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Title: (+)-Laccarin : a design template for novel heterocyclic scaffolds
Author: Sampson, Joanne B.
ISNI:       0000 0004 6057 871X
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2016
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Investigations into the biological activity of alkaloid (+ )-laccarin have been performed. This report is the first to identify the selectivity of this natural product for phosphodiesterase 5 and an X-ray crystal structure has been acquired revealing the key binding interactions of the compound in the enzyme active site. The synthesis of 4-des methyl laccarin was successfully completed via two intermediates: an alkyl iodide and an N-benzyl protected 1,3-cyc1ic sulfamidate. The latter route allows for the synthesis of analogues with stereochemically defined substituents on the piperidine ring. A key amine intermediate has been shown to react with a range of functionalised acyl chlorides, providing access to laccarin derivatives that can subsequently function as precursors to other structural variants. The tendency of the core ring system to undergo autoxidation has been revealed, which is strongly affected by the electronic properties of the C7-substituents. The versatility of the synthetic route has been further exploited for the synthesis of laccarin-like scaffolds with alternative ring sizes. The 5,5-scaffold derivative was successfully completed via a benzyl-protected 1,2-cyclic sulfamidate. The importance of a bis-protected amine substituent has been explored. A variety of alanine- and malonate-based intermediates have been synthesised and evaluated as precursors to the 6,6-scaffold structure. The attempted Dieckmann cyclisations of these compounds have proven to be more challenging than their glycine-based analogues, and evidence for competing oxy-anion cyclisation, fragmentation and hydrolysis pathways have been obtained. The 6,6-scaffold was synthesised and isolated; although, at present, the synthetic route remains low yielding.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available