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.