Professor Yang you research group of East China University of science and technology: DMF regulated α - stereoselective KDO glycosidation

Introduction 3-D eoxy-d-manno-oct-2-ulosonoic acid (KDO) is a unique acid octacarbon sugar on the surface of bacteria There are two configurations of natural KDO glycosides: α - KDO and β α - KDO is usually found in the core region of lipopolysaccharide of Gram-negative bacteria, while β - KDO is commonly found in the capsular polysaccharide and O-antigen of lipopolysaccharide on the surface of bacteria Due to the close interaction between KDO glycosides and natural and adaptive immune systems, it is considered as a potential target for developing carbohydrate vaccines and diagnostic tools, so the synthesis of KDO glycosides has attracted the interest of glycochemists However, due to the deoxygenation structure of 3-position KDO and the lack of stereo guiding group, it is difficult to obtain a single configuration of α - or β - KDO glycosides; the electron absorption effect of 1-position carboxyl group of KDO leads to the greatly reduced activity of KDO's glycosidization reaction and the formation of glycoene by-products, so the stereoselective glycosidization of KDO is very challenging Recently, Professor Yang You's research group of East China University of science and technology has developed a simple and direct α - stereoselective glycoside reaction of KDO, which is regulated by exogenous DMF, for stereoselective synthesis of α - KDO glycosides By using sphosauntf 2 as accelerant and DMF as regulatory molecule, a simple and easy-to-obtain α - stereoselective glycosidization reaction of the donor of all acetylated kdo-o-alkynylbenzoate with a variety of common receptors was realized Based on this method, we synthesized A-linked KDO disaccharide with a link arm at the reduction end by using the latent activation strategy In addition, the positive ion of α - KDO imine ester was first captured by low temperature nuclear magnetic resonance experiment, which provides strong evidence for explaining the mechanism of α - stereoselective KDO glycosidization regulated by DMF Relevant research results were published in org Lett (DOI: 0.1021/acs.orglett 9b04509) Brief introduction of Professor Yang You's research group Professor Yang you of East China University of science and technology was founded in September 2014 The main research directions of the research group are: (1) the synthesis methodology, total synthesis and chemical biology of glycoconjugates and glycoconjugates with important physiological activities; (2) the development of glycodrugs and glycovaccines; (3) the research on the interaction mechanism of glycoproteins and their application in new medical diagnosis tools There are 5 doctoral students and 10 master students in the research group The research group has been recruiting postdoctors and research assistants for a long time We warmly welcome the students who are interested in sugar chemistry and sugar medicine research to join us in the exploration of sugar science Prof Yang you: Professor of East China University of science and technology, doctoral supervisor In 2004, he graduated from the Department of chemistry, University of science and technology of China with a bachelor's degree Later, it was jointly cultivated by the University of science and technology of China and Shanghai Institute of organic chemistry of the Chinese Academy of Sciences In 2010, it received the doctorate of science from the University of science and technology of China, with the tutor of researcher Yu Biao From August 2010 to June 2014, postdoctoral research was conducted at Max Planck Institute of colloid and interface in Germany, under the guidance of Professor Peter H Seeberger In September 2014, he was an associate professor of the school of pharmacy, East China University of science and technology In September 2015, he was promoted to Professor and employed as doctoral supervisor Member of the sugar Chemistry Committee of the Chinese chemical society He is mainly engaged in the research of sugar chemistry and sugar drugs So far, nearly 40 SCI papers have been published in international famous journals such as chem Rev., J am Chem SOC., NAT Prod Rep., chem SCI., org Lett., green chem., chem Biol., J org Chem., etc., writing one chapter of English academic monograph, applying for 5 domestic and foreign invention patents (1 authorized) Among them, 4 articles were selected as ESI high cited papers or cover papers, and some research work was reported by chembeango, chemistry world, deutschlandfunk and other highlights Won the national "Thousand Talents Program" young talents (2015), Shanghai Pujiang talents (2015), East China University of science and technology young talents (2015), East China University of science and Technology Youth May 4th Medal (201 7), China Pharmaceutical Association - Servier young Pharmaceutical Chemistry Award (201 8), Royal Chemical Society "top 1% highly cited Chinese author" (201 8) (2019) as the spokesperson of item No 107 "element cycle table of Chinese young chemists" of China Chemical Society, and the fifth "President award of young talents" (2019) of East China University of science and technology Frontier research achievements: in recent years, many sugar chemistry researchers have been devoted to the development of highly stereoselective KDO glycoside reaction, which is regulated by DMF, for the construction of α - or β - KDO glycosides Up to now, most of the methods need to introduce three-dimensional guiding protecting groups on KDO donor, such as 3-iodo, 3-thio, 3-phenylseleno, 4,5-o-propyl, 4,5-di-o-tert-butyldimethylsilyl, 5,7-o-di-tert-butyldimethylsilyl and 5-ester to realize the α - stereoselective glycosidization of KDO However, the installation of additional stereoguide groups on KDO donor increases the synthesis