LAUSR

Halolactonization of alkenoic acids enables the construction of oxygen-heterocycles via intramolecular halonium-induced nucleophilic addition. Although the literature is currently inundated with halolactonizations of 5-aryl-4(E)-pentenoic acids that predictably afford the 6-endo cyclization adducts, methods that reliably alter the innate regioselectivity bias to instead deliver the thermodynamically less favored 5-exo cyclization products are relatively rare. Here, we attempt to bridge this gap and have found mild conditions for contra-thermodynamic halolactonization of lactam-tethered 5-aryl-4(E)-pentenoic acids that lead to the formation of trans-fused lactam-γ-lactones. The natural proclivity for these 5-aryl-4(E)-pentenoic acids to undergo 6-endo cyclization is overridden and 5-exo-trig cyclization predominates. The success of the approach hinges on the use of N,N-dimethylformamide (DMF) as the solvent and N-methylmorpholine oxide as the catalyst. The lactam-lactone products are synthesized in high diastereoselectivity, modularity, and chemoselectivity. Notably, most of the bicycles contain one benzylic quaternary stereocenter as well as an α-alkoxy quaternary stereocenter.