Saez, Fabienne B.; (2004) Novel Rearrangement of Sulfur Ylides and Application to the Synthesis of Tagetitoxin. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis presents the work undertaken towards the total synthesis of tagetitoxin. This phytotoxin was isolated in 1981 from a strain of Pseudomonas syringae bacteria, and was shown to specifically inhibit eukaryotic RNA polymerase III from a broad phylogenetic range. A structure has been proposed for tagetitoxin as a highly functionalised 9-oxa-3-thiabicyclo[3.3.1]nonane, but some ambiguity still remains over its absolute configuration and the position of carbonyl substituents. A synthetic route would allow to confirm or revise the proposed structure, provide a possible entry to analogues and increase supplies of the toxin for biological studies on transcription mechanism. A novel one-carbon ring expansion of 1,3-oxathiolanes was developed in view of constructing the core structure of tagetitoxin. A series of model substrates were successfully converted to the corresponding 1,4-oxathianes using ethyl (triethylsilanyl)diazoacetate and a copper catalyst. The reaction is expected to occur via an intermediate sulfur ylide, which rearranges to give the ring-expanded product. This methodology will be applied to a fully functionalised bicyclic precursor to assemble the tagetitoxin frame. Synthetic studies are described towards the synthesis of the precursor. An aldol reaction between methyl l,3-oxathiolane-5-carboxylate and a protected 2-azido-3,4- dihydroxybutanal was envisaged to form a functionalised branched 5-mercaptomethyl- 5-hydroxypentanal. Intramolecular thioacetal formation would give the fully substituted bicyclic substrate for ring-expansion. Three approaches to the azidoaldehyde fragment were carried out, which were based on regioselective azide opening of chiral epoxyalcohols. The methyl l,3-oxathiolane-5- carboxylate fragment was derived from L-serine, using a one pot cyclisation / sulfur deprotection reaction. Model reactions however showed that the enolate of the 1,3- oxathiolane ester was not stable under aldol conditions, possibly due to [beta]-elimination of the sulfur.

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