Enantioselective Total Synthesis of (–)‐Psiguadial A

The first enantioselective total synthesis of the antiproliferative natural product (–)‐psiguadial A is reported. This approach features the enantioselective synthesis of a complex tricyclic terpenoid precursor, the union of that precursor with a polyketide component by an enolate‐ortho‐quinone methide coupling reaction to form a highly congested carbon–carbon bond, and an acid mediated intramolecular hydration ring‐closure leveraging a fully substituted alkene to generate the unique oxepane core structure of the natural product.