Research group of you Shuli, Shanghai Institute of organic chemistry: palladium catalyzed asymmetric isopentenylation and dearomatization of indole derivatives

Lead isoamylation is an important process in vivo Many natural products with physiological activities have isoamyl groups, such as artemisinin, taxol, cholesterol and other terpenoids In addition, isopentenyl can also be embedded in small metabolites such as indole under the catalysis of enzyme to obtain some alkaloids with isopentenyl substituted pyrrole and indoline structure (Fig 1) However, the new chiral center usually depends on the chiral natural tryptophan substrate, and the scope of the substrate is limited due to the specificity of enzyme catalytic reaction Therefore, it is of great significance to develop new catalytic asymmetric methods to construct organic compounds with isopentenyl structure with high efficiency and enantioselectivity Recently, the research group of youshuli researcher of Shanghai organic Research Institute has made a new breakthrough in this field (nature catalyst 2018, 1, 601 – 608) Figure 1 Brief introduction of youshuli research group of some important natural products (source: nature Catalysis) containing isopentenyl ）With the development of the reaction, the strategy can simply and efficiently convert the plane aromatic compounds from a wide range of sources, which are cheap and easy to obtain, into complex chiral molecules with three-dimensional structure (angelw Chem Int ed 2012, 51, 12662; Chem 2016, 1, 830) Brief introduction of researcher you Shuli, researcher of State Key Laboratory of organometallic chemistry, Shanghai Institute of organic chemistry, Chinese Academy of Sciences Graduated from Nankai University in 1996 with a bachelor's degree In 2001, he received his Ph.D from Shanghai Institute of organic chemistry, under the guidance of academician Dai Lixin, a famous organic chemist in China From 2001 to 2004, he was engaged in postdoctoral research at the Scripps Research Institute, and his co tutor was Professor Jeffery W Kelly From 2004 to 2006, he worked as a researcher in the GNF Institute of the United States Since 2006, he has worked in Shanghai Institute of organic chemistry, Chinese Academy of Sciences Now, he is the director of the State Key Laboratory of metal organic In the same year, he was selected into the "hundred talents plan" of Chinese Academy of Sciences Researcher you Shuli has published more than 230 papers in high-level magazines such as JACS, angel Chem Int ed., nature catalyst., chem, etc., and his published papers have been cited more than 13000 times, with an H-index of 68 (until September 2018) His main awards include: Merck prize (2015) of the Royal Society of chemistry, he Liang and he Li fund Youth Innovation Prize (2016), the second batch of national "ten thousand talents plan" leading talents (2016), the second prize of National Natural Science (the first adult, 2017), the Novartis chemistry partnership (2018), etc Leading research achievements: palladium catalyzed asymmetric isopentenyl dearomatization of indole derivatives; organic chemists have always been interested in the synthesis of isopentenyl containing molecules due to their special biological activities and interesting structures However, the methods reported in the literature to construct such molecular structure always need multi-step transformation, and the synthesis efficiency is low Inspired by the enzyme catalyzed aromatization of isopentenyl, and a series of pioneering work in the early stage of asymmetric aromatization of indole derivatives (chem SCI 2014, 5, 1059; chem SCI 2015, 6, 4525), the research group of youshuli researcher thought whether it could be achieved through catalytic asymmetric aromatization (Cada ）A series of pyrrolidindoline alkaloids containing isopentenyl substitution were constructed However, compared with the common allylic substrate, isopentenyl shows more prominent steric effect, which leads to the lower activity of the corresponding π - allylic metal species, and the more difficult to control the selectivity of the reaction The research team initially tried to find that Trost, BINAP, phox and other ligands commonly used in allylic substitution reactions could not achieve satisfactory results; further research found that the use of carreira ligands can achieve medium yield (63%) and enantioselectivity (57% ee) As a breakthrough, our group designed and synthesized a series of new p-olefin ligands After optimizing the reaction conditions, we found that allylphos, a new developed p-olefin ligand, can promote the reaction to obtain excellent yield and enantioselectivity The substrate used in this method is simple and easy to obtain, which greatly widens the range of substrates for asymmetric isopentenyl dearomatization reaction The reaction can be enlarged to gram scale, and the amount of catalyst can be reduced to five thousandths (Fig 2) Figure 2 The substrate range (source: nature Catalysis) of palladium catalyzed asymmetric isopentenylation of indole derivatives Subsequently, the research team studied the practicability of the reaction Natural products such as (- - flustramine B, pseudophrynanol and mollenine a can be synthesized from isopentenyl products by simple conversion in several steps, which greatly shortens the synthesis steps of such natural products (Fig 3) The team also found that the use of dipeptide substrate 15 can produce a series of isopentenyl dearylation / lactonization reaction in one step, and can efficiently synthesize mollenine A and all its non enantiomers on a gram scale, and correct the wrong judgment of the structure of the natural product in the previous literature Using this method, a series of mollenine a analogues can be synthesized in one step, among which 18F and 18K are the biosynthetic precursors of some natural products with important physiological activities, fumitremorgin B, verruculogen and driventine a, which are of great significance for the synthesis of such alkaloids (Fig 4) Fig 3 Total synthesis of (-) - flustramine B, pseudophrynanol and mollenine a (source: nature catalyst is) Fig 4 Palladium catalyzed one-step synthesis of molleninea analogues (source: nature catalyst is) the research team did not stop at this point In the process of optimizing reaction conditions, they found that excessive palladium precursors were used It can promote the reaction, and the olefins in the newly developed ligand allylphos are also crucial to the reaction, so they conducted in-depth study on the mechanism of the reaction (Fig 5) The nonlinear effect experiment shows that the active catalytic species of the reaction only contains a single chiral ligand, and the cultivation of the complex single crystal proves that both C1 and C2 can catalyze the reaction The team also studied the kinetics of the reaction The results show that the excessive palladium precursor can greatly promote the reaction speed and avoid the induction period in the process of using a single complex C2 as catalyst Combined with these experimental results, they proposed that the active catalytic species of the reaction is the complex C3 of allylphos with palladium and olefin at the same time Figure 5 Research on reaction mechanism (source: naturecatalysis) was recently published on nature Catalysis (nature catalysis 2018, 1, 601 – 608) The authors of this paper are: Hang Fei Tu, Xiao Zhang, Chao Zheng, min Zhu and Shu Li you The above research work was supported by the Ministry of science and technology, the National Natural Science Foundation of China and the strategic leading science and technology program of the Chinese Academy of Sciences (category B) 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, 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.