This thesis is concerned with the development of ring-closing iodoamination and ringexpansion methodology and its subsequent application to the asymmetric syntheses of pyrrolidine and piperidine iminosugars. <strong>Chapter 1</strong> highlights the remarkable biological properties displayed by iminosugars and introduces methods for the formation of the pyrrolidine and piperidine sub-classes. <strong>Chapter 2</strong> describes investigations into the ring-closing iodoamination of bishomoallylic amines which occurs with concomitant <i>N</i>-debenzylation to give an iodomethyl pyrrolidine scaffold. Conversion to the corresponding aziridinium species followed by its regioselective intermolecular ring-opening by H₂O enabled the synthesis of (+)-2,5-dideoxy-2,5-imino-Dglucitol (DGDP). A protocol for the preparation of its 1-deoxy-1-amino analogue (+)-ADGDP was also developed. <strong>Chapter 3</strong> details studies into the ring-expansion of iodomethyl pyrrolidine scaffolds via the trapping of CO₂ (from NaHCO₃) to produce cyclic carbonates as single diastereoisomers. Subsequent deprotection of these piperidines allowed the syntheses of (−)-1-deoxymannojirimycin (DMJ) and (+)-1-deoxyallonojirimycin (DANJ) to be completed. <strong>Chapter 4</strong> delineates investigations into the trapping of alternative “X=C=Y” electrophiles, via the ring-expansion methodology developed in Chapter 3, initially utilising a model system. These studies culminated in the development of the trapping of <i>p</i>-TsNCO and the application of this methodology in the total asymmetric syntheses of (−)-ADMJ and (+)-ADANJ, the 2-deoxy-2-amino analogues of (−)-DMJ and (+)-DANJ, respectively. <strong>Chapter 5</strong> contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2, 3 and 4.

The Heck reaction has become a fundamental reaction for synthetic organic chemists over the last half century and is utilised heavily in the fine chemical industry and for natural product synthesis. This thesis describes some of the applications of the Heck reaction to modern day organic synthesis. Introduction: This section presents an overview of the Heck reaction starting from its conception during the late 1960s to present day understanding. A variety of ligand classes are described along with commonly accepted catalytic cycles for their activity during the reaction. Results and Discussion: In the first part of the thesis, the use of a cross-metathesis/Heck reaction protocol to synthesise a range of 2,4,6-trisubstituted pyridines is described. Attempts were made to expand the scope of the methodology by employing vinyl Weinreb amides, but this proved unsuccessful for the synthesis of pyridines. Nevertheless, the Heck reaction on vinyl Weinreb amides worked efficiently and the scope of this arylation was explored. Following on, the functionalisation of the Weinreb amide products was studied to generate a range of enone products, some of which would be difficult to synthesise via direct Heck reaction on the respective precursor enone. In the second part of the thesis, previous syntheses of inthomycin B and inthomycin C are described. The synthesis of inthomycin B and inthomycin C were then attempted using an unprecedented Mukaiyama aldol/cross-metathesis based approach to generate the triene core of both natural products.

This thesis investigates a total synthesis of the incednine aglycon by utilising alkenylsilane reagents to assemble the pentaenyl and tetraenyl systems through cross-coupling reactions. The early chapters develop methodology to access both cyclic alkenylsiloxanes and functionalised (E)-alkenylsilanes by the controlled hydrogenation of alkynylsiloxanes and silylolefination of aldehydes, respectively, and culminate in the synthesis of a C6-C13 bis(alkenylsilane)incednine fragment (Scheme 1). The C1-C5 and C14-C23 coupling partners are synthesised in three and ten steps from propargyl alcohol and L-alanine methyl ester through phosphorous-based olefination strategies. In the final chapter we describe our first generation approach to incednine which entails orthogonal cross-couplings to construct the C5-C6 and C13-C14 bonds (Scheme 2).

Asymmetric phase-transfer catalysis is a powerful technique that enables a wide range of transformations under mild conditions, often using inexpensive and environmentally benign reagents. By extending the applications of phase-transfer catalysis we have developed a highly diastereo- and enantioselective synthesis of functionalized indolines bearing two contiguous stereocentres, one of which is quaternary and all carbon, in a single synthetic step. The reaction proceeds with complete diastereoselectivity and with high levels of enantioselectivity (up to 99% ee). Despite the development of phase-transfer catalysis as a primary synthetic tool in organic synthesis, the mechanistic understanding of these reactions still remains a challenge, due mainly to the difficulty of studying the complex multi-phase systems. Therefore, a further aim of this project was to understand the reaction mechanism of our phase-transfer catalysed transformation. Investigations into the mechanism of our phase-transfer catalysed reaction have been carried out by studying the reaction kinetics. These have shown that the reaction follows a sigmoidal curve with an induction period present. A detailed kinetic investigation was carried out which demonstrated that an autocatalytic mechanism is operational.

