Site-Selective C–H Bond Functionalization of Native Sugars

Non-typical C-functionalized sugars represent a prominent yet hardly accessible class of biologically-active compounds. The available synthetic methodologies towards such sugar derivatives suffer either from an extensive use of protecting groups, requiring long and laborious synthetic manipulations, or from limited predictability and non-controllable site-selectivity of the employed C-functionalization reactions. In this work, we disclose an alternative synthetic methodology towards non-typical sugars that allows facile, site-selective, and stereocontrolled C-functionalization of native sugars through a traceless tethering approach. The described silyl-based redox-active tethering group appends directly to the unprotected sugar substrate and mediates the C-functionalization reaction through a photochemically-promoted 1,6-hydrogen atom transfer (HAT) mechanism, while transforming into a readily-removable silyl protecting group. The protocol is compatible with a variety of unprotected carbohydrate substrates featuring sensitive aglycons and a diverse set of coupling partners, providing a straightforward and scalable route to pharmaceutically relevant C-functionalized carbohydrate conjugates.