Palladium-catalyzed olefin dioxygenation is a powerful tool in the generation of complex and valuable substrates, one which may become complimentary to the well known Sharpless dihydroxylation. In this work the mechanism of this transformation is examined via reaction kinetics and Hammett studies, which corroborate a PdII/IV catalytic cycle and suggest that the rate determining step is the oxidation of PdII to PdIV. Olefin dioxygenation was also found to proceed in the presence of catalytic quantities of BF3•OEt2 or triflic acid, with stoichiometric hypervalent iodine oxidant and an acetic acid solvent. Furthermore, asymmetric variants of intramolecular palladium-catalyzed olefin dioxygenation were also investigated, which resulted in the formation of tetrahydrofuran products in up to 36% ee. Next, chelate-assisted C–H bond functionalization of indoles at the C7 position and of carbazoles at the C1 position was investigated with a variety of arylation, halogenation and oxygenation techniques. Lastly, our efforts towards the synthesis of a mono-phosphine based [5]helicene ligand via olefin metathesis and photocyclization strategies will be discussed.

Imaging membrane potential is a promising technique in the elucidation of the interactions of large networks of neurons. The membrane potential in a neuron varies as an action potential, the basic electrical signal of neuronal communication, travels along the length of the cell. Voltage sensitive dyes play a key role by providing an optical readout of the electric field generated across a neuron membrane by the action potential. However, none of the dyes reviewed in Chapter 1 generate sufficient signal change with changes in membrane potential; this sensitivity problem limits the ability of the imaging membrane potential technique to allow the high spatial and temporal resolution necessary for neuronal networks to be better understood. This thesis features two avenues of research that are expected to result in the necessary enhancements to voltage sensitive dyes to improve the signal change. The first avenue is based on the effect of an electric field upon the non-linear optical properties of a porphyrin macromolecule. The encouraging field sensitivity of a previous porphyrin monomer voltage sensor inspired an investigation which identified optimisations to enhance the voltage sensitivity (Chapter 2). The design, synthesis and initial characterisation of optimised porphyrin voltage sensors is detailed in Chapter 3. The second avenue is based on the effect of an electric field upon the rate of intermolecular electron transfer. In a suitably designed dye, the competition between electron transfer and fluorescence, following excitation by incoming light, allows the fluorescence intensity to act as an optical indicator of the electron transfer rate. New dyes were rationally designed and synthesised, as this effect had not been applied to voltage sensitive imaging before the research detailed in Chapter 4. The challenging purification of the new amphiphilic dyes synthesised also inspired research into a novel testing method which does not require amphiphilic dyes (Chapter 5).

This thesis describes our examination of the reactivity of allenylpalladium intermediates generated from the reaction of palladium(0) with propargylic electrophiles. Chapter 1 provides a general overview of the literature reported to date concerning the nature and reactivity of allenylpalladium intermediates. The coupling of a variety of propargylic electrophiles with aryl boronic acids to form allenes is examined in Chapter 2. However, when employing diastereomerically pure electrophiles, some erosion of stereochemistry was observed in the allene products. This effect was examined further, and epimerisation of the allene product was found to be the origin of the loss of stereochemistry. Evidence for the species likely responsible for this epimerisation is presented. The serendipitous formation of tetrahydrofurans (THFs) from propargylic 7-membered cyclic carbonates prompted an in-depth examination of this reactivity, as described in Chapter 3. The reaction of these cyclic carbonates was rendered stereoselective and the stereochemical outcome of the reaction elucidated. The methodology was extended to propargylic acyclic carbonates which allowed the formation of tetrahydropyrans (THPs). The effect of ring-size and substituents on the cyclisations was examined, culminating in the formation of two rings in a single step from diol-containing bis-carbonates. Chapter 4 describes the extension of this methodology to the formation of azacyclic products. This built upon foundation work conducted by a Part II student within the group, and further improved the selectivity of the reaction. Two diverse azacyclic skeletons could be formed from the same substrate by the employment of different bidentate phosphine ligands, and a variety of substrates were examined under these conditions. Chapter 5 draws general conclusions and sets out possible future directions for the methodology, and full experimental details are outlined in Chapter 6.

