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.

Synthesis of a Non-Symmetrical Disorazole C1-Analogue and Its Biological Activity

“…So far, only for disorazole Z, an X-ray exists to provide competitive data about the interaction of the molecule with the target protein tubulin [ 14 , 15 ]. Given the fact that more or less the same interactions take place with other disorazoles, only one half of disorazole C 1 is involved in protein binding to tubulin, and therefore, this can explain the activity differences with our compounds.…”

Diverse Site-Selective Transformation of Benzylic and Allylic Silyl Ethers via Organocatalytic Oxidation

“…Although selective deprotections based on steric hindrance are relatively easy, it is still difficult to deprotect a specific silyl ether in the presence of other silyl ethers with comparable steric hindrance . Therefore, different silyl groups are often selected to protect multiple alcohols with similar steric hindrance . In the transformation of silyl ethers, it can be inferred that oxidation exhibits selectivity that is independent of steric hindrance, as the selectivity often depends on the electronic nature of the α-position of the oxygen.…”