Study group of Tang Wenjun, Shanghai organic Research Institute, Chinese Academy of Sciences: palladium catalyzed large steric asymmetric α - arylation and efficient synthesis of viololine and other natural products

There are many natural products and drug active molecular structures with the lead benzyl chiral quaternary carbon center structure However, the efficient synthesis of this kind of chiral skeleton has been a problem in organic chemistry Palladium catalyzed asymmetric α - arylation is a simple and ideal method for the synthesis of benzyl chiral quaternary carbon centers, but the existing synthesis methods still have great limitations, especially the reaction yield and stereoselectivity of aryl halides with large steric hindrance are not ideal, which limits the asymmetric α - aromatization- Aromatization is widely used in the synthesis of natural products and drug molecules Tang Wenjun, State Key Laboratory of life organic chemistry, Shanghai Institute of organic chemistry, Chinese Academy of Sciences, successfully applied chiral Bi dime ligands to palladium catalyzed large steric asymmetric α- In the aromatization reaction, a series of aromatic CYCLOKETONE derivatives with benzyl chiral quaternary carbon center structure and large steric hindrance were synthesized, and many natural products such as Corydalis were synthesized efficiently (angel Chem Int ed 2018, DOI: 10.1002/anie.201807302) Introduction to Tang Wenjun research group since its establishment in 2011, Tang Wenjun research group has been focusing on the development of efficient, economic and environmentally friendly asymmetric catalytic reactions, the realization of efficient synthesis of drugs and bioactive natural products, and the promotion of green drug manufacturing and new drug research and development In view of the challenging problems in the synthesis of drugs and natural products, the research team focused on the development of large resistance asymmetric coupling and green reduction technology through the design of novel and unique phosphine ligands and catalysts, striving to realize a series of green synthesis processes of drug molecules; and carried out the efficient synthesis research of natural products and their analogues with multiple structures, so as to provide the leading synthesis for new drug research Things Recently, the research team has developed new chiral ligands and large steric resistance asymmetric coupling to realize the efficient synthesis of various challenging chiral fragments, including axial chiral fragments (j.am Chem SOC 2014, 136, 570 − 573), chiral tertiary alcohols (angelw Chem Int ed 2015, 54, 2520-2524; angelw Chem Int ed 2016, 55, 4527-4531; angelw Chem Int.ed 2016, 55, 5044-5048), chiral tertiary borate (j.am Chem SOC 2015, 137, 6746-6749), chiral quaternary carbon center (angelw Chem Int ed 2015, 54, 3033-3037; j.am Chem SOC., 2017, 139, 3360-3363), and developed efficient aryl alkyl coupling (angelw Chem., int ed 2015, 54, 3792-3796; j.am Chem SOC 2016, 138, 10774-10777; angelw Chem Int ed 2018, 57, 7176-7180) and new asymmetric coupling mechanism (J am Chem SOC 2017, 139, 9767-9770) Brief introduction to researcher Tang Wenjun: Dr Tang Wenjun graduated from fine chemistry department of East China University of science and technology in 1995; master's degree from Shanghai Institute of organic chemistry, Chinese Academy of Sciences in 1998; doctor's degree from Pennsylvania State University in 2003; postdoctoral research in Scripps Institute in 2003-2005; Boehringer in 2005-2011 Ingelheim pharmaceutical company's Pharmaceutical Technology Department has successively served as senior scientist and principal scientist; since July 2011, he has served as a researcher and research team leader of Shanghai Institute of organic chemistry, Chinese Academy of Sciences; at the same time, he has also served as a professor, doctoral director of the school of materials, Shanghai University of science and technology and doctoral director of the school of pharmacy, East China University of science and technology In the past few years, a series of single and double tooth chiral phosphine ligands with unique structure have been developed In many reactions, the selectivity and efficiency problems that the existing ligands can not solve or can not solve well have been solved Twenty eight ligands, such as Bi dime, antphos and wingphos, have been realized in strem Commercialization