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This thesis comprises three projects on the theme of C-H activation for the synthesis of functional materials. Chapter 1 describes the development of gamma C-H carbonylation of free aliphatic secondary amines to form secondary lactams. The diastereoselectivity of the reaction was found to be significantly influenced by the choice of reaction conditions. Under optimised conditions, a wide range of lactams were delivered in high yields and good d.r., with many different functional groups and substitution patterns being tolerated. Further transformation of the lactam was also demonstrated, yielding pyrrolidines and functionalised lactams. Chapter 2 describes the development of a carboxylate directed C-H arylation of azulene at the 2-position. This methodology enables the overriding of the natural reactivity of the 1, 3-position to conveniently access 2-arylated azulene, without regioselectivity issues and in moderate to high yields. The reaction was found to tolerate a wide range of aryl groups, including some heteroarenes. In-situ decarboxylation was also observed, allowing the carboxylate to act as a traceless directing group. This methodology was subsequently applied to the preparation of 2-functionalised azulene – fluorene polymers in chapter 3. These polymers were then tested for electrochromic applications and optical sensitivity to acidic environment. Functionalisation of azulene was found to significantly influence the properties of these polymers. In particular, electron-donating aryl groups were found to enhance the sensitivity of the polymers to acidic environments.

Enamides and allenamides are two versatile functional groups that offer a wide variety of alternatives for the inclusion of nitrogen-based moiety into an organic system. Nitrogen-containing structures are prevalent among medicinally interesting natural and unnatural products and, thus, are useful in developing new therapeutics. Their chemical utilities have been exploited by a number of research groups. They represent interesting functional groups and useful in organic synthesis. Photoredox catalytic approach was develop to synthetically transform enamides into useful products, N-acyl-N -aryl-N,N -aminals. A novel approach using iridium polypyridyl complex photoredox catalyst to initiate a three-component domino transformation of enamides to N-acyl-N -aryl-N,N -aminals via photoredox catalysed β-alkylation of enamide intermediates and their subsequent trapping with an arylamine was successfully developed. The N-acyl-N'-aryl-N,N'-aminal structural motif is prevalent within a wide range of biologically important compounds and have attracted considerable attention as building blocks for the synthesis of drug candidates. This method uses the addition of a radical precursor to an enamide, with subsequent interception of the cationic iminium intermediate with an arylamine. The reaction was found to be compatible with both electron-rich and electron-deficient arylamines, and moderate to good levels of diastereoselectivity were attained using a chiral enamide. The N-acyl-N -aryl-N,N -aminals formed were used as precursors to synthesis of valuable γ-lactams building blocks under a mild condition by cyclization. The γ-lactams were obtained by intramolecular cyclization of the N,N -aminals with the lone pair of the nitrogen atom of the arylamine as the nucleophilic centre attacking the electrophilic carbon of the carbonyl carbon of the ester in the molecule. This is a novel synthetic route to these valuable γ-lactams. The photoredox reaction procedure developed was also applied on allenamides. There are limited reports of radical reactions on allenamides, the major and seemingly single intermolecular radical cyclization involving allenamides was the one reported by Hsung. There are no reports of radical photoredox reactions on allenamides in the literature. The addition reaction was initiated by the electrophilic malonate radical generated by irradiation with blue light in the presence of iridium photoredox catalyst. The malonate radical attacked the central carbon of the allenic group which led to the formation of β-alkyl allenamide radical that was oxidized to an iminium ion intermediate. The iminium intermediate was subsequently trapped with an arylamine giving rise to α,β-addition product (N-acyl-N -aryl-N,N -aminals) with exo-methylene or β,γ-addition product leading to the formation of double bond substituted enamides. It was found that the α,β-adduct product is more favourable, however, the alternative product was formed when the α-position is sterically hindered by the substituents on the allenamide or the arylamine nucleophile.

