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

Abstract

Phase 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.

Computer Vision for Kinetic Analysis of Lab- and Process-scale Mixing Phenomena

“…Mixing is crucial to many process scale-up projects. [1][2][3][4] It affects a diverse range of chemically-intensive processes such as phase-transfer catalysis, [5][6][7][8] additive manufacturing, [9][10][11] fuel combustion, 12 flow chemistry, 13 powder formulation, 14,15 biotechnology, 16 and (most pertinent to this paper) myriad reaction scale-ups in tank reactors. [16][17][18][19][20] Mixing represents one of the most effective, non-chemical means of process improvement.…”

Comparison of glycosyl donors: a supramer approach

“…However, the reliable installation of sialic acid residues in oligosaccharides is a rather difficult issue and poor predictability remains characteristic of the sialylation reaction [ 16 – 21 ]. As in other glycosylation reactions [ 22 – 29 ], the result of sialylation is affected by a variety of variables [ 30 – 39 ] including the nature of protective groups on either partner [ 26 , 38 , 40 – 45 ] and concentration of reagents [ 31 , 33 – 34 37 , 39 , 43 – 44 46 ].…”

“…However, the reliable installation of sialic acid residues in oligosaccharides is a rather difficult issue and poor predictability remains characteristic of the sialylation reaction [16][17][18][19][20][21]. As in other glycosylation reactions [22][23][24][25][26][27][28][29], the result of sialylation is affected by a variety of variables [30][31][32][33][34][35][36][37][38][39] including the nature of protective groups on either partner [26,38,[40][41][42][43][44][45] and concentration of reagents [31,33,34,37,39,43,44,46]. During a study of a possible influence of remote acyl protective groups [23] on the sialylation outcome (which could become possible through participation in stabilization of glycosyl cation [24,47,48] in a conformation with all-axial substituents in the pyranose ring [49]…”

Computer Vision for Kinetic Analysis of Lab- and Process-Scale Mixing Phenomena

“…Mixing is crucial to many process scale-up projects. − It affects a diverse range of chemically intensive processes such as phase-transfer catalysis, − additive manufacturing, − fuel combustion, flow chemistry, powder formulation, , biotechnology, and (most pertinent to this paper) myriad reaction scale-ups in tank reactors. − Indeed, it is well established that mixing in tank reactors is subject to micro-, meso-, and macro-mixing phenomena, all of which are sensitive to the chemistry, temperature, reactor geometry, and impeller shape, among other parameters . Mixing represents one of the most effective, non-chemical means of process improvement.…”