Synthesis Of Mannose/Mannuronic Acid Disaccharides Sulfated Derivatives

Recently, alginate oligosaccharides including oligomannuronates andoligoguluronates, have showed a wide spectrum of bioactivities, such as antioxidant,neuroprotective, immunomodulatory, anti-inflammatory and anti-bacterial activities.Sulfated alginate oligosaccharides have showed anti-tumor, anti-coagulation andantivirus activities. The study of structure-activity relationship (SAR) of alginateoligosaccharides and their derivatives have been the hotspot in the research ofcarbohydrate-based drugs. It’s important to prepare structure-well-defined alginateoligosaccharides and sulfated derivatives for the study of SAR. In this dissertation, thechemical synthesis strategies of oligosaccharides were explored. Thestructure-well-defined mannose (mannuronic acid) disaccharides and their sulfatedderivatives were prepared for evaluation of bioactivity.1. Synthesis of glycosyl donors and acceptorsUsing4,6-O-benzylidene-protected1-thio mannoside as glycosyl donor, andconsidering of selective sulfation at O2, O3and(or) O4positions, three types ofglycosyl donors and acceptors were designed respectively. Three types ofthioglycoside donors5,7and10from mannose were synthesized with4,6-O-benzylidene protection and Bn or PMB group at the O2and O3positions.Three types of glycosyl acceptors15,19and23from mannose were synthesised withBn or PMB group at the O2and O3positions and Bz at the O6.2. Synthesis of Mannose (Mannuronic acid) disaccharides and their sulfatedderivativesFor the stereocontrolled direct synthesis of β-D-mannuronic acid glycosides, theglycosyl donors through α-mannosyl triflate were activated by DTBMP, DPSO andTf2O under the mechanism of SN2substitution. Deprotection of Bz at the O6inβ-Mannopyranoside24was followed by oxidation with TEMPO/BAIB and deprotection of the other protecting groups to give target compound28, Mannuronicacid disaccharide. Selective deprotection the groups on O6, O2’, O3’ or O4’inβ-Mannopyranoside24,38and43was followed by sulfation with SO3-Pyridine anddeprotection of the other protecting groups to give target compounds37,47,42and32.Selective deprotection the groups O4, O2’ and O6in β-Mannopyranoside43wasfollowed by sulfation with SO3-Pyridine and deprotection of the other protectinggroups to give target compounds53.The methyl mannuronic acid disaccharides and its monosulfated derivatives,methyl mannobiose and its mono-, disulfated derivatives were synthesized by moderncarbohydrate chemistry. This research provides chemical synthesis strategies andmethods for alginate oligosaccharides and their derivatives, which serve as a basis forrevealing the relationship between structure and bioactivity.