Zhou Ling, Professor of Northwestern University: Construction of axially chiral aryl benzoindole with chiral phosphoric acid catalysis and center to axis chiral transition strategy

There are a lot of lead chiral compounds in nature, and different enantiomers of chiral substances often show different physiological activities to organisms Therefore, the separation and preparation of optically pure enantiomers has always been a research hotspot and frontier in modern chemistry Chiral compounds usually refer to substances with one or more asymmetric elements, such as central chirality, surface chirality, axial chirality and helix chirality These asymmetric elements can realize mutual transformation under certain conditions, such as center to center, center to axis, axis to axis, axis to center, center to spiral, axis to spiral, etc Recently, a series of biaryl axis chiral compounds with benzoindole naphthol skeleton have been constructed by Professor Zhou Ling's research group of Northwest University Based on the strategy of chirality transition The related results were published online in Chemical Science (DOI: 10.1039 / c9sc00810a) Fig 1 biaryl axial chiral compounds (source: Chemical Science) based on center to axial chirality transition for the construction of axial benzoindole naphthol framework In May, the research direction is organic synthesis methodology, organic catalysis, etc some progress has been made in the catalytic substitution of Nitrogen Heterocyclic Carbene, asymmetric reaction catalyzed by chiral phosphoric acid, and oxidative dehydrogenation cycloaddition reaction, etc Prof Zhou Ling: Prof Zhou Ling, graduated from Lanzhou University in 2002 with a bachelor's degree, and obtained a doctor's degree in organic chemistry from Lanzhou University in 2007 From 2007 to 2009, he served as the research and development leader of Barcelona Pharmaceutical (China); from 2009 to 2011, he was engaged in postdoctoral research at the National University of Singapore Since 2012, he has served as a professor / doctoral supervisor in Northwest University He has published more than 40 research papers in J am Chem SOC., angelw Chem Int.ed., chem SCI., org Lett., chem Commin., and has been cited more than 1000 times Presided over and undertaken projects such as National Natural Science Foundation and Shaanxi Provincial Outstanding Youth Fund In 2012, he was selected as a special expert of Shaanxi Province; in 2013, he was supported by the outstanding young academic backbone program of Northwest University; in 2014, he was awarded "Thieme Chemistry Journals Award"; in 2017, he was awarded the first outstanding youth fund of Shaanxi Province Advanced research achievements: Construction of axially chiral aryl benzoindole by combining chiral phosphoric acid catalysis and center to axis chiral transformation strategy Axially chiral biaryl compounds are a kind of very attractive framework, which are widely found in natural products and bioactive drug molecules, and play an important role in catalyst research and development, ligand design, drug development and Material Science (j.am Chem SOC., 2012, 134, 3342; ACS catalyst., 2016, 6, 4814) Therefore, the asymmetric construction of this kind of skeleton has attracted the strong interest of many chemists However, most of the constructed axial chiral biaryl skeletons are based on benzene ring or naphthalene ring, and few biaryl axial chiral compounds are based on indole parent nucleus, which can be divided into: axial chiral compounds based on indole n (1) - aryl skeletons (chem - EUR J., 2010, 16, 6752; tetrahedron, 2016, 72, 5221; chem - EUR J., 2015, 21, 4954 ）; axial chiral compounds based on indole C (2 / 3) - aryl skeleton (ACS catalyst., 2017, 7, 5316; angelw.chem Int ed., 2017, 56, 116; NAT Chem., 2018, 10, 58; angelw Chem Int ed., 2019, 58, 3014) However, the biaryl axis chiral compounds based on indole C (2) - aryl skeleton have never been reported, and only one case of CM Phos is achiral (angelw Chem Int ed., 2008, 47, 6402; angelw Chem Int ed., 2008, 47, 8059) Therefore, it is of great significance to construct enantioselective axial chiral compounds of indole C (2) - aryl skeleton The central chiral transition strategy was proposed by Berson et al In 1955 (J am Chem SOC., 1955, 77, 450) Meyers et al First realized this concept in 1984, turning the central chiral of 4-naphthoquinoline into 4-naphthoquinoline biaryl axial chiral compounds (J am Chem SOC., 1984, 106, 1135) But the development and application of this strategy has been slow At present, only a small number of substrates with one, two or four chiral centers have been converted to one axial chiral product, and the range of substrates is very limited (angelw Chem Int ed., 1996, 35, 2662; J am Chem SOC., 2002, 124, 6512; J am Chem SOC., 2004, 126, 5358; J am Chem SOC., 2011, 133, 18; angelw Chem Int ed., 2016, 55, 1401; J Am Chem Soc.,
