Total Synthesis and Biological Evaluation of Exiguamines

High Resolution Image Download MS PowerPoint Slide A concise and divergent total synthesis of the marine indoloquinone natural product exiguamine has been accomplished. The synthetic strategy relies on a hydantoin linchpin approach that unites the tryptamine- and dopamine-derived subunits, setting the stage for efficient construction of the core framework. A Claisen rearrangement forges the critical C–C bond, and a subsequent oxidative cyclization cascade assembles the hexacylic skeleton, including the pyran and indolinium rings. Beyond the natural products exiguamines A and B, this route provided access to their constitutional isomers iso -exiguamines A and B, as well as the enantiomerically enriched exiguamine B and epi -exiguamine B through an asymmetric synthesis. These natural and unnatural exiguamines exhibit potent inhibitory activity against indoleamine 2,3-dioxygenase (IDO). The work described here establishes an efficient platform for the preparation and further biological studies of this distinctive class of catecholamine-derived alkaloids.