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Title: Studies towards the total syntheses of (-)- and (+)-peloruside A
Author: Atkinson, S. J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2007
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(+)-Peloruside A (ent-7), isolated in 2000 from the marine sponge Mycale hentscheli, is a potent antimitotic agent with a mechanism of action similar to taxol, in that it stabilises microtubules leading to arrest in the G2/M phase of the cell cycle. Evidence that peloruside binds to a different site on tubulin to that of taxol has further added to its interesting biological profile. This, combined with its novel macrolide structure makes peloruside a promising candidate for the development of a new anti-cancer agent. The introduction provides a survey of other microtubule stabilising natural products, a review of synthetic efforts from other academic groups and the production of (+)-peloruside by aquaculture of the parent sponge. The results section is divided into two parts. The synthesis of a fully functionalised linear polyol 129*, containing the full C1-C20 carbon skeleton of the unnatural antipode, (-)-peloruside is described first. The second section details the synthesis of seco-acid 181 (containing a hemiketal moiety) that is potentially two steps from (+)-peloruside A. Both synthetic routes have several features in common including two highly diastereoselective 1,5-anti aldol couplings of the C1-C6 (ent-63/63*), C7-C11 (ent-62/62*) and C12-C20 fragments (ent-61/61*), and two substrate directed reductions of the resultant aldol adducts. The three fragments were themselves prepared in both enantiomeric series using appropriate diastereoselective boron-aldol methodology and Sharpless asymmetric dihydroxylations. Hemiketal 181 was synthesised with the rationale that a favourable predefined conformation for macrolactonisation would be achieved. Successful hemiketalisation resulted after removal of the C5 and C11 triethylsilyl-protecting groups, with its formation likely stabilised by intramolecular hydrogen bonding. Seco-acid 181 was subsequently prepared as a highly advanced intermediate for (+)-peloruside.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available