Rapid assembly of oligosaccharides: a highly convergent strategy for the assembly of a glycosylated amino acid derived from PSGL-1

Abstract

P-Selectin and P-selectin glycoprotein ligand 1 (PSGL-1) are vascular adhesion molecules that play an important role in the recruitment of leukocytes to inflamed tissue by establishing leukocyte-endothelial and leukocyte-platelet interaction. P-Selectin binds to the amino-terminus of PSGL-1 through recognition of a sialyl Lewis(x) (SLe(x)) moiety linked to a properly positioned core-2 O-glycan and three tyrosine sulfate residues. We have developed a highly convergent synthesis of the PSGL-1 oligosaccharide linked to threonine based on the use of trichoroacetimidate donors and thioglycosyl acceptors that give products that can immediately be employed in a subsequent glycosylation step without the need for protecting group manipulations. Furthermore, by employing one-pot multistep glycosylation sequences the number of purification steps could be minimized. The process of oligosaccharide assembly was further streamlined by combining protecting group manipulations and glycosylations as a one-pot multistep synthetic procedure. The resulting PSGL-1 oligosaccharide is properly protected for glycopeptide assembly. It is to be expected that the strategic principles employed for the synthesis of the target compound can be applied for the preparation of other complex oligosaccharides of biological and medical importance.

Figure 1

Target molecule and building blocks.

Scheme 1

One-pot three component reaction; SDMP = 2,6-dimethylthiophenyl, dFBz = 2,5-difluorobenzyl.

Scheme 2

One-pot glycosylation followed by reductive opening of the benzylidene acetal.

Scheme 3

Synthesis of target molecule.