Chemical Synthesis Of The Repeating Unit Of Acinetobacter Baumannii 1053 Capsular Polysaccharide

As an opportunistic pathogen,Acinetobacter baumannii is a kind of aerobic gram-negative bacteria.It is widely distributed and can cause various infections in such settings as hospital,community,war and natural disasters.Though A.baumannii infection has no significant impact on a host with well-developed immune system,it can be fatal to a host with poor immune defense.A.baumannii exhibits a strong capability of adapting to the surrounding environment due to its simple nutritional requirements and strong tolerance to ultraviolet rays and various disinfectants.At present.the main clinical treatment includes antibiotics or combination therapy.Due to the increase of bacterial resistance and the slow-paced development of new antibiotics,there is a urgent need to develop new therapeutic strategies against this pathogen.Vaccination is considered as an effective means to treat A.baumannii infection and alleviate clinical economic burden.Capsular polysaccharides(CPSs)are one of the significant virulence factors of A.baumannii.Moreover,it has been demonstrated in some studies that CPSs possess high immunogenicity through animal experiments.Therefore,the immunogenicity of CPSs could be taken advantage of to develop a safe and effective sugar vaccine against A.baumannii infectionIn this paper,based on the structure of A.baumannii 1053 CPS,the trisaccharide hapten was synthesized by chemical methods for the first time.It is expected that the free amino group of the reducing end can be coupled with the carrier molecule for the research of glycoconjugate vaccine.This paper includes the following three chaptersIn the first chapter,a review is conducted on the epidemiology,drug resistance,drug resistance mechanism and vaccine research progress of A.baumannii,based on which a summary is made regarding the synthesis of relevant oligosaccharide fragments to A.baumannii 1053 and the construction of corresponding glycosidic bonds.In the second chapter,an introduction is made of the chemical synthesis process followed by the trisaccharide repeat unit of A.baumannii 1053.The trisaccharide repeat unit of A.baumannii 1053 CPS contains →4)-β-D-ManpNAcA-(1→4)-β-D-ManpNAcA-(1→3)-α-D-FucpNAc-(1→.The target trisaccharide 2-1 has great synthetic challenges,such as preparation of rare monosaccharides module,construction of 1,2-cis glycosidic bonds,preparation of adjacent amino mannuronic acids as well as orthogonality protection of amino groups.Herein,two synthetic routes were proposed.The fully protected trisaccharide compound 2-3 was constructed via a[2+1]glycosylation reaction by using the neighboring group participation.Then,the acetyl group of 2-3 was removed.The resulting C2-OH was transformed into C2-OTf,and sodium azide was applied for azide transposition to obtain the fully protected trisaccharide compound 2-2 in 36%yield for two steps.Then,different reaction reagents including trifluoroacetic acid,acetic acid and DDQ were employed to remove the p-methoxybenzylidene acetal and the p-methoxybenzyl protecting groups.However,all the reaction systems were problematic and the desired products were not obtained.Secondly,we started with the reducing end D-FucN,and adopted the[1+1+1]synthetic strategy to construct the trisaccharide skeleton.The neighboring acyl group participation effect was used to control β-glycosidic bonds formation.The acetyl group was removed after each step of glycosylation.C2-OH was trifluormethanesulfonated and the resulting C2-OTf was directly subjected to the nucleophilic displacement with sodium azide.Subsequently,oxidation was performed.Reduction of the azide groups and deprotection of the benzyl groups were carried out at the same time.Based on the above strategy,trisaccharide 2-35 was obtained.Thereafter,the desired product 2-36 was not detected upon a series of reaction conditions employed in deacetylation.A disaccharide fragment was identified by mass spectrometry in the presence of sodium methoxide,which may be attributed to the instability of glycosidic bond of the reaction substrate.The benzylidene acetal group instead of the acetyl group was removed in the presence of acetyl chloride.In the future,follow-up work will be conducted to obtain the desired target product by further improving and optimizing synthetic routes and protecting groups.All of the intermediates involved in this chapter were confirmed by NMR and HR MS.