Combretastatin A-4 (1) as the phosphate ester prodrug (3d) is a potent antineoplastic and antiangiogenesis substance and is in advanced preclinical development. For the purpose of improving the phosphorylation synthetic sequence from combretastatin A-4, new routes were investigated. The phosphorylation step was found to be considerably improved using in situ-generated dibenzyl chlorophosphite. Cleavage of the benzyl esters employing a trimethylchlorosilane/sodium iodide procedure, followed by treatment with sodium methoxide, led to the water-soluble prodrug (3d) in high yield.

The improved phosphorylation synthetic sequence from combretastatin A-4, using in situ-generated dibenzyl chlorophosphite and trimethylchlorosilane/sodium iodide, led to a water-soluble, antineoplastic and antiangio

Antineoplastic agents 389. New syntheses of the combretastatin A-4 prodrug.

Key Takeaway: The improved phosphorylation synthetic sequence from combretastatin A-4, using in situ-generated dibenzyl chlorophosphite and trimethylchlorosilane/sodium iodide, led to a water-soluble, antineoplastic and antiangio