A Highly Step‐Economical Synthesis of Dictyostatin

• DOI: 10.1002/anie.201302565
• Publication Date: 2013-05-10T20:03:13Z
• Authors: Stephen Ho; Cyril Bucher; James L. Leighton
• Keywords: Drug Design; Hydrazones; Antineoplastic Agents; Macrolides; Iodides; Microtubules; 01 natural sciences; Catalysis; 0104 chemical sciences; 3. Good health

In 1994 Petit reported the isolation and anti-cancer activity of the marine sponge-derived macrolide dictyostatin.[1] Wright subsequently isolated a sample that allowed initial biological characterization of dictyostatin as a potent inducer of tubulin polymerization,[2] and that was used by Wright and Paterson to make a full structural assignment in 2004.[3] This assignment was confirmed soon thereafter by total syntheses by Paterson[4] and Curran,[5] and the material thus obtained facilitated more detailed characterization of dictyostatin’s mechanism of action.[6,7] Total syntheses by Phillips[8] and Ramachandran,[9] formal syntheses by Micalizio[10] and Cossy,[11] a synthesis of C(9)-epi-dictyostatin by Gennari,[12] second generation syntheses by Paterson[13] and Curran,[14] and several fragment syntheses[15] followed these initial reports. In addition, the Paterson/Wright[16] and Curran/Day[17] teams have reported extensive SAR studies, while the Paterson/Diaz/Jimenez-Barbero[18] and Curran/Snyder[19] teams have advanced models for the interaction of dictyostatin with the taxane binding site on β-tubulin. Because dictyostatin and some of the prepared analogs are among the most potent microtubule-stabilizing agents characterized to date, there has been and continues to be intense interest in the possibility of advancing dictyostatin or an analog thereof into the clinic, a goal which might be facilitated by the development of a significantly more efficient and step-economical synthesis. As part of a larger program devoted to the development of new strategies and methods for the synthesis of complex and precious marine macrolides with high levels of step-economy, efficiency, and scalability,[20] we have developed and report herein a synthesis of dictyostatin that comprises just 14 steps in the longest linear sequence.