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Title: Total synthesis and structural assignment of antimitotic polyketides
Author: Findlay, A. D.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2008
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The first part of this dissertation describes the revised stereochemical assignment of the cytotoxic marine macrolide dolastain 19, isolated from the sea hare Dolabella auricularia, which was proposed and subsequently validated by completion of the first total synthesis. Based upon molecular modelling and common biogenetic considerations, four of the twelve stereocentres of the originally proposed structure 50 were inverted in configuration. The carbon backbone 56 of this stereochemically reassigned 14-membered macrolide 54 was assembled using an asymmetric vinylogous Mukaiyama aldol reaction, in combination with boron aldol methodology. A Mukaiyama glycosylation was employed to append the required L-rhamose-derived sugar unit 44. Overall the synthesis was completed in 23 steps and 1.7% overall yield. The second part of this dissertation focuses on the myxobacterium-derived natural product, spirangien A (124). Initial work centred on the preparation of an advanced diene degradation fragment 134, and the subsequent assignment of absolute configuration. The use of a common stereotetrad intermediate 149 was crucial in the development of a convergent and step-economic synthetic strategy. Two series of reactions were performed to access 234 and 148, before recombination via aldol coupling. Elaboration of linear spiroacetalisation precursor 244 provided synthetic spirangien diene 134. Measurement of the optical rotation and comparison with available literature data for natural 134 then enabled the confident assignment of the complete stereochemistry of spirangien A. Laterally, studies focussed on the extension of this synthetic strategy to enable the completion of the total synthesis of spirangien A.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available