Total synthesis and cytotoxicity of haterumalides NA and B and their artificial analogues

Haterumalides, isolated from Okinawan marine animals, are 14-membered macrolides with strong cytotoxicity against human cancer cell lines. We have achieved the total synthesis of haterumalides NA and B by using B-alkyl Suzuki-Miyaura coupling and Nozaki-HiyamaKishi coupling as key steps. Compared to our first-generation approach for ent-haterumalide NA methyl ester, this second-generation synthesis yielded the key intermediate in much better yield. This synthesis also established the relative stereochemistry of haterumalide B. Furthermore, the structure-cytotoxicity relationships of haterumalides were investigated. The combination of macrolide and side chain parts proved to be important to the strong cytotoxicity.