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Title: Investigating a novel reaction of pyridinium salts towards a new synthesis of halichlorine
Author: Dubois, Nathalie
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2013
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The work presented in this thesis describes the efforts towards the understanding of a novel sequential reaction of pyridinium salts and their application towards the structural complex spirocycllc natural product, halichlorine. Specifically, the reaction involves the l,4-conjugate addition of an external nucleophile to an α,β-unsaturated ester and subsequent trapping of the resulting enolate by reaction with the pendant pyridinium ring leading to quinolizidine products featuring a l,2-dihydropyridine. The Introduction chapter highlights the general reactivity of pyridine and pyridinium salts, specifically N-alkyl pyridinium salts. Nucleophilic substitution to pyridinium salts are discussed, with a particular interest to cyclisation reactions that directly lead to quinolizidine alkaloids, our targets. The Chapter 2 discusses the preparation of pyridinium salts via Zincke reaction and their transformation into quinolizidine scaffold by reaction with external nucleophiles. In particular, the Zincke reaction is shown to be compatible with primary amines at a quaternary centre proceeding in good yield. The novel sequential reaction of pyridinium salts with nucleophiles is next explored. Furthermore, evidence for reversibility of the final ring closing step is presented, and potential control of the regioselectivity for 3-substituted pyridinium salts by the substituents is demonstrated. Finally, the range of nucleophiles is evaluated. The Chapter 3 evaluates the potential application of the novel sequential addition-cyclisation reaction to pyridinium salt towards halichlorine. The chapter starts with the discussion of previous synthesis of halichlorine. The efforts towards the synthesis of the spirocyclic core of the natural product via a strategy involving the sequential reaction are discussed. For that, the expedient synthesis of a primary amine containing all the functionality in place starting from nitrocyclopentene is described, along with the Zincke reaction with this highly sterically encumbered amine. The Experimental section describes all procedures which were used to synthesise compounds disclosed In this thesis. Full spectroscopic data and characterisation is also provided.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available