The Amide Group in N-Acetylglucosamine Glycosyl Acceptors Affects Glycosylation Outcome

Abstract

Glycosylation of a disaccharide containing N-acetylglucosamine with rhamnosyl and mannosyl trichloracetimidates under triethysilyl triflate catalysis led to the competitive formation of glycosyl imidates. While the rhamnosyl imidate could be rearranged to the thermodynamically favored trisaccharide, the mannosyl analogue was resistant to rearrangement. Glycosylation with perbenzylated thiorhamnosides activated with methyl triflate (MeOTf) gave the trisaccharide as well as the methyl imidate trisaccharide. The less reactive alpha-thioethyl donor led to a higher relative amount of methyl imidate trisaccharide to trisaccharide than the more reactive beta-thioglycoside. When using a more reactive thioethyl fucoside only the trisaccharide was obtained. Interestingly, the acceptor treated with MeOTf gave the N-methyl imidate that could be easily rhamnosylated and subsequently converted to the N-acetamido trisaccharide. This strategy to glycosylate O-4 of N-acetylglucosamine is under further investigation. Alternatively, bis-N-acetylation of the glucosamine prevented the formation of imidates and allowed the efficient synthesis of two Lewis A trisaccharide analogues.

Synthesis of Chondroitin Sulfate A Bearing Syndecan-1 Glycopeptide

“…16 The amine moiety of GalN was protected as a trichloroacetyl (TCA) amide, which could direct β stereo-selectivity 8–10 and reduce the potential complications from the formation of side products/intermediates arising from the use of acetamide bearing building blocks. 17,18 Thus, ABC trisaccharide 3 , DE disaccharide 4 , and FGH trisaccharide 5 19 were designed first to access octasaccharide 2 .…”

Synthesis of 4” manipulated Lewis X trisaccharide analogues

“…We thus attempted the coupling of acceptor 23 and donor 12 under activation with excess MeOTf (5 equiv). Indeed, we have reported that such conditions allow glycosylation at O-4 of N -acetylglucosamine acceptors through the in situ formation of the corresponding N -methylimidate, temporarily masking the N -acetyl group in the acceptor [70–71]. Thus, we expected a similar in situ formation of the methyl imidate in acceptor 23 , which would further undergo fucosylation at O-3.…”

“…However, since methylimidates are unstable when purified on silica gel, they were converted back to the acetamido before purification. Thus, once TLC had shown that all of the acceptor had been consumed, the reaction was worked up and the crude mixture was treated with Ac 2 O–AcOH prior to purification by chromatography [70–71]. Under these conditions, the desired trisaccharide 26α was obtained pure and free of the β-anomer in 77% yield.…”

Obstacles and solutions for chemical synthesis of syndecan-3 (53–62) glycopeptides with two heparan sulfate chains

“…Reaction of donor 16 with pentasaccharide acceptor 25 failed to lead to any desired heptasaccharide 27 (Scheme 3a). To test the possibilities of acetamide 99 or the electron withdrawing benzyl ester groups negatively impacting glycosylation, donor 15 and idose/azide bearing thioglycosyl trisaccharide acceptor 28 were examined, which did not lead to successful glycosylation either. Several side products due to acceptor activation were observed from these reactions.…”