Fossils fuels are highly demanded in everyday life domestically or industrially. Fossil fuels are finite resources and they are rapidly depleting, as such alternative renewable feedstocks are sought to replace fossil fuels. Tall oil from paper processing and cashew nut shell liquid from the cashew nut industry are the two major renewable sources we studied, they are both waste byproducts, and have the potential to be converted into value-added materials. Tall oil from the paper industry mainly contained tall oil fatty acid, and under isomerising methoxycarbonylation with palladium catalyst, dimethyl 1,19-dimethyl nonadecanedioate can be obtained. This difunctional ester, dimethyl 1,19-dimethyl nonadecanedioate, is converted to diols, secondary and primary diamines by a hydrogenation reaction with ruthenium complexes of 1,1,1-tris(diphenylphosphinometyl)ethane (triphos) as catalysts in the presence of water, amine or aqueous ammonia respectively. In the case of aqueous ammonia it is necessary to use a two step reaction via diol to obtain 1,19-diaminononadecane. Diesters, diols and diamines are useful precursors for the synthesis of polyesters and polyamides. Difunctional substrates with 8-19 carbon chains are all tolerated under the reaction conditions and are successfully converted to the corresponding diols and diamines in high yields. Under similar hydrogenation conditions with the same ruthenium catalyst, cyclic products were predominantly produced with decreased chain length. N-heterocycles, which are important building blocks for the synthesis of drug molecules, were formed from the hydrogenation of diesters with 4-7 carbon chains in the presence of an amine. Another polymer precursor, ε-caprolactam, which is the precursor for Nylon 6, is obtained in a reasonable yield from both adipic acid and adipate esters together with aqueous ammonia in the presence of ruthenium catalyst. Cashew nut shell liquid was also converted into useful medical drugs, such as norfenefrine, rac-phenylephrine, etilefrine and fenoprofene in reasonable yields. Most of these drug molecules have been formed from 3-vinylphenol by catalytic hydroxyamination followed by methylation or ethylation. 3-Vinylphenol was synthesised from cardanol by ethenolysis to 3-non-8-enylphenol followed by isomerising ethenolysis, whilst the N-alkylation reactions used methyl or ethyl triflate to avoid dialkylation. Fenoprofene was formed by firstly O-phenylating cardanol then ethenolysis followed by isomerising ethenolysis to form 1-phenoxy-3-vinylbenzene. Methoxycarbonyation followed by hydrolysis formed the final product in good yield. Our methods start from renewable waste materials and avoid unpleasant reagents in the original stoichiometric synthesis of those drugs, for example, cyanide is no longer essential for the synthesis of fenoprofene.

The work described in this thesis focused on the use of nuclear magnetic resonance spectroscopy (NMR) to study two classes of metallo enzymes - the Fe(II)- and 2oxoglutarate (2OG)-dependent dioxygenases and the metallo β-lactamases (MBLs). These enzymes are involved in clinically important biological processes, i.e. the hypoxic response and antimicrobial resistance, respectively. Both protein systems are interesting from an NMR perspective because they have dynamic regions involved in catalysis and ligand interactions. The work included mechanistic studies, protein-ligand interaction studies, and method development for inhibitor discovery. NMR was applied to study the human prolyl hydroxylase domain-containing protein 2 (PHD2), which is crucially involved in the chronic hypoxic response. The results reveal that binding of the C- and the N-terminus of the oxygen dependent degradation domains CODD and NODD, respectively, induce different interactions with PHD2. The substitution of a single amino acid, as occurs with PHD2 variants linked to erythrocytosis and breast cancer, can alter the selectivity of PHD2 towards its ODD substrates. Studies with the Trichoplax adhaerens PHD provide insights into the evolutionary substrate preference of the PHDs. Using 13C-labelled peptidyl-substrates; NMR was applied to investigate proposed 'alternative' PHD2 substrates/interaction partners. The product release mechanism of PHD2 was investigated using NMR; the results reveal that the presence of 2OG strongly discriminates between the binding of CODD and hydroxylated CODD to PHD2. NMR was also applied to monitor PHD2 kinetics and inhibition. Competition and displacement assays were designed and applied to investigate PHD inhibitor binding modes. Comparative studies on the activities and selectivities of PHD inhibitors in clinical trials should aid in the work on the therapeutic manipulation of the natural hypoxic response. Protein-observe 19F-NMR was used to study the São Paolo MBL (SPM-1). The results provide new structural insights into SPM-1 catalysis and the requirements for inhibitor development. They also reveal that the hydrolysed β-amino acid products of MBL catalysis can bind to SPM-1. They illustrate the utility of 19F-NMR for detecting metal chelation, which is not always readily tractable in studies on metallo enzyme inhibition, new binding modes, and stereoisomer binding/epimerisation in solution. The interaction of a cyclobutanone analogue, a broad-spectrum MBL inhibitor, with SPM-1 was investigated. A combination of 1H, 19F, 13C-NMR and crystallographic analyses reveal that cyclobutanone binding may mimic formation of the oxyanion tetrahedral intermediate in β-lactam hydrolysis. The susceptibility of avibactam, the first clinically useful non-β-lactam β-lactamase inhibitor, to MBL-catalysed hydrolysis was studied. The results reveal that avibactam is not an MBL inhibitor and a poor substrate of most members of all three clinically relevant subclasses of MBLs. In some cases, avibactam undergoes slow hydrolysis in a process different from that observed with serine β-lactamases. Overall, the results illustrate the utility of NMR for studying dynamic aspects of enzyme catalysis and inhibitor binding.

