Total Synthesis of Annotinolide B via Sequential Quinoline Dearomatization

We report the first total synthesis of the complex cyclobutane-containing <i>Lycopodium</i> alkaloid annotinolide B. Our approach leverages a sequential quinoline dearomatization strategy that enables the transformation of this readily accessible heteroaromatic precursor to a tricyclic <i>N</i>-acyl dihydropyridone intermediate. Extensive studies aimed at forging the signature cyclobutane revealed a β-silyl acrylate to be essential for the success of a key [2 + 2] photocycloaddition reaction. Further functional group transformations and a final one-pot methylation/lactonization sequence furnish annotinolide B in 20 steps.