| Summary: | Aplyronine A (5) is a polyketide metabolite isolated in microscopic quantities from the Japanese sea hare <i>Aplysia kurodai</i> by the Yamada group. Aplyronine A displays potent cytotoxic activity both <i>in vitro</i> and <i>in vivo</i>, 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 <i>N-</i>methyl-<i>N</i>-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 C<sub>28</sub>-C<sub>34</sub> coupling partner, culminating in the synthesis of C<sub>28</sub>-C<sub>34</sub> ketone 136. Key steps in this synthesis include an asymmetric aldol coupling of ketone 60 and aldehyde 61, and the introduction of the <i>N</i>-methyl-<i>N</i>-vinylformamide moiety <i>via</i> 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 C<sub>1</sub>-C<sub>11</sub> iodide 57 and C<sub>15</sub>-C<sub>27</sub> aldehyde 58. These fragments were coupled together using a highly (<i>E</i>)-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 C<sub>1</sub>-C<sub>34</sub> carbon backbone of the aplyronines, with the 15 stereocentres correctly configured. This relies on a complex aldol coupling at C<sub>27</sub>-C<sub>28</sub> to introduce the side chain, followed by suitable elaboration into 222. Preliminary efforts to advance this intermediate to aplyronine C (7) are also described.
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