Exploration of the use of an acylsulfonamide safety-catch linker for the polymer-supported synthesis of hyaluronic acid oligosaccharides

Abstract

The synthesis of hyaluronic acid oligosaccharides on polyethylene glycol (PEG) using an acylsulfonamide linker has been explored. Hyaluronic acid is a challenging synthetic target that usually involves the condensation of highly disarmed glucuronic acid building blocks. Amine-ended PEG monomethyl ether was efficiently functionalized with a hydroxyl-terminated acylsulfonamide linker. Suitably protected D-glucosamine (GlcN) and D-glucuronic acid (GlcA) monosaccharide building blocks were coupled to the polymer acceptor using the trichloroacetimidate glycosylation method. The sulfonamide safety-catch linker enables simultaneous cleavage of the monosaccharide from the polymer and orthogonal functionalization for further (bio)-conjugation of the sugar sample. Subsequent glycosylation of PEG-bound glycosyl acceptor to generate hyaluronic acid oligosaccharide chain failed. Model glycosylation experiments in solution and on soluble support using the same unreactive acceptors and donors allows for the synthesis of an orthogonally protected hyaluronic acid disaccharide and suggest that the encountered difficulties could be attributed to the presence of the N-acylsulfonamide.

Acylsulfonamide safety-catch linker: promise and limitations for solid–phase oligosaccharide synthesis

“…With this novel linker, inherent but previously unknown limitations of the safety-catch concept for solid-phase oligosaccharide synthesis were discovered. The sulfamyl group can be attacked by excess glycosylating agent to give the unexpected resin-bound N -glycoside, which may block additional reaction sequences and extension of the oligosaccharide [28]. In addition, sodium methoxide can directly cleave the sulfamyl group, prohibiting its use in conjunction with safety-catch linkers in general.…”

Toward Automated Enzymatic Synthesis of Oligosaccharides

“…The classic acylsulfonamide safety-catch linker was published by Kenner and co-workers in 1971 . This linker has been used in the chemical synthesis of glycans but has not thus far been used in conjunction with enzymes (Figure ). Similarly, Tanaka and co-workers used a phenyl ether linker as a safety-catch linker in the fluorous-assisted chemical synthesis of oligosaccharides .…”

Chemical Synthesis of Glycosaminoglycans

“…The soluble PEG conjugate can be used for traditional chemistry in most of the common solvents and is then precipitated with diethyl ether. Although this method works with small molecules, peptides, and other bioactive entities, glycosaminoglycan syntheses with PEG supports are seldom realized despite select successful examples. ,, …”