Black Swan in Phase Transfer Catalysis: Influence of Mixing Mode on the Stereoselectivity of Glycosylation

Abstract

AbstractPhase transfer catalysis (PTC) is widely used for the preparation of anomerically pure aryl glycosides by glycosylation of phenols with glycosyl halides. Here, we attempted to synthesize 4‐(3‐chloropropoxy)phenyl (CPP) sialoside – a useful Janus glycoside for neoglycoconjugate synthesis. A batch glycosylation reaction under typical PTC conditions (N‐acetylsialyl chloride, 4‐(3‐chloropropoxy)phenol, Bu4NHSO4, AcOEt, 10 % aq Na2CO3) resulted in formation of CPP sialoside as a single anomer, albeit in low yield. Conversely, the PTC glycosylation in flow using Comet X‐01 micromixer doubled the yield of CPP sialoside, which was obtained as a mixture of anomers suggesting the change in the reaction mechanism apparently induced by the change in mixing mode. An increase in flow rate led to further loss of stereoselectivity while the use of T‐shaped mixer increased stereoselectivity. Similar results were obtained for N,N‐diacetylsialyl chloride and two other para‐alkoxy‐substituted phenols suggesting generality of the discovered phenomenon.