Regioselectivity of glycosylation reactions of galactose acceptors: an experimental and theoretical study

Abstract

Regioselective glycosylations allow planning simpler strategies for the synthesis of oligosaccharides, and thus reducing the need of using protecting groups. With the idea of gaining further understanding of such regioselectivity, we analyzed the relative reactivity of the OH-3 and OH-4 groups of 2,6-diprotected methyl α- and β-galactopyranoside derivatives in glycosylation reactions. The glycosyl acceptors were efficiently prepared by simple methodologies, and glycosyl donors with different reactivities were assessed. High regioselectivities were achieved in favor of the 1→3 products due to the equatorial orientation of the OH-3 group. A molecular modeling approach endorsed this general trend of favoring O-3 substitution, although it showed some failures to explain subtler factors governing the difference in regioselectivity between some of the acceptors. However, the Galp-(β1→3)-Galp linkage could be regioselectively installed by using some of the acceptors assayed herein.

d-Allose, a rare sugar. Synthesis of d-allopyranosyl acceptors from glucose, and their regioselectivity in glycosidation reactions

“…In our laboratory we have investigated the relative reactivity of OH-3 and OH-4 of 2,6-di- O -protected galacto- and glucopyranosyl derivatives in glycosidation reactions with different galactosyl donors. 15,16 In the case of d -Gal p acceptors, the formation of 1 → 3 disaccharides was favored, as expected, given the equatorial orientation of the OH-3 group vs. the axial one of the OH-4 group. However, the regioselectivities observed were different depending on the 2,6-substituents, the anomeric configuration of the acceptors, and the reactivities of the donors.…”

“…Rationalization of the OH-3/OH-4 reactivities by different molecular modeling approaches generally agreed with the experimental trend. 15 For d -Glc p acceptors, with both OH-3 and OH-4 equatorially oriented, the prediction is not trivial and, in line with this, the experimental behavior showed larger variations and less accurate agreement with the theoretical results. 16…”

“…In the glycosidation reactions of allosides and analogously to the case of d -Gal, 15 we would have predicted that OH-4 would be more reactive than OH-3, due to its equatorial orientation. 44 Nevertheless, acceptors 1 and 2 were more reactive at axial OH-3 with respect to equatorial OH-4 (Table 1 and Scheme 4).…”

The Synthesis of Blood Group Antigenic A Trisaccharide and Its Biotinylated Derivative

“…It is known that equatorial hydroxyl groups are usually more reactive than axial ones [ 31 , 32 ]. Based on this assumption, we suggest that a regioselective 3-O-glycosylation of diol 8 would be possible.…”

Improved α-Sialylation through the Synergy of 5-N,4-O-Oxazolidinone Protection and Exocyclic C-1 Neighboring Group Participation

“…Interestingly, the α-selectivity of 20 was significantly higher than 21 probably because of the β-1- O -methoxy at the reducing end, rendering 13 a higher reactivity than its α-anomer 14 . Although the lack of direct studies of 3-hydroxy galactosides, their 4-hydroxys of β-anomers are more reactive than that of α-anomers, which may pass to 3-hydroxy groups through intramolecular hydrogen bonding. For the important naturally occurring Sia-α-2,8-Sia linkage, using 8-hydroxy sialyl acceptor 14 , we could isolate dimer 22 in 86% yield with decent α-selectivity (α/β 4:1), the unexclusive α-selectivity is probably due to the intramolecular hydrogen bond between 8-OH and C 5-acetamide groups. ,, Nonetheless, in the coupling toward the challenging sialyl acceptors bearing the native 5-NHAc group, donor 4 represents promising reactivity compared to the picoloylated HAD donor (no product), 5 N – C 1 tethered sialyl donor (9% yield), or other donors. ,, It is possibly because the glycosyl intermediate is more stable in the presence of 4- O ,5- N -oxazolidinone and C-1 participating groups and thus avoid the 2,3-elimination product.…”