Elucidating the Curtin–Hammett Principle in Glycosylation Reactions: The Decisive Role of Equatorial Glycosyl Triflates

The
glycosylation reaction represents a crucial and challenging
reaction used in oligosaccharide synthesis. Specifically, attaining
complete stereocontrol during glycosylation reactions remains challenging.
Its complex nature is defined by the highly reactive intermediates
that form upon the activation of a glycosyl donor. Low-abundant species
may afford the major product via Curtin–Hammett kinetics and
have long been proposed to play a major role. Therefore, characterizing
these elusive stereodirecting intermediates is key to understanding
glycosylation reaction mechanisms. Herein, we applied a combination
of (exchange) NMR techniques to establish the equilibration rates
of glycosyl triflate reaction intermediates and their ensuing glycosylation
reaction kinetics. To this end, we studied the glycosylation reactions
of 6,3-mannuronic acid and 6,3-glucuronic acid lactone donors. Using
the complete set of reaction kinetics data, we constructed a computational
kinetic model that shows that these compounds indeed react according
to a Curtin–Hammett scenario. Furthermore, we were able to
rationalize the observed stereochemical reaction outcomes using quantum-chemically
computed potential energy surfaces for these glycosylation reactions.
Hence, this workflow can now be used to obtain a complete reaction
kinetics overview to retrieve the reaction pathway(s) that drive product
formation.