One‐Pot Synthesis of N‐Acetyl‐ and N‐Glycolylneuraminic Acid Capped Trisaccharides and Evaluation of Their Influenza A(H1 N1) Inhibition

Abstract

Human lung epithelial cells natively offer terminal N-acetylneuraminic acid (Neu5Ac) a(2!6)-linked to galactose (Gal) as binding sites for influenza virus hemagglutinin. N-Glycolylneuraminic acid (Neu5Gc) in place of Neu5Ac is known to affect hemagglutinin binding in other species. Not normally generated by humans, Neu5Gc may find its way to human cells from dietary sources. To compare their influence in influenza virus infection, six trisaccharides with Neu5Ac or Neu5Gc a(2!6) linked to Gal and with different reducing end sugar units were prepared using one-pot assembly and divergent transformation. The sugar assembly made use of an N-phthaloyl-protected sialyl imidate for chemoselective activation and a-stereoselective coupling with a thiogalactoside. Assessment of cytopathic effect showed that the Neu5Gc-capped trisaccharides inhibited the viral infection better than their Neu5Ac counterparts.

“One-Pot” Protection, Glycosylation, and Protection–Glycosylation Strategies of Carbohydrates

“…Building blocks, which were prepared by this protocol, had been applied to the synthesis of heparin and heparan sulfates, 64,188 alginates, 189 and influenza trisaccharides (Figure 1). 190 This protocol has been further streamlined by Wang and co-workers by incorporating a TMSOTf-catalyzed HMDS silylation by generating the per-O-trimethylsilylated glucosides 89 in situ. Therefore, tetraols could be used directly as the starting material for this elegant one-pot protocol.…”

“…This sialoside was further activated under NIS/TMSOTf conditions to couple with the acceptor 192, furnishing trisaccharide 193 in 64% yield and excellent stereoselectivity. 190 Boons and co-workers incorporated their α-selective glycosylation methodology by using (1S)-phenyl-2-(phenylsulfanyl) ethyl moiety at O2 position as the participating group in the chemoselective one-pot glycosylation endeavor. 91 As shown in Scheme 38, the imidate donor 194 bearing (1S)-phenyl-2-(phenylsulfanyl)ethyl moiety, upon activation with TMSOTf, led to the formation of the quasi-stable anomeric sulfonium ion 195 with a trans-decalin ring system.…”

“…Ito and co-workers developed a method for α-selective glycosylation of 2-deoxy-2-amino donors using a N-benzyl-2,3oxazolidinone group 190 in orthogonal one-pot glycosylation processes using a bromide/thioglycoside pair (Scheme 39). 365 Accordingly, bromide 200 was selectively activated by AgOTf and coupled with the thioglycoside donor−acceptor 201 to generate the corresponding thioglycosyl disaccharide.…”

One‐Pot Methods for the Protection and Assembly of Sugars

“…The elongation process thus generally occurs in the nonreducing end to the reducing end direction. For example, the exposure of the sialosyl imidate 49 and thioglycoside 50 to TMSOTf led to intermediate 51 , with the thiotolyl group intact and available for subsequent glycosylation under NIS/TMSOTf to afford the trisaccharide 53 (Scheme ) 38. However, thio group aglycone transfer, which reduces the chances of the second coupling process, is a problem occasionally encountered, particularly when the hydroxy group of the thioglycoside acceptor is poorly reactive in relation to the first donor 39.…”