Synthesis Of A Novel Armed Sialyl Donor And Its Sialylation Reaction Study

Sialic acids are the most structurally diverse group of carbohydrates and are widely distributed in living organisms.Among the 50 known sialic acids,N-acetylneuraminic acid(Neu5Ac)is not only the most widely occurring but also the most well studied member.The other prominent member of sialic acids is N-glycolylneuraminic acid(Neu5Gc)and KDN.Most sialic acids occur in the form of oligosaccharides,glycoproteins,and glycolipids and often as terminal substituents of cell surface glycoproteins and glycolipids.Thus,sialic acids play an important role in many other biological processes,including cell signaling,recognition,interaction and adhesion,as well as tumor growth and metastasis.Thus,efficient synthesis of oligosaccharides containing sialic acids is crucial for related studies in the field.Natural sialosides are ?-anomers.For example,in N-linked glycoproteins,sialic acids are found ?-(2?3)or ?-(2?6)-linked to galactose and ?-(2?6)-linked to N-acetyl galactosamine,whereas in O-linked glycoproteins,they are found ?-(2?6)-linked to galactose.Sialic acids also occur ashomopolymers in glycoproteins and glycolipids,where they are usually linked through ?-(2?8)or ?-(2?9)sialyl linkages.However,the distinctive structure of sialic acids makes it challenging for ?-sialylations in chemical synthesis.Both the electronic effect and the steric hindrance of C-1 carboxylic group make sialylations difficult to proceed.The lack of hydroxyl group at C-3 makes the strategy of using neighboring group to control streochemistry unavailable.In addition,the elimination and hydrolysis reactions of sialyl donors can futher decrease the overall glycosylation yield.Various modifications of sialyl donors have been developed to address these problems.However,the factors to influence sialylations are rather complex,which are still poorly understood.Therefore,the development of new sialyl donors that are applicable to various conditions has been one of the primary targets in this field.Based on these facts,this research mainly focuses on the synthesis of a novel sialyl donor and its applications to sialylation,which are discussed in detail in the thesis.The thesis consists of two parts:In Chapter 1,we provided a brief introduction to sialic acids and sialylation reactions.We have also discussed several modifications of sialyl donors.In Chapter 2,we first illustrated the design of a novel sialyl donor.Previous studies showed that the most convenient way to build ?-sialyl bond is the application of nitrile solvent effect when the hydroxyl groups of sialyl donor are protected as acetates.However,because of the electron withdrawing effect of the acetyl group,the activation of these donors becomes sluggish.Moreover,the effect of hydroxyl protecting groups on sialyl donors has only recently begun to be investigated.Based on Fraser-Reid's concept of "armed and disarmed" donors,we designed and synthesized an armed Neu5Ac donor which had the hydroxyl groups protected with benzyl groups.It helped us to investigate the relationship between the armed donor and nitrile solvent effect.We were the first to achieve extensive O-benzylation of sialic acid via reductive etherification.We have also found the main reasons of the low yield by structural identification of by-products,which helped to to optimize the reaction to get increased the yield.More importantly,we found that this armed donor gave a high ?-selectivity during the sialylation of primary alcohol acceptors,and confirmed that the nitrile solvent effect play a leading role in ?-sialylations when the donor was armed.Finally,upon hydrogenolysis,all the benzyl groups in a per-O-benzylated disaccharide product were removed in one step to give the free sugar in a high yield.All the result shave shown that this armed sialic acid donor has great value for ?-sialylations.