A Highly Step-Economical Synthesis of Dictyostatin

摘要

In 1994 Pettit reported the isolation and anti-cancer activity of the marine sponge-derived macrolide dictyostatin. Wright subsequently isolated a sample that allowed initial biological characterization of dictyostatin as a potent inducer of tubulin polymerization, and that was used by Wright and Paterson to make a full structural assignment in 2004. This assignment was confirmed soon thereafter by total syntheses by Paterson and Curran, and the material thus obtained facilitated more detailed characterization of dictyostatin's mechanism of action. Total syntheses by Phillips and Ramachandran, formal syntheses by Micalizio and Cossy, a synthesis of C(9)-epi-dictyostatin by Gennari, second-generation syntheses by Paterson and Curran, and several fragment syntheses followed these initial reports. In addition, the Paterson/Wright and Curran/ Day teams have reported extensive structure-activity relationship (SAR) studies, while the Paterson/Diaz/Jime-nez-Barbero and Curran/Snyder 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, we have developed and report herein a synthesis of dictyostatin that comprises just 14 steps in the longest linear sequence.