| Abstract
| - The total synthesis of cytostatin, an antitumor agent belonging to the fostriecin family of naturalproducts, is described in full detail. The convergent approach relied on a key epoxide-opening reaction tojoin 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 tothe C4−C6 stereoisomers of the cytostatin lactone, which were prepared and used to define the C4−C6relative stereochemistry of the natural product. In addition to the natural product, each of the C10−C11diastereomers of cytostatin was divergently prepared (11 steps from key convergence step) by this routeand used to unequivocally confirm the relative and absolute stereochemistry of cytostatin. Each of thecytostatin diastereomers exhibited a reduced activity toward inhibition of PP2A (>100-fold), demonstratingthe importance of the presence and stereochemistry of the C10-methyl and C11-hydroxy groups for potentPP2A inhibition. Extensions of the studies provided dephosphocytostatin, sulfocytostatin (a key analoguerelated to the natural product sultriecin), 11-deshydroxycytostatin, and an analogue lacking the entire C12−C18 (Z,Z,E)-triene segment, which were used to define the magnitude of the C9-phosphate (>4000-fold),C11-alcohol (250-fold), and triene (220-fold) contribution to PP2A inhibition. A model of cytostatin boundto the active site of PP2A is presented, compared to that of fostriecin, which is also presented in detail forthe first time, and used to provide insights into the role of the key substituents. Notably, the α,β-unsaturatedlactone of cytostatin, like that of fostriecin, is projected to serve as a key electrophile, providing a covalentadduct with Cys269 unique to PP2A, contributing to its potency (≥200-fold for fostriecin) and accountingfor its selectivity.
|
