Deng Weiping, Professor of East China University of science and technology, project team: palladium catalyzed asymmetric [4 + 3] cycloaddition of trimethylene methane to construct chiral fused azadiazepines

The lead azatrel skeleton is widely found in a variety of drug molecules and natural active compounds, and its efficient synthesis has been one of the most important research hotspots in organic synthesis and innovative drug research As one of the most direct and efficient means to construct the seven membered ring framework, the [4 + 3] cycloaddition reaction has an important application in the field of modern organic synthesis However, the efficient synthesis of chiral azadiazepines based on catalytic asymmetric [4 + 3] cycloaddition reaction has been an important challenge in this field Recently, Professor Deng Weiping's research group of East China University of science and technology has made a new breakthrough in palladium catalyzed asymmetric [4 + 3] cycloaddition of trimethylene methane (angelw Chem Int ed 10.1002 / anie 201909158) Brief introduction of Professor Deng Weiping's research group: Professor Deng Weiping's research group has been committed to the research of catalytic asymmetric synthesis Through the design of new chiral catalysts and ligands and the development of new catalytic asymmetric synthesis methods, it provides efficient and convenient methods for the asymmetric synthesis of structural important chiral molecules and chiral drugs, and has achieved a series of research results（ J Am Chem Soc 2010 , 132 , 17041-17044; Angew Chem Int Ed 2011 , 50 , 4897-4900;
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Professor Deng Weiping, Professor Deng Weiping, Professor of School of pharmacy, East China University of science and technology, doctoral supervisor, vice president of School of pharmacy In 2000, he received the doctor of Science degree from Shanghai Institute of organic chemistry, Chinese Academy of Sciences, and his tutor was academician Dai Lixin From 2000 to 2003, he conducted postdoctoral research in the National Institutes of health and the Department of chemistry, University of Rochester At the end of 2003, he joined s * bio, a new drug research and development company in Singapore, to carry out the research and development of small molecule anti-cancer drugs In August 2005, he was employed in the school of pharmacy, East China University of science and technology After returning to China, he has won a series of honors and titles, including: Shanghai Pujiang talent (2006), Ministry of Education New Century Excellent Talent (2007), Shanghai Yucai Award (2007), Shanghai Shuguang talent (2009), Shanghai returned overseas Chinese and family members of overseas Chinese advanced individual (2010) and Dongyue Tianding award, etc He also served as a member of the teaching guidance sub committee of pharmaceutical specialty of the Ministry of education, a member of the pharmaceutical chemistry special committee of Shanghai Pharmaceutical Association, and a editorial board member of China pharmaceutical industry journal It has successively undertaken more than ten research projects, including the National Natural Science Foundation of China and key projects of basic research in Shanghai More than 90 SCI papers have been published in international core journals such as J am Chem SOC.; angel Chem Int ed.; ACS catalyst.; chem Commun.; org Lett.; chem EUR J Brief introduction to Yang Wulin, associate researcher, doctor, specially employed associate researcher Born in October 1989, graduated from East China University of science and technology in July 2012 with a bachelor's degree, and obtained a doctor's degree from East China University of science and technology in September 2017, tutor: Professor Deng Weiping From September 2016 to August 2017, he was jointly trained in Rutgers University by NSFC From October 2017 to December 2019, he was engaged in postdoctoral research in the school of pharmacy, East China University of science and technology, and his co tutor was Professor Li Zhong In December 2019, he stayed in school as a specially appointed deputy researcher At present, as the first author or corresponding author, he / she is in the international core journal, angelw Chem Int ed., ACS catalyst., chem Commun., org Lett., chem EUR J, Adv synth Catalyst Et al Published nearly 20 SCI papers; in 2017, he was funded by the daily work of postdoctoral in Shanghai, and in 2018, he was selected into the "science and technology innovation action plan" Youth Science and technology talents sailing plan of Shanghai As the project leader, he presided over the youth program of NSFC (2019), the 12th batch of special grants of NSFC and 63 A number of research projects have been approved, such as general