Chen Gong and he gang of Nankai University: palladium catalyzed asymmetric carboboration of nonactivated olefins induced by a novel monodentate oxazoline ligand

Introduction: the traditional olefin functionalization reaction mainly involves the reaction of activated olefin substrate and organometallic reagent, which greatly limits the tolerance of functional groups and the application scope of substrate In recent years, transition metal catalyzed non activated olefin functionalization has developed rapidly, and a series of olefin hydrogenation functionalization and bifunctional reactions have been realized However, the asymmetric conversion of this kind of reactions is still very challenging Therefore, it is of great significance to develop new chiral ligands to realize the asymmetric conversion of this kind of reactions Recently, Chen Gong and He Gang group of Nankai University have successfully developed a new generation of monodentate oxazoline chiral ligands (moxca) derived from serine, which have been successfully applied to the asymmetric carboboration and amination of non activated olefins, It provides a new strategy for the asymmetric functionalization of nonactivated olefins, and expands the application scope of mono dentate oxazoline ligands in asymmetric reactions The related research results are published in ACS catalyst (DOI: 10.1021 / acscalal 9b01350) Chen Gong and He Gang project team of Nankai University Chen Gong and He Gang project team were founded in 2015 and are affiliated to the school of chemistry and the State Key Laboratory of elemental organic chemistry of Nankai University At present, the team has 1 postdoctoral researcher, 12 doctoral students and 13 master students The team has long been committed to the research of organic synthesis, chemical biology and organic synthesis methodology of complex glycopeptides (focusing on transition metal and nonmetal catalytic activation of hydrocarbon bond), and has made a series of breakthrough research progress since its establishment, successively in NAT Chem., NAT Catalyst., j.am Chem SOC., angel Chem Int ed, More than 30 papers were published in high-level magazines such as acc.chem.res The homepage of the research group: http://gongchenlab.com introduction to Professor Chen Gong, graduated from the Department of chemistry of Nanjing University in 1998, and obtained the doctor's degree of bioorganic chemistry from the Department of chemistry of Columbia University in 2004 In 2005-2008, he worked in Sloan Caitlin cancer research center of the United States as a postdoctoral researcher Since 2008, he has independently carried out teaching and research work in the Department of chemistry, Pennsylvania State University, and obtained tenure in 2014 Since 2015, he has worked full-time in the State Key Laboratory of elemental organic chemistry of Nankai University as a professor and doctoral supervisor Professor Chen Gong is mainly engaged in the research of organic synthesis and chemical biology of complex glycopeptide compounds He has published more than 70 academic papers on the academic journals such as nat.chem., NAT Catalyst., J am Chem SOC., angel Chem Int ed., acc chem Res It has won us-nsfcareer award, Amgen Young Investigator Award, Wuxi apptec Life Chemistry Research Scholar Award, acplectrureship award and National Foundation Committee outstanding youth fund and other awards Brief introduction to researcher He Gang, graduated from the school of chemistry, Nankai University in 2003-2009, and obtained a doctor's degree from Shanghai Institute of organic chemistry, Chinese Academy of Sciences; 2010-2014, engaged in postdoctoral research at Pennsylvania State University; 2015 Since, he has been working full-time in the State Key Laboratory of elemental organic chemistry of Nankai University, serving as a specially hired researcher and doctoral supervisor The research fields mainly include organic synthesis methodology, hydrocarbon bond activation, complex natural product synthesis and so on Leading scientific achievements: palladium catalyzed asymmetric carboboration of non activated olefins induced by a novel monodentate oxazoline ligand is one of the most important chemical raw materials in organic synthesis chemistry Olefin functionalization can be used to construct a series of complex functional organic molecules succinctly and efficiently, which are widely used in the production of various chemicals that people need Therefore, the functionalization of olefins has always been a hot topic in organic chemistry Among the many functional group conversion reactions of olefins, transition metal catalyzed asymmetric functional group reaction of olefins undoubtedly has greater application value However, most of the reactions reported in the literature are asymmetric functionalization of α, β - unsaturated carbonyl compounds, olefins with ring tension, dienes, styrene and conjugated dienes The asymmetric functional group reaction of non activated olefins is still a challenging topic In recent years, based on the strategy of guiding group assisted transition metal catalytic activation of olefins, researchers have successfully realized a series of single / bifunctional reactions of non activated olefins, solving the problems of olefin activity, chemical selectivity, regional selectivity and inhibition of β - H elimination of side reactions (Fig 1a) However, there is no doubt that the introduction of guiding group occupies the coordination site of metal catalytic center, which makes the asymmetric conversion of this kind of reaction more challenging The development of new chiral ligands and chiral induction systems is the key to the asymmetric functionalization of non activated olefins In 2018, Chen Gong and he gang research team of Nankai University independently designed and developed a new type of monodentate oxazoline chiral ligand (moxin) based on tryptophan skeleton, which was successfully applied to the asymmetric hydrogen aromatization of non activated olefins, with a maximum of 94% ee (Fig 1b, J am Chem SOC., 2018, 140, 3542) Recently, based