Total Synthesis and Evaluation of Phostriecin and Key Structural Analogues

Full details of the total synthesis of phostriecin (<b>2</b>), the assignment of its relative and absolute stereochemistry, and the resultant structural reassignment of the natural product previously represented as sultriecin (<b>1</b>), a phosphate versus sulfate monoester, are detailed. Studies with authentic material confirmed that phostriecin, but not sultriecin, is an effective and selective inhibitor of protein phosphatase 2A (PP2A) defining a mechanism of action responsible for its antitumor activity. The extension of the studies to the synthesis and evaluation of a series of key synthetic analogues is disclosed that highlights the importance of the natural product phosphate monoester (vs sulfate or free alcohol, both inactive and >250-fold), the α,β-unsaturated lactone (12-fold), and the hydrophobic <i>Z</i>,<i>Z</i>,<i>E</i>-triene tail (C12−C22, ca. 200-fold) including the unique importance of its unsaturation (50-fold, and no longer PP2A selective).