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J Org Chem. 2008 Oct 3;73(19):7574-9. doi: 10.1021/jo801117y. Epub 2008 Sep 4.

Convenient temporary methyl imidate protection of N-acetylglucosamine and glycosylation at O-4.

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Department of Chemistry, University of Guelph, Guelph, Ontario, N1G 2W1, Canada.


This paper expands on the scope and utility of the temporary conversion of N-acetyl groups to alkyl imidates when attempting to glycosylate at O-4 of N-acetylglucosamine acceptors. The optimized synthesis of alkyl imidate protected glucosamine acceptors at position 4 and carrying various protecting groups at O-3 is described. These imidates were prepared immediately prior to glycosylation by treating the 4-OH acceptors with 0.5 M MeOTf to obtain the corresponding methyl imidates still carrying a free 4-OH group. When preparing these imidates in diethyl ether as the reaction solvent, we observed the unexpected formation of ethyl imidates in addition to the desired methyl imidates. While the 3-O-allyl acceptors were too unstable to be useful in glycosylation reactions, the 3-O-acylated methyl and ethyl imidates of glucosamine were shown to behave well during the glycosylation of the 4-OH with a variety of reaction conditions and various glycosyl donors. Glycosylation of these acceptors was successfully carried out with perbenzylated beta-thioethyl rhamnopyranoside under MeOTf promotion, while activation of this donor under NIS/TMSOTf or NIS/TfOH proved less successful. In contrast, activation of the less reactive perbenzylated alpha-thioethyl and peracetylated beta-thioethyl rhamnopyranosides with NIS/TfOH led to successful glycosylations of the 4-OH. Activation of a peracetylated rhamnosyl trichloroacetimidate by TMSOTf at low temperature also gave a high yield of glycosylation. We also report one-pot glycosylation reactions via alkyl imidate protected acceptor intermediates. In all cases the alkyl imidate products were readily converted to their corresponding N-acetyl derivatives under mild conditions.

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