Organic Chemistry

Synthesis and Biological Evaluation of C(13)/C(13’)-Bis-Desmethyl-Disorazole Z



We describe the total synthesis of the macrodiolide C(13)/C(13')-bis-desmethyl-disorazole Z via double inter-/intramolecular Stille cross-coupling of a monomeric vinyl stannane/vinyl iodide precursor to achieve macrocycle formation. 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 (1). Likewise, C(13)/C(13')-bis-desmethyl-disorazole Z inhibits tubulin polymerization with the same potency as disorazole Z and it appears to be a more potent cell growth inhibitor.


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