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Title: Total synthesis of dictyostatin and novel structural analogues as promising anticancer agents
Author: Gardner, N. M.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2008
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The marine sponge-derived antimitotic polyketides discodermolide (12) and dictyostatin (16) are important natural product leads for the development of new anticancer agents. The first part of this thesis describes the design, synthesis and biological evaluation of a hybrid analogue 43 of discodermolide and dictyostatin. Installation of two Z-olefins in the key fragments 45 (C1-C7) and 44 (C8-C26) was achieved using the Still-Gennari HWE olefination reaction. A boron aldol coupling between these fragments using 1,6-anti stereoinduction established the complete 26-carbon backbone, which in 7 steps was elaborated to hybrid 43. The moderate selectivity of the C9 reduction step meant the synthesis of 9-epi-hybrid 81 was also possible. The second part describes the development of the SAR of dictyostatin with its tubulin target through the design, synthesis and biological evaluation of a library of twelve novel analogues. Insight into the importance of structural motifs within the C16 and C1-C11 regions were in turn realised by evaluation of their antiproliferative activity in a range of human cancer cell lines. All analogues were constructed exploiting the general synthetic strategy from the first-generation synthesis of dictyostatin, but modifications were made along the way in order to improve the efficiency of key steps. Notably, this ‘rapid’ generation of analogues relied upon a pivotal Still-Gennari olefination for the coupling of different combinations of C4-C10 β-ketophosphonates and C11-C26 aldehydes and the Yamaguchi lactonisation to construct the common 22-membered macrolide. The third part describes the development of an improved second-generation total synthesis of (-)-dictyostatin, and its application to the preparation of ca. 40 mg of this anticancer natural product. The endgame was given significant attention and employed a novel C4-C10 β-ketophosphonate having a C7 PMB ether.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available