Research group of Professor Kong Wangqing of Wuhan University: nickel catalyzed asymmetric reduction coupling reaction for the construction of 2,3-Fused cyclopentyl indoline

Introduction olefins are cheap and easy to obtain, and also easy to prepare, which are important chemical raw materials The transition metal catalyzed bifunctional reaction of olefins can introduce two different functional groups into the double bond at the same time through one step operation, so as to efficiently construct complex and valuable compounds with chiral centers It is one of the important chemical reactions in the field of organic synthesis Great progress has been made in the oxidation of olefins Professor Sharpless won the Nobel Prize in chemistry in 2001 for his asymmetric epoxidation Different electrophilic reagents can be introduced to both sides of the double bond simultaneously in the reduction of olefins, without the need to prepare organometallic reagents in advance, so it has better functional compatibility than the classic "oxidation-reduction neutral" reaction of olefins But controlling the region and stereoselectivity of the reaction is a challenging task The team of Kong Wangqing, Professor of Wuhan University, used cheap nickel as catalyst to realize the high stereoselective reduction of alkenes for the first time (j.am.chem.soc 2018, 140, 12364-12368) Based on the asymmetric reduction of alkenes with bifunctional groups, the research team also found the high regioselective and stereoselective reduction cyclization of aryl bromide with alkyne bromide or internal alkyne, and the related results were published in ACS catalyst (ACS catalyst 2019, 9, 7335-7342) Asymmetric reduction of alkenes with bifunctional reaction (source: Professor Kong Wangqing research group) introduction of Professor Kong Wangqing research group the research group was founded in September 2017 Since its establishment, it has been committed to the asymmetric catalytic reaction of cheap transition metal nickel and the efficient synthesis of bioactive natural products and drug molecules Over the past two years, the research group has published 9 papers in J am Chem SOC., angew Chem Int ed., ACS catalyst., org Lett And other internationally renowned academic journals Many papers have been introduced by synfacts, organic chemistry and other journals as highlights Introduction to Professor Kong Wangqing, Professor, doctoral supervisor, Institute of higher studies, Wuhan University From 2006 to 2011, he studied for his Ph.D at Zhejiang University under the guidance of Professor Ma Shengming, academician of the Chinese Academy of Sciences From 2011 to 2014, he joined the University of Zurich (UZH), Switzerland, and engaged in postdoctoral research His co tutor was Cristina Nevada From 2014 to 2017, he was engaged in postdoctoral research at the Federal Polytechnic University (EPFL) in Lausanne, Switzerland, and his co tutor was Jieping Zhu His main awards include: Baosteel outstanding student award (2009), Zhejiang outstanding graduate (2011), Zurich University postdoctoral Fund (2011), Novartis pharmaceutical postdoctoral Scholarship (2012) In 2017, he was selected into the "youth thousand plan" of the central organization department and joined the Institute of higher studies of Wuhan University full time to carry out independent scientific research Project team link: http://wqkong.whu.edu.cn/ frontier scientific research achievements: nickel catalyzed asymmetric reduction coupling reaction to construct 2,3- cyclopentanyl indoline 2,3- cyclopentanyl indole compounds are widely used in many synthesis or natural products, with a wide range of biological activities, such as Changchun flower base, Syringa oblata, cardamom base and theobromine (Fig 1) At present, many researchers have carried out a lot of research on this special structure However, their enantioselective preparation methods are still very limited Up to now, the strategy of constructing this tricyclic framework mainly depends on the [3 + 2] cycloaddition reaction between the functionalized indole derivatives and 1,3-dipoles Due to the diversity of structures of chiral cyclopentyl indoles in target molecules, it is still of great value to develop new synthesis strategies Fig 1 The representative natural product with cyclopentadienyindole ring (source: ACS Catalysis) the author envisages to realize the synthesis of 2,3-Fused cyclopentanyl indole compounds 3 through the series reaction of aryl bromide acrylamide 1 and alkynyl bromide 2 (Fig 2a) The author speculates that the possible catalytic cycle mechanism of the series reaction is shown in Figure 2B: first, arylbromoenamide 1 is oxidized and added with Ni (0), then the olefin is transferred and inserted into the molecule to obtain intermediate a; at the same time, arylalkyne bromine 2 is self coupled to generate 1,3-diyne 4, intermediate a and 1, At last, intermediate B was added to amide bond by intramolecular nucleophilic addition to obtain intermediate C, and the target product 3 and recyclable nickel species were obtained by protolysis Fig 2 Study on the synthesis of 2,3-Fused cyclopentyl indoles by nickel catalyzed series reaction (source: ACS Catalysis) The author optimized the reaction conditions with arylbromoenamide and phenylalkynyl bromide as substrates and NiCl2 (DME) as catalyst, and finally obtained a single configuration target product with a separation yield of 72% In order to explore the substrate adaptability of this series reaction, the author first uses arylbromoamide 2 with different electron donor and electron acceptor groups (such as methyl, methoxy, trifluoromethyl, halogen, etc.) For the substrate, we can get the three-way bicyclic products in medium yield; then, we can get 69% of the separation yield by reacting with different protective groups (such as benzyl) on nitrogen It is worth noting that when pyridine ring is used instead of benzene ring, the substrate can also adapt to the conditions, and the single crystal structure of the corresponding product can be obtained In addition, the author also found that the reaction can also be compatible with compounds with benzyl, phenyl and methoxymethyl groups on the alkenyl chain Finally, the author also examined various aryl and heterocyclic substituted alkynyl bromide 2, and also found that it has good functional group compatibility (Fig 3) The results show that the series reaction has a wide range of substrate adaptability Figure 3 Substrate application study (source: ACS catalyst) in order to better understand the reaction mechanism, the author also tried a series of control experiments (Figure 4) First of all, the author speculates that 5aa may be the intermediate of the reaction, but the target product 3AA has not been obtained under the standard conditions, so this possibility can be excluded (eq.1) In the experiment, the author found that alkyne bromide 2A can generate 1,3-diyne 4AA in situ in 70% yield by nickel catalysis, and then react with substrate 1a to obtain the target product 3AA, but the reaction time is longer than the standard conditions (eq.2, eq.3) Further experiments show that manganese bromide can accelerate the reaction (eq.4-6) In addition, the author also tried to add the previously reported complex 6 (J am Chem SOC 2018, 140, 12364-12368) to react with 1,3-diacetylene 4AA, and under the promotion of manganese bromide, the target product (Eq 8-10) with a yield of 74% was separated Figure 4 Mechanism research experiment (source: ACS catalyst) after a series of studies on the reaction mechanism, the author did not stop here They think that since diacetylene can participate in the reaction, in theory, internal alkynes should also be able to participate in the reaction The following experiments also prove the correctness of this conjecture It is gratifying that 2,3-Fused cyclopentyl indoles can be obtained with high regioselectivity (> 20:1) and stereoselectivity (82-96% ee) when chiral pyrox (L22) is used as the ligand In addition, a large number of functional group tolerance experiments have been carried out under standard conditions for different bromoenamide 1 and different internal alkyne 7 (Fig 5) Figure 5 Research on the application scope of substrate (source: ACS catalyst) was recently published on ACS catalyst (ACS catalyst 2019, 9, 7335-7342) The author of this paper is Yuanyuan Ping, Kuai Wang, Qipan, Zhengtian Ding, Zhijun Zhou, Ya Guo, and Wangqing Kong The above research work has been funded by the "1000 young talents plan", the National Natural Science Foundation and the basic research funds of 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 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.