Microtubule stabilizing antitumor agent

In the laboratory of J. Mulzer, the total synthesis of laulimalide, a microtubule stabilizing antitumor agent, was accomplished. The C9 stereochemistry of the natural product was introduced using the Jacobsen HKR on a diastereomeric mixture of a terminal epoxide. The epoxide mixture was prepared via the Corey-Chaykovsky epoxidation of citronellal. The HKR proceeded in high yield and high selectivity at room temperature, and the products were easily separated by flash chromatography. The did was converted into the diastereomerically pure epoxide in three steps. 

Ahmed, A., Hoegenauer, E. K., Enev, V. S., Hanbauer, M., Kaehlig, H., Oehler, E., Mulzer, J. Total Synthesis of the Microtubule Stabilizing Antitumor Agent Laulimalide and Some Nonnatural Analogues The Power of Sharpless Asymmetric Epoxidation. J. Org. Chem. 2003, 68, 3026-3042. 

The novel marine natural product laulimalide (65), a metabolite of various sponges, has received attention as a potential antitumor agent due to its taxol-like ability to stabilize microtubules. There has been considerable synthetic effort toward 65, culminating within not more than 2 years in as many as ten... 

As indicated above, the antitumor activity of Epo B is based on its ability to bind to microtubules and to alter their intrinsic stability and dynamic properties. (For excellent reviews on microtubule structure and function see ref. 6 and 47-49.) Epothilones prevent the Ca or cold-induced depolymerization of pre-existing microtubule polymers in cell-free systems at the same time, they promote the polymerization of soluble tubulin into microtubule-like polymers under conditions that would normally destabilize microtubules.As demonstrated by kinetic experiments, epothilones inhibit the binding of taxol to microtubules in a competitive manner and they bind to the taxol binding site on p-tubulin with affinities that exceed (Epo B) or are comparable (Epo A) to taxol affinity likewise Epo B is a more potent tubulin-polymerizing agent than taxol or Epo Structural studies on... 

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