A Mild Method For The Preparation Of Halogenated Sugars And Its Application In "one-pot" Stereoselective Construction Of Glycosidic Bonds

Carbohydrates are very important epitopes for biological recognition and key targets for drug discovery.Access to well-defined structure of carbohydrates is important to understand their physical properties and biological functions.The low abundance and heterogeneity of carbohydrates in nature make it impossible to isolate carbohydrates in acceptable purity and amounts from natural sources.Therefore,organic synthesis is an extremely valuable research tool for the source of carbohydrates with well-defined structures.Although enormous progress has been made in the area of the chemical O-glycoside synthesis,the assembly of complex oligosaccharides continues to be a time and labor consuming process,as a result of the lack of highly efficient glycosylation procedures and the many variables that play a role in a chemical glycosylation reaction.Developing new and efficient regional and stereoselective glycosylation strategies remain a maj or challenge and opportunity.Glycosyl halides(chlorides,bromides,iodides,and fluorides),which are widely used in the construction of O-,C-,and N-glycosides,show their special features in the stereoselective installation of the anomeric configuration.The configuration can be achieved with high stereoselectivity and switched just by the change of reaction concentration,reaction solvents,reagents and the addition of additives.A variety of methods have been reported for the preparation of glycosyl halides.However,new approach to glycosyl donors is still necessary with the advantages of mild reaction conditions,tolerance of acid-or base-sensitive protective groups and no use of toxic reagents.Thus,we propose in this thesis a new route to the synthesis of those halide donors with the expectation of those above-mentioned advantages.Furthermore,we would explore the potentials of the new route in the "One-Pot" glycosylation strategy for construction the ? and ? anomeric configuration.The following main topics have been conducted in the thesis:(1)Optimization of the condition of preparation of glycosyl halides.Treatment of peracetylated-D-glucopyranosyl gem-Dimethyl S-but3ynyl thioglycoside with IBr as a promotor resulted in the formation of the desired glycosyl bromide in different solvents.It turns out DCM is the best solvent for the efficient conversion of the alkynyl thioglycoside into the corresponding bromide donor.(2)Exploration of the substrate scopes.Eleven of alkynyl thioglycosides with different protective groups were prepared,including "disarmed" sugars(tetra-Oacetylated,tetra-O-benzoylated,diisopropylidene-protected sugars),and "armed"sugars(6-O-TBDMS protected and tetra-O-benzylated sugars).Under the optimized condition,23 of different glycosyl halides have been synthesized using the abovementioned 11 thioglycosides.The "disarmed" thioglycosides provided the corresponding glycosyl halides in 71%-96 yields with completes;selectivity.The"armed" thioglycosides also gave the corresponding glycosyl halides efficiently.It is worth to mention that those acid-sensitive protecting groups such as silyl group and diisopropylidene group are stable enough under this condition.(3)Mechanistic studies on the formation of the glycosyl halides.Due to the highly reactivity of glycosyl iodides and bromides with armed protecting groups,those halides could not be purified by regular chromatography,which would lead to the complete hydrolysis of the halide donors.The product could be obtained in high yield with high purity just by the evaporation of the reaction mixtures under reduced pressure.The structures of those products were confirmed and the mechanism of product formation via variable-temperature?1H NMR experiments.(4)Exploration of the "one-pot" glycosylation strategy.In view of the instability of glycosyl bromides and glycosyl iodides,a simple and practical method for the "onepot" glycosylation was established to construct?-glycosidic bond in high yield and stereoselectivity by the promotion of phosphine oxide.The glycosylation with glycosyl halides using acetonitrile as solvent and silver triflate as promotor furnished the ?glycosidic bond..In conclusion,we have established a general method for the preparation of glycosyl halides from gem-dimethyl S-but-3ynyl thioglycosides under mild conditions with good compatibility with sensitive protecting groups.The new method has a wide substrate scope for the synthesis of halide donors.Meanwhile,"one-pot" strategy for the construction of ? and ? glycosidic bond has been developed under different promotors using thus-formed glycosyl halides as donors without the purification of glycosyl halides.