Studies On Synthesis Of Glyconucleotides And α-thioderivatives

Glyconucleotides is the material basis for the biosynthesis of various carbohydrate compounds in cells.It is involved in the process of biological glycosylation and has a wide range of applications in biology and medicine.On the other hand,the synthesis of modified glyconucleotides by chemical methods is of great significance for the development and preparation of new antibiotic drugs.However,the efficient synthesis methods of glyconucleotides are limited.Therefore,it is of great significance to study the synthesis methods of glyconucleotides and their derivatives..This master’s thesis takes the method of synthesizing pyranonucleotide from the glycosphoacridine/TFA(trifluoroacetic acid)activation system(phosphorus(V)-nitrogen activation strategy)reported by our research group as the starting point,and further studies the new method of synthesizing sugar-1-phosphorylacridine with controllable configuration by the phenomenon of glycosylide isomerization of phosphoride terminal position,and applies this method to the synthesis of furanosnucleotides.In addition,a special nucleoside phosphoramiditemorpholine was used as a precursor to synthesize α-thioglycosucleotide by P(III)-P(V)coupling.The specific research content is as follows:In Chapter 2,it investigates the synthesis of glyco-1-phosphorylacridine with controllable configuration by glycosylisomerization of phosphorylide.In the previous study,we used acetyl protected sugar to synthesize glycosphoamides,and the two isomers of α/β obtained were difficult to separate,so in this study,benzoyl groups with greater steric hindrance were used as the protective groups of sugars,and four main conditions affecting the ratio of glycosylide isomerization A were studied: acid binding agent,solvent,concentration,temperature,and the effect of benzoyl protection on the isomerization process of glycophosphoryl protected by benzoyl groups.Through the optimization of reaction conditions,it was finally determined that the strong base DBU as base and Lewis base ether as solvent,at-40 °C,the concentration of 0.05 mol/L was the best conditions for the formation of benzoyl protected pyranose-1-α-phosphoramidite.Weak base triethylamine as base,1,2-dichloroethane as solvent,at 80 °C,concentration of 1 mol/L is the best conditions for the formation of pyranosy-1-β-phosphoramide,and the two glycosphotetraazendine isomers can be separated by silica gel column,and 10pyranose-1-phosphorylacridines were efficiently synthesized by this method.In addition,the study of benzoyl protected furanose showed that the conditions for the formation of α-and β-pyranose phosphoramide were not suitable for furanose,and it was finally determined that when Et3 N was used as alkali and ether as solvent,the temperature was 25 °C and the concentration was 0.2 mol/L,the proportion ofα-/β-furanose phosphoramide generated was appropriate,and the two isomers ofα-/β-could be obtained by a reaction,and they could be separated by silica gel column,and 6 kinds of furanose-1-phosphorylazetidine were efficiently synthesized by this method.It solves the problem that the α/β isomerization configuration of glycophosphoryl is uncontrollable and the target product is not easy to separate.In Chapter 3,it investigates the synthesis of furanosylidinucleotides from furanosphosidine/TFA activation systems.The benzoyl protected furanosyl-1-phosphorylacridine is efficiently coupled to nucleoside monophosphate to obtain furanosnucleotide precursors.When removing the protective group on furanose,the alkaline environment of the solution breaks the pyrophosphate bond,and finally ethanol with less polarity is used as the solvent to make the target product precipitate more quickly.The amount of cesium carbonate was reduced from 6 eq to4.5 eq,the alkalinity of the solution was reduced,and the deprotection yield of Galactofuran lactonucleotide was increased from 55% to 84%.Three furanonucleotides were efficiently prepared by this method,which provided a new method for the synthesis of furanos.In Chapter 4,it examines the formation of α-thioglycosucleotides by coupling P(III)-P(V).We were inspired by the use of P(III)-P(V)coupling to formα-heteronucleoside triphosphate,and tried to couple the nucleoside phosphoramidomorpholine with the monophosphate of glycan-protected sugars,and found that the activity of sugar monophosphate was much lower than pyrophosphate,and later by adding the activation reagent DCI,the coupling efficiency was greatly improved,and then the vulcanization reagent was added for in-situ oxidation,and then the protective group on α-P was removed to obtain the glycan and nucleoside protected α-thioglycosucleotide precursor.Due to the large increase in the polarity of the introduction of sulfur atoms,the precursor could not be purified by silica gel column,we used ethyl acetate to wash off small polar substances,directly used cesium carbonate/methanol system to remove the protective groups on sugars and nucleosides,obtained α-thioglycotide crude products,and separated by HPLC to obtain Rp,Sp two isomers,obtained excellent separation yields,and synthesized fourα-thioglycosucleotides by this method.It provides a new simple and efficient pathway for the synthesis of α-thioglycosinoside diphosphate.