Diastereoselective sp³ C–O Bond Formation via Visible Light-Induced, Copper-Catalyzed Cross-Couplings of Glycosyl Bromides with Aliphatic Alcohols

Abstract

Copper-catalyzed cross-coupling reactions have become one of the most powerful methods for generating carbon-heteroatom bonds, an important framework of many organic molecules. However, copper-catalyzed C(sp³)-O cross-coupling of alkyl halides with alkyl alcohols remains elusive because of the sluggish nature of oxidative addition to copper. To address this challenge, we have developed a catalytic copper system, which overcomes the copper oxidative addition barrier with the aid of visible light and effectively facilitates the cross-couplings of glycosyl bromides with aliphatic alcohols to afford C(sp³)-O bonds with high levels of diastereoselectivity. Importantly, this catalytic system leads to a mild and efficient method for stereoselective construction of <i>α</i>-1,2-<i>cis</i> glycosides, which are of paramount importance, but challenging. In general, stereochemical outcomes in <i>α</i>-1,2-<i>cis</i> glycosidic C-O bond-forming processes are unpredictable and dependent on the steric and electronic nature of protecting groups bound to carbohydrate coupling partners. Currently, the most reliable approaches rely on the use of a chiral auxiliary or hydrogen-bond directing group at the C2- and C4-position of carbohydrate electrophiles to control <i>α</i>-1,2-<i>cis</i> selectivity. In our approach, earth-abundant copper not only acts as a photocatalyst and a bond-forming catalyst, but also enforces the stereocontrolled formation of anomeric C-O bonds. This cross-coupling protocol enables highly diastereoselective access to a wide variety of <i>α</i>-1,2-<i>cis</i>-glycosides and biologically relevant <i>α</i>-glycan oligosaccharides. Our work provides a foundation for developing new methods for the stereoselective construction of natural and unnatural anomeric carbon(sp³)-heteroatom bonds.