Herein, we report the results of research continuing previous successI in the field of enantioselective organocatalytic reduction of imines with trichlorosilane. Syntheses of various precursors (ketones) and substrates (imines) for the reduction reaction and their reduction following the protocol (Scheme A1) are described in this thesis. 1. Aromatic heterocycles containing nitrogen – good yields of the reduced product (68-85 %), the enantioselectivity depended on steric bulk in proximity to the nitrogen, steric bulk improved the enantioselectivity (up to 78 % ee), probably due to thwarting the coordination of the nitrogen to HSiCl3. 2. Aromatic heterocycles containing sulfur – sulfur in the ring was tolerated well (89 % ee). 3. Aromatic heterocycles containing oxygen – generally good yields (62-90 %), dependence on position isomer was observed: furan-2-yl-derived substrates were reduced in moderate enantioselectivity (45-85 % ee), possibly due to the problem of coordination; in contrast, furan-3-yl derivatives were reduced in good enantioselectivity (77-91 % ee). 4. Non-heterocyclic aromatic or aliphatic – good yields (62-98 %) but varied enantiomeric excess (10-97 %). The high enantioselectivity values (76-97 % ee) were for substrates with significant contrast of the steric hindrance of the groups next to the reaction centre. Furthermore, an example of practical utilisation of the method is presented. Naturally occurring alkaloid N-acetylcolchinol was synthesised in 9 steps and overall 8 % yield (Scheme A2). The stereogenic centre was introduced using our method and afforded the desired enantioenriched amine in 96 % ee.

Understanding with the use of computational tools the mechanism of reactions in organic chemistry or the electronic transitions in solid state is a quite challeng- ing problem. The main methods utilised for this research are Density Functional Theory (DFT) and time dependent DFT. The software utilised is GAUSSIAN03 for the reaction mechanism studies and CRYSTAL06 for the study of the spin crossover transition in a Prussian Blue analogue. In chapter 2, we investigate the first two reaction steps of the synthesis reaction mechanism of Dihydro-Imidazo-Phenathridinium (DIP) derivatives, which are a novel class of compounds that intercalate DNA, possessing anticancer properties. In chapter 3, we examine the last step of the DIP synthesis reaction, which is a hydride transfer, in particular it is considered the solvent effect on the excitation energies of the molecules involved in the hydride transfer. In chapter 4, we consider the hydride transfer reaction of heteroaryl-dimethylbenz- imidazoline derivatives (HDBMZ-H) with benzyl-carbamoylpyridinium (BCPY) and benzyl-nitrosoquinolinium (BNIQ) ions. In chapter 5, we study the spin crossover transition (SCO) in the CsFeII[CrIII(CN)6] Prussian Blue analogue. This transition can be induced experimentally by varia- tions of temperature or pressure and more light on this mechanism can be useful in information processing and display technologies. Those fields, in fact can benefit from the application of molecular electronic bistabilities in which the SCO phe- nomenon can be classified.

New general methodology for the stereoselective synthesis of unnatural alpha-amino acids has been developed. Early work focussed on investigating methods for the generation of chiral allylic alcohols using cross-metathesis of a simple enone with various terminal alkenes, followed by an asymmetric ketone reduction. The allylic alcohols were then converted to protected allylic amines via Overman rearrangement chemistry. Oxidative alkene cleavage and hydrolysis of these intermediates generated a range of alpha-amino acid targets. Attempts were also made to apply the developed methodology to the synthesis of a simple alpha,alpha-disubstituted alpha-amino acid target. The Overman rearrangement was also applied to the generation of a late-stage intermediate which could be used in the synthesis of (2S,3S)-capreomycidine, a component of a number of peptides which exhibit antibacterial activity.

