Chapter 8
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Synthesis of N-5-Derivatives of Neuraminic Acid and Their Application as Sialosyl Donors Cristina De Meo Department of Chemistry, Southern Illinois University at Edwardsville, Edwardsville, IL 62026
As terminal constituents of glycoconjugates, sialic acids are involved in a wide range of biological phenomena. Different approaches and strategies have been developed to improve yield and stereoselectivity in sialylation reactions. Recently it has been reported that a substituent at the C-5 amino group in sialic acid influences the reactivity of both sialyl donors and acceptors. This review summarizes the latest accomplishments in sialylations using different N-substitued sialyl derivatives.
Sialic acids are a diverse family of more than 40 naturally occurring 2-keto3-deoxy-nononic acids amongst which N-Acetylneuraminic acid (Neu5Ac), Nglycolylneuraminic acid (Neu5Gc) and N-acetyl-9-O-acetylneuraminic acid (Neu5,9Ac ) are the three most widespread (Figure l ) . In particular, Neu5Ac is ubiquitous, while the others are not found in all species. Although free sialic acid can be detected in several types of human body fluids, it is mainly present as a component of the oligosaccharide chain in glycoconjugates (glycoproteins and glycolipids). In the cell, glycoconjugates are synthesized in the Golgi apparatus then transported in the cell membrane where they are involved in a wide variety of biological phenomena from cell growth and differentiation to cell adhesion. 1,2
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© 2007 American Chemical Society In Frontiers in Modern Carbohydrate Chemistry; Demchenko, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
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Figure i In addition, being in such exposed position, glycoconjugates are also the receptors for bacteria and viruses. Thus, it is not surprising that, found at the terminal position of the glycoconjugate chain, sialic acid is directly correlated to numerous biological phenomena. In N-linked glycoproteins, Neu5Ac appear essentially as terminal sugars, a(2-»3) or a(2-»6)-linked to galactosides or cc(2->6)-linked to N-acetyl-galactosaminides {e.a. Neu5Acct(2-»3)Gal, Neu5Acoc(2->6)Gal and Neu5Acoc(2-»6)GalNAc} whereas in O-linked glycoproteins, often terminal Neu5Aca(2-»6)GalNAc moieties can be found. The disialosyl structures Neu5Acct(2-»8)Neu5Ac and Neu5Aca(2->9)Neu5Ac have also been found as constituents of glycoproteins and glycolipids. " Although extensively explored, the chemical synthesis of sialosides in high yield with complete stereoselectivity is still a notable challenge. The presence of a destabilizing electron-withdrawing carboxylic group together with a tertiary anomeric center and the lack of a participating auxiliary often drive glycosylation reactions toward competitive elimination reactions resulting in poor stereoselectivity (P anomer) and in the formation of a 2,3 dehydro derivative (Scheme 1). In addition, Neu5Ac is also a poor glycosyl acceptor for the synthesis of a-linked (2-8) dimers, due to the intramolecular hydrogen bonds between 8-OH, the acetamido and/or the carboxylate group (Figure 2). 1,3
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Scheme 1.
In Frontiers in Modern Carbohydrate Chemistry; Demchenko, A.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.
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