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

The fungal-derived natural product curvularol (<b>3</b>) and its relative 8β-hydroxycurvularol (<b>4</b>) 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 <b>3</b> and <b>4</b> 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-<i>exo</i> dig radical cyclization gave rise to a concise strategy for constructing the curvularol-type molecular framework. In the course of this undertaking, bromo diepoxide <b>14</b> emerged as an appropriate precursor to both curvularol (<b>3</b>) and 8β-hydroxycurvularol (<b>4</b>). A zinc metal-mediated reduction of the carbon-bromine bond in <b>14</b> provided a satisfactory route to <b>4</b>, while Ding and Bentrude's radical debromo-deoxygenation method was needed to transform <b>14</b> into <b>3</b> and overcome the surprising reluctance of homoallylic alcohol <b>13</b> to undergo a hydroxyl-directed epoxidation.