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Title: The design and synthesis of eleutherobin analogues
Author: Chiang, G. C. H.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2003
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Eleutherobin (1.1) has previously been shown to be comparable with paclitaxel, a multi-million dollar drug, in terms of microtubule assembly stabilisation and was found to competitively bind in the paclitaxel domain. Herein, the total synthesis of a simplified analogue of eleutherobin 2.2, designed to retain the important structural features important for biological activity, is described. The 9- and 5-membered rings of the diterpene skeleton of eleutherobin (1.1) were constructed via a Claisen rearrangement from the cyclic ketene acetals 2.15, to form the 9-membered medium ring and RCM of the alkene 2.6 to form the 5-membered ring. Synthetic studies towards a second simplified analogue of eleutherobin 2.3, which is more similar to eleutherobin (1.1) are described. An interesting development in the RCM reaction to form the 5-membered ring in 2.3 was discovered. Formation of the 5-membered ring in 3.19 could not be accomplished via RCM and it was hypothesised that the distance between the pendant double books in 3.18 was crucial to the success of the RCM reaction. The RCM reaction of the diene 4.1 predicted to have more favourable double bond distances, was probed. Moreover, synthetic studies towards a second RCM substrate 4.6 are described. En route to 4.6, the first reported synthesis of a 9-membered lactone 4.7 containing a quaternary centre was accomplished via the Claisen rearrangement.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available