Acceptor-bound synthesis

Scheme 1. Solid-phase synthesis using the acceptor-bound method.

Fig. 3. Acceptor-bound solid-phase carbohydrate synthesis.

Our approach to oligosaccharide synthesis relied on the acceptor-bound solid-phase method. This method formally reduces the synthesis of carbohydrates to a repetitive cycle of glycosylation and deprotection events. It was reasoned that the repetitive nature of an acceptor-bound glycosylation method rendered it ideal for automation. Therefore, we set out to investigate the potential variables in such a scheme. 

Another important aspect of our acceptor-bound strategy was the delivery of donors in solution. In selecting donors we considered their stability, reactivity, ease of synthesis, and activation under homogeneous reaction conditions. The use of insoluble reagents (such as powdered molecular sieves) would not be compatible with an automated instrument. 

We have developed an automated solid-phase approach for the chemical synthesis of oligosaccharides. Using an acceptor-bound solid-phase... 

SCHEME 54. Major concepts for the polymer-supported/solid-phase oligosaccharide synthesis glycosyl acceptor bound approach (A) and glycosyl donor bound approach (B). 

The preceding sections discussed the strengths and weaknesses of the donor- and acceptor-bound synthetic strategies developed to date for the synthesis of complex oligosaccharides. Boons et al. recently described an approach that combines both strategies in a bidirectional solid phase oligosaccharide synthesis [67]. 

While it is usually considered most efficient to conduct polymer-supported glycosylation by an acceptor-bound strategy [132, 133], consideration of the hydrolytic and thermal instability of the mannosyl triflate intermediates initially led to the development of a donor-bound strategy for the supported synthesis of the p-mannopyranosides. Thus, a polystyrylboronate resin was employed to capture a 4,6-diol leading to a resin bound donor that was activated and coupled under the standard BSP conditions. Excellent p-selectivities were obtained and the products cleaved from the resin with aqueous acetone (Scheme 11) [88]. 

Scheme 33 Acceptor-bound approach to polymer-supported P-mannoside synthesis...

Ito and coworkers have combined the soluble polymer-supported synthesis with the catch-and-release protocol using the chloroacetyl (ClAc) tag (Scheme 16.20). Glucosamine acceptor bound to a low molecular weight polyethylene glycol (PEG) 70 was glycosylated with a thiogalactoside donor 71 in the presence of dimethyl(methylthio) sulfonium triflate (DMTST) in CH2CI2 to provide the disaccharide 72 in 94% yield. 

Scheme 4. Solid-phase enzymatic synthesis of a Lewis trisaccharide by use of a disaccharide acceptor bound to Sepharose. Reagents i) cacodylate buffer pH 6.8, 5 mM MnCh, 0.05% NaN3, FT, GDP-Fuc (5 eq.) 68% ii) 2-mercaptoethanol, 1 h, 60 °C, 91%.

Two general strategies are available for sohd phase ohgosaccharide synthesis, the acceptor-bound and the donor-bound strategy (Fig. 4). Both can also be combined in a bi-directional approach. 

If the synthesis starts from glucose molecules, then the initial step is the transfer of glucose residues from UDP-glucose onto an intermediary acceptor-dolichol phosphate (membrane-bound polyprenol phosphate). Dolichol phosphate assists in the synthesis of an... 

---