(_4\))\(_2\)[Zn\(_2\)(O\(_3\)PCH\(_2\)CH\(_2\)COO)\(_2\)]·5H\(_2\)O, prepared under hydrothermal conditions in a Teflon-lined autoclave. In common with many other MOFs, it has a low molecular weight and three-dimensional porous framework structure, with pores of ca.7.6 Å diameter providing potential access to a high internal surface area, but unlike most has the advantage of containing exchangeable ammonium cations within the pores. The ability to undergo ion exchange is of interest in its own right, but also enables fine-turning of the properties of these materials. MOFs have already shown considerable promise for hydrogen storage owing to their high uptake capacity at low temperature and excellent kinetics and reversibility. In some MOFs and zeolites the hydrogen physisorption properties have been successfully improved by varying the exchangeable cations or adding exposed metal sites. Here we report the results of ion exchange experiments on (NH\(_4\))\(_2\)[Zn\(_2\)(O\(_3\)PCH\(_2\)CH\(_2\)COO)\(_2\)]·5H\(_2\)O with a view to producing MOF materials with enhanced hydrogen physisorption properties.

The work described herein concerns the effect on the anticancer activity and the ability to reach their possible intracellular targets of certain steroidal metallodrugs and metallosupramolecular cylinders. Chapter 1 surveys the background to the project, surveying different DNA-binding modes, explaining their importance in the anticancer properties of metallodrugs and showing an overview of the different strategies used for enhanced delivery of these metallodrugs. In Chapter 2 the synthesis of new steroidal DNA covalent-binding platinum(II) complexes together with techniques to purify previously synthesised steroidal complexes are presented. Their cytotoxicity, cellular uptake and biomolecular interaction are investigated, showing that the coupling of the steroid confers activity to otherwise inactive complexes, modifying their DNA binding mode and cellular uptake and distribution. Chapter 3 explores the coupling of similar steroidal delivery vectors to non-covalent metallodrugs, presenting simple synthetic pathways to create such complexes in a single step. Their anticancer activity and DNA-binding affinity are investigated: surprisingly showing that this coupling has negative effects. In Chapter 4 the cytoxicity and cellular behaviour of metallosupramolecular cylinders are studied. It is shown that these complexes can cross the cellular membrane, concentrating in the nuclei where they can interact with cellular DNA.

A series of lanthanide complexes based on tetraphenyl imidodiphosphate ligand have been prepared in order to investigate the ligand ability to act as a sensitiser for f-f based luminescence for the visible and NIR emitting ions. Furthermore, novel bimetallic luminescent lanthanide complexes based on two imidodiphosphate binding sites have been prepared for the examination of dinuclear lanthanide complexes formation. The sensitising properties of the bistpOp have been investigated by luminescence spectroscopy. A new ligand based on biphenyl sensitisers has been developed utilising an imidodiphosphate binding site. The lanthanide complexes have been prepared and their photophysical properties analysed.

The size of the prenylated indole alkaloid family sharing the unique bicyclo[2.2.2]diazaoctane core ring system has grown steadily over the last decades. Due to the complex structures, and in some cases the potent biological activity, these molecules have been adopted as challenging targets for several synthetic groups. Chapter One gives an introduction to these alkaloids, their origin, biological activity and biosynthetic studies. Our strategies to deliver 5,6- and 6,6-fused diketopiperazines (DKPs) and monoketopiperazines (MKPs) are discussed in Chapter Two. Radical cyclisation of a phenylselenyl DKP 108 (Scheme 2.10) and a bromo MKP 140 (Scheme 2.22) gave mixtures of exo and endo products. An alternatizve thio-mediated radical approach allowed access to exo products (Table 2.2 and Scheme 2.28). Previous experiments on the established cationic cyclisation showed that the pyran ring present in the stephacidins is particularly sensitive to the presence of acid. These results prompted us to explore alternative approaches in which the formation of the pyran ring occurs after the key-step (Scheme 3.19 and 3.20). Our progress towards stephacidin A and previous syntheses are discussed in Chapter Three. Synthesis of a sulfide DKP 218 (Scheme 4.22) allowed access to indoline products via radical approach (Scheme 4.27). An oxidative radical approach as well as a cationic approach is also discussed in Chapter Four. In comparison with our new strategy there is also a review of all previously described approaches to assemble the bicyclo[2.2.2]diazaoctane framework. Among the different approaches to access the core structure of these natural products the radical cyclisation approach appeared to be the most efficient. Based on this strategy, synthesis of indolines 348/349 which is structural related to avrainvillamide is discussed in Chapter Five (Scheme 5.10). Our rapid radical methodology allows synthesis of these indolines in 6 steps and 28% overall yield.