Synthetic studies on the C(1)-C(9) unit of TA toxin using nucleophilic opening of chiral epoxides

Abstract

TA and TB toxins are host-specific phytotoxins produced by the fungus Altemaria altemata f. sp. Iycopersici, the causative agent of stem canker disease in tomato. The two toxins are similar in structure: TB lacks the C(5) hydroxy group present in TA toxin. Both compounds are isolated as an equilibrium mixture of the two esters formed by either the C(13) or C(14) hydroxy groups of the (2S,4R,5R,11R,13S,14R,15R)-1-amino-11,15¬dimethylhepta-decane-2,4,5, 13, 14-pentol backbone with the Re prochiral carboxy group of tricarballylic acid. The synthesis for these toxins is necessary in order to study their structure-activity relationships. The aim of the synthetic study outlined in this dissertation is the development and implementation of methodology for the synthesis of the C(1)-C(9) unit of the C17 aminopentol backbone of TA toxin with the appropriate stereochemistry. Retrosynthetic analysis of the C17 aminopentol backbone of TA toxin identifies (2R,4S,-5R,6R)-2,6-dimethyloctane-1.4,5-triol, synthon B, and (2S,4R,5R)-1-amino¬nonane-2,4,5,9-tetrol, synthon A as key intermediates for the proposed synthesis. Further analysis of synthon A identifies the C9 synthon (2S,4R,5R)-nonane-1,2,4,5,9-pentol, as the target molecule which can be derived from the C7 synthon (2S,3R)-1,2-epoxyheptane-3,7¬diol. The work presented in this dissertation shows that the protected intermediate corresponding to the abovementioned C7 synthon, can be prepared from 1,5-pentanediol by a number of functional group trans-formations using appropriate protecting group strategy (O-TBS, O-TBDPS and O-benzyl groups) and introduction of the two stereogenic centres by using Sharpless epoxidation/kinetic resolution methodology. Nucleophilic opening of the terminal epoxide using cyanide was successful but using chiral sulfoxide methodology for the introduction of the third stereogenic centre and the concomitant one¬-carbon chain extension, failed: in the case of both an acetonide and a dibenzyl protected C8 intermediate a rearrangement occurred. Alternative methods for nucleophilic opening of the terminal epoxide ring and concomitant or subsequent chain extension were investigated and as a result a different synthetic route is proposed.