Studies towards the synthesis of tagetitoxin

Gama, Yannick (2018) Studies towards the synthesis of tagetitoxin. Doctoral thesis, University of East Anglia.

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The natural product tagetitoxin is a phytotoxin which was first isolated from the bacterium Pseudomonas syringae pv. tagetis in 1981. Tagetitoxin is an inhibitor of chloroplast and bacteria RNAP and also selectively inhibits RNAP III in eukaryotes. Multiple biological mechanisms of inhibition and several structures have been proposed for tagetitoxin. The structural ambiguity and potential useful biological activity have driven the desire for a total synthesis of tagetitoxin’s proposed structures; none of which of yet have been successful.

This body of research describes the recent developments our group has contributed towards the synthesis of tagetitoxin. The main objective was to synthesize targets 323a and 323b which both contain the oxathiobicyclo[3.3.1]nonane ring system found in two of the proposed structures of tagetitoxin.

Our initial strategy focused on four synthetic routes derived from diacetone mannose (DAM). In this strategy, the route nearest to obtaining the bicyclic core of 323a and 323b was the dithiane-reduction route. In this route, the target precursors 389 and 415 (and analogues) were made, but attempted thioacetate deprotection and concomitant cyclization of the thiol/thiolate onto a ketone or sulfonate ester to yield the oxathiobicyclo[3.3.1]nonane ring system led to either decomposition or complex mixtures. This failure was attributed to the presence of isopropylidene groups hampering the cyclization by imposing steric constraints on ring closure.

We then conducted synthetic routes starting from D-galactose in the D-galactose and exo-glycal routes (avoiding the use of any isopropylidene groups). Failure to insert a hydroxyl-methylene group on the C-1 position by anomeric nitrile anion chemistry or ring-opening an anomeric spiro-epoxyacetal with TMSCN led us to attempt a hydroboration-oxidation on an exo-galactal derivative which was partially successful. Optimization of the hydroboration-oxidation pathway in the exo-glycal route is promising for future research.

Item Type: Thesis (Doctoral)
Faculty \ School: Faculty of Science > School of Chemistry
Depositing User: Users 9280 not found.
Date Deposited: 10 Jan 2019 11:34
Last Modified: 10 Jan 2019 11:34


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