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Title: Synthesis of an advanced macrolide intermediate for the aplyronines
Author: Blakey, S.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2001
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Aplyronine A (5) is a polyketide metabolite isolated in microscopic quantities from the Japanese sea hare Aplysia kurodai by the Yamada group. Aplyronine A displays potent cytotoxic activity both in vitro and in vivo, and has been shown to act as a novel actin depolymerising agent. It possesses a number of complex structural features including a 24-membered macrolide ring, a terminal N-methyl-N-vinylformamide moiety, 17 stereocentres and two amino acid residues. The aim of this project was to complete a highly stereocontrolled total synthesis of aplyronine A, using asymmetric aldol chemistry to assemble the carbon and oxygen skeleton. The first part of this dissertation describes the development of a suitable C28-C34 coupling partner, culminating in the synthesis of C28-C34 ketone 136. Key steps in this synthesis include an asymmetric aldol coupling of ketone 60 and aldehyde 61, and the introduction of the N-methyl-N-vinylformamide moiety via a Wittig olefination. The second part of this dissertation describes the optimisation and scale up of the Paterson group route to 24-membered macrocycle 59, involving the synthesis of the C1-C11 iodide 57 and C15-C27 aldehyde 58. These fragments were coupled together using a highly (E)-selective Horner-Wadsworth-Emmons reaction, and subsequently advanced to provide significant quantities of 24-membered macrocycle 59. The third and final part of this dissertation describes the synthesis of an advanced macrolide intermediate, containing the full C1-C34 carbon backbone of the aplyronines, with the 15 stereocentres correctly configured. This relies on a complex aldol coupling at C27-C28 to introduce the side chain, followed by suitable elaboration into 222. Preliminary efforts to advance this intermediate to aplyronine C (7) are also described.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available