Phase-Transfer Catalyzed Microfluidic Glycosylation: A Small Change in Concentration Results in a Dramatic Increase in Stereoselectivity

Abstract

Phase-transfer catalysis (PTC) is widely used in glycochemistry for the preparation of aryl glycosides by the glycosylation reaction. While investigating the possibility of synthesis of 4-(3-chloropropoxy)phenyl sialoside (Neu5Ac-OCPP) from N-acetylsialyl chloride with O-acetyl groups (1), we have recently discovered a strong dependence of the PTC glycosylation outcome on the mixing mode: under batch conditions, only α-anomer of Neu5Ac-OCPP was obtained, albeit in low yield (13%), while under microfluidic conditions the yield of Neu5Ac-OCPP increased to 36%, although stereoselectivity decreased (α/β ≤ 6.2). Here, we report that the outcome of this reaction, performed under microfluidic conditions using a Comet X-01 micromixer (at 2 μL/min flow rate), non-linearly depends on the concentration of N-acetylsialyl chloride 1 (5–200 mmol/L). The target Neu5Ac-OCPP was obtained in a noticeably higher yield (up to 66%) accompanied by enhanced stereoselectivity (α/β = 17:1–32:1) in the high concentration range (C > 50 mmol/L), whereas the yield (10–36%) and especially, stereoselectivity (α/β = 0.9:1–6.2:1) were lower in the low concentration range (C ≤ 50 mmol/L). This dramatic stepwise increase in stereoselectivity above critical concentration (50 mmol/L) is apparently related to the changes in the presentation of molecules on the surface of supramers of glycosyl donor, which exist in different concentration ranges.