Liao Jian, research group, Chengdu Institute of biology, Chinese Academy of Sciences: Bi one "sulfur" -- palladium catalyzed asymmetric carbonyl thioesterification of olefins promoted by chiral SOP ligands

Intercarboxylation of olefins is an effective way to obtain high value products from cheap and easily available raw materials in industry, and it is one of the organic synthesis reactions of green economy The research on this kind of reaction is mainly focused on regioselective regulation, and the reaction usually needs to be carried out under the harsh conditions of high temperature and high pressure How to achieve regioselectivity and high enantioselectivity is still a big challenge, with only a few successful cases As a special kind of olefin intercarboxylation sulfur esterification, the asymmetric intercarboxylation sulfur esterification is more challenging due to the free radical and toxic metal characteristics of mercaptan or thiophenol Therefore, it is of great theoretical significance and application prospect to develop a new catalytic asymmetric system for the synthesis of chiral thioesters with high enantioselectivity and high efficiency under mild conditions Recently, the research group of Liao Jian, researcher of Chengdu Institute of biology, Chinese Academy of Sciences, has made a new breakthrough in this research field By using the chiral sulfur-containing SOP ligands developed by their research group, the efficient asymmetric conversion of mercaptan to olefin has been realized The relevant achievements have been published on angelw Chem Int ed (DOI: 10.1002 / anie 201905905) Brief introduction to the research group of liaojian researcher since its establishment, the research group has been devoted to the design of chiral sulfoxide ligands and the research of asymmetric methodology of metal catalysis, and has established a distinctive research direction The asymmetric conjugation addition, asymmetric allyl substitution, bifunctionalization of asymmetric alkenes and hydrogen functionalization of asymmetric alkenes catalyzed by transition metals such as rhodium, copper and palladium promoted by chiral sulfoxide ligands have been realized, and many papers have been published in international first-class chemical journals such as J am Chem SOC., angel Chem Int ed., chem SCI Brief introduction to researcher Liao Jian, Ph.D., researcher and doctoral supervisor of Chengdu Institute of biology, Chinese Academy of Sciences He graduated from the Department of Applied Chemistry, Shanghai Jiaotong University in 1994, and obtained his doctorate in science from Chengdu Institute of organic science, Chinese Academy of Sciences in 2002 From 2003 to 2006, he worked as a postdoctoral fellow in the Department of materials and chemistry of Pennsylvania State University in the design and performance of conductive polymer and elastomer materials and asymmetric catalytic hydrogenation After returning to China in February 2006, he was employed as a researcher of Chengdu Institute of organic science, Chinese Academy of Sciences and vice director of Sichuan Key Laboratory of asymmetric synthesis and chiral technology Transferred to Chengdu Institute of biology, Chinese Academy of Sciences in September 2010 In 2012, it was selected into Sichuan thousand talents plan Currently, he is the director of natural products research center of Chengdu Institute of biology, Chinese Academy of Sciences, member of Academic Committee of Chengdu Institute of Biological Sciences, member of professional degree training Steering Committee of Chinese Academy of Sciences, member of Academic Committee of Sichuan transformation medical research hospital, Chinese Academy of Sciences, and member of the second drug safety expert committee of Sichuan Province Mainly engaged in the design of chiral ligands, asymmetric catalysis and the synthesis of natural products He has published more than 40 academic works in international core academic journals (including J am Chem SOC., angelw Chem Int ed., chem SCI., org Lett., etc.), and has obtained and applied for nearly 10 invention patents Frontier research achievements: asymmetric carbonylation of olefins catalyzed by palladium promoted by "double one sulfur" - chiral SOP ligands has attracted the attention of academia and industry due to its perfect atomic economy and easy availability of raw materials After decades of development, the research on the catalytic system and mechanism of olefin hydroesterification has become mature At present, the industrial conversion with an annual output of one million tons has been realized However, there are relatively few studies on asymmetric intercarboxylation, and only a few successful cases Such reactions usually need high temperature and high pressure conditions, so it is difficult to control the regioselectivity and enantioselectivity of the reactions at the same time As a special kind of olefin intercarboxylation, i.e sulfur esterification, because mercaptan or thiophenol is easy to produce free radicals and poison metals, asymmetric intercarboxylation sulfur esterification is more challenging So far, only one case of asymmetric intercarboxylation sulfur esterification of conjugated diene has been reported (Fig 1a, completed by W J Xiao and Alper) Figure 1 Palladium catalyzed asymmetric carbonylation of olefins (source: angelw Chem Int ed.) based on the research accumulation of the research team in the field of olefin asymmetric functionalization (j.am Chem SOC 2015, 137, 13760; angelw Chem Int ed 2016, 55, 13854; Acta chimica Sinica 2017, 75, 794; ACS catalyst 2017, 7, 2425; org Lett 2018 , 20, 1346; org Lett 2019, 21, 3913) Liao Jian's research team envisions whether the chiral sulfoxide phosphine (SOP) ligands