This dissertation describes work towards two marine alkaloid natural products of the manzamine family. The total synthesis of (–)-nakadomarin A, via two conceptually different strategies is described along with the development of a novel nitro-Mannich-Mannich cascade reaction, which has been applied in a synthesis of the diazatricyclic core of the madangamines. A short and highly stereoselective synthesis of (–)-nakadomarin A has been developed. A sequential alkyne ring-closing metathesis/syn selective reduction strategy enabled the stereoselective construction of the Z-configured alkene in the fifteen-membered macrocycle of the molecule. ‘Matched’ catalyst and substrate control facilitated a highly diastereoselective nitro olefin Michael addition to fix two of the four stereocentres in one key step. Furthermore, a nitro-Mannich/lactamization cascade, furan N-acyl iminium ion cyclisation and alkene ring-closing metathesis enabled the total synthesis of the natural product in 19 steps. In collaboration with Prof. Amir Hoveyda and Prof. Richard Schrock, an alternative approach to a highly Z-selective macrocyclic ring closure in the synthesis of (–)-nakadomarin A has been developed. Three diene substrates were prepared and the Z-selectivity of alkene ring-closing metathesis investigated using a range of molybdenum MAP (monoaryloxide pyrrolide) catalysts. Initial studies using these catalysts produced promising results (Z:E = ~1.2:1), relative to commercially available ruthenium metathesis catalysts (Z:E = 2:3). Using a recently developed chiral tungsten MAP complex, alkene ring-closing metathesis was found to proceed in excellent yield (90%) with exceptional Z:E-selectivity (Z:E ~1.2:1) and requiring only low catalyst loadings (5 mol%). A novel nitro-Mannich-Mannich cyclisation cascade has been developed allowing access to highly functionalized piperidines. Application of this unprecedented mode of reactivity using a substrate derived from a Michael-addition of methylcyanoacetate to a functionalized cyclic nitro olefin allowed the preparation of a cis-fused 6,6’-bicycle in excellent yield. Further elaboration of this 6,6’-bicycle enabled the synthesis of the diazatricyclic core of the madangamine alkaloids to be achieved.

<strong>Chapters 1</strong> and <strong>2</strong> of this thesis focus on the application manganese(III) and copper(II)-mediated oxidative radical cyclisation of alkenyl amidomalonates to the formation of pyrrolidinone-lactones and their subsequent use in the total syntheses of highly bioactive natural products. A novel concise total synthesis of (-)-salinosporamide A based on the oxidative cyclisation previously developed in the group is presented in <strong>chapter 1</strong>. The second chapter discusses the work towards the pyrrolidinone core of the oxazolomycin. Each chapter contains its own introduction to set in context the presented results, which discusses the isolation and the biological activity of the two families of natural products. Previous synthetic work toward salinosporamide A and the oxazolomycin family achieved in the group and reported in the literature is also described in the introduction of each chapter. The third chapter of the thesis succinctly presents the extension of the scope of the manganese(III) and copper(II)-mediated oxidative radical cyclisation reaction. The optimisation, development and scope of the rapid access to fused THF-lactones via the cyclisation of alkenyl oxymalonates is described. Preliminary synthetic manipulations of the resultant bicyclic products to study the application possibilities of the new reaction in future complex molecules syntheses are also presented. The final conclusion gives a summary of the results obtained and introduces the proposed future work that may arise from these three areas.

This thesis describes the development of synthetic strategies towards the densely functionalised pyrrolidinone core of the polyene &beta;-lactone-&gamma;-lactam antibiotic oxazolomycin A. <strong>Chapter 1 The oxazolomycins</strong> The oxazolomycins, a unique class of biologically active molecules containing a spiro-fused β-lactone-γ-lactam ring system are introduced. The isolation, structural elucidation and biological properties of the oxazolomycins as well as those of the structurally related inthomycins are reviewed. <strong>Chapter 2 Previous syntheses</strong> The two total syntheses of neooxazolomycin and the synthetic approaches to the pyrrolidinone core of oxazolomycin A and KSM-2690 B are evaluated. <strong>Chapter 3 Project aims</strong> An outline of the synthetic strategy employed in this project and details of the novel retrosynthesis of the pyrrolidinone core of oxazolomycin A are discussed. <strong>Chapter 4 Synthetic studies towards the pyrrolidinone core of oxazolomycin A</strong> The synthetic studies carried out towards the pyrrolidinone core of oxazolomycin A are described in detail. The preparation of an advanced intermediate containing the five chiral centres, four of which are contiguous, was achieved in twenty steps as a single diastereomer and as a single enantiomer. <strong>Chapter 5 Synthetic studies towards the middle fragment of oxazolomycin A</strong> A novel synthetic approach to the diene fragment contained in oxazolomycin A is reported. The formal synthesis of a dienyl iodide, in four fewer steps than previously reported was accomplished. <strong>Chapter 6 Conclusions and future work</strong> A summary of the synthetic work reported in this thesis and proposals for future study are presented. <strong>Chapter 7 Experimental</strong> Full experimental procedures and characterisation of compounds are reported. <strong>Chapter 8 References</strong> A complete list of citations employed in the previous seven chapters is provided.

