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

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.