Stereocontrolled Synthesis of 8-Hydroxycurvularol, a Sesquiterpene with a Modified Trichothecene Skeleton

The fungal-derived natural product curvularol (3) and its relative 8β-hydroxycurvularol (4) are a type of trichothecene with unique molecular skeletons and potential as anticancer agents. On the foundation of a known substituted cyclohexenone, 11-step stereocontrolled syntheses of compounds 3 and 4 were achieved. The adjacent quaternary stereocenters and crowded C5–C6 bonds in these compounds thwarted several seemingly promising strategies for synthesis. Ultimately, the combination of an intramolecular Darzens glycidic ester condensation with a stereoselective lactone propargylation/OH silylation sequence and a pivotal 5-exo dig radical cyclization gave rise to a concise strategy for constructing the curvularol-type molecular framework. In the course of this undertaking, bromo diepoxide 14 emerged as an appropriate precursor to both curvularol (3) and 8β-hydroxycurvularol (4). A zinc metal-mediated reduction of the carbon–bromine bond in 14 provided a satisfactory route to 4, while Ding and Bentrude’s radical debromo-deoxygenation method was needed to transform 14 into 3 and overcome the surprising reluctance of homoallylic alcohol 13 to undergo a hydroxyl-directed epoxidation.