Deng Weiping group of East China Science and technology: copper catalyzed asymmetric 1,3-dipolar cycloaddition to construct the framework of 3-azabicyclo [3.1.0] hexane with five consecutive chiral centers

As the basic structural unit of natural alkaloids and the preponderant framework of active drug molecules, lead chiral nitrogen-containing heterocycles are one of the most important research focuses in organic synthesis and innovative drug research The asymmetric 1,3-dipolar cycloaddition and Michael cycloaddition of ylide are important methods for the synthesis of chiral nitrogen-containing heterocycles and unnatural α - amino acids Deng Weiping, Professor of East China University of science and technology, has been committed to the catalytic asymmetric synthesis of novel chiral nitrogen-containing heterocycles and unnatural α - amino acids (angelw Chem Int ed 2011, 50, 4897-4900; org Lett 2011, 13, 6010-6013; org Lett 2015, 17, 4822-4825; org Lett 2015, 17, 4988-4991; org Lett 2018, 20, 3838-3842; Chem Eur J ., 2013 , 19 , 6739-6745; Chem Eur J 2015 , 21 , 10457-10465; Chem Eur J 2015 , 21 , 19048-19057; Chem Commun 2015 , 51 , 9212-9215; Catal Sci.Technol 2015 , 5 , 3568-3575; ACS Catal , 2016 , 6 , 652-656; ACS Catal , 2016 , 6 , 5685-5690; Org Chem Front ., 2017 , 4 , 52-56; Org Chem Front 2017 , 4 , 2343-2347; Org Chem Front 2018 , 5 , 70-74; J Org Chem., 2017 , 82 , 11141-11149; Adv.Synth Catal 2018 , 360 ,2191-2203; Adv Synth Catal 2018 , DOI: 10.1002/adsc.201800553 ）。 Recently, the research group has made progress in asymmetric construction of nitrogen-containing fused rings containing five consecutive chiral centers (DOI: 10.1021/acs.orglett.8b01686) Brief introduction to Professor Deng Weiping, Professor of East China University of science and technology, doctoral supervisor and vice president of School of pharmacy He graduated from Zhejiang Normal University in 1995 and obtained his Ph.D degree in science from Shanghai Institute of organic chemistry, Chinese Academy of Sciences in 2000 His tutor is 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 Singapore s * bio new drug research and development company to carry out the research and development of targeted 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 scholar (2009), Shanghai returned overseas Chinese and family members of overseas Chinese advanced individual (2010) 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 70 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 Translated "drug test" and "innovative drug discovery - practice, process and Outlook" Brief introduction to Dr Yang Wulin, doctor He graduated from East China University of science and technology in July 2012, and obtained his doctor's degree from East China University of science and technology in September 2017 His tutor is Professor Deng Weiping From September 2016 to August 2017, he went to Rutgers University for joint training under the support of NSFC During his doctorate, he won many honorary awards such as Shanghai excellent graduate (2017), national scholarship for postgraduate (2015) In September 2017, he received a doctor's degree and stayed in school Mainly engaged in asymmetric catalysis and synthesis of chiral drugs and intermediates As the first author or corresponding author in ACS catalyst., chem Commun., org Lett., chem EUR J, Adv.synth.catalyst And other international authoritative publications published more than 10 papers included in SCI; in 2018, he was selected into the Shanghai Youth Science and technology talents sailing plan, as the project leader, presided over one basic research business expense exploration research fund of the Ministry of education, one general project of China Postdoctoral Science Fund, and participated in many general projects of National Natural Science Fund Frontier research achievements: copper catalyzed asymmetric 1,3-dipolar cycloaddition to construct 3-azabicyclo [3.1.0] hexane framework with five consecutive chiral centers and 3-azabicyclo [3.1.0] hexane with bridgehead quaternary carbon chiral center as an important structural block widely exists in natural products and drug molecules However, there are few reports on the asymmetric catalytic construction of such skeletons with consecutive chiral centers Until recently, Cramer group successfully synthesized 3-azabicyclo [3.1.0] hexane skeleton (J am Chem SOC 2017, 139, 12398-12401) with three chiral centers by palladium catalyzed C-H activation / addition series reaction Therefore, it is still a major challenge to develop a more simple and efficient method to synthesize 3-azabicyclo [3.1.0] hexane framework with multiple chiral centers On the other hand, it is rarely reported that pyrrolidine containing two bridged quaternary carbon chiral centers was constructed by 1,3-dipolar cycloaddition of all substituted alkenes Recently, Professor Deng Weiping's research group of School of pharmacy of East China University of science and technology published a paper entitled "asymmetrical construction of 3-azabicyclo [3.1.0] hexaneskeleton with five consistent stereological centers by Cu catalyzed 1, In the paper of 3-dipolarcycloaddition of trisubstituted cyclopropenes, using Cu (I) / ph-phosferox as catalyst, 1-glycine ester Schiff base and trisubstituted cyclopropene were realized under mild conditions, 3-dipolar cycloaddition reaction provides a new efficient and simple method for the construction of multi substituted 3-azabicyclo [3.1.0] hexane skeleton compounds (Fig 1) Figure 1 Asymmetric synthesis of 3-azabicyclo [3.1.0] hexane skeleton (source: Organic letters) Firstly, the author optimized the reaction conditions (Table 1) The results show that the target product can be obtained in 97% yield and 99% ee value at 0 ° C with Cu (MeCN) 4bf4 / L6 complex as catalyst, CS 2CO3 as base and THF as solvent Table 1 Optimization of reaction conditions (source: Organic letters) In order to verify the universality of the reaction substrate, the type of glycine ester Schiff base was investigated first (Table 2) The change of ester group has no obvious effect on the reaction; the electron deficient, electron donating and neutral benzene ring can react smoothly; heteroaromatic aldehydes and glycine ester Schiff bases derived from low activity fatty aldehydes also show excellent tolerance Table 2 The type of glycine ester Schiff base (source: Organic letters) is closely followed by the type of prochiral cyclopropene (Table 3) Ester group, cyano group, amide and phenyl substituted cyclopropene can adapt to the reaction well, and electron deficient, electron rich benzene ring and methyl substituted cyclopropene also show excellent results Table 3 Type inspection of prochiral cyclopropene (source: Organic letters) To further verify the practicability of this method, the author used 1 mol% catalyst to enlarge the reaction to the scale of gram (3.0 mmol, figure 2a), and the ester group in the product can be reduced to hydroxyl group by LiAlH 4 (Figure 2b) By reducing the temperature and LiAlH 4 The amount of the single ester group can also be selectively reduced, and then GABA derivatives can be obtained by hydrolysis (Fig 2C) Figure 2 Gram scale reaction and product transformation (source: Organic letters) Summary: the research team developed Cu (I) / ph-phosferox catalyzed glycine ester Schiff base and trisubstituted cyclopropene 1, In the 3-dipolar cycloaddition reaction, the framework of 3-azabicyclo [3.1.0] hexane containing five consecutive chiral centers (two of which are quaternary carbon chiral centers) was constructed by using the desymmetry strategy The research results are mainly completed by Deng Hua, a doctoral student The corresponding authors of the paper are Professor Deng Weiping and Dr Yang Wulin The research was supported by the National Natural Science Foundation of China (21772038), the Shanghai Youth Science and technology talents' sailing plan (18yf140560), and the research fund for exploration of basic scientific research business expenses of the Ministry of education Professor Deng Weiping's group photo of the teacher and the graduate student about people and scientific research are increasingly valued in the economic life Today, China has ushered in the "node of the outbreak of science and technology" 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, chembeangoapp, 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.