This thesis describes the studies towards the synthesis of β-amino acids found in the microsclerodermins, a family of complex macrocyclic hexapeptides. These β-amino acids have four or five contiguous stereocentres and an aliphatic side-chain. The synthetic route utilised an aminohydroxylation reaction to install the most challenging moiety in the structure - the 1,2- amino alcohol. The work aimed to construct the core structure (five contiguous stereocentres) of the β-amino acids and install the side-chain later to enable the synthesis of multiple members (A, B, F, G, H and I) of the microsclerodermin family. The synthesis started with Roche ester, which contained the first methyl stereocentre. It was converted to the diene precursor in four high yielding steps. The next two stereocentres were installed via a Sharpless asymmetric dihydroxylation. With the appropriate protecting groups in place, the remaining two stereocentres were to be installed via a Sharpless asymmetric aminohydroxylation. Various reported reagents and conditions were used to effect the transformation, but the attempts were unsuccessful. This forced us to alter our synthetic plans, and the revised synthetic route involved the use of the tethered aminohydroxylation (TA) reaction developed by the Donohoe group. After the development of an efficient protocol to prepare the TA-precursor, the alkene, with three stereocentres already in place, was successfully converted to the desired stereopentad via the TA-reaction (10 steps, 11% overall yield). With the stereopentad in hand, installation of the side-chain of the β-amino acids through an alkenyl or alkyl linkage was investigated. For alkenyl-linked side-chains, the appropriate aldehyde was synthesised, but attempts to effect the transformation via a Horner-Wadsworth- Emmons reaction or a Witting reaction failed. With lessons learnt from those, we then focused our efforts on installing an alkyl-linked side-chain. In this case, we were able to install a side- chain via a copper-mediated displacement reaction, which gave us a protected form of the precursor of the β-amino acid of microsclerodermin B. Finally, various efforts to study the reactivity of the stereopentad and the investigations into finding the most effective set of protecting groups have been used to propose a synthetic route for the incorporation of the β- amino acid into the macrocycle.

The work presented in this thesis mainly describes the development of new reactions of &beta;-lithiooxyphosphonium ylides to access stereodefined substituted alkenes in a highly convergent fashion. Firstly, &beta;-lithiooxy ylides prepared from aldehydes and phosphonium ylides were shown to react with halogen electrophiles to provide a highly stereoselective route to E-alkenyl bromides and iodides. This methodology was successfully applied to the first total synthesis of naturally occurring (5E,9Z)-6-bromohexadeca-5,9-dienoic acid. Secondly, an experimentally straightforward method was developed for the stereocontrolled formation of trisubstituted Z-allylic esters by in situ trapping of &beta;-lithiooxyphosphonium ylides with readily available halomethyl esters. The synthetic utility of this methodology was demonstrated with the synthesis of plaunotol [(2Z,6E)-2-((E)-4,8-dimethylnona-3,7-dien-1-yl)-6-methylocta-2,6-diene-1,8-diol] and the first asymmetric synthesis of the naturally occurring geranylgeraniol-derived diterpene (6S,7R,Z)-7-hydroxy-2-((E)-6-hydroxy-4-methylhex-4-enylidene)-6,10-dimethylundec-9-enyl acetate. Furthermore, the chemistry of &beta;-lithiooxyphosphonium ylides was expanded to access synthetically useful disubstituted Z-allylic esters. The synthetic utility of Z-allylic esters was also demonstrated in a versatile and diastereoselective Ireland-Claisen rearrangement to access &gamma;,&delta;-unsaturated acids. Finally, the synthesis of the side-chain of the 6,7-dideoxysqualestatin H5 was also investigated. It was demonstrated that the side-chain of 6,7-dideoxysqualestatin H5 could be accessed by a convergent and stereoselective organozinc-based strategy.

