J. Am. Chem. Soc. doi:10.1021/ja500854q

Sorbiterrin A is a newly discovered member of the sorbicillin family of polyketides in which the unusual [3.3.1] ring system was proposed to be generated via an intramolecular aldol/dehydration reaction. Qi et al. now use this proposal to inspire a biomimetic synthesis of this compound. The authors drew on past syntheses of related molecules to design a consecutive Michael addition strategy to construct the quaternary carbon neighboring the aromatic ring, though unstable precursors and challenges in assigning stereochemistry of key spiro intermediates created initial difficulties in the planned approach. Though the authors cleverly used the different photocycloaddition reactivity of the spiro isomers to determine relative stereochemistry, further epimerization of the next, ring-opened intermediates stymied this solution. Treatment of the ring-opened intermediates using silica-supported silver nanoparticles successfully generated the aldol/dehydration product, which was followed by a final saponification to yield sorbiterrin A and its epimer. NMR and X-ray analysis of the saponified compounds confirmed the proposed structure of the natural product. The authors also investigated the role of the silver nanoparticles in promoting the aldol condensation, observing the formation of a radical species that supported two possible mechanistic explanations. This study provides a concise route to an intriguing natural product.