This thesis comprises an attempted total synthesis of the bacterial metabolite tagetitoxin.
Section 1 comprises a literature review covering tagetitoxin, its biological activity, the mechanism of biological transcription, the isolation and characterisation of tagetitoxin, previous synthetic efforts toward tagetitoxin in the Porter group, the successful total synthesis of tagetitoxin by the Baran group and a brief introduction to the computational methods used to investigate chemical reactions and predict nuclear magnetic resonance (NMR) spectra of key intermediates in the synthesis.
Section 2 comprises a summary of the aims of the project.
Section 3 comprises an explanation of the synthetic strategy planned for the project.
Section 4 comprises a discussion of the attempted synthesis of tagetitoxin. Several literature routes to retrosynthetic sub-targets were attempted and evaluated. Thereafter, the most advanced synthetic route developed is described, focusing on the synthesis of a highly functionalised cyclopentanoid. Key synthetic details include stereochemical induction via a nitroaldol reaction, 5-membered ring formation by 1,5-CH insertion and functionalisation of the formed ring by nucleophilic epoxidation and a series of intramolecular and substrate-controlled reactions to control the regio- and stereochemistry. The most advanced intermediate bears 4 of the 5 stereocentres of the 5-membered ring of tagetitoxin with the correct substituents and was synthesised from glyceraldehyde acetonide in 19.6% yield over 13 steps. After being unable to determine the stereochemistry of the final product, DFT NMR predictions were carried out to add support to the proposed stereochemistry of the final product.
Section 5 evaluates the synthesis and lays out future work that could be performed to complete the synthesis.