Radical translocation chemistry has classically been employed for the generation of carboncentred radicals as a means of remotely functionalising nominally unreactive sites. Previous work within the group had investigated vinyl radicals to effect translocation and had identified a need for a more reactive abstracting radical. In this regard, the high energy of alkoxyl radicals would facilitate rapid 1,5-hydrogen abstraction as opposed to simple reduction. This thesis describes the use of alkoxyl radicals, generated from N-alkoxyphthalimides, to abstract a hydrogen atom selectively from the α-position of a lactam ring. Alkoxyl radicals generated from precursors designed to lead to intramolecular trapping of the translocated radical were prone to β-scission in preference to 1,5-hydrogen atom abstraction. This is attributed to a combination of developing π-overlap in the transition state and stabilisation of the resulting radical both by nitrogen and the attached alkyl substituents. Incorporation of an alkenyl trap onto the lactam ring led to successful 1,5-hydrogen atom abstraction and stereoselective cyclisation, although β-scission remained the dominant pathway. Translocation initiated by nitrogen-centred radicals was investigated and it was found that 1,5-hydrogen abstraction occurred in preference to β-scission; intramolecular trapping of the translocated radical proved impossible either because the precursors were unstable to the reaction conditions or because increased steric bulk impeded hydrogen abstraction by the less reactive aminyl radical. Preparation of bicyclic pyrrolidinones via successive 5-endo-5-exo-trig cyclisations was investigated; the precursors were found to undergo direct reduction in preference to cyclisation. Alkyl or aryl groups attached to the a-acylamino carbon may lead to preferential 5-endo cyclisation by stabilisation of the developing radical in the transition state.

This thesis is concerned with the synthesis of functionalised piperidines. The piperidine unit is found in numerous alkaloids and other natural products, and has also been incorporated into synthetic compounds of significant therapeutic or strategic synthetic potential. Although numerous syntheses of individual piperidine compounds have been published, there are few general routes to this class of compounds, and there is therefore a need for such routes to be developed. Bicyclic lactams derived from (S)-pyroglutamic acid have been shown to be useful synthons in the synthesis of pyrrolidines. An analogous bicyclic lactam was therefore synthesised from (S)-lysine. Alkylations at the carbon atom a- to the lactam carbonyl group were studied in detail. A number of different groups could be introduced in good to excellent yield, and with moderate to good stereoselectivity. The selectivity of these reactions was believed to depend on the shape of the bicyclic system, and a stereoelectronic effect of the nitrogen lone pair. The bicyclic lactam was further elaborated to an activated enone. This was shown to be relatively unreactive to cycloaddition reactions. It is believed that this is because the activating ester group is not conjugated with the carbon-carbon double bond. However, conjugate addition could be achieved in high yield and excellent stereoselectivity using a zinc enolate Reformatsky reagent. An epoxide could also be formed in excellent yield and with excellent stereoselectivity. The Reformatsky adduct was shown to be a suitable substrate for a Pb(IV)-mediated arylation reaction. Examples of the functionalised lactams were deprotected to give hydroxymethyl piperidinones and cyclic amino acids. This route therefore allows access to the desired novel compounds.

