Li Ming group, Ocean University of China: silver salt promoted dehydro hydroxymethyl fluorination of sugars and divergent late modification of fluorosugars

4-substituted furoses / 5-substituted pyranose with unique lead structure not only exist widely in nature, but also play a key role in exploring enzymatic reaction mechanism and drug discovery as non natural functional molecules However, limited by the limited substrate applicability and complex experimental operation in the existing synthesis methods, the simple and universal methods to obtain these compounds need to be developed for further biological evaluation and research Recently, Professor Li Ming's research group of School of medicine of Ocean University of China has developed a kind of dehydromethyl fluorination reaction of sugar compounds promoted by silver salt The reaction conditions are mild, the operation is simple, and it has a wide range of functional group tolerance and substrate applicability It can be used for the transformation of nucleoside, trehalose, β - cyclodextrin and other complex sugar molecules The intramolecular hydrogen transfer experiment shows that the reaction undergoes a β - cracking process of first-order alkoxy radicals The obtained fluorosaccharides can not only be used as functional molecules, but also as advanced intermediates to react with various nucleophiles through Lewis acid activation to obtain rare sugars and high carbon sugars with various structures By using this program, the author developed a new synthesis route of SGLT2 inhibitor sogliptin and found a potential new SGLT2 inhibitor with the activity level of nanomolar The results were published in angew Chem Int ed (DOI: 10.1002 / anie 201914557) Li Ming, professor and doctoral supervisor of Ocean University of China In 1998, he received his bachelor's degree from Sichuan University; in 2003, he received his doctor's degree in organic chemistry from Dalian Institute of Chemical Physics, Chinese Academy of Sciences and Shanghai Institute of Organic Chemistry (Supervisor: Yu Biao and Han Xiuwen researcher); in 2006-2010, he received his bachelor's degree from University of Illinois at Chicago, Wayne State University, T he State University of New York is engaged in postdoctoral research in sugar chemistry and nucleic acid chemistry, with CO mentors of Professor David Crich and Professor Eric rozners Since March 2010, he has joined the school of medicine of Ocean University of China and has successively served as an associate professor, professor and project leader Professor Li Ming's current research interests include sugar chemistry and drug synthesis Leading scientific research achievements: silver salt promoted dehydro hydroxymethyl fluorination of sugar and divergent late modification of fluorinated sugar 4-substituted furan and 5-substituted pyranose are a kind of molecules with important physiological functions, including the only natural nucleoside containing fluorine (nucleocidin), SGLT2 inhibitor sotagliflozin, etc The traditional method of introducing substituents in this position of carbohydrate compounds (including the nucleophilic ring opening of glycinium ion / epoxy or the electrophilic functionalization of nucleoside methyl ester) has the disadvantages of violent reaction conditions and poor substrate stability (scheme 1-A) Furan-4-radical and pyranose-5-radical-radical are the common synthesis intermediates in sugar chemistry They can be obtained through the free radical decarboxylation / hydrogen extraction reactions of glucuronic acid and its derivatives, as well as the pre modified sugar, but the substrates of these reactions need to be obtained through multi-step reactions (scheme 1-B) Ferrier photobromination and subsequent carbobromination provide a convenient means for the synthesis of these compounds, but the conversion is limited to glucose and the yield is very low (scheme 1-C) Alkoxy radicals are generated directly from the primary hydroxyl groups of sugars, and then β - cleavage occurs to generate such radicals As there is no need to pre organize sugars, it has the advantages of economic synthesis route However, the current reports are usually limited to furan sugars Pyranose in 4C1 conformation passes through the first-order alkoxy radicals β because of the high bond energy of 5-lying hydroxymethyl -It is very difficult to produce pyranose-5-radical by pyrolysis Li Ming, Professor of Ocean University of China, has long been committed to the generation and subsequent transformation of sugar free radicals and their application in the synthesis of rare sugars Recently, with silver carbonate as accelerant, selectfluor as fluorine source and oxidant, the group has realized the dehydromethyl fluorination of sugar compounds through the intermediate of primary alkoxy radical of sugar, and activated the carbon fluorine bond of fluorine-containing sugar with BF 