This thesis is concerned with studies towards the total synthesis of the natural product neoliacinic acid using metal carbenoid methodology. The work described herein shows the most recent contribution to this field from our research group. Chapter 1 provides an introduction to metal carbenoids, their preparation and uses in organic synthesis. Cyclopropanation reaction, C-H insertion and oxonium ylide formation and their subsequent rearrangements are discussed in detail. The target molecule is described followed by previous synthetic attempts toward neoliacinic acid. The Clark group strategy toward neoliacinic acid is explained with a retrosynthetic analysis using two metal-carbenoid transformations: intramolecular C-H insertion and oxonium ylide formation followed by [2,3]-sigmatropic rearrangement. Chapter 2 describes efforts towards the total synthesis of the target molecule from commercially chiral pool materials. A synthetic route is described in which construction of the two precursors required for metal carbenoid formation is followed by the application of the two key reactions to build the oxabicyclic core of the natural product. Efforts to generate an advanced intermediate containing the third ring (the lactone) including all six stereocentres present in the natural product are detailed. Finally, various options for completion of the synthesis as future work are discussed.

The main aim of this project was to re-visit the area of copper and cerium containing catalysts for use in the methanol industry. The goals were not only to prepare more robust copper/cerium catalysts, but also to further investigate the species that contributed to the high activity of the copper/cerium intermetallic catalysts. Initially a series of copper and cerium catalysts supported on silica or alumina were prepared. The preparation method was chosen so as to maximise the metal dispersion over the support. Methanol decomposition was used to investigate the activity of the prepared catalysts. Ideally, for the catalyst to behave similarly to the Cu/Ce alloy catalysts, they would have to decompose methanol to produce predominantly carbon monoxide and hydrogen. However, on closer examination of these catalysts it was found that the presence of cerium in the catalysts led to an increase in the carbon dioxide:carbon monoxide ratio. A cerium hydride was prepared and a number of its properties were examined using small highly reactive molecules. The results showed that adsorbed hydrogen was reactive, readily available for exchange with deuterium and able to catalyse hydrogenation reactions. The cerium hydride selectively hydrogenated carbon to oxygen multiple bonds. Moreover, the presence of carbon monoxide or carbon dioxide did not poison the cerium hydride. The hydride reacted irreversibly with methanol to produce methane and hydrogen. Due to increasing interest in the water-gas shift reaction for the production of hydrogen for fuel purposes and its uses in industry, the copper/cerium mixed catalysts were examined for use in the water gas shift reaction. In general the mixed metal catalysts were found to be highly active for conversion of carbon monoxide from the reaction mixture. However on closer examination, surface oxygen appeared to have a strong influence on catalytic activity. Further experiments were used to determine the extent to which surface oxygen influenced the reaction products. Addition of cerium to copper-containing catalysts reportedly has the advantage of reducing the ‘pyrophoricity’ observed when reduced shift catalysts are exposed to air/oxygen. As a result of this investigation, it was found that the addition of cerium to copper-containing catalysts was treated with oxygen. During the course of the study, changes in reactivity of the silica-supported catalysts were observed which led to re-examination of a selection of the catalysts for their activity towards methanol decomposition and the hydrogenation of 1,3-butadiene. The changes in activity were attributed to aging of the catalysts.

The cladiellins (also known as eunicellins) are oxygen-bridged 2,11–cyclised cembranoids, isolated from gorgonian octocorals and soft corals. They present an unusual oxatricyclic ring system composed of a hydroisobenzofuran and an oxonene unit. The natural role of these cembranoids is proposed to involve predatation deterrence, and biologically they have been shown to exhibit in vitro cytotoxicity against various cancer cell lines, anti inflammatory properties antimicrobial activities. The Clark group has been interested in the synthesis of cladiellins for some time, and in 2007 Clark and co-workers reported the total synthesis of vigulariol. This thesis describes the investigation of the synthesis of both E- and Z-cladiellins using our general strategy. The key transformations in the synthetic route are ring formation reactions. Firstly, a SmI2-mediated reductive cyclisation forms the tetrahydropyran ring, then a tandem oxonium ylide formation [2,3]-sigmatropic rearrangement constructs the oxabicyclo[6.2.1]undecenone bicyclic core. Finally, a Diels-Alder cycloaddition reaction forms the third ring of the tricyclic core of the cladiellins. Particular interest was given to the tandem oxonium ylide formation [2,3]-sigmatropic rearrangement reaction. This transformation was studied in order to develop conditions allowing the selective formation of the E-oxonene ring needed for the synthesis of the E-cladiellin tricyclic core. Herein, is presented work towards the synthesis of ophirin B, a cladiellin bearing a Z-oxonene alkene, as well as the enantioselective total synthesis of eight cladiellins obtained from an E-cladiellin tricyclic core: (−)-cladiella-6,11-dien-3-ol, (−)-cladiell-11-ene-3,6,7-triol, (−)-3-acetoxycladiella-6,11-diene, 3-acetoxy-cladiellin-11-ene-6,7-diol, (−)-sclerophytin A, (−)-sclerophytin B, (+)-deacetylpolyanthellin A and (+)-polyanthellin A in 20 to 24 steps from our allylic alcohol precursor.