Iminosugars are known to behave as carbohydrate mimics in biological systems by virtue of their similar structures. However as the ring nitrogen prevents metabolism it means that iminosugars have the potential to become inhibitors of these systems. It is known, for example, that iminosugars can behave as mimics in the hydrolysis mechanism. This leads to possible medicinal applications of iminosugars. One such case is lysosomal storage disorders which arise as a result of a genetic defect which causes missense mutations coding for the N-acetylhexosaminidase enzymatic protein. N-Acetylhexosaminidases are a sub-member of the class of glycosidase enzymes. They are responsible for the cleavage of N-acetylhexosamine residues from glycoconjugates in the lysosome. Mutations in the gene coding for this protein lead to a deficiency in the enzymatic activity resulting in accumulation of unhydrolysed substrate in the lysosome. Lysosomal storage disorders have a phenotype of poor motor development and neurological problems. The infantile form usually leads to death before the age of five. An iminosugar mimic could give rise to a possible treatment for lysosomal storage disorders by acting as a molecular chaperone during protein folding, promoting correct folding by its intrinsic affinity for the native fold of the enzyme. Likewise in the treatment of cancer, the inhibitory ability of iminosugars has potential applications. In cancer, extracellular hydrolysis occurs which favours cancer cell survival. Macrophages, which attack and eliminate cancer cells, can be activated by macrophage activating factor (MAF) which displays an α-N-acetylgalactosamine residue that appears essential for the activation cascade. Cancer cells secrete an α-N-acetylgalactosaminidase enzyme that acts to decrease the potency of MAF, thus promoting cancer cell survival. Inhibition of cancer cell α-N-acetylgalactosaminidase may restore macrophage activation and generate potential therapeutics. Chapter 1 of this thesis contains extended discussion of the aforementioned, and related, diseases and the therapeutic applications of iminosugars. Some historically and biologically important iminosugars are described along with some current iminosugar drugs. Chapter 2 describes the synthetic strategies explored in an attempt to synthesise all the members of the 2-acetamido pyrrolidine iminosugars. An overview of the compounds synthesised towards this end by a past group member is given along with the work performed as part of this thesis to complete this goal. Both enantiomers with arabino- and ribo- stereochemistry and D-lyxo- were previously synthesised. The syntheses of both enantiomers with xylo- stereochemistry along with the L-lyxo- compound were completed as part of this thesis, from either D- or L-glucuronolactone and D-ribose, respectively. Chapter 3 details the synthetic strategy adopted to synthesise the enantiomer of D-DNJNAc, the first potent α-N-acetylgalactosaminidase inhibitor to be found. The synthesis towards another piperidine iminosugar, 6-deoxy DGJNAc, is presented in the second half of this chapter, along with two related compounds.

Iminosugars are polyhydroxylated alkaloids, and can be viewed as sugar analogues in which the endocyclic oxygen atom has been replaced with nitrogen. These compounds are highly medically relevant and their biological activity is largely due to their inhibition of glycosidases. Several examples of the iminosugar class are currently marketed as drugs, and many more are in earlier stages of development for a variety of diseases and disorders. The most fruitful approaches to the chemical synthesis of iminosugars have utilised carbohydrate starting materials as optically pure chiral building blocks, or chirons. Most of the monosaccharides are not readily available, but the relatively few naturally abundant cheap sugars have been exploited as chirons for over a century. The availability of the rare sugars is growing with the development of a new biotechnological approach to their synthesis, known as Izumoring. This thesis is primarily concerned with the chemical synthesis of iminosugars from carbohydrate starting materials. The synthesis of unnaturally functionalised sugar polyols and their suitability as substrates for the Izumoring process is also discussed. Chapter 1 provides a brief general overview of the history, natural occurrence and therapeutic application of iminosugars. General strategies for their synthesis from carbohydrate chirons are discussed. Chapter 2 concerns divergent syntheses of several iminosugar targets from both enantiomers of glucuronolactone and their biological evaluation. A new scaleable synthesis of the natural product 1-deoxynojirimycin is presented that has since been adopted for commercial purposes, as well as an efficient strategy for the synthesis of both enantiomers of 2,5-dideoxy-2,5-imino- mannitol and their novel amino acid analogues. Access to hexosaminidase inhibiting acetamido- substituted piperidines is presented, including 2-acetamido-1,5-imino-1,2,5-trideoxy-D- galactitol, which has been found to be one of the few known potent and specific inhibitors of α- N-acetyl-galactosaminidase. This inhibitory profile may allow the compound’s use for further investigation of a strategy for cancer treatment. Chapter 3 concerns the synthesis of carbon branched pyrrolidines and their biological evaluation. A novel and highly potent α-glycosidase inhibitor has been discovered, synthesised by a strategy that utilises the benzhydryl ether as key protecting group. A mild method for the introduction of this protecting group has been shown to be general to a range of sterically congested and/or acid/base sensitive carbohydrate lactones. Chapter 4 concerns the synthesis of deoxygenated and fluorinated sugar alcohols and their successful biotechnological transformation into ketoses by the Izumoring process. Publications arising from this work are included in the Appendix.

