An Yb(OTf)₃‐Mediated Indirect Activation Strategy for the Stereoselective Synthesis of α‐Sialosides from 2‐Fluorosialyl Donors

Most of chemical sialylation reactions are conducted at extremely low temperatures to achieve the formation of challenging sialic acid linkages with high stereoselectivities. Performing chemical sialylation at room temperature independent of enzymatic methods represents an effective approach, particularly significant in biological and biochemical research. Our study aims to develop a convenient method of providing α-sialyl glycosides. Herein, we carry out sialyation using Yb(OTf)₃ as an activating promoter at room temperature in tetrahydrofurane and obtain excellent stereoselectivities when reacting the N-acetyl-5-N,4-O-carbonyl-2-fluorosialyl donor with galacto- or glucopyranosides. The advantages of this method include an over eight-month shelf life of the sialyl donors and minimal formation of the hydrolyzed or eliminated side-products. Sialylation of the C3 hydroxyl group in galactosides affords exclusive α-selectivities, and a one-pot synthesis of trisaccharide is accomplished by application of this method. Finally, we anticipate that this sialylation strategy can compensate for the limitations of the current enzymatic synthesis of complex glycans.