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There is a profound need for new antibiotics which overcome bacterial resistance. The predominant source for these is natural products; however, they are often quickly rendered ineffective due to antibiotic resistance. A proven method in drug discovery is improving the properties of natural products through diverted total synthesis (DTS). Of particular interest is promysalin, which is produced by Pseudomonas putida, and selectively inhibits the growth of Gram-negative pathogenic bacteria Pseudomonas aeruginosa at nanomolar concentrations. The work herein describes modifications to the side chain which were shown to modulate antibacterial potency and specificity. A similarly inspired approach to countering antibiotic resistance is the targeted modification of a single carbon to silicon, motivated by the proven success of this substitution shown in pharmaceuticals and amino acids. The target for this modification is albocycline, a known macrolactone antibiotic that exhibits potent antibiotic activity against S. aureus. Replacing the C4 carbon of albocycline with silicon will provide sila-albocycline with enhanced hydrogen bonding properties and altered lipophilicity due to the slight changes from the carbon to silicon atom. In addition, there is anticipated intrinsic stability of the silanol toward rearrangement reactions than carbon-based. The proposed synthesis diverts from the known total synthesis of albocycline, as reported by the Andrade Group. This work details the efforts made towards the total synthesis of sila-albocycline. Lastly, there is untapped potential for UV-promoted photochemistry to create molecular scaffolds, which may lead to novel synthetic routes to complex molecules in addition to providing new polycycles that may expand current medicinal products. The work herein describes the synthesis of tethered chloro- and methoxy-substituted benzyl alcohols to 2-pyridones and the resulting products when exposing the solution to ultraviolet light. This generated new polycycles with complex structures which have unexplored biological or medicinal properties. / Chemistry

Conformationally constrained ligands and their flexible analogues were prepared as inhibitors of the Grb2 SH2 domain in order to study the structural and energetic effects of ligand preorganization in protein-ligand interactions. The compounds were prepared by using trans-cyclopropane-containing amino acid mimics, macrocyclization, or [alpha,alpha]-disubstituted amino acid residues. All trans-cyclopropane containing peptides were more potent than their corresponding succinate containing analogues due to an enthalpic advantage. Surprisingly, the binding of constrained peptides to the domain was entropically disfavored relative to their flexible controls. Effects of proton transfer and desolvation as being the source of the unprecedented entropic penalty for the constrained ligands relative to their respective controls were precluded, and X-ray crystallographic studies revealed that the binding conformations for the respective cyclopropane and succinate containing ligands were similar. This led us to believe that differential changes in protein dynamics may occur upon binding of the constrained and flexible ligands, which could contribute to the observed binding energetics. Two 23-membered macrocyclic ligands were slightly more potent than their corresponding linear controls. The amino acids used to link the N- and C-termini of the linear peptides to form the macrocycles were found to affect the energetics of binding. In one case, the 23-membered macrocycle was more potent than its control due to an entropic advantage, whereas the other 23-membered macrocycle was more potent than its control because it benefited from an enthalpic advantage. [alpha,alpha]-Disubstituted and [alpha]-monosubstituted residues that varied in hydrophobic character were incorporated into Grb2 SH2 domain binding tripeptides, and binding became more favorable as nonpolar surface area increased only for the set of tripeptides possessing cyclic [alpha,alpha]-disubstituted residues. The increase in affinity was due to an increasing enthalplic term, whereas the entropy of binding became less favorable. A total synthesis of (±)-lycopladine A was achieved in five steps from known compounds. The tricyclic core of the natural product was prepared utilizing a novel two-step sequence comprising a conjugate addition of a metalated picoline derivative followed by an intramolecular enolate arylation. It was demonstrated that the natural product existed in a solvent dependent equilibrium with its isomeric lactol. / text

The study of the biosynthetic logic of natural products has established itself to be one of the more exciting areas of research and have become an important part of modern drug discovery and development efforts. Therefore, understanding the pathway and the chemical mechanism of the biosynthesis of natural products is important in that knowledge on these processes can be applied for combinatorial biosynthesis to generate new natural product derivatives with enhanced biological activities. In addition to the practical value, a lot of unprecedented chemical mechanisms can be found in the enzymes involved therein, which will significantly advance our understanding of enzyme catalysis. The works described in this dissertation focus on elucidating the chemical mechanism of a number of enzymes involved in natural product biosynthesis by utilizing the versatility of synthetic chemistry to prepare enzyme substrates and mechanistic probes. First, SpnF and SpnL responsible for constructing the tetracyclic architecture of spinosyn A have been investigated. In vitro assay revealed the importance of the highly conjugated system for the [4+2]cycloaddition catalyzed by SpnF. Biochemical studies strongly suggest that SpnL employs the Rauhut-Currier mechanism for the second cyclization step in the biosynthesis of spinosyn A. It was also demonstrated that SpnL requires SAM for its activity. Second, a radical SAM enzyme DesII involved in the desosamine pathway has been investigated. It has been demonstrated that DesII can catalyze the dehydrogenation of TDP-D-quinovose as well as the deamination of the natural substrate, which makes DesII unique among radical SAM enzymes. In vitro assays revealed that DesII requires stoichiometric amount of SAM, which. EPR study firmly established the intermediacy of a C-3 radical in the DesII-catalyzed dehydrogenation of TDP-D-quinovose. Finally, the chemical mechanism of AXS responsible for the biosynthesis of UDP-apiose has been investigated. In vitro activity assay using UDP-2F-glucuronic acid showed that the analog is a competitive inhibitor of AXS. A coupled assay strategy was also developed to investigate the chemical mechanism of AXS in the reverse direction. In addition, the stereospecificity of two separate hydride transfer steps of AXS reaction has been firmly established. / text

