Total Synthesis of (+)-Discorhabdin V

Abstract

The discorhabdin natural products are a large subset of pyrroloiminoquinone alkaloids with a myriad of biological activities. Despite garnering much synthetic attention, few members have thus far been completed, particularly those featuring a bridging carbon-nitrogen bond that is found in numerous discorhabdins, including discorhabdin V. Herein we report the first total synthesis and full stereochemical assignment of (+)-discorhabdin V. To access the pyrroloiminoquinone we developed a convergent N-alkylation/oxidative aminocyclization/bromination cascade that joins two key components, which are both made on multigram scale. An intramolecular Heck reaction then forms the quaternary carbon center in an intermediate containing the carbon-nitrogen bridge, and a reductive N,O-acetal cyclization sequence introduces the final piperidine ring. Furthermore, we have established the relative configuration of (+)-discorhabdin V through experimental NOESY data and DP4 NMR probability calculations. The absolute configuration of the natural product has also been determined by circular dichroism and the use of an amino acid derived chiral starting material. Our work represents one of only two reports of a total synthesis of a nitrogen-bridged discorhabdin and paves the way for future biological evaluation of such compounds.

Keywords: Alkaloids; Heterocycles; Natural Products; Structure Determination; Total Synthesis.