Highly chemoselective oxidative dimerization of indolosesquiterpene alkaloids: a biomimetic approach to dixiamycin

Dimeric indolosesquiterpene alkaloids, typically N-N- and C-N-linked xiamycin dimers, feature a pentacyclic framework with four contiguous stereogenic centers at the periphery of a trans-decalin scaffold to which a carbazole unit is attached. In comparison with actual biosynthetic dixiamycin derivatives, we designed C-C-linked xiamycin dimers, aiming to use them as a powerful tool to create unique scaffolds as drug candidates. In this work, we disclose the first synthetic route to access a C-C dimeric indolosesquiterpene skeleton, featuring a hypervalent iodine (PIFA)-catalyzed oxidative dimerization reaction in a single-step operation with overwhelming control over the chemoselectivity and regioselectivity. This strategy has been successfully applied to the synthesis of a C-C dimer of xiamycin A (3) and xiamycin A methyl ester (15) that demonstrates a new synthetic pathway for dimeric indolosesquiterpene alkaloids. A late-stage biomimetic highly chemoselective oxidative dimerization of naturally occurring indolosesquiterpene alkaloids, xiamycin A (5) and xiamycin A methylester (14), led to the concise total syntheses of dixiamycin (3) and dixiamycin methylester (15), respectively.