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Title: Towards the synthesis of the oxaspirobicyclic unit of tetronothiodin
Author: Wang, Wei-Wei Océane
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2012
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The work described in this thesis is focused on the preparation of the oxaspirobicyclic tetronic acid fragment of the CCK-B receptor antagonist tetronothiodin. An isomer of this compound has already been synthesized within the Page group, however this was found to have the opposite stereochemistry at the spiro centre to that reported for the natural product. The thesis (chapter I) first entails the biology and chemistry related to tetronothiodin and its cholescystokinin receptor. Cholescystokinin (CCK) is a 33-amino acid peptide, which functions as a digestive peripheral hormone in the mammalian gastrointestinal tract and as a neurotransmitter in the central nervous system, where it is more widely distributed. Tetronothiodin is a novel brain-type CCK receptor antagonist, isolated from the culture broth of Streptomyces sp. NR0489. Various strategies of oxaspirobicyclic fragment synthesis using the Diels-Alder reaction as the key step have been detailed, especially the work previously performed within the Page group. The second part of the thesis covers research work towards the synthesis of the oxaspirobicyclic unit. The synthetic route was proposed following the work previously conducted in our laboratories and a solid knowledge acquired about the target molecule. The different investigations carried out within the Page group have led to a new approach, based on a non-selective α-hydroxylation of a silyl enol ether moiety, resulting in the formation of a mixture of two diastereoisomers in a 5:3 ratio, including the more hindered isomer with the desired stereochemistry at the pro-spiro centre as the minor adduct. However, as the separation of the mixture was rather challenging, we decided to attempt different methods such as the inversion of configuration of the pro-spiro carbon atom bearing the hydroxyl group. Obtainment of the desired hydroxyaldehyde from a silyl enol ether is followed by a Pinnick reaction to give the corresponding carboxylic acid. The remaining synthetic steps to reach the oxaspirobicylic unit are rapidly described.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available