Synthesis and biological evaluation of (−)-dictyostatin and stereoisomers

• Published in: Tetrahedron Vol. 63; no. 35; pp. 8537 - 8562
• Main Authors: Shin, Youseung, Fournier, Jean-Hugues, Brückner, Arndt, Madiraju, Charitha, Balachandran, Raghavan, Raccor, Brianne S., Edler, Michael C., Hamel, Ernest, Sikorski, Rachel P., Vogt, Andreas, Day, Billy W., Curran, Dennis P.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 27-08-2007
• Subjects: Discodermolide; Macrolactone; Microtubule; Paclitaxel; Discodermolide; Microtubule; Macrolactone; Paclitaxel
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2007.05.033

Total syntheses of (−)-dictyostatin, 6,16-bis-
epi-dictyostatin, 6,14,19-tris-
epi-dictyostatin, and a number of other isomers and analogs are reported. Three main fragments—top, middle, and bottom—were first assembled and then joined by olefination or anionic addition reactions. After appending the two dienes at either end of the molecule, macrolactonization and deprotection completed the syntheses. The work proves both the relative and absolute configurations of (−)-dictyostatin. The compounds were evaluated by cell-based measurements of increased microtubule mass and antiproliferative activity, and in vitro tubulin polymerization assays as well as competitive assays with paclitaxel for its binding site on microtubules. These assays showed dictyostatin to be the most potent of the agents and further showed that the structural alterations caused from 20- to >1000-fold decreases in activity.
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