Convergent Synthesis of a Bisecting N‐Acetylglucosamine (GlcNAc)‐Containing N‐Glycan

Abstract

The chemical synthesis of a bisecting N-acetylglucosamine (GlcNAc)-containing N-glycan was achieved by a convergent synthetic route through [4+2] and [6+2] glycosylations. This synthetic route reduced the number of reaction steps, although the key glycosylations were challenging in terms of yields and selectivities owing to steric hindrance at the glycosylation site and a lack of neighboring group participation. The yields of these glycosylations were enhanced by stabilizing the oxocarbenium ion intermediate through ether coordination. Glycosyl donor protecting groups were explored in an effort to realize perfect α selectivity by manipulating remote participation. The simultaneous glycosylations of a tetrasaccharide with two disaccharides was investigated to efficiently construct a bisecting GlcNAc-containing N-glycan.

Recent Advances in the Chemical Biology of N-Glycans

“…Unverzagt et al achieved convergent synthesis of complex-type N-glycans with bisecting glucosamine and/or core fucose [9][10][11][12]. We have also reported the synthesis of N-glycans [13,14]. In addition, Ito et al [15], Boons et al [16][17][18], Wang et al [19], Wong et al [20,21], and Schmidt et al [22] have achieved N-glycan synthesis.…”

Chemical Synthesis of Sialyl N‐Glycans and Analysis of Their Recognition by Neuraminidase

“…Kim and co‐workers reported remote participation in mannosylation: [18] O ‐3 and O ‐6 acyl protection of the mannosyl donor enhanced the α‐selectivity. We have also demonstrated the usefulness of remote participation in the construction of N ‐glycan branched structure [14b] . Unverzagt and co‐workers synthesized various N ‐glycans through a convergent route (Figure 1, route A) and often used peracyl‐protected donors to realize perfect α‐selectivity [11] .…”

“…In these syntheses, glycosylations to construct the branched structure was achieved in high yields by using the ether solvent effect to stabilize the oxocarbenium ion intermediate [14a] . In addition, stereoselectivity issue was overcome by using remote participation, in which acyl protection of O ‐3 and O ‐6 of mannose realized the α‐selectivity glycosylations without neighboring group participation [14b, 18] . We have also reported a “diacetyl strategy” for the efficient synthesis of sialyl glycans [14a, 19] .…”

The Essential Functions and Detection of Bisecting GlcNAc in Cell Biology

“…Thus, only synthesizing the sequence of proteins, but not the glycan chains, is insufficient for protein function. Syntheses of glycans or glycoproteins containing bisecting GlcNAc structures have been reported in many papers (Wang et al, 2009 ; Castilho et al, 2011 ; Luber et al, 2018 ; Manabe et al, 2018 ; Yang et al, 2018 ). Synthesis of glycans or glycoproteins containing bisecting GlcNAc structures is helpful for glycomic and glycoproteomic research and will improve the development of protein-based therapeutics and the generation of glycan-engineered therapeutic antibodies (Castilho et al, 2011 , 2015 ).…”

“…The chemical synthesis of a bisecting GlcNAc could also be achieved through [4+2] and [6+2] glycosylations. This synthetic method reduces the number of reaction steps but faces two difficulties, namely, low yields and poor synthesis selectivity for key glycosylations (Manabe et al, 2018 ). A modular synthesis of 16 cores of mammalian complex-type N-glycans with optional core fucose and bisecting GlcNAc has been established by Unverzagt et al, and core fucosylated and bisected N-glycans could be synthesized with unprecedented efficiency and purity by integrating a one-pot protocol (Luber et al, 2018 ).…”