Contra-thermodynamic halolactonization of lactam-tethered 5-aryl-4()-pentenoic acids for the flexible and stereocontrolled synthesis of fused lactam-halolactones.

Halolactonization of alkenoic acids enables the construction of oxygen-heterocycles intramolecular halonium-induced nucleophilic addition. Although the literature is currently inundated with halolactonizations of 5-aryl-4()-pentenoic acids that predictably afford the 6 cyclization adducts, methods that reliably alter the innate regioselectivity bias to instead deliver the thermodynamically less favored 5 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()-pentenoic acids that lead to the formation of -fused lactam-γ-lactones. The natural proclivity for these 5-aryl-4()-pentenoic acids to undergo cyclization is overridden and 5 cyclization predominates. The success of the approach hinges on the use of ,-dimethylformamide (DMF) as the solvent and -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.