Site-Selective Modification of (Oligo)Saccharides

Abstract

Oligosaccharides, either as such or as part of glycolipids, glycopeptides, or glycoproteins, are ubiquitous in nature and fulfill important roles in the living cell. Also in medicine and to some extent in materials, oligosaccharides play an important role. In order to study their function, modifying naturally occurring oligosaccharides, and building in reactive groups and reporter groups in oligosaccharides, are key strategies. The development of oligosaccharides as drugs, or vaccines, requires the introduction of subtle modifications in the structure of oligosaccharides to optimize efficacy and, in the case of antibiotics, circumvent bacterial resistance. Provided the natural oligosaccharide is available, site-selective modification is an attractive approach as total synthesis of the target is often very laborious. Researchers in catalysis areas, such as transition-metal catalysis, enzyme catalysis, organocatalysis, and photoredox catalysis, have made considerable progress in the development of site-selective and late-stage modification methods for mono- and oligosaccharides. It is foreseen that the fields of enzymatic modification of glycans and the chemical modification of (oligo)saccharides will approach and potentially meet each other, but there is a lot to learn and discover before this will be the case.

Scheme 1. (A) Epimerization of the Low-Cost Monosaccharide Methyl-Glucose Leading to Methyl-Allose; (B) trans-to-cis Epimerization of β-Glucosides by Transient Trapping of the Epimerization Product; (C) cis-to-trans Epimerization of Galactosides

Right panel: explanation of the stereoselectivity in the epimerization reactions. The blue spheres represent the hydride/hydrogen atom that is being abstracted.

Scheme 2. (A) Examples of Monosaccharides as Reactivity-Based Probes; (B) Diastereoselective Reduction Leading to Methyl 3-amino Glucose; (C) Single Step Conversion of Carbohydrates in Affinity-Based Probes by Site-Selective Propargylation

Scheme 3. Site-Selective Oxidation in Oligosaccharides; (A) Reactivity Differences among Glucosides, Galactosides and mannosides; (B) Pd Catalyzed Oxidation of the Gluco-Configured Residue in Neomycin; (C) Site-Selectivities of Quinuclidine and Decatungstate Mediated Reactions in Raffinose; (D) Site-Selective Oxidation and Further Functionalization of Oligomaltosides

The blue spheres represent the hydride/hydrogen atom that is being abstracted.

Scheme 4. Site-Selective Amidation of Neomycin, Using RNA-Aptamers

Representation of neomycin bound to the RNA aptamer was generated from PDB code: 1NEM with UCSF Chimera version 1.14.

Scheme 5. Site-Selective Oxidation of a Glycopeptide, Followed by Ligation with a Biotin Label Enables the Detection of Glucosylated Peptides

Scheme 6. (A) Schematic Representation of Complexation-Induced Glycosidic Bond Forming Reactions with Unprotected Glycosides as Proposed by Miller and Schepartz; (B) Protecting Group Free Site-Selective Glycosylation of Sucrose; (C) Protecting Group Free Site-Selective Glycosylation of Peptides and Thioglycosides; (D) Protecting Group Free Glycosylation Procedure Developed by Fairbanks