Total Synthesis of the Humulene-Derived Sesquiterpenoid (-)-Integrifolian-1,5-dione

Abstract

The oxygenated sesquiterpenoid (-)-integrifolian-1,5-dione, which originates from a plant that finds widespread use in South American traditional medicine, is distinguished by a rigid bicyclic framework consisting of a cyclopropane that is cis-annulated to a cyclodecane ring. The first total synthesis of this demanding target is described, which relies on a highly selective cyclopropanation reaction of an α-stannylated-α-diazoester catalyzed by a heteroleptic dirhodium paddlewheel complex, followed by an unprecedented Stille-type cross coupling of the resulting stannylated cyclopropane with methyl iodide as the electrophilic partner to form the all-carbon quaternary stereocenter at one of the bridgehead positions. Equally decisive was the bicyclization strategy based on lactonization/ring expansion that ultimately allowed the strained ten-membered carbocycle to be forged.