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Title: Synthesis of Huperzine A and analogues
Author: Lucey, Cathal Daniel
ISNI:       0000 0001 3613 7111
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2008
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Abstract:
Huperzine A is a natural product, originally isolated from the Chinese club moss Huperzia serrata, which is currently undergoing clinical trials in the U.S. and has already been approved in China for the treatment of Alzheimer's disease (AD). This sesquiterpene alkaloid of the Lycopodium family is an eXGellent selective and reversible inhibitor of acetylcholinesterase (AChE), which is an established target in the palliative treatment of AD. Huperzine A has been the target of several syntheses and a number of analogues have also been prepared. However, all of the synthetic approaches to date have been essentially linear and thus not ideal for analogue preparation. This thesis describes the completed development of the first formal convergent synthesis of (±)-huperzine A, starting from commercially available cyclohex-2-enone and aminopicoline. A key step in the synthesis is an intramolecular Heck cyclisation, which gives the core tricycle of the natural product Optimisation of the intramolecular Heck reaction allowed for it to be carried out on a multi-gram scale and in 72% yield. Once completed, th~ converg~nt synthesis could now be used in the preparation ofnovel huperzine A analogues, which would be tested for AChE inhibitory activity and also for broad range CNS activity. Initial analogue work described in this thesis has proved promising, with a nitrogen atom having been successfully incorporated into the tricyclic core at two different positions via Beckmann rearrangements. This thesis also describes the resolution of a key intermedi~te in the newly-developed racemic synthesis, thus allowing for the synthesis of enantiomerically-pure huperzine A or related analogues.
Supervisor: Not available Sponsor: Not available
Qualification Name: Queen's University Belfast, 2008 Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.485064  DOI: Not available
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