Unified Total Synthesis of Phrymarolin and Haedoxan Natural Products

We disclose a unified synthetic route to the furofuran lignans phrymarolin I and II as well as the insecticidal natural products haedoxan A and D. The furofuran core was constructed using a formal [3 + 2] cycloaddition between an α-silyloxy aldehyde and a styrene, followed by a samarium(II) iodide promoted-cyclization of a β-formyloxy ketone. While this sequence enabled the synthesis of phrymarolin I and II in eight steps, attempts to unmask the <i>ortho</i>-quinone necessary for a bioinspired formal [4 + 2] cycloaddition were unsuccessful, initially preventing access to the haedoxans. Revising the choice of the arene substitution pattern enabled the formation of the requisite <i>ortho</i>-quinone followed by a bioinspired cyclization to the 1,4-benzodioxane motif of the haedoxan framework. Finally, late-stage diversification at the acetal position enabled completion of the synthesis of haedoxan A and D and their analogues in 13 steps. The synthetic route facilitated insecticidal screening of fully synthetic analogues modified at the <i>O</i>-aryl residue.