Highly regioselective oxidative Csp2–H amination for indolosesquiterpene alkaloids: total synthesis of (+)-dioridamycin

Abstract

Dimeric indolosesquiterpenoids have drawn significant interest in the synthetic community due to their higher potential for biological activity than their monomeric congeners. Biosynthetically, it has been shown that xiamycin A (2a) could be dimerized under oxidative conditions to form the more potent all-possible N–N, C–N, and C–C dimers. The pursuit of effective methods for creating these linkages has driven the advancement of synthetic chemistry, leading to new strategies and tools that enhance the ability to produce these biologically significant molecules. To date, the synthesis and biological evaluation of the dimer of oridamycin A remain unexplored. Herein, we have described a synthetic design towards the concise total synthesis of dioridamycin (1a) and the C–C dimer of xiamycin A (1b) following the strategic use of hypervalent iodine(III) to forge intramolecular cross-amination leading to the indolosesquiterpenoid pentacyclic core under mild and atom-economical conditions. Our study reveals the utility of PhI(OAc)₂ for the introduction of intramolecular C–N bonds for indolosesquiterpenoids, which has conventionally been viewed as challenging, is functional group effective and provides a wider variety of products in good to excellent yields.