The total synthesis and structure–activity relationships of a highly cytotoxic depsipeptide kulokekahilide-2 and its analogs

We successfully completed the total synthesis of kulokekahilide-2, a cytotoxic depsipeptide from the Cephalaspiedean mollusk Phillinopsis speciosa. We have revised the absolute stereochemistry of kulokekahilide-2 to 21-l-Ala, 24-d-MePhe, 37-l-Ile, 43-d-Ala, 15-d-Hica, and 5S,6S,7S-Dtda. We also investigated the cause of the mis-assignment of the configuration in the originally proposed kulokekahilide-2 and concluded that methanolysis using MeONa caused partial racemization, which led to the mis-assignment. The structure–activity relationships of kulokekahilide-2 and its analogs indicate the importance of an l-amino acid at position 21.

Kulokekahilide-2 (1d), a potent cytotoxic cyclodepsipeptide from marine mollusk Phillinopsis speciosa, and its analogs were synthesized, revised the reported structure and revealed the structure–activity relationships. Figure optionsDownload as PowerPoint slide