Efficient Polymer‐Assisted Strategy for the Deprotection of Protected Oligosaccharides

Abstract

Oligosaccharides play important roles in cell-surface events through carbohydrate-protein and carbohydrate-carbohydrate interactions.[1] The chemical synthesis of structurally defined oligosaccharides would be highly desirable in structure-activity studies because oligosaccharides from natural sources can be produced in only limited qualities. Recent progress in oligosaccharide synthesis has resulted in a number of new and efficient glycosidation methodologies, which are amenable to the synthesis of protected oligosaccharides 1 by standardized and routine protocols.[2] However, deprotection of the protected oligosaccharides 1!2, including the cleavage of various O-protecting groups and the replacement of Nprotecting groups with N-acetyl groups is difficult to achieve by standardized protocols (Scheme 1). The complete deprotection of protected oligosaccharides frequently requires careful selection of the reaction solvents to prevent the partially deprotected intermediates from precipitating. Herein, we describe an efficient method for the deprotection of protected oligosaccharides based on a polymer-assisted strategy and its application to the synthesis of dimeric and trimeric Lewis X derivatives.Our polymer-assisted strategy for the deprotection of protected oligosaccharides 1 is illustrated in Scheme 1. The solid-supported protected oligosaccharide 3 linked through a tetrahydropyranyl (THP) linker was designed as a key intermediate. The solid-supported complex oligosaccharides would smoothly undergo deprotection because they are aggregated to only a very limited extent. A Birch reduction was adapted for removing the solid-supported benzyl ethers and esters on 3.[3] The THP linker would survive deprotection reactions and can be cleaved under mildly acidic conditions to release the fully deprotected oligosaccharide 2 without anomerization or cleavage of the glycosidic bonds. [4,5] The ease of handling of solid-supported compounds would be effective not only for the high-speed synthesis of a single target oligosaccharide but also for the deprotection of a protected oligosaccharide library.[6] The polymer-supported protected oligosaccharide 3 can be prepared using the following methodology: 1) acetal formation of the protected saccharides 1 with prelinker 4 containing a dihydropyranyl (DHP) moiety and an activated ester and 2) subsequent Scheme 1. Polymer-assisted strategy for deprotection of the protected oligosaccharides 1. Bn= benzyl, PNP = para-nitrophenyl, Phth = phthalyl, Troc = 2,2,2-trichloroethoxycarbonyl.Scheme 2. Reagents and conditions: a) LiAlH 4 , THF; b) tert-butyl bromoacetate, NaH, DMF; c) 1 n aq. NaOH, dioxane; d) 4-nitrophenol, EDCI, DIEA, CH 2 Cl 2 , 42 % from 6. DMF = N,N-dimethylformamide, EDCI = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, DIEA = diisopropylethylamine.

Efficient Synthesis of an α(2,9) Trisialic Acid by One-Pot Glycosylation and Polymer-Assisted Deprotection

“…Recently, we developed an efficient method for the synthesis of oligosaccharides that is based one-pot glycosylation and polymer-assisted deprotection. − The one-pot glycosylation involved sequential chemo- and regioselective glycosylation to provide oligosaccharides from several simple building blocks in one pot . The polymer-assisted deprotection involved deprotection of solid-supported, protected oligosaccharides followed by their release from the solid supports.…”

“…The linker 3 undergoes acetalization with the protected trisialic acid 5 at the 8 and/or 8′ positions; amidation with an amino group on ArgoPore thereafter immobilizes the trisaccharide 5 onto a solid support. The ArgoPore resin enables deprotection of solid-supported, protected oligosaccharides via debenzylation through Birch reduction . The ester unit in the carbon linker chain of 3 exhibits enhanced stability under basic conditions.…”

Oligosaccharide Synthesis on Solid, Soluble Polymer, and Tag Supports

“…On the other hand, an efficient polymer-assisted method for deprotection of the protected oligosaccharides has been demonstrated by Takahashi and coworkers (Scheme 16.22). 67 The deprotection of synthesized oligosaccharides, including the cleavage of various O-protecting groups and the replacement of N-protecting groups with N-acetyl group, is sometimes troublesome under standard conditions. Furthermore, the complete deprotection of the synthesized oligosaccharides frequently requires careful selection of the reaction solvents to prevent the partially deprotected intermediates from participating.…”

Principles of modern solid-phase oligosaccharide synthesis

“…There have been reports, however, that demonstrate that global deprotection of immobilized sugars is possible, provided that the proper resin is selected. 72,73 For example, Wong and Kanie have shown that hydrogenolysis using Pd-nanoparticles permits global deprotection of sugars immobilized to PEGA resin. More recently, the Takahashi group has shown that benzyl ethers on oligosaccharides immobilized to ArgoPore resin can be removed using a Birch reduction.…”

“…77 By modifying a commercially Scheme 11 Takahashi's use of global deprotection on solid-phase to afford a trimeric Lewis X oligosaccharide. 73 available peptide synthesizer, they demonstrated it was possible to program the instrument to construct oligosaccharides. Using both glycosyl phosphate and trichloroacetimidate donors, a number of oligosaccharides including a β-glucan dodecasaccharide were synthesized.…”