Synthesis Of Heparin Oligosaccharides

Heparin,a kind of glycosaminoglycan,is alinear sulfated polysaccharide composed by disaccharide repeating unit of uronic acid and glycosamine through 1,4-glycosidic linkage.Heparin is mainly found in mast cells and can be isolated from porcine intestine and bovine lung.Heparin has been found to interact with hundreds types of proteins.It plays a variety of roles in many important physiological processes,including body growth and development,wound healing,immune response,angiogenesis,cell adhesion,regulation of tumor growth and metastasis,coagulation,signal transduction,lipid metabolism assisted antiviral and bacterial infections.Heparin was first isolated in 1917 and widely used in clinic as an anticoagulant ever since.The heterogeneity of heparin sugar chain restricts the development of studies of the interactions between heparin and proteins.To synthesize various heparin oligosaccharides with specific sulfation patterns can provide a good solution.Carbohydrates are polymers of aldehydes or ketones with polyhydroxyl groups.In the traditional process of carbohydrate synthesis,in addition to glycosylation and end group activation,most of the other chemical operations are the manipulation of protective groups,including introduction,substitution and removal of protective groups,which accounts for 70-90%.So it can be said that the synthetic chemistry of oligosaccharides is the chemistry of protective groups.Heparin oligosaccharides have many complex structures,and their chemical synthesis has always been one of the most challenging fields in organic synthesis.In this paper,we solve several problems in the process of total chemical synthesis of heparin disaccharide repeating units,including:(1)The stereoselective construction of 1,2-cis-glycosidic linkage(a-configuration)with GlcN and L-Ido is achieved.(2)Selection of appropriate protectlive groups.The structure of heparin oligosaccharides is complex,largely due to the variable sulfation pattern at different hydroxyl groups.In addition,the amino groups on GlcN can be either sulfated or acetylated.These functional groups should be differentiated from each other to achieve site-specific sulfation and extension of carbohydrate chains.The selection of protective groups can be crucial,in that it affects the reactivity of glycosyl donors and acceptors and potential participation of neighboring groups in the formation of glycosidic linkages.(3)Three different protective groups were screened including benzyl(Bn),2-naphthalaldehyde(2-NAP)and p-methyl benzyl(PMB)at the extension sites of sugar chains.(4)Different activation systems for thioglycoside was screened,among which the pre-activation system p-toluenesulfonyl chloride(p-TolSCl)in line with silver trifluoromethanesulfonate(AgOTf)and 2,4,6-Tri-tert-butylpyrimidine(TTBP)showed the best result.