Directed Hydrogenations and an Ireland–Claisen Rearrangement Linked to Evans–Tishchenko Chemistry: The Highly Efficient Total Synthesis of the Marine Cyclodepsipeptide Doliculide

Two new convergent total syntheses have been developed for the cytotoxic, actin microfilament‐stabilizing marine cyclodepsipeptide doliculide ( 1 ). A key strategic element of both routes is the establishment of the central stereogenic center of the characteristic polydeoxypropionate stereotriad by means of a hydroxyl‐directed catalytic hydrogenation of a trisubstituted double bond. The requisite olefin substrates were obtained through a modified Suzuki–Miyaura coupling or through Ireland–Claisen rearrangement of a propionate ester, respectively; the latter was the direct result of a highly selective Evans–Tishchenko reduction of a hydroxy ketone that had been obtained in a stereoselective Paterson aldol reaction. Doliculide ( 1 ) was finally obtained in a total number of 17 or 15 (14) linear steps, respectively, which represents a substantial improvement over previous syntheses of this highly bioactive natural product.