Studies on the stereoselective synthesis of the C17 backbone of the Alternaria toxins using chiral sulfoxide methodology

Abstract

TA and TB toxins are host-specific phytotoxins produced by the fungus Alternaria alternata f. sp. Iycopersici, the causative agent of Alternaria stem canker disease in tomato. Both compounds are isolated as an equilibrium mixture of the esters formed by either the C(13) or C(14) hydroxy groups with the Re prochiral carboxy group of tricarballylic acid. The design and execution of syntheses for these toxins is necessary in order to study structure-function relationships for T A and TB toxins and their application as natural herbicides. The aim of the synthetic study presented in this thesis is to develop and implement a methodology for the synthesis of the C(1)-C(9) unit of the C17 amino¬pentol backbone of the TA and TB toxins with the required functional groups and appropriate stereochemistry using a chiral sulfoxide as an auxiliary to control the stereochemistry in key steps of the synthetic route. (2R,4S,5R,6R)-2,6-Dimethyloctane-1 ,4,5-triol, synthon B, and (2S,4R,5R)-1-aminononane-2,4,5,9-tetrol, synthon A were identified by retrosynthetic analysis of the C17 aminopentol backbone of TA toxin as key intermediates for a proposed synthesis. Further analysis of synthon B identified a C5 synthon that can be obtained from (2S)-malic acid by functional group transformations, chiral sulfoxide methodo¬logy and an appropriate protective group strategy. The work presented in the thesis shows that a protected intermediate corresponding to the abovementioned C5 synthon, (2S,4S)-2,4,5-trihydroxy:-pentanal can be prepared from (2S)-malic acid, but that using either Sharpless methodology or chiral sulfoxide methodology for the introduction of the third stereogenic centre and chain extension to a C9 unit, failed as a result of the steric crowding caused by the acetonide protecting group. As a result a different synthetic route is proposed. The results obtained in the work on TA toxin were applied to the synthesis of the C(1)-C(9) aminotetrol unit of the backbone of TB toxin.