E7389, a fully synthetic macrocyclic ketone analog of the marine natural product halichondrin B, was recently discovered at Eisai Research Institute and is now undergoing Phase I clinical evaluation as a new anti-cancer drug candidate. Although the structure of E7389 is substantially simplified relative to the natural product (E7389 contains 19 vs. 32 stereogenic centers and a 35 vs. 54 carbon backbone as compared to halichondrin B), the discovery and development of this halichondrin B analog by total synthesis still represents a significant challenge. The foundation for starting these R&D efforts was provided by the first and to date only total synthesis of halichondrin B by Kishi and co-workers at Harvard University. Amongst the synthetic issues to be addressed in order to provide the necessary quantities of E7389 for full clinical evaluation are: 1) large-scale procurement of the three fragments, representing C.1-C.13, C.14-C.26, and C.27-C.35, 2) practical stereo- and chemo-selective coupling of these three fragments, 3) large-scale C-C bond formation to generate a 27 membered macrocycle and 4) controlled establishment of the polycyclic ketal and aminoalcohol functionalities. This talk will present the current status of synthetic studies at Eisai which address these issues and have enabled the total synthesis of E7389 on a multi-gram scale.
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