Sehailia, M.; (2011) Studies towards the total synthesis of tagetitoxin. Doctoral thesis , UCL (University College London).

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Abstract

Tagetitoxin is a phytotoxin produced by the bacterium Pseudomonas syringae pv. tagetis. It is a selective inhibitor of RNA polymerase III in eukaryotic cells and RNA polymerase in bacteria. To date, no total synthesis of the proposed structure of tagetitoxin has been reported. While there is some ambiguity surrounding the structure of tagetitoxin, the most likely structure incorporates a unique 9-oxa-thiabicyclo[3.3.1]nonane core, with six stereogenic centres and a range of functional groups. This thesis describes the development of a novel synthetic route towards tagetitoxin. The first task was the introduction, at C-5 of D-glucose, of a carbon substituent which could later be transformed to the carboxylic acid moiety of tagetitoxin. Initial studies showed that, while incorporation of a hydroxymethyl substituent was straightforward, problems arose in attempts to selectively functionalise one of the two primary hydroxyl groups in the resulting molecule. Alternatively, incorporation of a vinyl moiety at C-5 of D-glucose was achieved using a procedure described by Rama Rao et al. This led to the formation of 1,6-anhydro-5-C-vinyl- D-glucose, which was successfully functionalised at C-1 via incorporation of a TMS acetylene group following a method described by Vasella and co-workers. The next task was to introduce a nitrogen substituent at C-3 of the sugar while inverting the configurations at both C-2 and C-3; for this purpose, conversion to a 2,3-β-epoxide was achieved in six steps. Unfortunately, attempted ring opening of the epoxide with various azide sources failed to give the desired product. A modified route was thus investigated in which the vinyl group at C-5 was converted to a less sterically demanding nitrile group. In this case, the 2,3-β- epoxide, when subjected to treatment with sodium azide in the presence of lithium perchlorate, furnished the desired azido compound with inversion of configuration at C-3. While time constraints did not allow further progress to be made towards tagetitoxin, the remaining tasks are to further introduce a thiol group at C-6, a phosphate at O-4 and oxidation of the acetylene moiety to a methyl ketoester which upon cyclisation should give the desired tagetitoxin molecule.

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