Development of Dendritic Glycosylation Methodology towards One-Pot Synthesis of High-Mannose Glycans

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Development of Dendritic Glycosylation Methodology towards One-Pot Synthesis of High-Mannose Glycans

Lucio Usui 1 , Kyohei Nitta 1 , Akira Koizumi 1 , Taiki Kuribara 1 , Kiichiro Totani 1

1 Seikei University, Kichijoji-kitamachi, Musashino-shi, Japan

Various high-mannose type glycoprotein oligosaccharides play important roles in glycoprotein quality control. To analysis their biological functions, there is problematic in rapid access to obtain sufficient amount of various high-mannose glycans by chemical synthesis or isolation from organic sources. Thus, the facile methodology to obtain a series of high-mannose glycans is still required.

To overcome this subject, we designed the one-pot strategy called dendritic glycosylation contributing synthesis of various branched high-mannose glycans. In this methodology, the following issues should be improved: (a) achievement of complete stereoselectivity in each glycosylation steps, and (b) facile purification and isolation technique for the resulting glycosylation product mixture. In this study, we prove the feasibility of the dendritic glycosylation through model experiments towards synthesis of the B- and C-branch structures of high-mannose glycans (Figure 1).

In the first step of the glycosylation, the Pre-M7 trisaccharide was synthesized from 3,6-di-OH mannosyl accepter and fluorinated mannosyl donor with perfect α-selectivity in the glycosylation. We intentionally suspended the subsequent second dendritic glycosylation to obtain not only the Pre-M9, but also the intermediate product of Pre-M8B and Pre-M8C in a one-pot. The glycosylation was performed by decreasing the equivalent of the donor to suspend dendritic glycosylation in inadequate progress. As a result, the dendritic glycosylation produced the four kinds of branched structures of pre-high-mannose glycans in the same reaction mixture. These compounds were also synthesized in complete α-selectivity. These glycosylation products were completely purified and isolated by only once refinement of Medium Pressure Liquid Chromatography (MPLC). Pre-M8B and Pre-M8C, the structural isomers, were identified with two-dimensional NMR (COSY, HMQC and HMBC). We believe this framework can be used to improve the future obtainment of high-mannose glycans. Application of the dendritic glycosylation to obtain the full-set of complete high-mannose glycans are also in progress.

Figure 1. Elongation of the branched structures by dendritic glycosylation.

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