Total Synthesis and Evaluation of Cytostatin, its C10–C11 Diastereomers, and Additional Key Analogues: Impact on PP2A Inhibition

The total synthesis of cytostatin, an antitumor agent belonging to the fostriecin family of natural products, is described in full detail. The convergent approach relied on a key epoxide-opening reaction to join the two stereotriad units and a single-step late-stage stereoselective installation of the sensitive (Z,Z,E)-triene through a β-chelation-controlled nucleophilic addition. The synthetic route provided rapid access to the C4−C6 stereoisomers of the cytostatin lactone, which were prepared and used to define the C4−C6 relative stereochemistry of the natural product. In addition to the natural product, each of the C10−C11 diastereomers of cytostatin was divergently prepared (11 steps from key convergence step) by this route and used to unequivocally confirm the relative and absolute stereochemistry of cytostatin. Each of the cytostatin diastereomers exhibited a reduced activity toward inhibition of PP2A (>100-fold), demonstrating the importance of the presence and stereochemistry of the C10-methyl and...