Characterization of glycosyl dioxolenium ions and their role in glycosylation reactions

Abstract

Controlling the chemical glycosylation reaction remains the major challenge in the synthesis of oligosaccharides. Though 1,2-trans glycosidic linkages can be installed using neighboring group participation, the construction of 1,2-cis linkages is difficult and has no general solution. Long-range participation (LRP) by distal acyl groups may steer the stereoselectivity, but contradictory results have been reported on the role and strength of this stereoelectronic effect. It has been exceedingly difficult to study the bridging dioxolenium ion intermediates because of their high reactivity and fleeting nature. Here we report an integrated approach, using infrared ion spectroscopy, DFT computations, and a systematic series of glycosylation reactions to probe these ions in detail. Our study reveals how distal acyl groups can play a decisive role in shaping the stereochemical outcome of a glycosylation reaction, and opens new avenues to exploit these species in the assembly of oligosaccharides and glycoconjugates to fuel biological research.

Automated Assembly of Starch and Glycogen Polysaccharides

“…Esterification on 6-OH­(entries 2–7, and entries 2–14 in Table S1) resulted in higher stereoselectivity than deoxyfluorination (entry 13), even though ester groups are less electron withdrawing than fluorine. These results further supported the ester remote assistance hypothesis during glycosylation. ,, The argument whether the ester group really stabilized the intermediate by forming a covalent glycosyl dioxolenium ion during glycosylations has not been settled, although this intermediate can be detected under extreme conditions. − We observed that 6-OH esterification alone does not ensure excellent selectivity during α (1–4) glycosylations. Selectivities for the glycosylation of isopropanol ranged from 1.5–3:1 (α/β) as changes in the electronic and steric properties of ester groups had little effect (entries 2–7, and entries 2–14 in Table S1).…”

Microwave-Assisted Automated Glycan Assembly

“…The Lev group was positioned at the C-3 as O-3 ester groups are reported to assist with strong α-selectivity. 23 It was found that the Fmoc was best positioned at the C-4 position, as a C-4 AcCl group tended to migrate to the primary C-6 hydroxy group upon a C-6 Fmoc cleavage. As a result, the AcCl was used to protect the primary C-6 position in mannose building block 7 .…”

Metal-free glycosylation with glycosyl fluorides in liquid SO2

“…Due to the absence of a neighboring group at C2 position, the stereoselective synthesis of 2-deoxy glycosides is challenging [ 72 – 74 ]. We hypothesize that the stabilization of the oxocarbenium ion intermediate in a form of a dioxolenium ion by the remote protecting group in C3 or C6 position could be the reason for such a good α-selectivity in liquid SO 2 [ 75 ].…”