Studies On Synthesis Of Sulfated α-Mannopyranosyl Glycoside

Sulfated oligosaccharides possess unique structure together with polyanionic properties and play a significant role in many diseases, such as antitumor, antivirus, immunomodulation and antimalaria. Among the numerous sulfated manno-oligosaccharides, PI-88 as a heparan sulfate mimetic comes to the front. It has been reported that PI-88 is a mixture of monophosphorylated and highly sulfated oligomannsaccharides composed of a fragement ranging from disaccharides to pentasaccharides. PI-88 as an efficient inhibitor of tumor growth and metastasis performs on antitumor mainly by inhibiting the interactions with heparan sulfate and vascular growth factors. Recently it is undergoing the phase â…¡ clinical trials with a promising prospect of advanced malignancies. Accordingly, the studies on synthesis of sulfated α-mannopyranosyl glycosides were conducted.1) Synthesis of mannopyranosyl trisaccharide and pentasaccharide The glycosyl N-tosyl benzimidate 50 was prepared through a series of protective operations of mannose. In the presence of a catalytic amount of TMSOTf, glycosyl donor 50 reacted with acceptor 47 to stereoselectively give disaccharide 55 in 85% yield and removal of benzoyl groups in 55 to obtain acceptor 56, reacted with 50 to give trisaccharide 57 in 79% yield. Then double glycosylation was used for synthesis of trisaccharide 62 with diol acceptor 54 and donor 50 in 78% yield. After removal of benzoyl groups in 62 to lead to diol acceptor 63, treatment of 63 with N-tosyl benzimidate 50 furnished pentasaccharide 64.2) Synthesis of cholestanyl trimannoside and pentamannoside The cholestanol was obtained by hydrogenative reduction of 5,6-double bond of cholesterol. Glycosylation of cholestanol 66 with trimannosal trichloracetimidate 68 in the presence of TMSOTf gave the α (1â†'3)/α(1â†'6)-linked glycoside 71 after deprotection. Cholestanyl pentamannoside 72 was obtained following a reaction sequence involving debenzoylation of 69 and subsequent glycosylation with donor 58.3) Synthesis of sulfated cholestanyl trimannoside and pentamannoside For synthesis of sulfated glycosides, two approaches were tried. First, attempting to obtain the sulfonated oligosaccharides with 2,2,2-trichloroethyl sulfury 2-methylimidazolium triflate as sulfonation reagents, however, the efforts were not rewarded. Second, the microwave-assisted sulfation was applied to synthesis of sulfate oligosaccharides. Using SO3·pyridine complex as sulfonating reagent and pyridine as the free base, sulfated saponins 85 and 89 bearing benzyl and benzoyl protective groups were obtained in the solvent of CH3CN at 100℃ with the irradiation of microwave. Although subsequent debenzylation by hydrogenolysis and debenzoylation resulted in a species showing the corrected molecular ion peaks by ESI, a clear 1H NMR spectra for the desired sulfonated saponins 39 was not acquired. Further studies are necessary to figure out the problems.In conclusion, the structurally defined cholestanol trisaccharide and pentasaccharide have been achieved. Their sulfonations have also been explored. We hope this thesis would pave a way for studies on biological activities of sulfated glycosides, and be helpful for developing new carbohydrate drugs.