Iron-Carbene-Mediated Catalytic Activation of Conventional Thioglycosides for Stereoselective 1,2-cis-Furanosylations

The catalytic activation of glycosyl donors using earth-abundant metals, particularly iron (Fe), remains a significant challenge in achieving 1,2-cis glycosylations. Accessing the most catalytically activated donors requires multiple steps and a carefully designed process including the most stable and commonly used thioglycoside donors. Conventional thioglycosides, which are readily accessible, often necessitate stoichiometric amounts of activators or harsh reaction conditions for activation, making it quite challenging to achieve stereoselective glycosylation, especially 1,2-cis selectivity. In this work, we developed an iron-carbene-mediated catalytic activation method for conventional thioglycosides. This one-pot approach exhibits high chemoselectivity, favoring S-insertion into the carbene over the insertion into the O–H, resulting in a sulfur ylide, a suitable leaving group. Upon elimination, the resulting sulfonium ion generates an oxocarbenium ion, which, through C2–O–iron coordination, directs incoming glycosyl acceptors from the cis-face, ensuring high 1,2-cis stereoselectivity. The induction of high 1,2-cis selectivity through an iron-chelation mechanism is further supported by density functional theory (DFT) studies. This methodology demonstrates broad applicability, accommodating various glycosyl donors such as d-ribose, d-arabinose, and l-arabinose, along with a wide range of glycosyl acceptors. We successfully applied this strategy to synthesize the challenging 1,2-cis ribotetrafuranoside, further underscoring its synthetic utility.