funding, the exploration and research fund of the Ministry of education for basic research business fees, etc Leading scientific research achievements: palladium catalyzed asymmetric [4 + 3] cycloaddition of trimethylene methane (TMM), as an important all carbon 1,3-dipoles, has been widely used in the synthesis of cyclopentane, five membered heterocycles and natural products However, due to the existence of adverse entropy and ring tension, there are few reports about the [4 + 3] cycloaddition reaction, especially the catalytic asymmetric [4 + 3] cycloaddition reaction Considering the important value of azadiazepines in the synthesis of natural products and the research of innovative drugs, Professor Deng Weiping's research group envisages that using orange ketimine as azadiene to realize palladium catalyzed asymmetric [4 + 3] cycloaddition reaction of trimethylene methane, and efficiently construct a series of new structured chiral fused ring azadiazepines However, to realize the above idea, the following key problems need to be solved: (1) the problem of selective control of [4 + 3] and [3 + 2] cycloaddition regions in the reaction process; (2) the problem of control of enantioselectivity and non enantioselectivity in the reaction process (Figure 1) Fig 1 The [4 + 3] cycloaddition of trimethylene methane and neroleimine (source: angel Chem Int ed.) through the optimization of reaction conditions, finally with excellent yield (84% - 98%), highly specific regional selectivity and excellent non enantioselectivity and enantioselectivity (9:1 - > 20:1 Dr, 94% - > 99% ee) achieved the asymmetric [4 + 3] cycloaddition reaction of two kinds of trimethylene methane with different substituents (imino, cyano) and orange ketimine, and constructed a series of benzofuran azadiazepines with various substituents (40 cases) It is worth noting that the cycloaddition products of CIS and trans configuration are obtained from the imino and cyano substituted trimethylene methane substrates, respectively This discovery also provides a new idea for stereodiversity synthesis (Fig 2) Fig 2 Substrate application range of palladium catalyzed asymmetric [4 + 3] cycloaddition reaction of trimethylene methane (source: angelw Chem Int ed.) subsequently, the practicability of the reaction was studied A gram scale-up reaction (Fig 3a) can be achieved with 3 mol% catalyst dosage The yield of [4 + 3] cycloaddition product 3AA can still be obtained with 96% yield and excellent stereoselectivity (> 20:1 Dr, 97% ee) The product is free of benzophenone protecting group under the action of dilute hydrochloric acid, and then p-toluenesulfonyl group is further removed under the condition of hydrobromic acid / phenol, and then the exposed amino substituted benzofuranzazezhuo compound 7 is obtained, and the EE value is as high as > 99% (Fig 3b) Figure 3 Gram scale reaction and product transformation (source: angelw Chem Int ed.), in addition, the transition state model of the reaction was further studied When investigating the non-linear relationship between the EE value of ligand L1 used in the reaction and the EE value of product 3AA, it was found that there was a positive non-linear relationship between the EE value of ligand and the EE value of product 3AA in the reaction Combined with the previous research of Trost research group, the author proposed that there was a ml 2 type catalytic active complex in the reaction (FIG 4A) Based on this, a possible transition state model is proposed to explain the stereoselectivity in the reaction (Fig 4b) Figure 4 Research on reaction transition state (source: angelw Chem Int ed.) In recent years, the results are as follows: "palladium catalyzed asymmetric [4 + 3] cyclization of trimethylenemethane: regio -, diastereo -, and enantioselective construction of Benzofuro [3, 2-B] azepine skeletons "was published in angew Chem Int ed (DOI: 10.1002 / anie 201909158) The first author is Dr Liu Yangzi, and the corresponding authors are Professor Deng Weiping and Dr Yang Wulin (thesis authors: Yang Zi Liu, Zhongao Wang, Zesheng Huang, Xing Zheng, Wu Lin Yang, * and Wei Ping Deng *) The research was supported by NSFC (21772038), Shanghai Youth Science and technology talent development program (18yf140560), China Postdoctoral Science Foundation (2018m632037) and the exploration and Research Fund for basic scientific research business expenses of the Ministry of education It should be noted that almost at the same time, Professor Trost of Stanford University and Professor Shao Zhihui of Yunnan University reported similar palladium catalyzed asymmetric [4 + 3] cycloaddition of trimethylene methane (angelw Chem Int ed 2019, 10.1002/anie.201911537; chin J chem 2019, 37, 10.1002/cjoc.201900430) 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.