steps of KDO donor, and makes the determination of the stereostructure of the synthesized KDO glycoside more complex Professor Yang You's research group is committed to developing a simple and direct high stereoselective KDO glycoside reaction for rapid and efficient construction of α - and β - KDO glycosides Previously, the research team reported the β - stereoselective glycosidization of total acetylated KDO o o-alkynylbenzoate donor promoted by PPh3 auotf, and applied it to the synthesis of β - linked GalNAc KDO disaccharide antigen on the surface of Klebsiella aureus kk01 (carbohydr Res 2017, 448, 161; org BIOMOL Chem 2019, 17, 1694) On this basis, the author hopes to reverse the β - stereoselectivity of the glycoside reaction into α - stereoselectivity, so as to achieve the purpose of constructing different configuration of KDO glycosides with the same simple and easy donor Recently, Professor Yang You's research group has developed a simple and direct α - stereoselective KDO glycoside reaction by introducing DMF as a regulatory molecule, which is used for stereoselective synthesis of α - KDO glycosides For the first time, the positive ion of α - KDO imine ester has been observed, which provides evidence for the possible mechanism of α - stereoselective KDO glycoside reaction regulated by DMF First of all, through the condition screening, the author found that under the promotion of 2-equivalent sphosauntf 2 and 6-equivalent DMF, the glycosidization reaction of total acetylated kdo-o-alkynylbenzoate donor 1 and n-heptanol 2 can obtain KDO glycoside in almost quantitative yield, and α - KDO glycoside is the main product (Table 1) In addition, when trifluoromethylsulfonic acid is added to the system, the amount of sphosauntf 2 can be reduced to achieve similar glycosidation reaction, but at the same time, the α - selectivity of the glycosidation reaction can be slightly reduced Table 1 The screening of glycosidization reaction conditions of total acetylated kdo-o-alkynylbenzoate donor 1 and heptanol 2 (source: org Lett.) after determining the optimal conditions of glycosidization reaction (Table 1, entry 4), the author inspected the universality of the reaction (Figure 1) When the donor 1 reacts with the simple primary alcohol receptor (2 and 4a), it can obtain the KDO glycoside product with high yield When the donor 1 reacts with the secondary alcohol and tertiary alcohol (4b-4d), the α - selectivity of the glycoside reaction is obviously improved When the donor 1 reacts with the glycosyl receptor (4e-4j), including the KDO receptor ）In the reaction, α - KDO glycosides can be constructed with high yield and stereoselectivity, and α - (2 → 4) - and α - (2 → 8) - linked KDO disaccharides have been successfully constructed Fig 1 Study on the substrate application scope of DMF regulated α - stereoselective KDO glucosylation (source: org Lett.) because glycosyl-o-alkynylbenzoate donor can be easily prepared from stable glycosyl-o-iodobenzoate intermediate, the author based on the DMF regulated α - stereoselective KDO glucosylation method, The latent activation synthesis of KDO disaccharide with linkage arm at the reduction end was completed (Fig 2), showing the potential of DMF regulated KDO glycoside reaction in the latent activation synthesis of oligosaccharides Fig 2 The latent activation synthesis of KDO disaccharide 13 (source: org Lett.) in order to explore the mechanism of DMF regulated α - stereoselective KDO glycoside reaction, the author captured the α - configuration of KDO imine ester cation 14 formed by KDO donor 1 and DMF under the promotion of sphosauntf 2 at - 40 ℃ by low-temperature NMR experiment (Fig 3) The decomposition temperature (higher than - 10 ℃) of the intermediate was determined by the temperature changing NMR experiment It is suggested that the positive ion of α - KDO imine ester with lower activity but more stable is in equilibrium with the positive ion of β - KDO imine ester with higher activity The alcohol receptor has a nucleophilic attack similar to SN2 on the more active positive ion of β - KDO imine ester, thus forming α - KDO glycoside stereoselectively Fig 3 Low temperature nuclear magnetic resonance experiment to capture KDO imine ester positive ion intermediate 14 (source: org Lett.) Summary: Professor Yang You's research group has developed a simple and direct method of α - stereoselective KDO glycosidization regulated by DMF In this method, a simple and easy-to-obtain all acetylated KDO o o o-alkynylbenzoate was used as the donor, and no additional stereo guide protecting group was needed on the KDO donor, which accelerated the efficient synthesis of α - KDO glucoside Then, this method is applied to the synthesis of KDO disaccharides with linkers at the reduction end, which is expected to be further applied to the study of glycoprotein conjugates and glycochips Finally, the positive ion of α - KDO imine ester was detected for the first time by low-temperature NMR experiment, which provides strong evidence for explaining the mechanism of DMF regulated α - stereoselective KDO glycoside reaction The research results were recently published in organizational letters (DOI: 10.1021/acs.orglett 9b04509) Lou Qixin, a master's degree graduate student, is the first author of the article, and Professor Yang you is the corresponding author The above research work has been supported by the National Natural Science Foundation of China, the national "thousand talents plan" youth project, and the special fund for basic scientific research business fees of central universities Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information website, chembeangoapp, chembeango official micro blog, CBG information wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the representative research groups in China, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.