A Chlorine-Atom-Controlled Terminal-Epoxide-Initiated Bicyclization Cascade Enables a Synthesis of the Potent Cytotoxins Haterumaimides J and K
journal contributionposted 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 hatJC18 oxygenation and C2 chlorinationresisted 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.
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hatJgroup arrangementcancer cell linesChlorine-Atom-Controlled Terminal-Epoxide-Initiated Bicyclization Cascade Enables18- step stereoselective synthesis features applicationsstereocontrol elementacetylated congener hatKC 2-chlorine atomchiral poolauxiliary-based stereocontrolPotent Cytotoxins Haterumaimides JK Haterumaimide Jlissoclimide familycytotoxic membernucleophilic terminatorlabdane diterpenoidsterminal epoxide-based cation -π bicyclizations