C-sialosides

The ability of the 4-0,5-iV-oxazolidinone group to limit glycal formation prompted Crich and coworkers to revisit the use of electrophilic sialyl donors for the formation of C-sialosides. Their effort resulted in the discovery that the /V-acetyloxazolidone-protected dibutylphosphates, on activation with TMSOTf at -78°C in the presence of... 

Sml2 Reformatsky methodology is now sufficiently robust that Linhardt employed Reformatsky-type addition to carbon electrophiles in a solid-phase synthesis of C-sialosides (see Chapter 7, Section 7.3).146 The use of a-halo ketones in intermolecular Reformatsky reactions is less common and is typically restricted to simple coupling partners. For example, Ohta showed that... 

Linhardt employed Reformatsky-type additions to carbon electrophiles (see Chapter 5, Section 5.5) in a solid-phase synthesis of C-sialosides.43 Immobilised sialyl donor 9 was treated with Sml2 in the presence of ketone and aldehyde... 

The compounds of the present study were prepared from the C-allyl sialic acid derivative described by Paulsen et al.102 and Vasella, et al.103 The ethyl ester of this compound was converted to the amide, shown. Completion of the synthesis involved reductive animation to the illustrated glucose based polymer thus giving the product. In one particular instance, the starting materials were combined to yield a product containing approximately 30% of the sialic acid analog. This polyvalent C-sialoside inhibited infection by influenza virus with an IC50 of 0.2 M. 

Recently, based on inspection of the crystal structure of the complex of TcTS with sialyllactose as substrate, a series of novel C-sialosides were devised as potential inhibitors. Employing ruthenium-catalyzed cross metatheses, a number of derivatives were synthesized and modified [60]. For these novel acceptor mimetics the affinities were studied by surface plasmon resonance (SPR) using immobilized TcTS [61]. Quite interesting values for compounds 103-105 were measured (Fig. 17). Furthermore, using an NMR-based approach [47], considerable reduction of the TcTS reaction rate was observed in the presence of the most active C-sialoside ligand 103 (Fig. 18) [61]. 

Fig. 17 C-Sialoside TcTS Ugands with acceptor mimetic affinities to immobilized TcTS by SPR [61]...

Fig. 18 Influence on TcTS reaction rates by C-sialoside ligand 103 [61]...

Very recent work in the Tomalia-Baker group [174] has shown that certain classes of dendritic architecture offer distinct advantages as scaffolding for presenting C-sialoside groups. For example, use of dendrigraft architecture [175] as... 

S. A. Kalovidouris, O. Blixt, A. Nelson, S. Vidal, W. B. Turnbull, J. C. Paulson, and J. F. Stoddart, Chemically defined sialoside scaffolds for investigation of multivalent interactions with sialic acid binding proteins, /. Org. Chem., 68 (2003) 8485-8493. 

In brief, the use of acetonitrile as solvent and the selection of an appropriate C-5 amino protecting group and reactive promoter system are critical for achieving high a-selectivities and yields in the synthesis of sialosides. 

S- [51], and C- [49,52] a-sialosides have been prepared using copolymerization or grafting methods. More complex sialylohgosaccharide-containing polymers have also been prepared, including GM3 [53], sialyl Lewis [54], sialyl Lewis [55], and a related 3 -sulfo-Lewis analog [56, 57], including polymerized liposomes [58]. 

S. Sabesan, S. Neira, F. Davidson, J. Duus, and K. Bock, Synthesis and enzymatic and NMR-studies of novel sialoside probes Unprecedented, selective neuraminidase hydrolysis of and inhibition by C-6-(methyl)-Gal sialosides, J. Am. Chem. Soc. 776 1616 (1994). 

T. J. Pritchett, R. Brossmer, U. Rose, and J. C. Paulson, Recognition of monovalent sialosides by influenza virus H3 hemagluttinin, Virology 160 502 (1987). 

M. von Itzstein Carbohydrate-recognising proteins as targets for drug research J. C. Paulson Sialoside sweet spots. 

An efficient a-sialylation that took advantage of the highly reactive sialyl donors having C5 cyclic imides, especially phthalimide (NPhth), by virtue of the fixed-dipole moment effects, was also reported [42], For example, the use of the sialyl donor 4 and acceptor 6 at -78°C supplied the sialoside 7 as a only with 92% yield on 50 mg scale. The scale-up in batch process, however, significantly decreased the yield and stereoselectivity. This decrease in sialylation efficiency might be a result of... 

Efficient activation of the N-acetylated sialyl donor required l.Oequiv. of the Lewis acid under -78°C, giving the disaccharide 16 in 77% yield with excellent a selectivity (a/p=96/4, Table 8.2, entry 1). The conditions in entry 1 were reproducible under the microfluidic conditions (entry 2, 89% yield, a/p=94/6). Because the excess donor 15 inhibited the purification of sialoside 16 from the glycal by-product due to similar polarities on silica gel, the ratio between the donor and the acceptor... 

---