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.
Swiss Federal Institute of Technology (ETH) Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, HCI H405, Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland), Fax: (+41) 44 633 13 69.
Tao
T
Chen
Swiss Federal Institute of Technology (ETH) Zürich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, HCI H405, Vladimir-Prelog-Weg 4, 8093 Zürich (Switzerland), Fax: (+41) 44 633 13 69. karl-heinz.altmann@pharma.ethz.ch.
Karl-Heinz
KH
Altmann
Claisen rearrangement; actin; doliculide; hydrogenation; total synthesis