A brief summary of the use of palladium as a catalyst, the characteristic reactivity of palladium complexes and the commonly used palladium-catalysed cross coupling reactions is given, with a special focus on the palladium-catalysed α-arylation of enolates and its application to the synthesis of aromatic heterocycles. The synthesis of aromatic heterocycles via both traditional methods and more recent metal-catalysed approaches is discussed in the context of isoquinolines. The palladium-catalysed oxidation of dihydrofurans bearing an ortho-bromophenyl group at the 2-position to the corresponding 2-phenyl furans is disclosed along with some preliminary mechanistic investigations. A novel synthetic route to isoquinolines is detailed involving the palladium-catalysed α-arylation of ketone enolates with an appropriate ortho-substituted aryl halide to furnish a protected 1,5-dicarbonyl intermediate. The versatility of these intermediates is demonstrated with their conversion into isoquinolines, isoquinoline N-oxides and naphthols. The scope of the synthetic procedure is fully exemplified across more than 30 different scaffolds covering the full spectrum of electron-rich to electron-deficient moieties. The intermediates were shown to be amenable to functionalisation with electrophiles, leading to isoquinolines bearing additional substitution at the C4 position. Sequential one-pot procedures were developed allowing three and four component couplings to directly deliver highly-substituted isoquinolines from commercially available starting materials. This methodology was utilised in the total synthesis of the natural product berberine in 26% overall yield and a longest linear sequence of six steps.

Caged compounds are a class of photosensitive reagents used to stimulate cells with spatial control down to a sub-cellular level, and millisecond temporal control. They comprise of biologically important molecule which is modified with a photolabile protecting group. In the absence of light, caged compounds are physiologically silent but irradiation with light induces the release of biologically active species. Illumination under two-photon conditions is particularly advantageous as it enables restriction of the photolysis volume to ~1 fL and it provides deeper penetration into scattering samples. This thesis reports the development of new protecting groups for two-photon uncaging in neuroscience. Mechanistically, the deprotection in these novel groups is designed to operate via an intramolecular photoinduced electron transfer (PeT) between the absorbing unit (electron-donor) and the release module (electron-acceptor). The modular design of these cages ensures separation of absorption and release steps, and allows each process to be tuned and optimized independently. Chapter 1 provides an introduction to the two-photon absorption phenomenon and a historic overview of the uncaging technique. It also discusses recent advances in the development of two-photon sensitive probes used in neuroscience. Chapter 2 describes the exploration of molecular designs for novel protecting groups. A two-photon absorbing dye (electron-donor; fluorene dye) and three different release units (electron-acceptors; nitrobenzyl, pyridinium and phenacyl) were identified as suitable building blocks for the current project. Efficiency of the intramolecular electron transfer between chosen units was evaluated using model dyads which constitute covalently linked electron-donor and acceptor species. Chapter 3 is devoted to the synthesis and photophysical evaluation of nitrobenzyl-based protecting group. Chapter 4 describes the preparation of pyridinium-derived protecting group and demonstrates PeT-mediated release of tryptophan and GABA under one- and two-photon excitation. Hydrolytic instability of pyridinium esters is highlighted. Chapter 5 reports the synthesis, hydrolytic stability and one-photon uncaging efficiency of phenacyl-based derivatives. Chapter 6 discusses properties of developed caged compounds and compares them with other compounds reported in literature. It contains overall conclusions and outlook for the current project. Chapter 7 details the experimental procedures and the characterization of compounds synthesized during this work.

The primary objective of this research project was to develop a novel protocol for the synthesis of densely functionalized optically enriched indanes through a chiral cation directed 5-endo-trig ring closure. In chapter two, a convergent strategy for the construction of the cyclization precursors is reported, which employs two easily adapted fragments. In chapter three, a range of quaternary ammonium salts are screened to establish the optimal phase-transfer conditions for this system. A variety of substrates were evaluated to probe the scope and limitations of this methodology. Finally, two potential mechanistic pathways for this enigmatic process are outlined and discussed in chapter four.

This thesis is concerned with the application of the conjugate addition of functionalised lithium amides in the asymmetric syntheses of (−)-morphine and all members of the homalium alkaloids. Chapter 1 introduces the conjugate addition reaction as an important bond forming reaction, and explores its utility in the asymmetric synthesis of a variety of natural products. The conjugate addition of secondary lithium amides derived from α-methylbenzylamine is discussed, along with its application to the asymmetric synthesis of alkaloids. Chapter 2 describes two distinct attempts towards the asymmetric synthesis of (−)-morphine, both reliant upon the lithium amide conjugate addition and an intramolecular Diels-Alder reaction to set the five required stereogenic centres. The use of the novel and highly functionalised reagent lithium (R)-N-[2′-(7-methoxybenzofuran-3-yl)ethyl]-N-(α-methylbenzyl)amide and its derivatives is reported. Chapter 3 focuses on the use of the novel reagent lithium (R)-N-(3-chloroprop-1-yl)-N-(α-methylbenzyl)amide and its derivatives in the asymmetric synthesis of two of the homalium alkaloids, (−)-(S,S)-homaline and (−)-(R,R)-hopromine, culminating in the most efficient syntheses of these alkaloids to date. Further, a sample of the (4′R,4′′S)-diastereoisomer of hopromine was synthesised, serving to confirm the proposed absolute configuration within natural (−)-(R,R)-hopromine. Chapter 4 extends the methodology developed in chapter 3 to the asymmetric synthesis of all possible diastereoisomers of the remaining homalium alkaloids, (−)-hopromalinol and (−)-hoprominol. These syntheses were used to propose the absolute configurations within these alkaloids, and therefore represented the first asymmetric syntheses of natural (−)-(4′S,4″R,2‴R)-hopromalinol and (−)-(R,R,R)-hoprominol. Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2, 3 and 4.