This dissertation describes four synthetic organic chemistry projects and two computational organic chemistry efforts centered on the Castagnoli-Cushman reaction (CCR) of imines with anhydrides and their derivatives. Chapter one includes a literature review and detailed background on the current state of the CCR, including mechanistic hypotheses and recent catalytic examples. Chapter two details the development of conjugate addition reactions of imines with cyclic enolizable anhydrides to afford β-enaminoketone products. Chapter three describes efforts toward an acid-catalyzed Mukaiyama-type CCR reaction of 2,5-bis(trimethylsilyloxy) furan, including a stereochemical proof by computational NMR. Chapter four describes progress toward the synthesis of the elusive bis-?-lactam natural product bisavenanthramide B-1 by way of the Mukaiyama CCR. Finally, chapter five discusses the mechanistic investigation of the multicomponent variants of the CCR, leading to a new mechanistic proposal for reactions of these type.

The first project addressed in this dissertation involved the synthesis of highly strained, bridged sultams and lactams. With a primary focus on the sultams, triplet-sensitized irradiation in acetone solution gave rise exclusively to a tetracyclic sultam through a regiospecific di-pi-methane rearrangement. A strong preference for benzo-vinyl bridging distal to the sulfonamide functional group was observed. This transformation constituted a facile means for accomplishing the ring contraction of a bridgehead sultam. In a continuing exploration of the photoactivation of sultam and lactam systems, a convergent strategy was developed to access bridgehead sultams and carboxamides of varying sizes bearing a diene unit. The key reactions in these syntheses were the use of a Grubbs I mediated ring-closing metathesis, an intramolecular Heck reaction providing the desired tricyclic intermediates, and a twofold dehydrobromination mediated by tetrabutylammonium fluoride in DMSO. Irradiation of the azatricyclosultam led principally via SO2-N bond homolysis and [1,5] sigmatropic rearrangement to 5,6-dihydro-4bH-10-thia-6-azabenzo[a]azulene 10,10-Dioxide. The methano-bridged carboxamide proceeded via disrotatory cyclization to the exo cyclobutenamide, and the ethano-bridged carboxamide resisted photoisomerization. Based on the prior set of results, a non-bridged planar arrangement was postulated to elicit similar chemical transformations in structurally related systems. A parallel strategy allowed access to a pair of pyridoisoindolones and their previously unknown sultam counterparts. Detailed study of the excited-state chemistry of 4H-pyrido[2,1-a]isoindol-6-one and 10b-methyl-10bH-pyrido[2,1-a]isoindol-6-one showed both lactams to be subject to [4+2] dimerization under acetone-sensitized conditions. No dimers could be isolated from the sultam photolysates under any conditions. While the 4b-methylazafluorene 9,9-Dioxide underwent extensive polymerization, 8H-azafluorene 9,9-dioxide was transformed via direct irradiation at 350 nm into a thienopyridine and benzoisothiazole via [1,3]-sigmatropy involving the S-N bond and heterocyclic ring cleavage, respectively. Next to be addressed was the total synthesis of salicifoline. Salicifoline was isolated from Euphorbia salicifolia in Budapest, Hungary during 2001, and represents the first example of a cembranoid derived tricyclic jatrophene diterpene polyester containing a novel bicyclo[5.5.1]core. Aside from the evident synthetic challenge, there is a pronounced interest in cembranoid jatrophenes due to their inherent multi-drug resistance reversing properties. The final project deals with the total synthesis of pseudolarolide E. This triterpene dilactone was isolated from Pseudolarix kaempferi and is commonly used in traditional Chinese medicine to treat a variety of skin conditions. This structure holds synthetic interest due to the rare 11-membered core it possesses.

The purpose of this investigation was to provide a systematic study of the cycloaddition pf (N-alkyl-N-phenylamino)- methoxy-and dichloroketenes to various imines and to investigate the stereochemistry of these cycloadditions.