Diacetyl strategy for synthesis of NHAc containing glycans: enhancing glycosylation reactivity via diacetyl imide protection

Koichi Fukase; Yoshiyuki Manabe; Atsushi Shimoyama

doi:10.3389/fchem.2023.1319883

Diacetyl strategy for synthesis of NHAc containing glycans: enhancing glycosylation reactivity via diacetyl imide protection

Front Chem. 2023 Dec 5:11:1319883. doi: 10.3389/fchem.2023.1319883. eCollection 2023.

Authors

Koichi Fukase^{1

2}, Yoshiyuki Manabe^{1

2}, Atsushi Shimoyama^{1

2}

Affiliations

¹ Department of Chemistry, Graduate School of Science, Osaka University, Osaka, Japan.
² Forefront Research Center, Graduate School of Science, Osaka University, Osaka, Japan.

Abstract

The presence of NHAc groups in the substrates (both glycosyl donors and acceptors) significantly reduced the reactivity of glycosylation. This decrease was attributed to the NHAc groups forming intermolecular hydrogen bonds by the NHAc groups, thereby reducing molecular mobility. Hence, a diacetyl strategy involving the temporary conversion of NHAc to diacetyl imide (NAc₂) was developed for the synthesis of NHAc-containing glycans. This strategy has two significant advantages for oligosaccharide synthesis. The NAc₂ protection of NHAc substantially enhances the rate of glycosylation reactions, resulting in improved yields. Moreover, NAc₂ can be readily reverted to NHAc by the simple removal of one acetyl group under mild basic conditions, obviating the necessity for treating the polar amino group. We have achieved the efficient synthesis of oligosaccharides containing GlcNHAc and N-glycans containing sialic acid using the diacetyl strategy.

Keywords: amide; amide bond; flow reaction; glycan; glycosylation; oligosaccharide.

Publication types

Review

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was financially supported by JSPS KAKENHI grants 20241053 and 21106008 in Integrated Synthesis; 23241074, 26560447, and 15H05836 in Middle Molecular Strategy; 16H01885, 16H05924, 18H03934, 19KK0145, 20H00404, 20H05675, 20K05727, 20H04709, and 21H05074; JST CREST grants JPMJCR20R3; AMED grants 20ek0109444h0001 and 20fk0210079h0001; Japan Initiative for World-Leading Vaccine Research and Development Centers, a Naito research grant, and a Nikki Saneyoshi research grant.