Rh/H~+ Catalyzed Glycosylation Reaction

Carbohydrates,which play an important role in life activities,can be used not only as energy substances and structural substances,but also as conductors of biological signals in life.Many carbohydrate compounds of natural origin have important biological activities and are one of the important sources of modern drug development.The structural complexity and strong hydrophilicity of carbohydrate compounds make it difficult to obtain from natural resources.Chemical synthesis is an important way to obtain them.In the chemical synthesis of carbohydrates,the core issue is the construction of glycosidic bonds.The method of constructing glycosidic bonds can be divided into many types according to different donors.Among them,thioglycoside donors have become one of the most widely used donors due to their various advantages.However,the existing thioglycoside activation methods usually use stoichiometric accelerators,which are often difficult to be compatible with the sensitive groupsn in the substrate,making it difficult to synthesize complex drugs and natural products.Therefore,it is of great significance to develop a milder method of thioglycoside activation.Due to its low catalytic equivalent and mild reaction condition,transition metal-catalyzed organic chemical reactions are gradually applied to glycosylation.In addition to some traditional donors that have been shown to be catalyzed by transition metals,a number of new donors have been developed,such as the use of Au(I)catalyzed ortho-alkynylbenzoate donors.However,there are still few reports on the use of transition metals for catalytic activation of thioglycoside donors.Inspired by the vinyl sulfonium-mediated [n + 2] cyclization reaction,we have developed a novel thioglycoside activation method that is continuously catalyzed by divalent rhodium and Bronsted acid.In our method,thioglycoside donor reacting with rhodium carbenoid was converted into a glycosyl sulfonium ylide intermediate,and then protonated with a protonic acid catalyst to form a glycosyl sulfonium ion intermediate,which finally completed glycosylation with the acceptor.For the reaction substrates with different activities,we developed two reaction modes of “one-shot” method and “stepwise” method by simply adjusting the order in which the materials are added to the reaction system.The existence of sulfur ylide intermediate was verified by means of separation and verification of by-products in the reaction system and NMR monitoring of the reaction process.We have also explored the substrate range of this method.A large number of high-activity or low-activity thioglycoside donors,as well as many substrates that are sensitive to acid and require high steric hindrance,are well compatible.This method can also be used to prepare a variety of new donors from simple thioglycoside donors,providing new synthetic strategies for carbohydrate chemistry and natural product synthesis.In addition,we also preliminarily tried to use this method for iterative one-pot glycosylation,proving that this method has a potential great application in oligosaccharide synthesis.In summary,we have developed a mild glycosylation reaction based on a completely new thioglycoside activation method to provide an effective method for the synthesis of complex carbohydrate drugs and natural products.