Professor Yang you, East China University of science and technology research group: synthesis of three carbon branched KDO analogues based on the Sonogashira coupling reaction between three iodo KDO glycones and terminal alkynes

The abuse of lead antibiotics has led to the emergence of drug-resistant bacteria, and the research and development of drug-resistant bacteria has attracted extensive attention of scientists In the biosynthesis of lipopolysaccharide on the surface of bacteria, the assembly of lipopolysaccharide through the metabolism of 3-deoxy-d-mannose-2-octanone-glycolic acid (KDO) plays an important role in the survival of bacteria Therefore, it is of great significance to construct new KDO analogues and develop them into effective inhibitors of CMP KDO synthetase in KDO biosynthesis Recently, Professor Yang You's research group of School of pharmacy of East China University of science and technology developed the Sonogashira coupling reaction between three iodo KDO glycones and terminal alkynes, and realized the stereospecific synthesis of 2-deoxykdo monosaccharides and disaccharide analogues connected by three carbon vertical bonds for the first time by using substrate controlled asymmetric hydrogenation (J ORG Chem 2018, DOI: 10.1021 / ACS JOC 8b00356) 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 3 doctoral students, 10 master students and 1 Research Assistant in the research group The research group has been recruiting postdoctors and research assistants for a long time We warmly welcome students who are interested in sugar chemistry and sugar drug research to join our research team to explore the field of sugar science together 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, he conducted a postdoctoral research 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 May 2015, he was employed as a special professor of East China University of science and technology In September 2015, he was promoted to Professor and employed as doctoral supervisor He is mainly engaged in the research of sugar chemistry and sugar drugs Up to now, nearly 30 SCI papers have been published in Chem Rev., J am Chem SOC., NAT Prod.rep., chem SCI., green chem., chem Biol And other internationally renowned journals One chapter of English academic monograph has been written, and four invention patents (one authorized) have been applied for at home and abroad Many papers were cited by ESI, or reported by chemistryworld magazine of Royal Society of chemistry and deutschlandfunk Selected young talents of the national "Thousand Talents Program" (2015), Shanghai Pujiang talents (2015), young talents of East China University of science and Technology (2015), Youth May 4th Medal of East China University of science and Technology (2017) Frontier research achievements: Based on the Sonogashira coupling reaction between 3-iodo-kdo-glycones and terminal alkynes, the C-C bond of 3-carbon-branched KDO analogues has a strong stability for in vivo hydrolase, so the carbon-branched-sugar analogues have great potential in the development of glycoside hydrolase and transferase inhibitors In the previous work, Professor Yang You's research group and Yu Biao, researcher of Shanghai Institute of organic chemistry, Chinese Academy of Sciences, worked together to elaborate the synthesis method of carboglucoside for the first time from the perspective of the type of glycosyl donor, providing a rich and detailed guide for researchers in sugar science and related fields (chem Rev 2017, 117, 12281) In view of the application prospect of new KDO analogues in the development of drug-resistant bacteria, three carbon branched KDO analogues attracted the interest of the research group However, KDO is a unique octaketose acid Due to the influence of no hydroxyl group at position 3 and electron absorbing carboxyl group at position 1, the stereocontrolled synthesis of KDO monosaccharide and disaccharide analogues at position 3 is more challenging than that of aldose analogues at position 2 Recently, based on the Sonogashira coupling reaction between three iodo glycones and terminal alkynes, Professor Yang You's research group has realized the efficient synthesis of three carbon branched KDO monosaccharides and disaccharide analogues for the first time Moreover, through asymmetric hydrogenation and saponification, these three carbon branched KDO monosaccharides and disaccharide analogues can be stereospecific transformed into 2-deoxy-b-carboxyl KDO analogues, laying a good foundation for further development of CMP KDO synthetase inhibitors First of all, KDO ester generates KDO saccharene under the action of TMSOTf, which can be converted into 3-iodo-kdo-saccharene under the promotion of NIS and TMSOTf (Fig 1) Considering that TMSOTf is the common accelerant of the two steps, Kdo ester can be directly converted into 3 position iodated Kdo Glycone in one step under the promotion of NIS and TMSOTf, with the yield up to 90% Fig 1 Efficient preparation of 3-iodo-kdo-saccharene (source: J org Chem.), then, the author tried the heck coupling reaction of 3-iodo-kdo-saccharene and methyl acrylate under the catalysis of palladium acetate, which may be affected by the electronic effect of 1-carboxyl group In this reaction, only 53% yield of 3-carbon branched kdo-diene analogues was obtained (Fig 2) Next, the author explored the palladium acetate catalyzed Sonogashira coupling reaction of 3-iodo-glycosylene and terminal alkyne, which has a wide range of substrates, and can react with different types of terminal alkyne including levonorgestrel, a drug molecule, to generate a series of 3-carbon branched kdo-alkyne analogues, with a yield of 66 – 85% (Fig 3) Fig 2 Heck coupling reaction of 3-iodo-candosene with methyl acrylate (source: J org Chem.) Fig 3 Sonogashira coupling reaction of 3-iodo-candosene with terminal alkyne (source: J org Chem.) In order to further prove the feasibility of Sonogashira coupling reaction between 3-iodo-kdo-glycone and terminal diyne, the terminal diyne with different length of alkyl chain was selected as the coupling substrate With the extension of the alkyl chain length in the terminal diyne, the yield of the obtained 3-position carbon branched kdo-diyne analogues increased significantly, indicating that the steric hindrance between the two KDO units in the resultant coupling product may have a great influence on the yield of the coupling reaction (Fig 4) Figure 4 Sonogashira coupling reaction of 3-iodo-glycone with terminal diyne (source: J org Chem.) after obtaining 3-carbon-branched KDO monosaccharide and diyne analogues, the author studied the hydrogenation of these compounds With PD (OH) 2 / C as catalyst, the C ≡ C triple bond on these alkyne analogues is completely reduced, while the C = C double bond is only CIS added from the bottom under the influence of the internal stereochemistry of the KDO framework, so the KDO monosaccharide and disaccharide analogues of 2-deoxy-b-carboxyl group are obtained stereoscopically and specifically in high yield (Fig 5) Fig 5 Asymmetric hydrogenation of 3-carbon-branched KDO alkyne analogues (source: J org Chem.) finally, the author removed the protective group from 3-carbon-branched KDO analogues (Fig 6) Under alkaline condition, all ester groups on KDO analogues were removed by saponification, and KDO alkyne analogues with three carbon branches and 2-deoxy-b-carboxyl groups were obtained respectively This method will lay a foundation for the future synthesis of 2-deoxy-b-kdo analogues with three carbon branches and the evaluation of their potential as enzyme inhibitors Figure 6 Synthesis of three carbon branched KDO analogues (source: J org Chem.) the research results are published in the Journal of Organic Chemistry (DOI: 10.1021 / ACS Job 8b00356) Fan Wenjing, a master's student, is the first author of the paper, and Professor Yang you is the corresponding author The research was supported by the national "Thousand Talents Program" youth program, Shanghai Pujiang Talents Program and the special fund for basic scientific research business expenses of the Central University 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, chembeango app, chembeango official microblog, CBG wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the domestic representative research group, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.