2017 , 139 , 2140; Angew Chem Int Ed , 2018 , 57 , 7136 ）。 It is not clear whether the substrate containing one or more chiral centers can be transformed into the product containing more than one chiral axis The mechanism of chiral transformation needs to be further explored In recent years, the research group has made some progress in asymmetric reactions catalyzed by chiral phosphoric acid A series of molecules containing all carbon quaternary carbon chiral centers have been obtained by the use of monoimidiquinone for the de aromatization of 2-naphthol compounds (chem EUR J 2017, 23, 5831), with excellent yields and enantioselectivity The asymmetric [3 + 2] cycloaddition of o-alkenol and p-benzoquinone catalyzed by chiral phosphoric acid has also been developed, which can efficiently prepare benzodihydrofuran compounds containing two consecutive chiral centers (org Lett 2018, 20, 2929) In the related fields of oxidative dehydrogenation and cycloaddition reaction, some Diels alder reactions of oxidative dehydrogenation have been developed and detailed mechanism studies have been carried out, which can efficiently prepare compounds with potential activity (adv synth Catalyst 2019, 361, 2268; org Lett 2018, 20, 5774; adv synth Catalyst 2015, 357, 940) Based on these previous studies and literature research, the author designed an asymmetric [3 + 2] cycloaddition reaction of 1-styryl-naphthol and azonaphthalene catalyzed by chiral phosphoric acid, and constructed a series of chiral indoline skeletons, and then constructed a series of biaryl axial chiral compounds based on indole C (2) - aryl skeletons by further oxidative dehydrogenation The author first used benzoyl (BZ) protected azonaphthalene to react with 1-styryl naphthol After the optimal reaction conditions were established through system optimization, the applicability of the reaction was investigated (Fig 2) The results show that all kinds of substrates can obtain good yield and stereoselectivity (EE value is generally close to 99%, Dr value is more than 20:1), and a series of [3 + 2] cycloaddition products containing naphthol benzoindoline framework are effectively synthesized Fig 2 substrate expansion of asymmetric [3 + 2] cycloaddition reaction (source: Chemical Science) Fig 3 center to axis chiral transition substrate expansion (source: Chemical Science) On this basis, the author attempts to realize the construction of axially chiral biaryl compounds through chiral transition strategy Firstly, in order to avoid the formation of the products, the hydroxyl groups of naphthol were protected Trifluoromethylsulfonyl group, p-bromobenzenesulfonyl group and p-methylbenzenesulfonyl group were tried respectively The results showed that when p-methylbenzenesulfonyl group was used as the protecting group, it was beneficial for further oxidation to construct axial chirality After determining the protecting group, the author then investigated the oxidation conditions and found that DDQ had the best oxidation effect At the same time, the author found an abnormal temperature effect Higher reaction temperature can get better EE value After the establishment of the optimal oxidation conditions, the substrate of the products was expanded All the raw materials can obtain the intermediate products protected by TS in almost quantitative yield, and there is no loss of enantioselectivity in the reaction process Finally, these intermediate products undergo chiral transformation under the optimal oxidation conditions From the experimental results, the position of substituents, steric resistance and electronic effect have little effect on the enantioselectivity of the products In general, all the intermediate products can be oxidized smoothly, and get better yield (79% - 95%) and excellent enantioselectivity (87% - 99% ee) (Fig 3) The results of thermoracemic experiments show that the biaryl framework has excellent stability at room temperature (half-life is about 460000 years) It is worth mentioning that this method can effectively prepare products containing two axes of chirality, and it is the first time to realize the conversion of two chirality centers into two chirality axes Fig 4 synthesis and application of new chiral phosphine ligands (source: Chemical Science) However, the research team did not stop here According to the center to axis chiral transformation strategy, the author prepared a novel structure of single phosphine axial chiral ligands 9 with 99% ee value after six steps of chemical transformation , and applied it to asymmetric allylation reaction, achieving medium enantioselectivity (68% ee, FIG 4) For the mechanism of the chiral transition, the author thinks that DDQ oxidation dehydrogenation is the decisive step of the chiral transition Once the dehydrogenation produces carbon positive ions, the configuration of the axial chirality will be established Nuclear magnetic experiments show that there are two dominant conformations in the central chiral compounds The selective NOE and 1D EXSY experiments show that the products are transformed from the non dominant conformation raw materials After further DFT calculation, the author proved the reaction process (Fig 5 and Fig 6) Fig 5 energy level distribution diagram of center to axis chirality transition participated by DDQ (source: Chemical Science) Fig 6 3D structure diagram of substrate and transition state (source: Chemical Science) This achievement was recently published in Chemical Science (DOI: 10.1039/c9sc00810a), doctoral candidate Hu Yulong (middle), graduate student Wang Zhe Yang Hui (first from left) and Yang Hui (second from left) are the co first authors, and Professor Zhou Ling (first from right) is the corresponding author Under the guidance of Lei Yibo and Xu Wenhua, Wu Zibo (second from right), an undergraduate of Northwest University, calculated the reaction mechanism Thanks to Zhao Yanxia and Yang Guoping of Northwest University for their analysis of single crystal diffraction data Thanks for the financial support from the National Natural Science Foundation of China (21672170), Shaanxi Provincial Distinguished Young Scholars Fund (2018jc-020), natural science basic research plan (2018jm2029), and China Postdoctoral Science Fund (2018m643705) 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.