Selective epimerization of GlcNAc to GalNAc through steady-state tuning under kinetic network control.

Complex reaction networks can reach out-of-equilibrium steady states governed by multiple kinetic terms arising from multiple product-determining elementary steps. Here we report the optimization of a four-component 'square' kinetic network that allows for selective photochemical epimerization of N-acetylglucosamine (GlcNAc) to N-acetylgalactosamine (GalNAc). Network-level mechanistic studies reveal how changes in reaction conditions lead to high selectivity through kinetic adjustments across multiple steps in the network. Although lacking in molecular detail, this network-scale analysis pinpoints kinetically controlling connections for further interrogation. Subsequent molecular-level mechanistic studies reveal that coordination by a boronic ester co-catalyst alters both the site selectivity of hydrogen-atom abstraction and the diastereoselectivity of hydrogen-atom donation, synergistically favouring the formation of GalNAc over other isomers. The optimal reaction conditions enable access to diverse glycosides and glycans of interest in carbohydrate synthesis. This work further establishes kinetic network control to be a versatile paradigm for selective catalysis in out-of-equilibrium systems.