and industrial application of the company; development of a number of challenging and practical asymmetric coupling and hydrogenation, which provides an efficient synthesis method for a number of chiral drug molecular blocks or large steric resistance chiral segments; use of the developed catalysts and synthesis methods to complete the efficient synthesis of a series of important bioactive natural products, which provides for biological research and new drug creation Material basis More than 70 papers have been published in famous international chemical journals; more than 5000 papers have been cited by others; more than 20 domestic and international patents have been obtained, and patents have been transferred for many times; in 2012, it was selected into the seventh batch of national "Thousand Talents Program" (Youth Program), and in 2017, it was funded by National Science Fund for Distinguished Young Scholars Leading scientific research achievements: palladium catalyzed asymmetric large steric hindrance α - arylation and efficient synthesis of corydalis and other natural products, also known as scorpion flower, heartbroken grass, poppy family plants, with the functions of heat clearing, detoxification, insecticidal and antipruritic Corynoline, the main component of Corydalis, is an acetylcholine inhibitor, which has significant sedative and anti leptospiral effects However, there are two kinds of enantiomers in the natural products, and there is still a lack of pharmacological research on optical pure corydalis One of the important reasons is the lack of efficient asymmetric synthesis method for optical pure corydalis In recent years, Tang Wenjun, State Key Laboratory of life organic chemistry, Shanghai Institute of organic chemistry, Chinese Academy of Sciences, has focused on the development of asymmetric cross coupling reactions with high steric resistance promoted by chiral monophosphonic ligands Based on the excellent activity and stereoselectivity of the chiral monophosphonic ligands in the large steric hindrance aryl coupling reaction, Dr Rao Xiaofeng, Dr Li Naikai and Mr Bai Heng of the research group successfully applied the chiral Bi dime ligands to the palladium catalyzed large steric hindrance α - arylation reaction under mild reaction conditions (80 ° C) and low catalyst dosage (1 mol%) ）A series of aromatic CYCLOKETONE derivatives with benzyl chiral quaternary carbon center structure and large steric hindrance were synthesized (Fig 1) Fig 1: PD Bi dime catalyzed asymmetric α - arylation with large steric hindrance (source: angelw Chem Int ed.) research team took asymmetric α - arylation as the main synthesis strategy Starting from simple and easily available raw materials, efficient asymmetric synthesis of (-) - Corydalis was realized by only five steps of reaction (Fig 2) Under the catalysis of PD - (s) - Bi dime, 5,6-methyleneacetaldehyde indenone 1 and aryl bromide 2 were coupled, and the chiral CYCLOKETONE 3 was prepared in 70% yield and 92% stereoselectivity Then, the piperidine ring was successfully constructed by two steps of free radical double Bromination and nucleophilic substitution with methylamine to form the polycyclic structure 5 The author successfully constructed 6 by a clever B ü chner - Curtius - schlotterbeck reaction, and finally successfully synthesized (-) - viololine by lah reduction In addition, the research team only prepared (- - den corynoline with the same important physiological activity in three steps, and synthesized the natural product (+ - scenetium A-4 in four steps This work will actively promote the efficient synthesis and pharmacological research of natural products and drugs with chiral quaternary carbon center structure Figure 2: highly efficient asymmetric synthesis of natural product (-) - Corydalis (source: angelw Chem Int ed.) This work was recently published in German Applied Chemistry (angelw Chem Int ed 2018, DOI: 10.1002/anie.201807302) Rao Xiaofeng, Li Naikai and Bai Heng are the co first authors, and Shanghai Institute of organic chemistry of Chinese Academy of Sciences is the first unit The research work has been greatly supported by NSFC, the strategic leading science and technology program of Chinese Academy of Sciences (class B), Chinese Academy of Sciences, Shanghai Science and Technology Commission and the State Key Laboratory of life organic chemistry 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.