Photocatalyzed, C-5 selective functionalization of β-fucosides via HAT mechanisms

The modification of carbohydrates plays a crucial role in drug design and development. However, while functionalization at the anomeric position is widely explored, C-H bond activation still remains underdeveloped. In this context, photocatalysis allows access to traditionally hindered reactivity1 and Hydrogen Atom Transfer (HAT) reactions pave the way towards the direct editing of the sugar backbone.2 In the course of our research program on the fucose-specific bacterial lectin BC2L-C, we became interested in modifying the position 5 of β-fucosides. In this work, this is achieved using decatungstate anion (TBADT) as catalyst: the oxygen centers in TBADT excited state are highly electrophilic and can extract H-atoms from a wide range of substrates. We have recently reported that TBADT can activate a wide range of tri-O-acetylfucosides 1, generating an oxygen-stabilized tertiary nucleophilic radical in position 5, which undergoes Giese-type alkylation (2).3 Here we disclose that the same radical can be engaged in an electrophilic fluorination reaction, affording 5-fluoro-fucosides 3 (Figure 1). Figure 1: C-5 functionalizations of β-fucosides. Both these reactions were performed on a set of β-fucosides, with variable yields, depending on the nature of the anomeric substituent. Full regio- and stereoselectivity was always achieved. To the best of our knowledge, this is first example of selective radical functionalization of a monosaccharide in the C-5 position. Ongoing studies on additional monosaccharides aim to elucidate the origins of regioselectivity and further expand the scope of this methodology. References: [1] D.J. Gorelik, S.P. Desai, S. Jdanova, J.A. Turner, M.S. Taylor, Chem Sci 2024, 15, 1204-1236. [2] L. Capaldo, D. Ravelli, M. Fagnoni, Chem. Rev. 2022, 122, 1875-1924. [3] S. Mazzotta, M. Piro, E. Cassera, M. Gerola, M. Fagnoni, D. Ravelli, A. Bernardi, Green Chem. 2026, 28, 2319-2327.