In many natural products, heterocycles, such as cyclic ethers, are important features. While there are many different approaches to the formation of these ethers, there are only a few methods available for the synthesis of substituted cyclic ethers with good diastereoselectivity and even less so with good enantioselectivity. The rearrangement of oxonium ylides has proved to be a versatile method for the stereoselective synthesis of cyclic ethers. However, to date, there is no general efficient enantioselective method for the rearrangement of oxonium ylides. This project aimed to develop an enantioselective synthesis of O-heterocycles from chiral copper carbenoids. Screening of various catalysts generated in situ from [Cu(MeCN)4]PF6 and chiral ligands led us to identify a class of ligands, specifically chiral bisoxazoline ligands, that generally resulted in asymmetric induction during the [2,3]-sigmatropic rearrangement of oxonium ylides. Unfortunately, while asymmetric induction was obtained, generally the rearrangement reaction resulted in quite low enantiomeric excess. During the course of this project, iridium-mediated reactions was also investigated. It was found that the catalyst [Ir(COD)Cl]2 could be used for the same transformation as the copper catalysts, which to the best of our knowledge was the first example of the use of an iridium catalyst for the tandem oxonium ylide generation and subsequent [2,3]-sigmatropic rearrangement of diazoketones. As only rather low asymmetric induction was obtained during this transformation, our attention turned towards achieving a greater mechanistic understanding of this reaction, as good mechanistic understanding is essential for enantioselective development. Isotopic labelling of the diazoketone starting materials provided information on the rearrangement products, from which conclusions could be drawn as to the rearrangement mechanism. It was concluded that the rearrangement reactions in question, that take place via copper or iridium carbenoid-mediated reactions, either do not proceed through a free oxonium ylide, but rather through the metal-associated oxonium ylide derivative, or follow a major competing non-ylide route that delivers apparent [2,3]-sigmatropic rearrangement products of oxonium ylides. With regard to rhodium-catalysed reactions, firm conclusions could not be drawn, although there is some suggestion that this reaction also does not proceed solely through the free oxonium ylide pathway. Further investigations of the iridium-catalysed reaction through crossover experiments suggest that the metal-associated oxonium ylide derivative dissociates during the reaction to give an allylic cation and an iridium enolate, which then recombines to give the apparent [2,3]-rearrangement product.

Manzamine A has been isolated from various Okinawa Sponges of the genus Haliclona and was first characterised by Higa and co-workers in 1986. The unusual and synthetically challenging structure consists of a pentacyclic core containing an array of 5-, 6-, 8-, and 13-membered rings with a pendant -carboline unit. The complex structure of manzamine A combined with its biological activities has made it a highly attractive synthetic target. The synthetic endeavors in the Clark group to develop a novel approach towards the total synthesis of manzamine A (i) with the main focus on the synthesis of the ABC ring fragment as advanced intermediates will be disclosed. In the first synthetic approach towards the total synthesis of manzamnine A (i), bicyclic enone iii was constructed from amine ii and served as a model system to validate the proposed intermolecular Diels-Alder reaction. Despite several attempts utilising various dienes, the Diels-Alder adduct was not obtained and an alternative bicyclic system was investigated. After accomplishing the synthesis of the simple AB fragment v from propargylamine (iv), the Diels- Alder reaction was yet again investigated. Due to the failure of the Diels-Alder reaction, this route towards the total synthesis of manzamine A (i) was abandoned. The second approach introduces the conjugate addition reaction towards the total synthesis of manzamine A (i). Instead of the Diels-Alder approach, 1,4 addition to enone v was explored. Initial attempts to perform the 1,4-addition reaction and subsequent aldol condensation reaction afforded the dehydrated aldol condensation products vii via silyl enol ether vi. Additional investigations to prevent the dehydration reaction taking place proved unsuccessful. Thereafter, various methods for the introduction of a substituent in the position to the ketone were investigated. These included alkylation using chloromethyl phenylsulfide, halogenation using NBS or NCS, Rubottom oxidation using DMDO, direct amination using manganese(V) complexes, azidation using sodium azide and CAN as well as aziridination using PhI=NTs. A number of adducts viii-x were succesfully prepared. Finally, the last part of the thesis describes the efforts towards the synthesis of a model system resembling the CD ring-system. The macrocyles xiii and xiv were easily synthesised from dienes xi and xii, although the RCM of diene xi gave rise to isolation problems.

