Phase-transfer-catalysed synthesis of N-acetylneuraminic acid alpha-thioketosides and inhibitor studies with Clostridium perfringens sialidase

The alpha-thioketosides of methyl 5-acetamido-4,7,8,9-tetra-O-acetylneuraminate with thioacetic acid, thiophenol, 4-nitrothiophenol, 4-aminothiophenol, 2-mercaptopyridin and mercaptobenzothiazol as aglycones were synthesized by phase-transfer catalysis in good yields. The methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2-thioacetylneuraminate is the analogous thio compound to the methyl 5-acetamido-2,4,7,8,9-penta-O-acetylneuraminate and can be used as intermediate for preparing S-ketosides of Neu5Ac. By Zemplen saponification and mild hydrolysis of the methyl-ester group the free Neu5Ac-alpha-thioketosides with thiophenol, 4-nitrothiophenol, 4-aminothiophenol and 2-mercaptopyridin could be prepared. These ketosides were found to be inhibitors of C. perfringens sialidase with Ki-values between 2.3mM and 6.6mM. The free Neu5Ac-alpha-mercaptobenzothiazolyl ketoside could not be prepared by this procedure. It was completely hydrolysed during Zemplen saponification and methyl-ester hydrolysis in alkaline medium.