developed by the research team can be used to realize palladium catalyzed asymmetric carbonylation of olefins under mild conditions (Fig 1b) After screening a series of reaction conditions with styrene as the substrate, the researchers found that the reaction can be carried out well when using electron rich dialkylsulfoxide phosphine ligand (SOP), especially when using cyclopentanylsulfoxide phosphine ligand (L2), the reaction can obtain excellent NMR yield (96%) and enantioselectivity (95% ee) (figure 2) Fig 2 Optimization of palladium catalyzed asymmetric intercarboxylation of styrene (source: angelw Chem Int ed.) in order to improve the operational safety of the reaction, the research team used molybdenum hexacarbonyl as a substitute for carbon monoxide, and adopted a two chamber reaction system to evaluate the reaction by preparing carbon monoxide on site The results show that under this condition, the reaction can be carried out well, and 88% separation yield and 90% enantioselectivity can be obtained (Fig 3) Fig 3 Co substitution for palladium catalyzed asymmetric intercarboxylation of styrene (source: angelw Chem Int ed.) based on the optimal conditions, the research team investigated the substrate range (Fig 4) All kinds of styrene with different functional groups in para and meta position can obtain high yield and excellent enantioselectivity by palladium catalyzed asymmetric thioesterification of aromatic olefins promoted by SOP (L2) Because of the steric hindrance, the enantioselectivity of the reaction will be reduced The chiral thioester compound 3oa obtained by the reaction of substrate 3O has good yield and high enantioselectivity Although norbornadiene has medium yield, its selectivity is low It is interesting to note that both (E) - and (z) - β - methylstyrene produce thioester 3YA with the same configuration, which indicates that the stereochemical orientation is mainly due to the presence of benzene ring The chemical selectivity of allylbenzene and 1-octene is poor Other alkenes, such as vinyl heteroaromatics, inactive internal alkenes, ethyl acrylate and vinyl acetate, are not active in this system Next, the team tried to use other mercaptans or thiols for reaction (Figure 4b) It is gratifying to note that under the optimal conditions, except benzyl mercaptan, primary, secondary alkyl mercaptan and aryl mercaptan can be easily converted into corresponding thioesters with good yield and high enantioselectivity The conversion of tert butyl mercaptan and 2-naphthalene mercaptan with high steric hindrance is low, but the enantioselectivity is high Figure 4 Substrate range investigation and molecular modification (source: angelw Chem Int ed.) later, the research team studied the practicability of the reaction Firstly, the group modified the bioactive molecules and cysteine dipeptide with this method (Fig 4C) It is gratifying that the yield and stereoselectivity of the target thioester compounds are satisfactory by this method, and this method has been successfully applied to the binding of two bioactive parts (3H) Secondly, the research group transformed the chiral thioester compounds (Fig 5), successfully realized the gram level synthesis of (R) - ibuprofen and the synthesis of α - chiral ketone Figure 5 Product transformation (source: angelw Chem Int ed.) the research team did not stop here Next, a series of studies were carried out on the reaction mechanism First, the kinetic experiments were carried out The results show that the reaction process is zero order relative to the substrate and one order relative to the catalyst The results of 31P spectrum analysis showed that only electron rich alkyl SOP could form a relatively stable complex in this system, and p-toluenesulfonic acid (TsOH) played an important role in the formation of PD ii-h The controlled deuterium experiment showed that PD ii-h was derived from p-methylbenzenesulfonic acid, and TsOH participated in the catalytic cycle as a proton shuttle The single crystal structure of ipr-sop (L1) / PdCl2 reveals the coordination mode of PD and SOP ligand, which indicates that Pd atoms coordinate with s and P atoms to form a stable 5-membered ring complex DFT calculation shows that there is an energy difference of 2 kcal / mol between the transition state ts2-3a and ts2-3b, which makes the chiral PD ii-h species more favorable to attack from the re surface of styrene (Fig 6) to obtain the R-configuration product Figure 6 DFT calculation - the surface selectivity of chiral PD ii-h species to styrene (source: angelw Chem Int ed.) based on the above mechanism study, the team proposed the following possible reaction mechanism (Figure 7) First, PD 2 DBA 3 is complexed with the alkyl SOP ligand to form PD species a with zero valence This species generates PD ii-h species B by oxidation addition of TsOH, then forms C by coordination with styrene, then forms species d by insertion of PD ii-h into styrene, and then forms acyl PD species e by CO insertion The sulfur atom of mercaptan is then coordinated with PD to form intermediate F, which releases protons and regenerates TsOH Finally, the intermediate f was eliminated by reduction, and the target product was regenerated to form palladium species a Figure 7 Mechanism circulation diagram (source: angelw Chem Int ed.) was recently published on angelw Chem Int ed (10.1002 / anie 201905905) The authors of this paper are: Xihong Wang (Wang Xihong), Bing Wang, Xuemei Yin, Wangzhi Yu, Yang Liao, Jialin ye, min Wang, Lianrui Hu and jianliao The above research work has been funded by NSFC, the biological resources project of Chinese Academy of Sciences and the science and Technology Department of Sichuan Province 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