Solid phase polysaccharide synthesis

The solid phase polysaccharide synthesis is performed on Metrifield s polystyrene resin functionalized with 4-octenediol linker. This linker is stable during the synthesis cycles but can be cleaved by Gmbbs catalyst (cross-metathesis reaction) resulting in fuUy protected polysaccharide, which can be used for further functionalization or deprotected in its native state. The final purification is achieved by high-performance hquid chromatography, which in some cases also can be used to separate the different stereoisomers of the final products [58]. 

FIGURE 3.49 Schematic view of the solid phase polysaccharide synthesis. 

Carbohydrates and polysaccharides, on the one hand, and peptides and proteins, on the other, have been considered as separate classes of natural products for a long time. Fundamental chemical methodology for the synthesis of both saccharides and peptides was developed by Emil Fischer et al. at the beginning of the 20th century. 1,2 However, the harsh conditions employed in early solution and solid-phase peptide synthesis hindered the combination of peptide and carbohydrate chemistry, i.e. glycopeptide synthesis. Considerable efforts were made to combine the two branches of natural product chemistry, and the state of the art within glycopeptide synthesis has improved dramatically during the last decades, as described in a number of reviews. 3 23,512"514 ... 

Cellulose is an unbranched polysaccharide consisting of 1,4-linked 3-D-glucose and can attain lengths of up to 15000 pyranose units. It neither dissolves nor swells in most solvents, but can be hydrolyzed upon prolonged treatment with acids. Cellulose powder was the first type of support to be used (with limited success) for solid-phase peptide synthesis [208]. Limitations were mainly due to the low loading (0.1 mmol/g) attained in these initial experiments, and the high reactivity of cellulose. Despite these... 

Although the solid-phase technique was first developed for the synthesis of peptide chains and has seen considerable use for this purpose, it has also been used to synthesize chains of polysaccharides and polynucleotides in the latter case, solid-phase synthesis has almost completely replaced synthesis in solution. The technique has been applied less often to reactions in which only two molecules are brought together (nonrepetitive syntheses), but many examples have been reported. 

The potential of solid-phase synthesis in combinatorial chemistry has been the focus of many reviews and will not be discussed here [37]. Polysaccharide-based drags are still not favored by most pharmaceutical companies. They are metabolically very labile and also suffer from poor oral absorption in intact form. In addition, binding of polysaccharides to their targets often requires multivalent interactions to achieve significant effects... 

Figure 2.15 Automated solid phase oligo-/polysaccharide synthesis. Glycosyl donor (A) is coupled to a solid phase Merrifield-like resin through an alkenyl alcohol linker. The double bond allows for clean removal of product at the end of solid phase synthesis by metathesis using Grubb s catalyst in the presence of ethylene gas. For protecting groups, see Fig 2.13. Trimethyl silyltriflate (TMSOTf) activates the glycosyl donor through controlled removal of the trichloroacetamidate.

Glycosylation. The use of DMTST continues to be an important way to activate thioglycosides for the synthesis of polysaccharides and other O-glycosides (e.g., eq 2), including the immobilizing of monosaccharide donors in solid-phase synthesis... 

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