This work describes the design and synthesis of a set of four organic molecules that are intended to hydrogen-bond to each other in a pairwise manner. The four hydrogen-bonding units, termed ‘A’, ‘B’, ‘C’ and ‘D’, when placed in solution together, are designed so that A binds only to B, and C binds only to D. Each unit does not bind to itself, nor to either of the other two units to which binding is not intended. For example, A binds to B, but not to A, C, or D. Each unit contains an array of four hydrogen-bonds for strong binding to its partner, is designed to be as rigid as possible, as non-tautomeric as possible, and utilises a staggered non-symmetrical architecture. Of the four intended compounds, three were successfully synthesised (A, B and D). Units B and D were soluble in CDCl₃, but Unit A was not. Therefore, the design and synthesis of Unit A was amended, and two variants of Unit A that are both soluble in CDCl₃ were successfully synthesised. ¹H NMR binding experiments were performed between Unit B and each of the two variants of Unit A. Their binding behaviour was described. A binding constant could not be calculated because the units did not bind in a 1:1 fashion.

Introduction: The introduction provides a survey of the natural product and pharmaceutical targets accessible from dihydropyridines and dihydropyridones as well as an overview of previous work carried out towards the synthesis of these valuable intermediates. The mechanism, scope and limitations of the various approaches are covered, along with the goals of this project. Results and Discussion: A Regioselective Route to Dihydropyridones. The regioselective addition of nucleophiles to a range of disubstituted pyridinium salts has been achieved, with selectivity determined by hard/soft factors. Certain nucleophiles can be added with complete regioselectivity to either C-2 or C-6 of these salts, depending on the conditions employed. Addition at C-2 allows the generation of a quaternary centre in high yield. The conditions discovered can be applied to pyridinium salts with different substitution patterns and an effective procedure has been developed for the removal of the nitrogen protecting group post reduction. The Preparation of Enantiopure Dihydropyridones.After unsuccessful attempts to find a reagent-controlled asymmetric synthesis of dihydropyridones, a highly diastereoselective and non-chiral auxiliary based substrate-controlled procedure has been developed. By prompting an intramolecular hydride migration from a secondary silyl ether onto the pyridinium core, the corresponding dihydropyridones are available in high yield, with the diastereoselectivity being controlled by the minimization of 1,3-allylic strain between the N-allyl group and the hydride-bearing side chain. Thus, an enantiopure pyridyl alcohol may be converted to the corresponding dihydropyridone without loss of enantiomeric purity. Furthermore, the dihydropyridones can be easily converted to complex bicyclic systems via a ring closing metathesis reaction. Experimental: Full experimental procedures and spectroscopic characterization of compounds are provided.

In this thesis, the effect of fluorinating reagents on a selection of transition metal-mediated organic transformations was investigated. The first four chapters are focused on gold-catalysed nucleophilic addition processes performed in the presence of “F⁺” sources. Chapter 1 provides a general introduction to homogeneous gold catalysis and summarises the aims and objectives of the project. The effect of the electrophilic fluorinating reagent Selectfluor (82) on the gold-catalysed rearrangement of propargyl acetates 85 is discussed in Chapter 2. α-Fluoroenones 92 resulting from fluorodeacetylation of an allenyl acetate intermediate were delivered as the major products of these reactions (Scheme i). [Scheme i Gold-Catalysed Rearrangement-Fluorodeacetylation of Propargyl Acetates 85.] By contrast, performing the gold(I)-catalysed cyclisation of allenoates 102 in the presence of Selectfluor (82) led to products of oxidative coupling. The “F⁺” source in these processes most likely acts as an external oxidant in an Au<sup>I</sup</Au^III redox cycle. In Chapter 3, the cascade cyclisation-intramolecular arylation of benzyl-substituted substrates is discussed whilst the extension of the methodology towards intermolecular homocoupling and intermolecular alkynylation is presented in Chapter 4 (Scheme ii). [Scheme ii Gold-Catalysed Cyclisation-Oxidative Coupling of tert-Butyl Allenoates 102.] In Chapter 5, the feasibility of palladium-catalysed allylic [¹⁸F]radiofluorination was investigated using high-specific-activity [¹⁸F]fluoride. This study led to the development of the first transition metal-mediated C-¹⁸F bond-forming process of relevance for the preparation of radiotracers for PET imaging (Scheme iii). [Scheme iii Palladium-Catalysed Allylic [18F]Radiofluorination of Allylic Methyl Carbonate 227b.] Chapter 6 gives full experimental procedures and characterisation data for all compounds.