The main focuses of this research were to examine the capabilities of solution techniques to attempt to monitor the nucleation process in crystallisation, and to investigate structural outcomes of crystallisation processes, with reference to polymorphism and intermolecular interactions. To achieve this, work on the investigation of nucleation and early-stage crystallisation was carried out at the Department of Pharmaceutical Sciences at the University of Strathclyde and also at the central synchrotron facility of Station 2.1 at the SRS Daresbury. Small angle X-ray scattering (SAXS) was carried out on solutions of methyl-4-hydroxybenzoate (pMHB) and 2-bromobenzoic acid. These studies were carried out after developing solution methods to enable us to determine the point at which crystals emerged from solution. This was achieved using Focussed Beam Reflectance Measurements. Structural studies were also carried out on pMHB to examine its polymorphic behaviour and crystal structures were solved at various temperatures from 100K to 300K. The crystal structure of methyl-2,5- dibromobenzoate was also solved at 100K after discovering it sublimes at room temperature. This structure could only be solved from a twinned crystal and indicated the appearance of interesting halogen interactions occurring. Structural studies have also been carried out using the bromanilic acid molecule as a focus to generate a number of co-crystal complexes to examine their halogen bonding capability and to determine any structural significances in their formation. Co-crystal complexes of bromanilic acid and a variety of molecules were made in 1:1 and 1:2 ratios to see if any additional halogen interactions could be observed or induced, in addition to the expected hydrogen-binding interactions. The co-crystals included a range of picolines and lutidines as well as bromo-substituted pyridines to attempt to induce halogen interactions. This generated a number of new compounds whose structures were determined using single crystal X-ray diffraction and the interactions were monitored to observed whether any defined patterns with regards to the tendency of bromanilic acid co-crystallisations to produce predictable patterns of intermolecular interactions could be determined.

Over the past thirty years, numerous fused polycyclic ether natural products have been isolated from small marine organisms. These compounds revealed a variety of interesting biological properties, which has attracted the interest of many synthetic groups. The common structural characteristic of these compounds is an array of trans-fused ether rings. Several iterative strategies have been reported to build six- and seven-membered cyclic ethers, which are the two most common units in these natural products. The objective of work described in the first part of this thesis was to develop new synthetic methodology to access these motifs. Each unit must be built in the minimum number of steps and the new methodology must be flexible enough to obtain both six- and seven-membered rings from a common precursor. They key reaction of the strategy will be ring-closing metathesis, as previous work in our group showed that this is a powerful reaction to create cyclic ethers. The second part of this thesis focus on the total synthesis of one of the marine polyether natural products, gambieric acid A. This compound was isolated in 1992 and has so far eluded total synthesis. First, the synthesis of the tricyclic B-D core, which has been developed in our group, was optimised and performed on a large scale. The synthetic route relies on the ring-closing metathesis reaction to construct two of the cyclic ethers from a commercially available glucose derivative. Several strategies for the coupling with the tetrahydrofuran A ring were then investigated. The initial method envisioned for the fragment coupling was a nucleophilic substitution of an alkyl iodide by a lithiated dithiane. However, this strategy revealed unsuccessful. Instead, a more converging approach using a diastereoselective Tsuji reaction was developed, which allowed the formation of the complete carbon skeleton of the A-D fragment.