Mechanistic Investigation On Sulfoxide Activation-Based Glycosylations In The Synthesis Of Carbohydrate Drugs

Carbohydrates are the most abundant biomolecules on the earth while performing as important information substances in living organisms.The occurrence and development of many diseases are closely related to carbohydrates.With the development of carbohydrate science,the therapeutic filed of carbohydrate drugs covers almost all kinds of diseases.Therefore,the construction of foundation course such as the synthesis methods and strategies of carbohydrates is particularly important.And mechanism is the keypoint of a chemical reaction.Only by reaserching the mechanism thoroughly can we truly understand the reaction.Thus,the reaction can be effectively optimized and extensively expanded.In 2015 and 2016,our group developed interrupted Pummerer reaction mediated glycosylation with O-2-[(propan-2-yl)sulfinyl]benzyl(OPSB)glycosides and S-2-[(propan-2-yl)sulfinyl]benzyl(SPSB)glycosides as glycosyl donors respectively.In the study of glycosylation methods,we have speculated and verified the mechanisms of these two glycosylation reactions.When the OPSB glycosyl donor was activated,the anomeric leaving group was recovered as a benzyl alcohol(PSBOH)which didn't affect the glycosylation efficiency.To investigate the mechanism of the occurrence of this alcohol,an ¹⁸O isotopic labeling reaction was carried out to track the leaving group.It was found that the benzyl alcohol was generated during the aqueous work up process from an inactive cyclic oxo-sulfonium ion intermediate.It was also proved that H₂O prefer to attack the sulfur atom position during the hydrolysis of the intermediate.When the SPSB glycosides acted as glycosyl donors,the anomeric leaving groups were recovered in the forms of thiosulfinate,disulfide and thiosulfonate.These products were presumed to be obtained by the hydrolysis and disproportionation of a cyclic thio-sulfonium intermediate.In this study,mass spectrometry and NMR studies were carried out which confirmed that the cyclic thio-sulfonium intermediate exists.Further ¹⁸O isotopic labeling reactions revealed that the cyclic thio-sulfonium ion was hydrolyzed to thiosulfinate which further disproportionated to disulfide and thiosulfonate.This study clarifies the activation process of the SPSB glycosides involved glycosylation reactions.In 1989,Kahne and co-workers successfully employed glycosyl sulfoxides as donors in glycosylation reaction.The invention of Kahne glycosylation forwards a big step on the carbohydrate chemistry.Despite an extensive series of studies,the precise mechanism of Kahne glycosylation is still not fully understood.To address these 30-year puzzles,the far side of Kahne glycosylation is explored in this study.Other than the known side and co-products,several unprecedented species including oxygen are observed.In the control and tracking experiments numbers of important intermediates including glycosyl oxo-sulfonium ion,glycosyl oxadithiiranium ion and sulfenic anhydride(Crich's intermediate)are identified to be responsible for the complex reaction pathway.It also reveals that in addition to the conventional ionic glycosylation pathway,a novel free radical pathway also contributes to the Kahne glycosylation with convincing evidence.In summary,we reasonably speculated on the mechanism of OPSB,SPSB and Kahne glycosylation reaction while verified the key intermediates.These studies not only provide deep understanding of the sulfoxide-related glycosylation reactions,but also sheds light on how to improve the efficiency of glycosylation especially sulfoxide-related glycosylation.