Effects of the Picoloyl Substituent on Chemical Sialylations

Sialic acids are a family of forty-three carbohydrates frequently expressed at the terminal positions of glycoconjugates. Sialic acid-containing glycoconjugates are involved in a wide range of biological processes, including signal transduction, cellular differentiation, cancer metastasis, and pathogenic recognition. As monosaccharides, all sialic acid derivatives are nine-carbon sugars, although they almost always occur naturally as oligo- and polysaccharides. Most sialic acid derivatives are C-3 deoxy sugars with a carboxylic acid moiety at C-1 and an amide moiety at C-5, while C-7, 8, and 9 comprise a glycerol chain. The most common derivative of sialic acid in humans, N-acetylneuraminic acid, occurs exclusively in nature in an alpha-glycosidic configuration. It was found recently that the picoloyl substituent can assist greatly in the formation of highly stereoselective glycosidic linkages. The picoloyl group, an ester bearing a 2-pyridyl moiety, was first explored as a hydrogen-bond acceptor by Demchenko et al., delivering high syn facial selectivities in glucosyl, galactosyl, and mannosyl donors. Using sialyl donors tested under the same glycosylation conditions, the picoloyl group does not deliver as high of facial selectivities. It was found recently in the De Meo group, however, that in the presence of excess triflic acid, the same 4-O-picoloylated donor gives much higher yields and more favorable stereosel-ectivities. Concomitantly, Tsai found that in the presence of excess triflic acid, an 8-O-picoloylated donor bearing benzoyl groups at positions 4,7, and 9 produced favorable stereoselectivities using a standard benzylated primary glucosyl acceptor. The benzoyl substituent has proven to be β-directing in sialic acid, however. Thus, in an effort to improve upon methods already published and to understand better the effects of the picoloyl substituent, a comprehensive synthesis of sialyl donors mono-picoloylated at positions C-4, C-7, C-8, and C-9 (and acetylated elsewhere) was carried out. Sialylations then were promoted with each donor in the presence of excess triflic acid to evaluate their efficacy. Furthermore, the 8-O-picoloylated donor was subjected to glycosylations using different reaction concentrations to evaluate the effects of intermolecular hydrogen bonding. Finally, glycosylations were promoted using varying stoichiometric ratios of triflic acid to better understand its effect in conjunction with the picoloyl group