ABSTRACT C ‐Glycosyl flavonoids are structural isomers and metabolically stable analogues of the corresponding flavonoid O ‐glycosides. O → C rearrangement of O ‐glycoside substrates offers a promising route to C ‐glycosyl compounds, but its synthetic exploitation requires efficient (bio)catalytic methods. Here, we uncover activity of the C ‐glycosyltransferase from Fortunella crassifolia ( Fc CGT) for uridine 5′‐diphosphate (UDP)‐dependent deglycosylation of phlorizin (phloretin 2′‐β‐ O ‐glucoside). This activity is undetectable in the reverse direction ( O ‐glycosylation of phloretin) due to the enzyme′s strong preference for C ‐glycosylation. Phlorizin deglycosylation releases UDP‐glucose and phloretin, which are subsequently used by the enzyme in a C ‐glycosylation step to selectively form nothofagin (phloretin 3′‐β‐ C ‐glucoside). O → C rearrangement of phlorizin in the presence of additional UDP‐glucose affords phloretin 3′,5′‐di‐β‐ C ‐glucoside as a single product in quantitative yield at a concentration of up to 25 mM (~15 g/L). Trilobatin (phloretin 4′‐β‐ O ‐glucoside) is not accepted by Fc CGT for O → C rearrangement, but can undergo C ‐glycosylation to yield a mixed O , C ‐diglucoside of phloretin. O → C rearrangement provides excellent atom economy for C ‐glucoside synthesis. Owing to the higher solubility of the O ‐glycosylated substrate compared to the free aglycone, C ‐glucoside synthesis via O → C rearrangement eliminates the need for solubilization strategies such as organic cosolvents or inclusion complexation.
Li et al. (Wed,) studied this question.