Synthesis and Biological Evaluation of C(13)/C(13')-Bis(desmethyl)disorazole Z

Abstract

We describe the total synthesis of the macrodiolide C(13)/C(13')-bis(desmethyl)disorazole Z through double inter-/intramolecular Stille cross-coupling of a monomeric vinyl stannane/vinyl iodide precursor to form the macrocycle. The key step in the synthesis of this precursor was a stereoselective aldol reaction of a formal Evans acetate aldol product with crotonaldehyde. As demonstrated by X-ray crystallography, the binding mode of C(13)/C(13')-bis(desmethyl)disorazole Z to tubulin is virtually identical with that of the natural product disorazole Z. Likewise, C(13)/C(13')-bis(desmethyl)disorazole Z inhibits tubulin assembly with at least the same potency as disorazole Z and it appears to be a more potent cell growth inhibitor.

Keywords: Cross-Coupling; Cyclodimerization; Disorazoles; Microtubule-Interacting Agents; Total Synthesis.