Thesis
Evolved P450 mutants as general oxidation catalysts for target synthesis via C–H activation
- Abstract:
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This thesis describes synthetic studies towards three natural product precursors: the tricyclic core of the abietane diterpenoids, a bicyclic lactone intermediate on Danishefsky’s route towards eleutherobin, and the hydrocarbon core of Taxol®. These syntheses were followed by an investigation into biocatalytic oxidation with particular focus on kinetic resolution.
Chapter 1 provides an introduction to contemporary chemical and biocatalytic C–H functionalisation for the introduction of oxygen and its use in natural products synthesis.
Chapter 2 describes the synthesis of an abietane tricycle and an investigation into kinetic resolution through oxidation by CYP102A1 enzymes. In the case of one P450 variant a study was carried out into the origin of the kinetic resolution process alongside the use of this reactivity in the synthesis of a natural product, margocin.
Chapter 3 explores the synthesis of a bicyclic lactone and its biocatalytic oxidation with cytochrome P450 variants. Kinetic resolution was observed with three enzyme variants and, through alteration of the enzyme variant employed, control of the major metabolite and its enantiomeric excess was possible.
Finally, chapter 4 outlines a synthetic study towards a taxane diterpenoid, again with a view to an investigation into its behaviour upon reaction with CYP102A1 variants. Submission of the taxane substrate to biocatalytic conditions showed a complex reaction profile, with clear evidence of kinetic resolution processes again observed.
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(Preview, Dissemination version, pdf, 15.1MB, Terms of use)
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Authors
Contributors
- Institution:
- University of Oxford
- Division:
- MPLS
- Department:
- Chemistry
- Sub department:
- Organic Chemistry
- Oxford college:
- Brasenose College
- Role:
- Supervisor
- ORCID:
- 0000-0002-6809-8265
- Institution:
- University of Oxford
- Division:
- MPLS
- Department:
- Chemistry
- Sub department:
- Inorganic Chemistry
- Oxford college:
- St Hugh's College
- Role:
- Supervisor
- ORCID:
- 0000-0003-4875-1092
- Funding agency for:
- Moloney, JG
- DOI:
- Type of award:
- DPhil
- Level of award:
- Doctoral
- Awarding institution:
- University of Oxford
- Language:
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English
- Keywords:
- Subjects:
- Deposit date:
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2022-06-10
- ARK identifier:
Terms of use
- Copyright holder:
- Moloney, JG
- Copyright date:
- 2022
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