Research group of Professor Zhou qianghui, School of chemistry and molecular science, Wuhan University: developing a new catelani reaction with epoxide as alkylating agent

Catelani reaction is a kind of catalytic synthesis method for the preparation of polysubstituted aromatic compounds In this reaction, palladium and norbornene or their derivatives were used to catalyze the functionalization of the C-H bond in the ortho position of iodoaromatic, and the substitution of the C-I bond in the base position was used to terminate the reaction With the efforts of the founders, Professor catelani, Professor lautens and many research teams, the connotation of the response system has been enriched In recent years, most of the research work has focused on the research and development of C-I bond termination reagents, in order to expand the application of the reaction in synthesis, while the development of C-H bond alkylation reagents is relatively weak In view of the challenges faced by the development of catelani reaction, recently, Professor Zhou qianghui, School of chemistry and molecular science, Wuhan University, creatively developed the low-cost and easily available epoxy compounds as alkylating agents, greatly expanding the scope of application of this reaction, and providing new directions and ideas for the development of this field The method developed by the group has the advantages of simple operation, mild reaction conditions, cheap raw materials and high atomic economy In addition, the product obtained by this method is a very useful intermediate, and an important pharmacophore isochroman structural unit can be obtained by one-step transformation, thus providing a new strategy for the synthesis of many biologically active natural products and drug molecules (angel.chem.int.ed., 2018, DOI: 10.1002/anie.201800573) In addition, the paper was selected as a front cover by German Applied Chemistry (angel Chem Int ed., 2018, DOI: 10.1002 / 201801898) The cover design takes the old yingding library and the main gate of Wuhan University as the background, which not only highlights the core elements of the research work, but also shows the profound cultural heritage of Wuhan University (the cover is designed by Deng Jun, teacher of Wuhan University Urban Design Institute) The first author of this paper is Dr Cheng Honggang of Professor Zhou qianghui's research group (source: angelw Chem Int ed.) introduction to Zhou qianghui's research group "natural product synthesis laboratory" of Wuhan University was established in June 2015 Its research direction is high-efficiency and full synthesis of rare active natural products, as well as related research on synthesis methodology, chemical biology and pharmaceutical chemistry The aim is to create a novel synthetic methodology for the rare active natural products with important value, and to develop an efficient and practical total synthetic route on this basis, so as to lay a solid material foundation for further chemical biology and pharmaceutical chemistry research Specifically, it is divided into four research directions: 1 The development of novel synthesis methods and synthesis strategies; 2 The development of efficient and practical synthetic routes of active natural products; 3 The chemical biology and pharmaceutical chemistry of important active natural products, drug molecules and their analogues; 4 The new process development of important drug molecules In 2005, he graduated from the school of chemistry and molecular science of Peking University and obtained a bachelor's degree In July 2010, he graduated from Shanghai Institute of organic chemistry, Chinese Academy of Sciences and obtained a doctor's degree From 2010 to 2011, he was an assistant researcher of Shanghai Institute of organic chemistry, Chinese Academy of Sciences From 2011 to 2015, he worked in the Scripps Research Institute in the United States as a postdoctoral researcher In 2015, he was selected as the Sixth Batch of experts of "youth millennium plan" of the central organization department Since 2015, professor and doctoral supervisor of School of chemistry and molecular science, Wuhan University We are interested in the efficient synthesis of active natural products and drug molecules, as well as the related synthesis methodology, chemical biology and pharmaceutical chemistry The aim is to create a novel synthesis methodology for rare and complex active natural products and drug molecular weight with important value, and develop an efficient and practical total synthesis route on this basis, so as to lay a solid material foundation for further chemical biology and drug chemistry research Leading scientific research achievements: the development of a new catelani reaction with epoxy as alkylating agent is a kind of catalytic synthesis method for the preparation of polysubstituted aromatic compounds In this reaction, palladium and norbornene or their derivatives were used to catalyze the functionalization of the C-H bond in the ortho position of iodoaromatic, and the substitution of the C-I bond in the base position was used to terminate the reaction With the efforts of the founders, Professor catelani, Professor lautens and many research teams, the connotation of the response system has been enriched In recent years, most of the research work has focused on the research and development of C-I bond termination agent in order to expand the application of the reaction in synthesis, while the development of C-H bond functional reagent is relatively weak (Figure 1) Figure 1 catelani reaction (source: angelw Chem Int ed.) in response to the challenge of catelani reaction development, Professor Zhou qianghui, School of chemistry and molecular science, Wuhan University, creatively developed epoxy compounds as alkylation reagents, greatly expanding the scope of application of the reaction In this work, low-cost and easy to obtain iodine substituted aromatic compounds, epoxy compounds and electron deficient olefins are used as raw materials Through screening, the optimal reaction conditions were selected, with palladium acetate as catalyst, xphos as ligand, norbornenate as cocatalyst and base, N-methylpyrrolidone as solvent Finally, the template reaction product was obtained in 91% yield (Figure 2) After that, the group studied the role of each component in the reaction system through comparative experiments, and confirmed that palladium acetate, ligand xphos and cocatalyst norbornene (N2) were essential for the reaction It is worth mentioning that the experiment and template reaction of norbornene (cocatalyst) and cesium acetate (base) instead of potassium norbornene have achieved the same results, which shows that potassium norbornene plays a dual role of cocatalyst and base in the reaction system The use of cheap and easily available norbornenate potassium not only provides an advantage in the cost of the reaction, but also makes the reaction system more convenient in the subsequent purification because of its washable characteristics in the subsequent treatment process Fig 2 template reaction (source: angelw Chem Int ed.) this work has investigated the application scope of aromatic iodide, epoxide and unsaturated olefin successively The experimental results show that a series of aryl iodides with different substituents can participate in the reaction well and produce corresponding products in medium to excellent yields More importantly, the catalytic system can be applied not only to acrylate, but also to acrone, acrolein, acrylonitrile, acrylamide, vinyl sulfone and simple styrene compounds (Fig 3) Figure 3 substrate development of aryliodide and olefin compounds (source: angelw Chem Int ed.) in addition, the catalytic system is also very compatible with epoxy compounds of different structures For the optically pure epoxy compounds, the stereostructure is not affected in the reaction process and can be completely maintained In addition, epoxy compounds derived from some complex natural products (gibberellin, estrone, and cholic acid) can also obtain the target products with good to excellent yields It is worth noting that the reaction also has very good chemical selectivity, other functional groups such as: hydroxyl, ketone, ester, lactone and so on are not affected After that, the author also introduced the epoxy structure and double bond into the same compound, designed and synthesized a kind of bifunctional substrate, and successfully applied it to the reaction system (4O ″ and 4P ″), which provided a new idea for the synthesis of macrocyclic compounds (Figure 4) Fig 4 substrate development of epoxy compounds (source: angelw Chem Int ed.) the method has the advantages of simple operation, mild reaction conditions, cheap and easy to obtain raw materials, high atomic economy and easy to enlarge operation (gram level preparation) In addition, the obtained product is a very useful intermediate, and an important pharmacophore isochroman structural unit can be obtained by one step transformation, thus providing a new strategy for the synthesis of many bioactive natural products and drug molecules At present, this method has been successfully used to synthesize the core structure of the analogues and the natural product penicillinolf of the leading drug molecular sonopiperazole (u-101387) (Figure 5) Fig 5 gram level experiment and synthetic application (source: angelw Chem Int ed.) the research work was supported by the "overseas talent introduction project" of Wuhan University, the "youth thousand talents plan" of the Central Organization Department, the "national key R & D plan" and the innovation team of Wuhan 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.