Skeletal Editing via Diastereoselective Ring Expansion Enables Enantioenriched Tetrasubstituted Δ³‑Oxepenes

Seven-membered oxygen heterocycles, particularly Δ³-oxepenes, are prevalent motives, found, for example, in natural products, but remain synthetically challenging due to ring strain and limited asymmetric methods. Here, we describe a new strategy that uses Brønsted acid-promoted skeletal editing to convert enantioenriched dihydro-1,2-oxazinesreadily prepared via an enantioselective catalytic nitroso-Diels-Alder reactioninto highly substituted Δ³-oxepenes bearing four diastereo-controlled stereocenters. As supported by DFT studies, which also provide insight into the origin of the diastereoselectivity, the transformation proceeds via a transient aziridine intermediate and a regioselective nucleophilic ring-opening, enabling the incorporation of diverse nucleophiles, including thiols, alcohols, and indoles. Operating under mild conditions, this methodology delivers tetrasubstituted Δ³-oxepenes in decent yields and excellent enantiomeric excesses.