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While the mechanism of action in vivo is unknown, phorboxazole arrests the cell cycle at S phase without interfering with microtubule stability. Because of the antimitotic bioactivity, structural complexity, and extreme natural scarcity of the compound, efforts have been underway for the total synthesis of this natural product.
The Petasis-Ferrier rearrangement was utilized to construct two tetrahydropyran rings in the phorboxazole macrolide ring, along with an extension of the Julia olefination and application of a novel bifunctional oxazole linchpin. This sequence gave an overall yield of 3-6% in a stereocontrolled, highly convergent Stille coupling to unite the macrocycle with the sidechain. Structure-activity relationship studies on phorboxazole analogs and initial biological screening in leukemia, breast cancer, and brain tumor cell lines have demonstrated extremely potent anticancer activity.