Site-Selective C─H Bond Functionalization of Sugars

Non-typical C-functionalized sugars represent a prominent yet hardly accessible class of biologically-active compounds. The available synthetic methodologies toward such sugar derivatives suffer either from an extensive use of protecting groups, requiring long and laborious synthetic manipulations, or from limited predictability and noncontrollable site-selectivity of the employed C-functionalization reactions. In this work, we disclose an alternative synthetic methodology toward nontypical sugars that allows facile, site-selective, and stereocontrolled C-functionalization of 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.