3 · OET 2 as catalyst through the later stage modification strategy, through the reaction with a variety of nucleophiles The synthesis of rare sugars and high carbon sugars (scheme 1-D) (source: angelw Chem Int ed.) through the optimization of the reaction conditions, the author finally determined the optimal conditions: in acetone / water, with Ag 2CO 3 (0.5 equivalent) as the promoter, select fluor (5 equivalent) as the fluorine source and oxidant, at room temperature for 1-24 hours Then, the substrate expansion of the reaction was carried out under the optimal conditions (Table 1) The experimental results show that the reaction has no effect on the functional groups commonly used in sugar chemistry, such as acetyl, benzoyl, fluoroside, azide, phthalimide and even exposed primary hydroxyl groups; monosaccharides, including glucose, galactose and ribose, are compatible with the reaction; furan, pyranose and uridine (2O) with branched chains ）All of them can be transformed smoothly, and a variety of different linked oligosaccharides including trehalose (2R) and β - cyclodextrin (2Z) can also react, which proves that the reaction conditions are mild and applicable to different substrates (source: angelw Chem Int ed.) based on literature reports and work basis, the author thinks that the reaction has experienced a first-order alkoxy radical intermediate, so the author designed substrate 3, which is intended to capture alkoxy radicals through intramolecular hydrogen extraction reaction of alkoxy radicals Under the standard conditions, the dehydromethyl fluorination of 3 was carried out The results showed that the monofluorinated product 4 and the bifluorinated product 4 ′ At the same time, the author adopts the method of step-by-step activation to mix the silver salt and selectfluor in advance It is found that the light green silver carbonate fades and dissolves to form a colorless water-soluble silver salt solution, and then adds 3 to the system After the reaction continues, similar results are obtained It is proved that the colorless water-soluble silver salt is the active form of silver in the reaction Based on the above results, the author proposed the following reaction mechanism (scheme 2): a G (I) was first oxidized into water-soluble Ag (II) in the reaction system, the active silver salt oxidized the primary glycosyl hydroxyl to the first alkoxy radical a through single electron oxidation, the radical can be directly generated into glycosyl radical B through β - cleavage, and the radical fluorinated to produce product 4; in addition, a The intermediate C can also be formed by 1,6-hat in the transition state of the seven membered ring, and D can be produced by free radical fluorination, and then the product 4 'can be obtained by dehydromethylation fluorination of D (source: angelw Chem Int ed.) fluoroglycosides are important glycosyl donors in Glycochemistry due to their thermodynamic stability and reactivity Therefore, the author considers that the fluorocarbon bond can be activated by glycosidization to realize the divergent transformation of fluorosugar (Table 2) After adjusting the protective group of the sugar ring to obtain a more active fluoroglycoside donor 6, the author used BF 3 · OET 2 as a catalyst to activate the fluorocarbon bond to generate onium ions, which reacted with different nucleophiles The experimental results show that organosilicon reagent, enol silicone ether, heteroaromatic ring, mercaptan, hydroxy group and phosphite can be used as acceptors to successfully transform into high carbon sugar and rare sugar, which shows the advantages of the fluorosugar as a high-level synthesis intermediate (source: angel Chem Int ed.) soglitazine, developed by Sanofi, a French pharmaceutical giant, is a double inhibitor of sodium glucose cotransporter-1 / 2 (SGLT1 / 2), which can be regarded as the product of dehydromethylation and sulfurization of dagglitazine The synthesis and various modifications of soglitazine were realized by the dehydromethyl fluorination of the primary hydroxyl group of sugar and the activation of the fluorocarbon bond In the process of modification, the author found that the 5-azide analogues of soglitazine are good lead compounds for the development of new SGLT2 inhibitors (source: angelw Chem Int ed.) Li Ming research group of Ocean University of China has developed a demethylation fluorination reaction of primary hydroxyl group of carbohydrate compounds and used the generated fluorosaccharides for further sugar diversification Through the mechanism study, the author confirmed that the reaction experienced the β - cracking process of alkoxy radicals Through this method, the synthesis and structural modification of SGLT2 inhibitor soglifloxacin were carried out, which laid a foundation for the research and development of new SGLT2 inhibitor 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.