General consideration on sialic acid chemistry

Abstract

Sialic acids, also known as neuraminic acids, are a family of negatively charged α-keto acids with a nine-carbon backbone. These unique sugars have been found at the termini of many glycan chains of vertebrate cell surface, which play pivotal roles in mediating or modulating a variety of physiological and pathological processes. This brief review covers general approaches for synthesizing sialic acid containing structures. Recently developed synthetic methods along with structural diversities and biological functions of sialic acid are discussed.

Figure 1.

Three basic forms of naturally occurring sialic acids.

Figure 2.

Common sialic acid-containing structures with different sialyl linkages.

Figure 3.

Representative sialic acid-containing tumor-associated carbohydrate antigens (TACAs).

Figure 4.

Biosynthetic routes of Neu5Ac and CMP-Neu5Ac in eukaryotes (route a) and bacteria (route b).

Figure 5.

A general chemical sialylation approach and related elimination process.

Figure 6.

Intramolecular hydrogen bonding network of C-8 hydroxyl group of Neu5Ac acceptor.

Figure 7.

Schematic illustration of using C-3 auxiliary groups to improve sialylation stereoselectivity.

Figure 8.

Examples of C-5 modified sialyl donors.

Figure 9.

Sialyl chloride as a donor for sialylation under Koenigs-Knorr glycosylation conditions.

Figure 10.

Representative 2-thio sialyl donors.

Figure 11.

Sialylation using di-N-acetyl thiosialoside donor.

Figure 12.

α-Stereoselective sialylation via solvent participation.

Figure 13.

Sialylation using C-5 N-acetyl versus C-5 azido thiosialoside donors.

Figure 14.

1,5-Lactam sialyl acceptors/donors for the synthesis of gangliosides HLG-2 and Hp-s6.

Figure 15.

5-N,4-O-Carbonyl protected sialyl donor and acceptor for the synthesis of oligosialic acids.

Figure 16.

Sialylation using 2-phosphite sialyl donors.

Figure 17.

One-pot glycosylation using a 5-N-acetyl-5-N,4-O-carbonyl 2-phosphate sialyl donor.

Figure 18.

Sialylation using trifuloroacetimidate sialyl donors.

Figure 19.

Dehydrative sialylation approaches using C-2 hemiketal Neu5Ac derivative as a sialyl donor.

Figure 20.

Sialyltransferase-catalyzed formation of four common sialyl linkages.

Figure 21.

Sialyltransferase-catalyzed sialylation with CMP-sialic acid regeneration.

Figure 22.

One-pot three-enzyme system for chemoenzymatic synthesis of sialoside libraries.

Figure 23.

Representative α2–3-linked sialosides prepared using the one-pot multienzyme chemoenzymatic approach described in Figure 22.

Figure 24.

Representative α2–6-linked sialosides prepared using the one-pot multienzyme chemoenzymatic approach described in Figure 22.

Figure 25.

Enzymatic synthesis of fluorinated sialic acid derivatives as mechanistic probes for sialic acid processing enzymes.