Green Synthesis And Deuteration Of Rare 6-Deoxysugars Based On Aqueous Dehalogenation

Rare 6-deoxysugars and deuterium-labeled derivatives serve vital purposes and contribute significantly to the pharmaceutical field.The former serve as the basic building blocks for different kinds of drug molecules and naturally bioactive substances,while the latter have the potential to enhance the pharmacokinetic properties of corresponding prototype molecules while preserving their biological potential.Unfortunately,rare6-deoxysugars are currently expensive,difficult to obtain in large quantities,and frequently necessitate the use of toxic or hazardous reagents in their preparation.Moreover,due to the incompatibility of classical deuterium-labeling reaction with the active hydrogen species in reaction system,the acquisition of deuterium-labeled derivatives is often cumbersome or requires large consumption of deuterium sources.To address these problems,we first developed a safe,environmentally friendly,and cost-effective method for obtaining rare 6-deoxysugars based on aqueous dehalogenation,and then further developed a method for efficient deuterium labelling in the aqueous phase based on a careful study of the mechanism of aqueous dehalogenation.In the first part of this thesis,we provided an ecologically friendly and cost-effective synthesis scheme for rare 6-deoxysugars based on calcium hypophosphate-mediated dehalogenation in aqueous,which was founded on the guiding principle of green chemistry in drug synthesis.In this approach,we use cheap methyl glycosides as raw materials,and through selective halogenation,dehalogenation,acetylation,and acetolysis,we can efficiently access high value-added D-quinovose(6-deoxy-D-glucose),D-rhamnose(6-deoxy-D-mannose)and D-olivose(2,6-dideoxy-D-glucose)from dozens to hundreds of grams.It should be noted that this method requires no column chromatography purification or only a single column chromatography purification operation.Mechanistic studies of the aqueous dehalogenation step in the synthetic scheme revealed that the cheap and safe calcium hypophosphite used as a reductant,and this reductant is predominantly oxidized to non-toxic and water-insoluble calcium phosphite,enhancing the safety of rare6-deoxysugars production.In addition,water played vital roles during the procedure.It is not only a precipitant for organophosphates in halogenation,but also a solvent,reagent and calcium phosphite precipitant for dehalogenation,and it is also a desalting agent for acylation.This strategy takes advantage of the usage of water to lower both the environmental pollution and the expense of synthesis.This approach offers convenience for pharmaceutical research involving the rare 6-deoxysugar.In the second part of this thesis,based on aqueous dehalogenation reaction,we developed a deuterated hypophosphate-mediated deuteration reaction.Compared with conventional deuteration,this approach avoids the adverse effects of residual active hydrogen species in the system(water or hydroxyl,etc.)on deuterium incorporation.Specifically,since there is no H/D exchange between deuterated hypophosphite and H2 O within p H 2.5~11.7,using deuterated hypophosphite as the deuterium reagent,we can efficiently achieve deiodo-deuteration through radical dehalogenation reaction in the aqueous phase(H2O).Whereas deuterated hypophosphite is a shelf-stable,non-toxic,cost-effective and environmentally friendly deuterium reagent.This method provides an economical and safe deuterium labelling method for the study of deuterated drugs.