In this work, a new methodology for the synthesis of a number of silylated bicyclic dienes has been reported. These bicyclic dienes allowed access to a variety of enones and phenols in 2 further steps. The stabilities and reactivities of different dialkylisopropoxy silanes have been evaluated,revealing relative instability of the dimethylisopropoxy silyl group towards chromatography. When using the analogous diethylisopropoxy silyl group instead, the products showed greater stability towards chromatography, however a higher temperature was necessary to oxidise the more sterically hindered silyl group to the desired hydroxyl moiety. A powerful cascade cyclisation for the synthesis of the CDE-core of rubriflordilactone A was then demonstrated and was successfully used for the synthesis of two systems, 284 and 333. The phenolic oxygen has been successfully installed by oxidation of a dialkylisopropoxy silane. The synthesis of these ring systems provides a solid foundation for the completion of the total synthesis of rubriflordilactone A. Finally the synthesis of suitable diynes 405 for the synthesis of the acyclic precursor of the cyclisation has been achieved. The stabilities of theses silanes towards a range of reaction have been demonstrated.

Tetrahydrofuran (THF) and tetrahydropyran (THP) rings are commonly found in a wide range of natural products and biologically active compounds. In total synthesis, the formation of THF/THP motifs is often the key step but existing methods often involve numerous steps and low overall efficiencies. Part one of this thesis details the development of a practical method for the synthesis of THF rings by the controlled mono-addition/cyclisation of organolithium species to C2-symmetric diepoxides (Scheme A-1). This method can also be applied to the synthesis of bis-THF rings from triepoxides and has potential applications in more complex cascade reactions. A similar cyclisation process providing THF rings from epoxyaldehydes is also described. Part two of this thesis details our efforts towards the synthesis of the marine macrolide neopeltolide. Wright and co-workers reported the isolation of neopeltolide 211 from a deep-water sponge of the family neopeltidae off the north coast of Jamaica. The structure, which was assigned by NMR and HRMS studies and reassigned by total synthesis, contains a 14-membered macrolactone, a 2,6-cis THP ring and an unsaturated oxazole side-chain. Chapter four describes the synthesis of the C2-C8 and C9-C16 fragments (Scheme A-2). Chapter five details our initial attempts in the coupling of subunits 268 and 320, as well as a revised synthetic strategy that allowed us to successfully couple C2-C9 alkyne 347 with C10-C16 aldehyde 348 and the preparation of an advanced intermediate 364 (Scheme A-3).

This thesis describes the development of robust methodology to access cyclic alkenylsiloxanes, and their subsequent application in Hiyama-Denmark cross couplings. An early chapter shows the identification of Lindlar reduction conditions capable of generating cyclic alkenylsiloxanes from alkynylsiloxanes in high yields. The use of such species in Hiyama-Denmark cross coupling is then examined, with particular emphasis on the development of fluoride-free conditions, previously unreported for this class of organosilane. A ring-size dependent orthogonality is revealed, where 5-membered cyclic alkenylsiloxanes cross couple under basic conditions, while 6-membered analogues are inert. The origins of this effect are investigated experimentally and theoretically, leading to the proposal of detailed mechanisms for coupling. In the final chapter, the methodology that has been developed is applied to total synthesis. The great potential of the orthogonality uncovered is demonstrated with the highly convergent construction of anti-inflammatory natural product resolvin D3 by sequential, one-pot, orthogonal cross couplings.

The first part of this thesis describes my research towards the valorisation of lignin. Due to environmental and political pressures, there has been a drive to start the transition from a fossil fuel based economy to a renewable based one. This will require the development of novel routes to renewable chemicals, one source of which may be the biopolymer lignin. Through the synthesis of advanced lignin model compounds, the chemistry of real lignin is explored. This work culminates in the development of a novel method for the depolymerisation of real lignin to simple mixtures of aromatic chemicals that could be useful building blocks for the chemical industry. One of the key steps in this process is the oxidation of the β-O-4 linkages in lignin using catalytic amounts of DDQ and molecular oxygen as the terminal oxidant. The second part of this thesis details the first synthesis of melohenine B and O-ethyl-14-epimelohenine B, two medium sized ring containing natural products. The key step in the synthesis of these natural products was the photo-sensitised oxidative cleavage of an indolic substrate by molecular oxygen. Additionally, the use of residual dipolar coupling (RDC) analysis for the conformational analysis of these molecules in solution has been explored. Finally, the absolute configurational assignment of the natural products was established and their biological activities investigated.