Caged compounds are biologically active molecules that are rendered inert by masking an important functionality with a photolabile protecting, ‘caging’, group. The caging group can be removed by irradiation with light to reveal the active compound with restored pharmacological activity with high spatial and temporal control. This technology provides an ideal tool for the study of many chemical, physiological and biological systems. This DPhil dissertation highlights several projects in which caging technology has been employed to address biological problems and questions. The first example of spatially controlled mitochondrial inactivation is reported - a tool for the study of the role of mitochondria in Ca2+ signalling. Caged TRPV1 agonists and antagonists have been developed to probe TRPV1, specifically the location of the agonist-binding site. T cell activation has been controlled with light as a tool to gain insight into the adaptive immune response. Caged sodium channel blockers have been investigated. Wavelength-orthogonal photolysis in a neuronal system has been demonstrated using the neurotransmitters glutamate and GABA - this represents a significant advancement in caging technology. This dissertation also includes investigations into the development of novel caging groups.

This thesis describes the development of new osmium-mediated methodologies providing novel applications through the use of a third generation of reoxidant for osmium. Chapter 1, The introduction: Summary of past and present methodologies towards the synthesis of the 1,2 amino alcohol motif. Chapter 2, Intramolecular processes: The studies of the tethered aminohydroxylation (TA) of amide and urea derivatives are being investigated. Chapter 3, Investigations towards an intermolecular process: The transposition of the TA methodology to an intermolecular process and the requirements involved are discussed. The role of acetamide is being investigated. Chapter 4, Successful transition to an intermolecular process: Amino acid derivatives became for the first time possible nitrogen sources and were efficiently employed through osmium-mediated reaction to afford interesting biological scaffolds. Chapter 5, Experimental: Full experimental procedures and characterisation of compounds are reported. References: A complete list of citations employed in the previous five chapters is provided. Appendix: Full documentation of X-ray crystal structures, key NMR spectra and HPLC traces is provided.

This thesis is concerned with the development and application of methods for the stereoselective cyclopropanation of allylic amines and derivatives. Firstly, a highly chemo- and stereoselective cyclopropanation of N,N-dibenzyl-protected allylic amines was developed using the highly reactive Shi’s carbenoid [CF₃CO₂ZnCH₂I]. Subsequent mechanistic studies revealed that the high diastereoselectivity of the reaction was likely to be due to coordination of the amine to the zinc carbenoid reagent. It is then shown that the reaction is general for a wide range of both cyclic and acyclic substrates giving the corresponding cyclopropanes in high yields and diastereoselectivities. Secondly, a novel stereodivergent cyclopropanation of allylic carbamates and amides was developed. It was found that reaction of cyclic allylic carbamates with the Wittig-Furukawa reagent [Zn(CH₂I)₂] typically gives the syn-diastereoisomer in high yields and diastereoselectivities, whilst treatment of the same substrates with Shi’s carbenoid [CF₃CO₂ZnCH₂I] gives the corresponding anti-diastereoisomers in high yields and diastereoselectivities. Mechanistic investigations suggested that reactions with the Wittig-Furukawa reagent proceed via a N-directed intramolecular cyclopropanation step whilst those with Shi’s carbenoid proceed via a sterically directed intermolecular cyclopropanation step. Unsuccessful investigations into an asymmetric variant of the cyclopropanation reaction utilising chiral carbamate protecting groups are then described. Finally, studies towards the total synthesis of the potential anti-obesity therapeutic trans-SCH-A and its epimer cis-SCH-A are described. A stereodivergent route towards the epimeric products was developed through the cyclopropanation of a common allylic carbamate intermediate with either the Wittig-Furukawa reagent or Shi’s carbenoid to give the corresponding trans-2-amino-5-arylbicyclo[3.10]hexane or cis-2-amino-5-arylbicyclo-[3.10]hexane intermediates respectively.