This thesis is concerned with the development of transannular iodoamination methodology for the synthesis of pyrrolizidine, indolizidine and tropane alkaloids. Chapter 1 introduces the concept of a ‘transannular cyclisation’ and outlines the utility of such cyclisations in the synthesis of a range of [x.y.z]-azabicyclic alkaloids. Chapter 2 describes the development of a three step lithium amide conjugate addition, ring-closing metathesis and transannular iodoamination protocol for the preparation of the pyrrolizidine scaffold ([3.3.0]-azabicycle). Cyclisation of a hexahydroazocine occurs with concomitant N-debenzylation to give a single diastereoisomer of the corresponding C(7)-iodopyrrolizidine product, which is then elaborated to the known pyrrolizidine, (−)-7a-epi-hyacinthacine A1. Chapter 3 delineates an extension of the methodology described in Chapter 2, and an investigation into accessing alternate diastereoisomeric pyrrolizidine scaffolds via the transannular iodoamination process. These studies culminate in the synthesis of two pyrrolizidine alkaloids, (−)-hyacinthacine A1 and (−)-hyacinthacine A2. Chapter 4 details investigations into the further elaboration of the C(7)-iodopyrrolizidine scaffold synthesised in Chapter 2. A nucleophilic displacement reaction with azide leads to the synthesis of novel 7-deoxy-7-aminoalexine analogues, whilst radical-mediated substitution of the iodide by oxygen allows the synthesis and isolation of the pyrrolizidine alkaloid (−)-1-epi-alexine. Chapter 5 outlines the development of the transannular iodoamination reaction to facilitate the synthesis of the tropane architecture ([3.2.1]-azabicycle). A tandem lithium amide conjugate addition and aldol reaction sequence is followed by ring-closing metathesis to give the required aminocycloheptene. Subsequent treatment with iodine results in transannular cyclisation to give a single iodotropane product which, following elaboration culminates in the synthesis of (+)-pseudococaine. Chapter 6 contains full experimental procedures and characterisation data for all compounds synthesised in Chapters 2, 3, 4 and 5.

The prostaglandins are a unique family of natural products found in all mammalian life, including humans. Their biological significance is profound, and they are responsible for a vast array of bodily functions. This importance, coupled with their low concentration in vivo, has made them attractive targets for total chemical synthesis. The work herein describes synthetic efforts towards their synthesis using an oxidative radical cyclisation to construct the key [3.3.0]-bridged bicyclic lactone, from which the prostaglandin skeleton may be derived. Key to this was the development of manganese(III) acetate and copper(II) triflate as optimal reagents for this cyclisation of unsaturated malonate/malonic acid derivatives. To study this, several model substrates for this crucial cyclisation were synthesised, and their cyclisation analysed. Chapter 5 describes the design and synthesis of several model substrates containing malonate groups for the oxidative radical cyclisation. The results of the cyclisation with manganese(III) and various copper(II) salts influenced the design of the substrates, and led to the use of malonic acids as more effective substrates for the formation of [3.3.0]-bicyclic lactones. A catalytic process, in which atmospheric oxygen is the terminal oxidant was also developed. Chapter 6 describes the studies towards a total synthesis of the prostaglandin family. Two potential routes are followed, the first of which used a key asymmetric epoxidation to install asymmetry. A Suzuki coupling was used to deliver the desired diene required for the cyclisation substrate, which was successfully cyclised using manganese(III) acetate and copper(II) triflate, creating the desired [3.3.0]-bicyclic lactone in good yield and with excellent diastereomeric control. A second, shorter route to the same lactone was also developed, using a novel asymmetric deconjugative aldol condensation to establish asymmetry. Cyclisation of this analogous substrate was also successful, delivering the same lactone after olefin metathesis.

This thesis describes the synthesis and reactivity of previously unprecedented bicyclic methylene aziridines via rhodium(II) catalysed cyclisation of α-allenic N-tosyloxycarbamates. These aziridines undergo reaction with organocuprates to give cis- disubstituted oxazolidinones by nucleophillic attack at the vinylic centre; plausible mechanisms for this process are discussed. Similar rhodium(II) catalysed cyclisations of β-allenic sulfamates afford cyclic enamines, aminocyclopropanes or bicyclic methylene aziridines; the product ratio depends on the allene substitution pattern. Suitably-designed substrates undergo trapping of the proposed intermediate amino allyl cation by internal nucleophiles or by cycloaddition. Finally, thermally-induced intramolecular cycloadditions of γ-allenic azides are described that give triazolines or [1,2,3]-triazoles.