A stereoselective approach for the synthesis of alpha sialosides
De Meo, Cristina
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Sialic acids are a diverse family of naturally occurring 2-keto-3-deoxy-nononic acids that are involved in a wide range of biological processes. Sialic acids normally appear at terminal positions of oligosaccharides of glycoproteins and glycolipids where they are a(2,3) or a(2,6) linked to galactosides or a(2,6) linked to 2-acetamido-galactosides. The disialosyl structures Neu5Aca(2-8)Neu5Ac and Neu5Aca(2-9)Neu5Ac have also been found as constituents of oligosaccharides of glycoproteins and lipids. While relatively efficient methods have been developed for the introduction of Neu5Aca(2-3)Gal and Neu5Aca(2-6)Gal glycosidic linkages, the synthesis of oligosaccharides that contain a(2®8)-linked fragments is complicated by the low reactivity of the C-8 hydroxyl of Neu5Ac. The latter glycosides have been successfully synthesized by indirect sialylation approaches, whereas direct sialylation often leads to either low yields or formation of unnatural b-sialosides.|It is obvious that a versatile sialyl donor needs to be developed that gives excellent yields and high a-anomeric selectivities in direct glycosylations with a wide range of acceptors of different reactivities. Such a donor would allow efficient synthesis of oligosaccharides of biological or medical importance that contain multiple sialic acids of different linkage type.|As a part of the program to develop novel synthetic approaches a new method for the stereoselective a-sialylation has been developed. It has been shown that the readily available sialyl donor, methyl(methyl 4,7,8,9-tetra-O-acetyl-3,5-dideoxy-2-thio-5-trifluoroacetamido- D-glycero-b-D-galacto-nonulopyranosid) onate (1), gives good yields and excellent a-anomeric selectivities in direct glycosylations with a variety of glycosyl acceptors ranging from sterically hindered C-8 hydroxyls of a sialic acid (e.g. 2) to reactive primary alcohols such as C-6 hydroxyls of galactosides. It has been shown that the new sialylation approach allows efficient synthesis of Neu(2-3)Gal derivatives especially when sterically hindered alcohols are used as glycosyl acceptors.|The versatility of the donor allowed a highly efficient synthesis of a range of biologically important compounds. For example, the human melanoma associated antigen GD 3 derivative (5), which has multiple Neu5Ac residues.