Total synthesis of trifluorobutyryl-modified, protected sialyl Lewis X by a convergent [2+2] approach

Abstract

Structural and quantitative changes in the expression of sialic acid residues on the surface of eukaryotic cells profoundly influence a broad range of biological processes including inflammation, antigen recognition, microbial attachment, and tumor metastasis. Uptake and incorporation of sialic acid analogues in mammalian cells enable structure-function studies and perturbation of specific recognition events. Our group has recently shown that a trifluorobutyryl-modified sialic acid metabolite diminishes the adhesion of mammalian cells to E and P-selectin, presumably by leading to the expression of fluorinated sLex epitopes on cell surfaces, and interfering with the sLex-selectin interactions that are well known in mediating tumor cell migration.1 For studies directed towards understanding the molecular basis of this reduced adhesion, chemical synthesis of trifluorobutyrylated sialyl Lewis x (C4F3--sLex) was crucial. We have developed a highly efficient [2+2] approach for the assembly of C4F3-sLex on a preparative scale that contains versatile protective groups allowing the glycan to be surface immobilized or solubilized as needed for biophysical studies to investigate selectin interactions. This strategy can, in principle, be used for preparation of other N-modified sLex analogues.

Design of α-Selective Glycopyranosyl Donors Relying on Remote Anchimeric Assistance

“…There are few examples when bis‐acylated donors were successfully applied for the preparation of complex oligosaccharides containing 1,2‐ cis ‐linkages. In particular, 3,4‐di‐O‐acylated fucosyl donors were extensively used for the preparation of sulfated oligofucosides and fragments of Lewis X structures . They were also used in other, stereoselectivity unrelated, investigations in which they proved to be completely α‐selective …”

Synthesis and Antibody Binding Studies of Schistosome-Derived Oligo-α-(1-2)-l-Fucosides

“…The 6-azidohexan-1-ol linker was installed using a protocol we recently developed for the installation of 1,2- cis linkages to relatively reactive (primary) alcohol acceptors. To this end, we transformed the thioglycoside 2 into the corresponding imidate 4 [ 17 , 18 ]. As it was possible to separate both anomers, the following conditions were applied to pure α-imidate, pure β-imidate, and an α/β (2/1) mixture.…”

Total Synthesis of a PSGL-1 Glycopeptide Analogue for Targeted Inhibition of P-Selectin

“…In principle, total chemical synthesis should provide an expedient route to C2- O -sLe X as a common building block for glycosulfopeptide mimics of PSGL-1, as well as many other biologically important glycopeptides. However, significant limitations inherent to all reported schemes have hindered large-scale synthesis of both an appropriately derivatized sLe X − intermediate and the related C2- O -glycan hexasaccharide bearing amino acid. − Characteristic of the few reported synthetic routes to achieve these important intermediates, Kunz et al described a 15-step scheme to synthesize a C2- O -sLe X hexasaccharide ready for solid phase peptide synthesis (SPPS) on milligram scale with a mere overall yield of 0.29% …”