Stereoselective Synthesis of S‑Linked α(2→8) and α(2→8)/α(2→9) Hexasialic Acids Chien-Fu Liang, Ting-Chun Kuan, Tsung-Che Chang, and Chun-Cheng Lin* Department of Chemistry, National Tsing Hua University, 101 Section 2, Kuang Fu Road, Hsinchu 30013, Taiwan * S Supporting Information ABSTRACT: A new approach for the synthesis of S-linked α(2→8) and alternating α(2→8)/α(2→9) oligosialic acids by S-alkylation has been developed, using chemo- and stereo- selective alkylation of a C2-thiolated sialoside donor (nucleophile) with either a C8- or C9-iodide-activated sialoside acceptor (electrophile). An efficient intramolecular acetyl group migration from the C7 to C9-position of the sialoside under mild basic conditions was used to generate the C8-iodide, the key sialyl acceptor (electrophile). Using this strategy, the syntheses of S-linked α(2→8) and α(2→8)/ α(2→9) hexasialic acids were achieved. 1. INTRODUCTION Sialic acids are implicated in a multitude of biological processes including cellular adhesion, the inflammatory response, cell signaling, and cell differentiation. 1a,b Sialic acid (Neu5Ac, N- acetylneuraminic acid) is typically located at the nonreducing terminus of glycoconjugates such as the glycoproteins and glycolipids of vertebrates, and is a component of the capsular polysaccharides of pathogenic bacteria. 2a,b Three kinds of linear homopolymers of polysialic acids have been identified on mammalian or bacterial cell surfaces, including α(2→9) (1a), α(2→8) (2a), or the alternating α(2→8)/α(2→9) (3a) Neu5Ac unit, as shown in Figure 1. 3 Recent advances in glycobiology suggest that α(2→8) and α(2→9) di/oligosialic acid and polysialic acids play critical roles in the biological events that occur on the cell surface. 4a-c For example, polysialic acids isolated from the causative agent of meningitis, Neisseria meningitides serogroup B and C strains, differ in their chemical and immunological properties. 5 In addition, α(2→8)-linked di/ trisialic acid residues are common structural units of ganglio- sides, and an α(2→9)-linked disialosyl structure was identified at the terminals of longer poly lactosaminyl glycans isolated from PA1 human embryonal carcinoma cells. 6 Moreover, the α(2→9)-linked polysialic acids were found on C-1300 mouse neurobrastoma cells (NB41A3), 7 and in sea urchin sperm flagella. 8 Due to their presence on bacterial and cancer cell surfaces, oligosialic acids are considered good targets for the development of vaccines. 9 To better understand the interactions between polysacchar- ides and their receptors, it is necessary to use chemically pure oligosaccharides as biochemical probes. However, the inter- glycosidic bonds of polysaccharides, especially in polysialic acid, are very labile under even mildly acidic or basic conditions, and are susceptible to degradation by glycosyl hydrolases. Thus, carbohydrate mimics resistant to hydrolysis are required for glycobiology studies instead. 10 Replacement of the glycosidic oxygen atom by another heteroatom such as sulfur has been shown to enhance the stability of the glycosidic linkage toward hydrolysis by either chemical or enzymatic means 11 while maintaining the parent oligosaccharides biochemical activities. Recently, both Bundle et al. 12 and Schmidt et al. 13 have synthesized sialic acid-containing tumor antigens, in which the sialic acid at the nonreducing end was linked to reducing end saccharides via a S-glycosidic bond. Furthermore, when the S- linked ganglioside analogues were conjugated with tetanus toxoid, the antibodies produced in mice by the above vaccines showed specific recognition of the parent O-linked antigens 12b,c as well as a longer half-life of S-linked vaccines. This work strongly suggests that the synthesis of chemically pure S-linked oligosialic acid antigens for the development of carbohydrate- Received: August 6, 2012 Published: September 7, 2012 Figure 1. Structures of O- and S-linked α(2→9), α(2→8) and alternating α(2→8)/α(2→9) sialosides. Article pubs.acs.org/JACS © 2012 American Chemical Society 16074 dx.doi.org/10.1021/ja307797x | J. Am. Chem. Soc. 2012, 134, 16074-16079