This thesis describes a new approach towards a formal synthesis of the marine natural product diazonamide A. Firstly, the biological anti-cancer activity of diazonamide A is explained. The investigations towards the synthesis of the C-10 quaternary centre by numerous laboratories are then reported, as well as the successful total and formal syntheses. Secondly, our strategy is presented. One of the difficulties of the synthesis is the generation of the quaternary centre at C-10. This project aims to construct this stereocentre based on a novel strategy, involving the synthesis of a 3,3- disubstituted chiral oxindole using an oxidative rearrangement of indoles. Approaches to the synthesis of the required precursor, namely a 2,3- disubstituted indole, are described herein. Our first route involves functionalisation of the indole at C-3 with the introduction of an oxazole ring before coupling of a tyrosine fragment at C-2. In the second route, the indole is functionalised at C-2 first with the introduction of the tyrosine fragment and the oxazole ring is attached at the C-3 position afterwards. Macrocyclisation of the 2,3-disubstituted indole is then detailed. Next, the oxidative rearrangement was investigated on both a macrocyclised precursor and an acyclic precursor. Thorough analysis of the results obtained from various systems led to a successful oxidative rearrangement, and therefore successful installation of the C-10 quaternary centre. Further optimisation is needed to complete the formal synthesis of diazonamide A. Finally, the experimental procedures are reported.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:582017 |
| Date | January 2012 |
| Creators | David, Nadege |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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