Late-Stage “Benzenoid-to-Troponoid” Skeletal Modification of the Cephalotanes: Total Synthesis of Harringtonolide and Computational Analysis

Inspired by the biosynthesis of the cephalotane natural products, we envisioned that a “single-atom insertion” into the framework of the benzenoid subfamily would provide access to the troponoid congeners — representing the reverse of the proposed biosynthesis (i.e., a “contra-biosynthesis” approach). Computational evaluation of our designed transformation prompted us to investigate a Büchner–Curtius–Schlotterbeck reaction of a p-quinol methylether, which ultimately resulted in the synthesis of harringtonolide in two steps from cephanolide A, which we had previously prepared. Additional computational studies revealed that unconventional selectivity outcomes were driven by the choice of a Lewis acid and the nucleophile, which should inform further developments of these types of reactions.