Computational Study\non Flavin-Catalyzed Aerobic Dioxygenation\nof Alkenyl Thioesters: Decomposition of Anionic Peroxides

Flavin-dependent catalysts are widely applied to aerobic\nmonooxygenation/oxidation\nreactions. In contrast, flavin-catalyzed aerobic dioxygenation reactions\nexhibit higher atomic economy but are less reported, not to mention\nthe relevant mechanistic studies. Herein, a density functional theory\nstudy on flavin-catalyzed aerobic epoxidation-oxygenolysis of alkenyl\nthioesters was performed for the first time. Different from the previous\nmechanistic proposal, a pathway featuring two catalytic stages, monoanionic\nflavin-C(4a)-peroxide/oxide intermediates, and a reverse reaction\nsequence (epoxidation goes prior to oxygenolysis) was revealed. In\ncomparison, the pathways involving dianionic flavin catalysts, monoanionic\nflavin-N(5)-(hydro)peroxide/C(10a)-peroxide, or neutral flavin-C(4a)-hydroperoxide/hydroxide/N(5)-oxide,\nand the pathways where oxygenolysis goes prior to epoxidation are\nless favored. Epoxidation goes through intramolecular substitution\nof the O–O bond of anionic flavin-C(4a)-peroxide by β-carbon,\nwhile the resulting flavin-C(4a)-oxide accomplishes the oxygenolysis.\nFurthermore, two other reaction modes, i.e., concerted O–O\ncleavage/1,2-shift of α-substituents and dyotropic rearrangement\nwere discovered for the decomposition of other anionic peroxides,\nand preliminary rules were summarized for understanding the chemoselectivity\nfor this process. This study sheds light on the different reaction\nfeatures of numerous flavin-dioxygen derivatives, providing deeper\ninsights into flavin-catalyzed dioxygenation reactions, and is expected\nto inspire experimental design based on unconventional anionic peroxides.