Total synthesis of fostriecin (CI-920)

The first total synthesis of the potent antitumor agent fostriecin (CI-920) is described, confirming the relative and absolute stereochemistry assignm ents. Fostriecin is a unique phosphate monoester which exhibits weak topois omerase II inhibition (IC50 40 muM) and more potent and selective protein p hosphatase 2A and 4 (PP2A and PP4) inhibition (IC50 = 40-3 nM and 1.5 nM), resulting in mitotic entry checkpoint inhibition. Phase I clinical trials w ith fostriecin, which were the first to explore the potential of this novel mechanism of action, were halted even before therapeutic concentrations we re reached or dose-limiting toxicity established due to problems of drug st ability observed during storage of naturally derived material. The synthesi s of fostriecin detailed herein is the first stage of efforts that may serv e to address these limitations to the clinical examination of this or relat ed promising new antitumor agents.