Synthesis of discodermolide and related microtubule stabilising agents

• Main Author: González, O. D.
• Published: University of Cambridge 2006
• Subjects: 547.6
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599491

Discodermolide (1) and dictyostatin (211) are polyketide metabolites, isolated from marine sponges, which display potent activity as antimitotic agents with a similar mechanism of action to Taxol^® (paclitaxel), by stabilising microtubules and promoting the polymerisation of tubulin. They represent important natural product leads for the development of new anti-cancer agents, particular for the treatment of multidrug resistant tumours. The first part of this thesis describes the development of a practical second generation synthesis of discodermolide. The identical stereochemical triad, repeated three times in the structure of discodermolide (C₂-C₅, C₁₀-C₁₂, C₁₈-C₂₀), allowed the construction of key fragments 80 (C₁-C₅), 122 (C₉-C₁₆) and 53 (C₁₇-C₂₄) from a common precursor, 1,3-diol 82. The subsequent fragment couplings and the efficient elaborations to the natural product are also detailed. The synthesis of (+)-discodermolide was completed in 25 steps and 7.8% overall yield from methyl (<i>S</i>)-3-hydroxy-2-methyl propionate. Notably, the route relies solely on substrate control to configure all the remaining stereocentres. The methodology developed for the synthesis of discodermolide was exploited for the synthesis of novel analogues, 185 and 185, with the aim of varying the hydrogen bonding/donor acceptor sites in the C₁₄-C₁₈ region of the linear polyketide backbone. The second part of this thesis deals with the structural determination and total synthesis of the novel 22-membered macrolide, dictyostatin (211). The relative stereochemistry in 266 was determined based on a combination of extensive high field NMR studies, including <i>J</i>-based configuration analysis, and molecular modelling. Confirmation of this proposal was sought by total synthesis of the proposed stereostructure 266. The final chapter describes the synthesis of the three key fragments, 271(C₈-C₁₇), <i>ent-</i>230 (C₁-C₇) and 270 (C₁₈-C₂₆), and the studies towards their coupling.