Efficient and stereoselective synthesis of α(2→9) oligosialic acids: from monomers to dodecamers.

most common a(2!8) polysialic acid (1) is found in mammalian tissues and bacteria (Neisseria meningitidis B, Escherichia coli K1, Morexella nonliquefaciens, and Mannheimia haemolytica A2), and the less common a(2!9) polysialic acid (2) and alternating a(2!8)/a(2!9) polysialic acids (3) were discovered to form extracellular capsules of N. meningitidis C and E. coli K92, respectively. Human pathogens encapsulated with polysialic acids cause invasive diseases such as meningitis and urinary tract infections. In pathogenic bacteria, these acidic polysaccharides serve as extracellular shields against the defense systems of their mammalian host. Therefore, polysialic acids are considered good targets for the development of bactericidal agents and antibacterial vaccines. For example, the current vaccines against meningococcal group C diseases are glycoconjugates of isolated a(2!9) polysialic acids and a carrier protein such as diphtheria or tentanus toxoid. However, these kinds of vaccines are often heterogeneous or contaminated with other antigenic components because of the difficulty of purifying polysialic acids from natural sources. An effective method to synthesize pure polysialic acids having a well-defined structure will not only simplify the complexities of vaccines but also provide a better understanding of the structure– activity relationships of polysialic acids in various biological events. Chemical sialylation is complicated as a result of the intrinsic structural features of sialic acid, thus resulting in poor yields or stereoselectivities. Even though notable progress toward the development of sialic acid donors for efficient a sialylation have been reported in the last decade, 12] the synthesis of poly/oligo sialic acid with satisfactory yields and excellent a selectivity is still very challenging. The advancement of donor development led to many approaches for the synthesis of a-specific oligosialic acids, including the synthesis of a(2!9) trisialic acid using C5-azido sialyl phosphite as donor, the synthesis of a(2!9) oligosialic acid using C5-TFA sialyl phosphite as a donor and C5-TFA thiosialoside as an acceptor, and the synthesis of a(2!8) tetrasialoside, a(2!9) trisialoside, and a(2!9) tetrasialoside using 5N,4O-carbonyl-protected thiosialosides. When using 5N,4O-carbonyl-protected thiosialosides as donors, the sequence of assembly starts from the reducing end to the nonreducing end, thus providing an opportunity to stereoselectively elongate the sugar chain one residue at a time. However, this approach has not successfully been used to synthesize an a-specific oligosialic acid polymer that is longer than a tetramer. In principle, convergent block synthesis is an intrinsically better strategy for the preparation of oligomers or polymers and has been applied to the synthesis of some carbohydrate polymers. However, this strategy is hindered by the limited choice of leaving groups to ensure a proper reactivity and Figure 1. Structures of polysialic acids.