Novel highly convergent synthesis of biologically important oligosaccharides and glycopeptides

Abstract

The past couple of decades have seen a great improvement in chemical and enzymatic synthesis of structurally well-defined oligosaccharides. Mutant glycosidase enzymes have been developed which have made possible to synthesize oligosaccharides previously inaccessible due to the lack of corresponding glycosyltransferases. Chemoselective and orthogonal glycosylation techniques have allowed researchers an access to a number of fully synthetic oligosaccharides such as heparan sulfate, the tumor associated STn-antigen, blood group antigens (Lex, Ley), and Globo-H.

In order to further streamline the process of oligosaccharide synthesis, we developed a new class of one-pot reactions that addresses some of the shortcomings of the above approaches. We have combined triflic acid promoted glycosylations of trichloroacetimidates with reductive opening of benzylidene acetals using triflic acid and triethylsilane as one-pot procedures to provide access to a wide range of disaccharides and branched trisaccharides. The attraction of the approach is that it makes it possible to assemble branched oligosaccharides by a one-pot procedure, a task that cannot readily be accomplished by chemoselective, orthogonal, and iterative glycosylations.

In chapters III and IV of this dissertation we describe our efforts towards the synthesis of the glycopeptide recognition domain of PSGL-1 and analogs thereof. PSGL-1 has clearly been demonstrated to mediate the adhesion of leukocytes to selectins, resulting in transmigration of leukocytes to the site of injury. Uncontrolled migration of leukocytes can lead to chronic inflammation. Inhibition of leukocyte adhesion to selectins by blocking PSGL-1 represents a promising therapeutic approach against diseases in which inflammation has a destructive role (e.g.; ischemia, venous thrombosis, hemorrhage, atherosclerosis, asthma, skin inflammation and autoimmune diseases). 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. We also demonstrate here for the first time a novel approach toward the synthesis of glycosulfopeptide mimics of PSGL-1 by exploiting the Huisgen [3 + 2] cycloaddition reaction to conjugate the oligosaccharide with the peptide.