Total Synthesis of an Oxepine Natural Product, (±)-Janoxepin

The total synthesis of (+/-)-janoxepin, a novel antiplasmodial D-leucine derived oxepine-pyrimidinone-ketopiperazine isolated from the fungus Aspergillus Janus, is described. The cornerstones of the synthetic route are pyrimidinone preparation, ring-closing metathesis, aldol introduction of the enamide, and dihydro-oxepine elaboration. This synthetic route proved very efficient for the formation of a number of janoxepin analogues, including dihydro-janoxepin and tetrahydro-janoxepin.