Stereoselective Construction of β‐Mannopyranosides by AnomericO‐Alkylation: Synthesis of the Trisaccharide Core ofN‐linked Glycans

Abstract

An ew and efficient approach for direct and stereoselective synthesis of b-mannopyranosides by anomeric O-alkylation has been developed. This anomeric O-alkylation of mannopyranose-derived lactols is proposed to occur under synergistic control of ak inetic anomeric effect and metal chelation. The presence of ac onformationally flexible C6 oxygen atom in the sugar-derived lactol donors is required for this anomeric O-alkylationt ob ee fficient, probably because of its chelation with cesium ion. In contrast, the presence of aC 2oxygen atom playsaminor role.T his glycosylation method has been successfully utilized for the synthesis of the trisaccharide core of complex N-linked glycans.Protein glycosylation is known as one of the major types of post-translational modifications.I ng eneral, there are two types of glycans attached to proteins:1 )N-linked glycans attached to asparagine and 2) O-linked glycans attached to serine or threonine.[1] Recent biological studies have demonstrated that the glycans of glycoconjugates play essential roles in numerous biological [2] and cellular processes. [3] Cell-surface glycans serve as receptor ligands for proteins,f or example, enzymes, [4] antibodies, [5] and lectins. [6] In addition, it was also found that the degree of cell-surface carbohydrate antigen expression is closely associated with tumor progression, and diagnostic results may guide the use of corresponding approach for cancer treatment. [7,8] Furthermore,c arbohydrate moieties are known to stabilize protein folding [9] and modify physical, chemical, and biological properties of their carrier molecules.Because of the heterogeneous glycoforms of glycoproteins,i tis difficult to understand the exact function of these complex glycans.T oa ddress the challenge,r esearchers seek to obtain single glycoforms of biologics by either total chemical synthesis [10] or chemoenzymatic synthesis. [11] Although great progress has been achieved, [10,11] the synthesis of complex N-linked glycans remains ad aunting task. In particular,s tereoselective construction of the b-mannopyranoside,o ne of the key glycosidic linkages existing in structurally complex N-linked glycans,i salong-standing challenge in glycosylation chemistry.[12] Over the past several decades,numerous efforts have been dedicated to addressing this difficulty to facilitate the chemical synthesis of N-linked glycans for studies of their biological function. Those efforts include:1)use of anonparticipating group [13] for protection of O2 and insoluble silver salts for activation of mannopyranosidic halide; [13a-d] 2) inversion of the C2 stereochemistry of bglucopyranosides [14] or stereoselective reduction [15] of b-2-ulosyl glycosides;3 )den ovo synthesis of b-mannopyranosides by a-selective quenching of C1-alkoxy radicals by suitable hydrogen-atom donors; [16] 4) synthesis of b-mannopyranosides involving intramolecular aglycone delivery; [17][18][19][20] 5) use of 4,6-O-benzylidene- [21] or 4,6-O-silylene-protected [22] a-mannopyranosyl triflates;6 )use of...

A Natural Lipotrisaccharide and Its Derivatives Selectively Lyse Streptococcus pneumoniae via Interaction with Cell Membrane

“…Derivatives 2a−2j (Figure 1) were directly synthesized from the key intermediate 8, which was derived from the chemical linkage of building blocks 5 18,19 and 6 20 (Table 1 and Scheme 1). The final product, 1a, was obtained by β-mannnosylation with acceptor 8 with donor 7 21,22 (Scheme 2). The intermediates 5 and 6 for synthesis of 8 and 7 were prepared from commercially available β-D-glucosepentaacetate, 1,2:5,6-di-O-isopropylidene-α-D-glucose, and mannose via five, six, and six steps, respectively, in yields from 36 to 48% (see the Supporting Information).…”

“…General Procedure of Glycosylation of 6′-OH with Mannose 7 To Prepare 18. A mixture of phthalic anhydride (1.1 mmol), 4 Å MS, donor 7 22 (1.0 mmol), and DBU (1.2 mmol) in 15 mL of DCM under an argon atmosphere was stirred for 15 min. Next, the mixture was transferred to a −78 °C solution of DTBMP (2.2 mmol, 451.7 mg) in 5 mL of DCM and Tf 2 O (2.2 mmol, 370 μL) by a syringe and stirred for 15 min at −78 °C.…”