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Studies towards the total synthesis of Tagetitoxin

Sandhu, AK; (2008) Studies towards the total synthesis of Tagetitoxin. Doctoral thesis, UCL (University College London).

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Abstract

Tagetitoxin is a phytotoxin which was isolated in 1981 from the plant pathogenic bacterium, Pseudomonas syringae pv. tagetis. It is an inhibitor of chloroplast and bacterial RNA polymerases, but more importantly, it is the only known natural product which is a selective inhibitor of eukaryotic RNA polymerase III. Synthesis of this compound would therefore be useful for biologists studying transcription. The proposed structure of tagetitoxin is highly functionalised and consists of two bridged heterocyclic rings, however the absolute configuration is not known and other ambiguities remain. Recently, the validity of this structure has been challenged and has provided further motivation for its synthesis. Our initial route to form the tagetitoxin core involved a carbene-mediated ring expansion strategy which had been successfully tested on monocyclic substrates. We planned to form the ring expansion precursor, a 1,3-oxathiolane, from the corresponding tert-butyl ß-hydroxysulfide using a novel reaction developed in our group. Methodology work was carried out on simpler substrates in order to investigate the scope of this reaction. It was found that this reaction worked well on substrates containing a range of functional groups and moderate to good yields were obtained in general. Although this provided a basis for the final stages of the synthesis, many difficulties were encountered during during the initial stages which led to an alternative strategy being adopted. During other work in the group, the first synthesis of the bicyclic tagetitoxin core was achieved via the cyclisation of a thiol onto an electrophilic ketoester. This strategy was thus employed in approaches to an analogue of the natural product, decarboxytagetitoxin, and tagetitoxin itself. Starting from a carbohydrate precursorm and advanced intermediate for the synthesis of decarboxytagetitoxin was prepared, although time constraints prevented completion of the synthesis. Difficulties in forming a diol intermediate through Payne rearrangement meant that only limited progress was made towards the synthesis of tagetitoxin.

Type:Thesis (Doctoral)
Title:Studies towards the total synthesis of Tagetitoxin
Language:English
UCL classification:UCL > School of BEAMS > Faculty of Maths and Physical Sciences > Chemistry

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