Total Synthesis of the Norcembranoid Scabrolide B and Its Transformation into Sinuscalide C, Ineleganolide, and Horiolide
Davy S. Lin, Georg Späth, Zhanchao Meng, Lianne H. E. Wieske, Christophe Farès, Alois Fürstner
Abstract
It was recognized only recently that the sister norcembranoids scabrolides A and B have notably different carbotricyclic scaffolds. Therefore, our synthesis route leading to scabrolide A could not be extended to its sibling. Rather, a conceptually new approach had to be devised that relied on a challenging intramolecular alkenylation of a ketone to forge the congested central cycloheptene ring at the bridgehead enone site; the required cyclization precursor was attained by a lanthanide-catalyzed Mukaiyama-Michael addition. The dissonant 1,4-oxygenation pattern was then installed by allylic rearrangement/oxidation of the enone, followed by suprafacial 1,3-transposition. Synthetic scabrolide B was transformed into sinuscalide C by dehydration and into ineleganolide by base-mediated isomerization/oxa-Michael addition, which has potential biosynthetic implications; under basic conditions, the latter compound converts into horiolide by an intricate biomimetic cascade.