Sialic acids chemical synthesis

H. Sashiwa, Y. Shigemasa, and R. Roy, Chemical modification of chitosan. 10.1. Synthesis of dendronized chitosan-sialic acid acid hybrid using convergent grafting of preassembled dendrons built on gallic acid and tri(ethylene glycol) backbone, Macromolecules, 34 (2001) 3905-3909. 

Several enzymatic procedures have been developed for the synthesis of carbohydrates from acyclic precursors. Aldolases appear to be useful catalysts for the construction of sugars through asymmeteric C-C bond formation. 2-deoxy-KDO, 2-deoxy-2-fluoro-KDO, 9-0-acetyl sialic acid and several unusual sugars were prepared by a combined chemical and enzymatic approach. Alcohol dehydrogenases and lipases have been used in the preparation of chiral furans, hydroxyaldehydes, and glycerol acetonide which are useful as building blocks in carbohydrate synthesis. 

N-Acetvlneuraminic Acid Aldolase. A new procedure has also been developed for the synthesis of 9-0-acetyl-N-acetylneuraminic acid using the aldolase catalyzed reaction methodology. This compound is an unusual sialic acid found in a number of tumor cells and influenza virus C glycoproteins (4 ). The aldol acceptor, 6-0-acetyl-D-mannosamine was prepared in 70% isolated yield from isopropenyl acetate and N-acetyl-D-mannosamine catalyzed by protease N from Bacillus subtilis (from Amano). The 6-0-acetyl hexose was previously prepared by a complicated chemical procedure (42.) The target molecule was obtained in 90% yield via the condensation of the 6-0-acetyl sugar and pyruvate catalyzed by NANA aldolase (Figure 6). With similar procedures applied to KDO, 2-deoxy-NANA and 2-deoxy-2-fluoro-NANA were prepared from NANA. 

Ito Y (1990) Chemical Reactions Induced and Probed by Positive Muons. 157 93-128 Itzstein von M, Thomson RS (1997) The Synthesis of Novel Sialic Acids as Biological Probes. 185 119-170... 

Asymmetric C-C bond formation is the most important and most challenging problem in synthetic organic chemistry. In Nature, such reactions are facilitated by lyases, which catalyze the addition of carbonucleophiles to C=0 double bonds in a manner that is classified mechanistically as an aldol addition [1]. Most enzymes that have been investigated lately for synthetic applications include aldolases from carbohydrate, amino acid, or sialic acid metabolism [1, 2]. Because enzymes are active on unprotected substrates under very mild conditions and with high chemo-, regio-, and stereoselectivity, aldolases and related enzymes hold particularly high potential for the synthesis of polyfunctionalized products that are otherwise difficult to prepare and to handle by conventional chemical methods. 

The difference between then and now can be attributed in major part to the advent of enzymes in organic synthesis. Aldolases are nature s catalysts for the poor man s chemical aldol reaction. These remarkable enzymes can produce rare and important deoxyulosonic acids such as sialic acid and KDO on a small or large scale. 

Synthesis and antigenic properties of sialic acid based dendrimers. [R. Roy, D. Zanini, S. J. Meunier, A. Romanowska, in Synthetic Oligosaccharides, (Ed. P. Kovac), American Chemical Society, Washington, DC, 1994] [ 1837]. 

Extensive research has focused on the synthesis of structurally modified sialic acid derivatives and sialylmimetics as probes or potential inhibitors of specific sialic acid-recognizing proteins, and several comprehensive overviews have been published [26, 30-34], An underlying theme in efforts directed toward the development of novel sialic acid derivatives as biological probes is the complexity of the chemical manipulations associated with sialic acids [30, 32], The chemical strategies and conditions for sialylation are discussed in Chapter 5. 

Chemical synthesis of sialosides is considered one of the most difficult glycosylation reactions because of a hindered tertiary anomeric carbon and the lack of a participating auxiliary functionality in the carbon next to the anomeric carbon in sialic acids (55, 56). Sialyltransferase-catalyzed glycosylation is believed to be the most efficient approach for the production of sialic acid-containing structures. 

Figure 2 One-pot three-enzyme chemoenzymatic synthesis of sialosides containing sialic acid modifications. In this strategy, mannose or ManNAc derivatives are chemically or enzymatically synthesized. These compounds are then used by a recombinant coli K-12 sialic acid aldolase to obtain sialic acids and their derivatives followed by an N. meningitidis CMP-sialic acid synthetase for the formation of CMP-sialic acids. From which, sialic acids can be transferred to lactose, LacNAc, galactose, GalNAc, or their derivatives by a multifunctional P. muitocida sialyltransferase (PmSTl) or a P, damseia a2,6-sialyltransferase (Pd2,6ST) to form a2,3- or a2,6-linked sialosides in one pot without the isolation of intermediates.

Ogawa and coworkers have also extensively described synthetic studies on glycoprotein oligosaccharides and mannose-containing glycosphingolipids using similar reactions [26,27, 28,29] (O Scheme 9). For instance, the reaction of 14 with disaccharide 15 afforded 16 (o = 1.1 1), which was used as the key intermediate in their first chemical synthesis of a sialic acid-containing complex-type undecasaccharide [30]. 

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