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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.


This article was originally published open access in RSC Advances. The full-text article from the publisher can be found here.


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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License


© 2022 The Author(s). Published by the Royal Society of Chemistry

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