Abstract
Gangliosides play important roles in essential biological events including cellular recognition, cell-cell interaction, cell differentiation, and cellular transduction. In addition, the slight modification of terminal sialic acid (N-acetylneuraminic acid, Neu5Ac) in the oligosaccharide chain of ganglioside imparts changes in biological activities of the parent gangliosides. The O-methylation and O-sulfation at C-8 position of non-reducing end Neu5Ac are the two most common modification, especially found in ethinodermatous gangliosides (EGs). The C-8 methylated or sulfated EGs displayed a broad spectrum neuritogenic activity on rat pheochromocytoma PC-12 cell in the presence of nerve growth factor. Consequently, EGs are regarded as potential drug to cure nervous system diseases such as Parkinson's disease. In order to synthesize C-8 modified Neu5Ac derivatives, this thesis has developed a new chemical strategy by changing N3 in place of NHAc at the C-5 position of Neu5Ac to avoid competing N-methylation. The C-8 modified Neu5Ac derivatives, Neu5Ac8Me and Neu5Ac8SO3-Na+, were successfully synthesized by a linear 17-and 13-step sequences, with an overall yields of 12% and 20%, respectively, starting from Neu5Ac. Furthermore, the C-8 modified non-reducing end disialic acid (8-OMeNeuGcα2→11NeuGcα2) of the LLG-5 ganglioside was also prepared by following similar approach. On the other hand, the fatty acyl chain of the ganglioside LLG-5 was synthesized via the Wittig reaction using acetonide-protected (S)-glyceraldehyde 48 and phosphonium salt 46. The assembly moieties of the C-8 modified 8-OMeNeuGcα2→11NeuGcα2 disialic acid and the fatty acyl chain towards the synthesis of LLG-5 is currently underway.