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Title: Formal synthesis of salinosporamide A
Author: Villanueva Margalef, Isabel
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2008
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Salinosporamide A (1) is a secondary metabolite that was isolated in 2003 by Fenical and co-workers from marine actinomycete bacteria of Salinospora strain CNB-392. Salinosporamide A is a highly potent and specific inhibitor of the 20S proteasome. The proteasome, a multicatalytic proteolytic complex that regulates protein degradation within the cells, is receiving considerable attention as a target for treating cancer. It contains a densely functionalised fused γ-lactam-β-lactone bicyclic ring structure, with five contiguous stereocentres. Due to the impressive biological activity, as well as its complex chemical structure, this compound has become an important target for the synthetic community. This thesis describes the investigations undertaken towards the synthesis of 1. After studies on several different approaches, a concise formal synthesis was achieved. This route employed a sequential Ni-catalysed reductive aldol cyclisation-lactonisation reaction in the construction of the γ-lactam core of 1, which contained the required stereochemistry. This approach represents an attractive method to install the C2 side-chain with simultaneous protection of the C5 oxygen and saves several steps over alternative routes. The producer of the cyclisation-lactonisation sequence as readily transformed into an intermediate in the synthesis of 1 by Corey and co-workers, which had been converted into salinosporamide A in four steps.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available