on the in-depth exploration of previous research work, the team has successfully developed the second generation of monodentate oxazoline chiral ligands (moxca) derived from serine, and successfully applied them to the asymmetric carboboration and amination of non activated olefins, with a maximum of 97% ee (Figure 1c) Figure 1 Palladium catalyzed asymmetric carboboration of nonactivated olefins (source: acscatal) The author first applied the moxin ligand l1-l8 developed in the early stage to the reaction It is gratifying that the ligand L2 can give 93:7 Er value However, after a series of modifications to the skeleton, the author could not obtain higher enantioselectivity Therefore, after a series of designs and attempts, the author developed the second generation of chiral mono dentate oxazoline ligands (moxca: L9) It can be seen that L9 gives better results than moxin in yield and selectivity Encouraged by this, the author modified the carbazole ring of L9 and optimized the optimal ligand structure L19 The yield of template reaction can reach 98% and the enantioselectivity can reach 98:2 The ligands have the advantages of simple synthesis and strong adjustability Starting from the serine methyl ester hydrochloride, sulfonate 6 was obtained by condensation, reduction and upper protective group, and then by SN2 substitution and Suzuki coupling reaction, the optically pure moxca ligand l9-l26 was obtained Figure 2 After the ligand selection of palladium catalyzed asymmetric carboboration of nonactivated olefins (source: acsactalc.) has determined the optimal ligand, the author has expanded the substrate In general, a series of CIS olefin substrates can be used with indole nucleophiles to obtain asymmetric carboboration products (5a - 10) with high yield, high enantioselectivity and enantioselectivity However, for the trans olefin substrate (r = ET), a pair of enantiomers (5a and 5A ') with Dr = 1:1.1 was obtained, and the enantioselectivity was 96:4 and 97:3, respectively The crystal structure shows that the Dr value is due to the different C γ centers of 5A and 5A ' When 1,3-diketones are used as nucleophiles, the hydrocarbon products can only be obtained with high enantioselectivity (11) Figure 3 Substrate expansion of asymmetric carboboration (source: acsactal3.) in addition, in this reaction system, when 3-butenamide is used as the substrate and imides are used as nucleophiles, asymmetric carboboration products (12-13) can also be obtained with high enantioselectivity and medium yield However, it is a pity that the γ - substituted alkene substrate has no reactivity The carboboration product can efficiently obtain chiral amino alcohols (15) in high yield under the condition of hydrogen peroxide oxidation (Fig 4) Fig 4 Asymmetric amine boration substrate expansion (source: acscatal.) is based on the experimental phenomenon that Dr value of z-alkene product is higher (> 20:1), while Dr value of e-alkene product is lower (1:1.1) The author speculates that the reaction may involve the isomerization process of e-alkene to z-alkene The experimental results show that in the reaction system, the olefin / Pd complex int0-e can be converted into int0-z The addition of ligand L19 will further promote the conversion, which may be due to the fact that int1-e is more cationic and prone to isomerization after the addition of L-type chiral ligand In order to further understand the specific mechanism of the chiral ligands, Professor Chen Gong and Peng Qian of Nankai University worked together to study the chiral induction model of the reaction by DFT theoretical calculation The stereoselectivity in this reaction is due to the selectivity of the metal center to the two sides of olefin when it is coordinated with olefin Different surface selectivity can be distinguished by the orientation (up / up and down / down) of the end substituents of alkenes The results show that for e-olefin substrate, int1-eup-ca down is 1.5kcal/mol more stable than that of int1-edop-ca down, and the energy of transition state ts-e-s is 2.6kcal/mol lower than that of transition state ts-e-r; for z-olefin substrate, int1-z up-ca down is more stable than that of intermediate int1-z down-ca up, and the corresponding transition state ts-z-r is 2.6kcal/mol lower than that of transition state ts-e-r Ts-z-s energy is 2.1 kcal / mol lower The calculated results are in good agreement with the experimental results At last, the author concludes that the reaction of z-alkenes directly undergoes the intermediate of int1-z up-ca down to generate target products with high enantioselectivity and enantioselectivity, while the reaction of e-alkenes undergoes the direct reaction of int1-e up-ca down and the reaction of isomerization of z-alkenes undergoes the intermediate reaction of int1-z up-ca down, resulting in low enantioselectivity of products (Fig 5) Figure 5 Mechanism analysis (source: acscatal.) in the research process of this project, Professor Engle's research group of Scripps Institute in the United States also realized the asymmetric carboboration of non activated olefins (ACS catalyst 2019, 9, 3260) using the first generation of monodentate oxazoline ligands (moxin) developed by Chen Gong and He Gang Conclusion: Chen Gong and He Gang team developed the second generation of novel monodentate oxazoline chiral ligands (moxca), which efficiently realized the asymmetric carboboration and amine boration of non activated olefins Based on the detailed analysis of the reaction process, the key steps of ligand promoted isomerization of E / Z olefins were proposed This reaction provides a new strategy for the asymmetric functionalization of nonactivated alkenes, and expands the application scope of the monodentate oxazoline ligands in asymmetric reactions The corresponding authors of this paper are Professor Chen Gong, researcher He Gang and researcher Peng Qian from Nankai University Bai Zibo, a doctoral candidate of Nankai University, is the first author of this paper, and Zheng Sujuan, a master's student, is responsible for the work of computational chemistry Besides,