This thesis firstly describes a synthesis of the natural product taurospongin A, a potent DNA polymerase beta inhibitor. Sharpless asymmetric dihydroxylation on olefin <b>E-1.60</b> followed by selective deoxygenation at C(2) via Barton‒McCombie reaction delivers the desired C(1)–C(10) carboxylic acid core. Subsequent esterification of the C(1)–C(10) fragment with C(1′)–C(25′) fatty acid furnishes the natural product in 13.5% yield. The structure of an unnamed natural product <b>2.14</b> isolated in 1974 is proven to be misassigned by previous studies within the Robertson group. As described in this thesis, two proposed structures A and B are obtained via total synthesis in order to reveal the identity of the natural product. A synthesis of key intermediate spirocycles <b>2.148</b> and <b>2.158</b> with desired trans- diol moiety is described by a dihydroxylation reaction on an electron deficient gamma-keto unsaturated acid with subsequent spirocyclisation reaction. Finally, methodology for generating high-value synthetic intermediates by an asymmetric, one-pot enzymatic di/polycarbonyl reduction is described. The concept of such methodology is first proven by the synthesis of (3R)-hydroxybutyl (3R)-hydroxybutanoate <b>3.20</b>. This thesis then describes substrate scope studies and corresponding stereochemical proof to provide more information about this methodology.

Small rings are frequently found in natural products as well as incorporated into drugs and agrochemicals in which they impart valuable properties on the biological activity of these compounds. Cyclopropanes are also extremely useful as reagents in organic synthesis, in particular as “umpolung” reagents, allowing access to products which would otherwise be more difficult to synthesise. This thesis will describe forays into the synthesis and further substitution of small rings as well as the iminium-catalysed ring-opening of cyclopropanes. The introduction will outline the uses and properties of cyclopropanes, and will also describe some of the more common ways for incorporating cyclopropanes into larger structures. This will include the Horner–Wadsworth–Emmons procedure which has previously been developed by the group. The second chapter describes efforts towards the iminium-catalysed nucleophilic ring-opening of cyclopropanes. This is followed by Chapter 3, in which the Horner–Wadsworth–Emmons methodology for the synthesis of the cyclopropanes used in Chapter 2 is investigated as a procedure for the synthesis of 4-membered heterocycles. Chapter 4 describes the development of a decarboxylative method for the protodecarboxylation of cyclopropanecarboxylic acids. This was developed as the first step towards decarboxylative cross-coupling of cyclopropanes. Decarboxylative cross-couplings have been extensively developed as environmentally friendly and facile alternatives to the current cross-coupling methods. In Chapter 5 the attempted development of a decarboxylative cross-coupling reaction of cyclopropanes is described. Conclusions and future work are outlined in Chapter 6, followed by the experimental details in Chapter 7.

This work describes developments in new azetidine and azetine chemistry; specifically, methods developed for the introduction of functionality α- to nitrogen in both ring systems, with additionally in situ formation of the latter system, from azetidine substrates. Chapter 1 discusses the growing importance of azetidines, and the current methods available for making substituted azetidines by ring formation. Further discussion comprises of current sp³ C–H activation approaches α- to nitrogen in heterocyclic compounds as potential methods for sp³ C–H activation on azetidines to give substituted azetidines. Previous work by the Hodgson group in this area is detailed. Chapter 2 describes the advance made towards 2,3-disubstituted azetidines using the thiopivaloyl protecting/activating group, where the latter plays a key role. Optimisation, scope, selectivity and mechanistic insight into the α-deprotonation–electrophile trapping of a 3-hydroxy azetidine system is discussed, which successfully gives access to a range of 3-hydroxy-2-substituted azetidines. Preliminary investigations with 3-alkyl-2-substituted azetidines are also described. Chapter 3 describes the development of a straightforward protocol to make 2-substituted-2- azetines, a rarely studied and difficult to access 4-membered azacycle subclass, from readily accessible azetidine starting materials using α-deprotonation–in situ elimination followed by further α-lithiation–electrophile trapping. Extension of this methodology by transmetallation from the intermediate organolithium to the organocuprate, resulting in greater electrophile scope, is also described.