Abstract
Oxygen heterocycles are common structural features of bioactive natural products and are often present in pharmaceutical agents. Mupirocin is a polyketide antibiotic isolated from Pseudomonas fluorescens which is active against MRSA. During biosynthesis, the tetrahydropyran ring is constructed via an enzyme cascade involving oxidation of the 8-methyl to the 8,16-epoxide by monooxygenase MupW, followed by cyclisation controlled by epoxide hydrolase MupZ. We aimed to investigate if MupZ could be used more widely as a biocatalyst for the selective cyclisation of 4,5-epoxy alcohols to tetrahydropyrans. Chapter 1 describes the synthesis of model substrate 25 to probe the stability of 4,5-epoxy alcohols as potential substrates for MupZ. Investigations revealed that spontaneous 5-exo cyclisation of 25 to 54 can be suppressed but not completely prevented. Comparison of bioassays of 25 with MupZ and a no enzyme control showed that such substrates are unstable to the reaction conditions. It was concluded that due to the instability of the required substrates, it is unlikely that MupZ can be used in biocatalysis.Metabolites from Phomopsis fungi are a rich source of oxygen-containing polyketides such as decanolides, characterised by a ten-membered lactone core. A series of decanolides named phomolides were isolated from Phomopsis sp. A123. Previous total syntheses have led to structural revision of some phomolides and calls into question the proposed structures of phomolides which have not yet been synthesised. Chapter 2 describes an investigation into different strategies towards the first total synthesis of phomolide F which has undefined stereochemistry at C-11. A route to prepare a key intermediate towards phomolide F using organocatalytic 𝛼-aminoxylation has been developed and shows promise as a viable synthetic strategy. Preparation of both epimers of phomolide F and comparison with the spectroscopic data of the natural product will allow the relative and absolute stereochemistry of phomolide F to be confirmed.
| Date of Award | 18 Mar 2025 |
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| Original language | English |
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| Supervisor | Chris L Willis (Supervisor) & Matthew P Crump (Supervisor) |