Total Synthesis Of Ganglioside SM1a And Its Derivatives

Alteration of ganglioside expression in tumor cell surface has attracted more at-tentions in recent 20 years. Tumor-associated glycolipids as tumor markers can help diagnosis, classification and prognosis of tumor in different stage. Now the develop-ment of tumor-associated carbohydrate antigens vaccines has been the research focus of chemical glycobiology. SMI a is a kind of endogenous sulfoglycolipid with the structure of Galβ3GalNAcβ4(3-O-sulfate)Galβ4GlcCer. Study showed that SM1a may be a tumor-associated carbohydrate antigen. It can be recognized by monoclonal antibody AE3 which is most specific to detect human epithelial carcinoma antigen. However, the biological functions of SM1a have not been elucidated because of its difficulty to isolation from organism. A great deal of effort has been placed on the ef-ficient synthesis of such glycolipids. In this dissertation, the chemical synthesis of SM1a and its derivatives was explored to construct a strategy for the efficient synthe-sis of ganglio series sulfatides for future evaluation of bioactivity.Through retrosynthetic analysis, five building blocks were designed and a con-vergent strategy was used to synthesize SM1a. In order to evaluate the ceramide’s af-fection on bioactivity, two derivatives were designed by replacing the ceramide with the double-tailed alcohol bis(tetradecyl) carbinol (SM1B) and azidopropyl (SM1N) respectively. Moreover, the azidopropyl-type SMIN can be used for further conjuga-tion with carriers and probes in future bioacitivity evaluation.1. Synthesis of trisaccharide donor Galβ(1â†'3)GalNAcβ(1â†'4)Gal (G)Through convergent strategy, trisaccharide building block (G) bearing a potential sulfation position was conjugated with a cyclic glucosyl ceramide (GlcCer) acceptor (H) to synthesize the target compounds.The silyl-protected galactoside receptor 1d (buding block C) which has a poten-tial sulfation position was prepared from p-methoxyphenyl galacoside 15 by a regi- oselective silylation. Two regioselective acetylation reactions were used in the effi-cient synthesis of GalNAc donor 22 (building block B). Glycosylation of 22 and 1d to produce the disaccharide, which was regioselectively acetylated to afford Gal-NAcβ(1â†'4)Gal 24 (building block F) with free C3’-OH. The thioglycoside donor 28 (building block A) with benzylidene group at the C-4,6 positions was glycosylated with 24 to produce a trisaccharide, then converted into trichloroacetimidate donor 26 (G) of Galβ(1â†'3)GalNAcβ(1â†'4)Gal.2. Synthesis of cyclic glucosyl ceramide acceptor (H) and derivative accep-torsStart from D-xylose, ceramide 46 (building block E) was prepared by the method developed by Yu-Lin Wu.1,2-D-glucopyranosylorthoester strategy was used in the preparation of thioglycoside 55 with groups of 3-PMB and 2-Bz.46 and 55 were linked by succinic acid, then intramolecular glycosidation produced the cyclic gluco-syl ceramide acceptor 71 (H). Derivative acceptors H’ and H" were prepared by gly-cosidation the corresponding alcohol with thioglucoside donor 72, followed by hy-drolysis of benzylidene and selective protection of Bz at O6.3. Synthesis of natural product SMla and derivatives SM1N, SM1BThe glycosylation of trisaccharide donor 36 with acceptor 74 and 77 respectively prodeuced the tetrasaccharide sequences successively. Then deprotection of 3’-TBDMS group was explored to avoid the acetyl migration. The derivatives SM1N and SM1B were obtained after sulfation and global deprotection.The glycosidation of donor 36 with acceptor 71, followed by deprotection of TBDMS, sulfation and global deprotection to give target compound SM1a.In the total synthesis SM1a and its derivatives, a strategy for the efficient synthe-sis of ganglio series sulfatides was constructed, which served as a basis for the study of structure-activity relationship of glycolipids.