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A Chlorine-Atom-Controlled Terminal-Epoxide-Initiated Bicyclization Cascade Enables a Synthesis of the Potent Cytotoxins Haterumaimides J and K

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journal contribution
posted on 26.05.2019, 00:00 by Sharon E. Michalak, Sangkil Nam, David M. Kwon, David A. Horne, Christopher D. Vanderwal
Haterumaimide J (hatJ) is reportedly the most cytotoxic member of the lissoclimide family of labdane diterpenoids. The unusual functional group arrangement of hatJC18 oxygenation and C2 chlorinationresisted our efforts at synthesis until we adopted an approach based on rarely studied terminal epoxide-based cation-π bicyclizations that is described herein. Using the C2-chlorine atom as a key stereocontrol element and a furan as a nucleophilic terminator, the key structural features of hatJ were rapidly constructed. The 18-step stereoselective synthesis features applications of chiral pool starting materials, and catalyst-, substrate-, and auxiliary-based stereocontrol. Access to hatJ and its acetylated congener hatK permitted their biological evaluation against aggressive human cancer cell lines.