Why Is Direct Glycosylation with N-Acetylglucosamine Donors Such a Poor Reaction and What Can Be Done about It?

Abstract

The monosaccharide N-acetyl-d-glucosamine (GlcNAc) is an abundant building block in naturally occurring oligosaccharides, but its incorporation by chemical glycosylation is challenging since direct reactions are low yielding. This issue, generally agreed upon to be caused by an intermediate 1,2-oxazoline, is often bypassed by introducing extra synthetic steps to avoid the presence of the NHAc functional group during glycosylation. The present paper describes new fundamental mechanistic insights into the inherent challenges of performing direct glycosylation with GlcNAc. These results show that controlling the balance of oxazoline formation and glycosylation is key to achieving acceptable chemical yields. By applying this line of reasoning to direct glycosylation with a traditional thioglycoside donor of GlcNAc, which otherwise affords poor glycosylation yields, one may obtain useful glycosylation results.

Glycosylation: The Direct Synthesis of 2‐Acetamido‐2‐Deoxy‐Sugar Glycosides

“…As expected, the glycosylation of the 6‐OH glycosidic acceptors needed extended reaction times, producing good yields with the Bi III or Fe III catalysts (Scheme ). As observed with all other GlcNAc glycosyl donors, the challenging synthesis of a β‐1,4‐glycosidic linkage with 4‐OH glycosidic acceptor supplied only very moderate yields of the β‐glycoside . Activation of the benzylated β‐acetate donor 159 (5 mol‐% of the catalyst, 1 h at reflux in CH 2 Cl 2 with allyl alcohol) was reported earlier with the Fe III catalyst in presence of TTBP under microwave irradiation at 80 °C (45–180 min), the same conditions used for the acetylated β‐acetate donor 1 (see section 3.6.1) .…”

“…While screening a variety of Lewis acids, Bi(OTf) 3 , Fe(OTf) 3 or Sc(OTf) 3 turned out to be the most efficient catalysts concerning the reaction time, in activating the benzylated β‐acetate donor 159 (5 mol‐% of the catalyst, 1 h at reflux in CH 2 Cl 2 with allyl alcohol) . As expected, the glycosylation of the 6‐OH glycosidic acceptors needed extended reaction times, producing good yields with the Bi III or Fe III catalysts (Scheme ).…”

“…We could speculate that if complexation to the NHAc carbonyl group is strong enough to (partially) prevent the oxazoline formation by decreasing the Lewis basicity of the carbonyl group, then a direct S N process could operate. Noteworthy, it was recently revealed that controlling the oxazoline formation and the glycosylation reaction resulted in better chemical yields …”

Advances in Stereoselective 1,2‐cisGlycosylation using C‐2 Auxiliaries

“…Furthermore, this strategy is also applicable to the synthesis of 2-deoxy-2-amino-glycosides using amine-protecting groups that can performN GP.H owever, care needs to be taken when using an N-acetyl group for NGP as the corresponding glycosyl oxazoline is ac ommonly formed byproduct, but can be avoided by using Lewis acid catalysis. [8] Alternatively,o ther amine protecting groups that can perform NGP such as phthalimido, tetrachlorophthalimido, trichloroacetyl, allyloxycarbonyl, and 2,2,2-trichloroethyloxycarbonyl can be used. [9] In contrast, the introductiono f1 ,2-cis glycosidic linkages is much more challenging and requires glycosyl donors having a non-assisting functionality at C-2.…”

A Direct Method for β-Selective Glycosylation with an N-Acetylglucosamine Donor Armed by a 4-O-TBDMS Protecting Group

“…For the syntheses of glycoconjugates containing GlcNAc residues, it is necessary to use glycosamine (GlcN) donors activated by a phthaloyl [ 5 ] and 2,2,2-trichloroethoxycarbonyl [ 6 , 7 ] attached to the amine function. Unfortunately, however, methods using GlcNAc donors suffer from several disadvantages: (1) GlcNAc donors are less reactive than N -modified GlcN donors; (2) harsh conditions (reflux heating [ 8 , 9 ] and microwave irradiation [ 10 , 11 ]) are required to achieve the desired glycosylations; and (3) the corresponding oxazoline byproducts are formed in many cases. In 2008, Christensen and coworkers reported that scandium(III) trifluoromethanesulfonate (Sc(OTf) 3 ) could serve as an effective activator for β-GlcNAc tetraacetate donor 1 and the glycosylation of simple alcohols in refluxing dichloromethane ( Figure 1 a) gave the desired β-glycosides in high yields [ 11 ].…”