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Updated: Aug 24, 2025

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Synthesis and Biological Evaluation of C(13)/C(13')-Bis(desmethyl)disorazole Z
Christian Paul Bold1, Daniel Lucena-Agell2, María Ángela Oliva2
1Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zürich, Vladimir-Prelog-Weg 4, 8093, Zürich, Switzerland.
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.
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