Studies On Dehydrative Glycosylation In The Synthesis Of Carbohydrate And Carbohydrate Drugs

Carbohydrates are not only structural and energy substances but also indispensable information substances in various life activities.Carbohydrates and carbohydrate drugs play a vital role in daily life and disease treatment.The in-depth study of their biological activities and further exploration of their medicinal value depend on acquiring a large number of carbohydrate compounds.At present,chemical synthesis is one of the most effective means to obtain saccharide molecules with a definite structure and uniform composition.The efficient construction of glycosidic bonds and rapid assembly of oligosaccharides are the core research contents in carbohydrate chemistry.Relying on the in-depth study of sulfoxide glycosylation,we developed a novel dehydrative glycosylation reaction mediated by the comproportionation reaction of dithioacetal monosulfoxide.In order to solve the problem that an excess amount of phosphine oxide reagent was used in traditional phosphine oxide-promoted dehydrative glycosylations,we developed a catalytic dehydrative glycosylation strategy by using（2-hydroxybenzyl）diarylphosphine oxide as organocatalyst.In the first part of this thesis,we designed and screened thirteen kinds of dithioacetal monosulfoxide（1,3-dithiane 1-oxide）with different structures and found that two of them could be used to mediate dehydrative glycosylation reactions,which was successfully employed to the preparation of eighteen kinds of representative glycoside products.The key of this method was using Tf₂O to selectively activate the sulfoxide functional group to form the sulfonium intermediate,which reacted with C1-hemiacetal and generated the mixed monothioacetal glycoside intermediate.The terminally tethered sulfenyl triflate（RSOTf）moiety of temporary anomeric leaving group activated the intramolecular monothioacetal structure along with the cleavage of one equivalent of aromatic aldehyde and 1,2-dithiolane.The important oxocarbenium ion intermediate in glycosylation was released and finally coupled to the acceptor to generate the glycosyl products.This method had broad applicability to both high-and low-reactive hemiacetal donors and various acceptors.Besides,2-phenyl-1,3-dithiane 1-oxide was useful for benzylidene acetal protection of diol compounds.It is worth mentioning that the two oxidation states of sulfur element in the dithioacetal monosulfoxide reagent（0 in the sulfoxide and-2 in the sulfide）converted into one oxidation state（-1）in the disulfide derivative through a comproportionation reaction.In the second part of this thesis,we screened fifteen kinds of phosphine oxide organocatalysts different structures and found that one of the（2-hydroxybenzyl）diaryl phosphine oxide reagent could efficiently catalyze the dehydrative glycosidation reaction,which was successfully employed to the preparation of seventeen kinds of representative glycoside products.The key of this method was that the phosphine oxide reagent could react with Tf₂O to form the cyclic oxyphosphonium salt intermediate first with the participation of its intramolecular phenolic hydroxyl group.Then,the cyclic oxyphosphonium reacted with C1-hemiacetal to form the glycosyl oxyphosphonium salt intermediate,which was further cleaved and converted into oxocarbenium ion and coupled with acceptor to furnish a glycosidic bond.At the same time,the phosphine oxide reagent was regenerated and continued to participate in the next catalytic cycle.After the glycosylation finished,the phosphine oxide catalyst could be recovered efficiently.This method could effectively activate various hemiacetal donors and was applicable to acceptors such as alcohols,phenols,and carboxylic acids.In conclusion,the two novel dehydrative glycosylation reactions developed in this thesis offered new examples for the applications of dithioacetal monosulfoxide and phosphine oxide in oligosaccharide synthesis.At the same time,they provided new options for constructing glycosidic bonds and new tools for the development of carbohydrate drugs.