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Title: Synthesis of novel biologically active tropanes
Author: Wallis, Anna L.
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 1999
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Diels-Alder cycloaddition between 1,3-cycloheptadiene (or its derivatives) and benzyl nitrosoformate produced intermediates from which the N-methyl-8-aza-bicyclo-[3.2.1]octane (tropane) ring system, 8-aza-bicyclo-[3.2.1]octane (nortropane) ring system and a range of oxygenated and 6,7-dehydro- derivatives were constructed. Homoepidbatidine, a homologue of the alkaloid epibatidine, was synthesised using a Heck-type coupling reaction to introduce a chloropyridyl group at the C6 position of the tropane ring system. 1H NMR spectroscopy was used to prove the exo-stereochemistry of the chloropyridyl moiety. Homoepidbatidine is one of the most potent epibatidine analogues to be synthesised to date. Indeed, nicotinic receptor binding assays have shown that the activity of Homoepibatidine is comparable to that of epibatidine itself. The first synthesis of 1-hydroxytrophacocaine, an alkaloid recently isolated from Erythroxylum novogranatense variants, is described. Adaptation of the synthesis produced 1-hydroxynortropacocaine, which was subsequently found to occur in nature, 1-hydroxytropanes exist as mixtures of tautomers in which the bicyclic hemi-aminal is in equilibrium with the monocyclic amino-ketone. The tautomeric preferences of 1-hydroxytropacocaine were studied using VT NMR. It was established that 1-hydroxytropacocaine exists predominantly as the bicyclic tautomer, although the ratio of the bicyclic hemiaminal and monocyclic amino-ketone could not be measured quantitatively. Similar tautomeric preferences were observed for 1-hydroxynortropacocaine. Two biosynthetic routes to 1-hydroxtropanes have been proposed which involve tropinone N-oxides as key intermediates. The first proposal involves thermal or base-induced rearrangement of tropinone N-oxides. The second, alternative route, centres on Meisenheimer rearrangement of tropinone N-oxides. Synthetic routes are developed to key doubly-labelled (18O, 2H) intermediates for use in feeding experiments to investigate these proposals.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available