Professor Xu Pengfei's research group of Lanzhou University: the introduction of axial chirality on the carbon ring of indole by using chiral hydrogen bond catalysis

Lead indoles are widely concerned by synthetic chemists because of their application value in pharmaceutical chemistry and synthetic chemistry However, the synthesis and modification of lead indoles mainly focus on heterocycles of indoles, which is due to the high reactivity of heterocycles of indoles The C-H functionalization of indole inert carbon ring can be achieved by some transition metal catalyzed strategies At the beginning of 2018, Professor Xu Pengfei of Lanzhou University successfully introduced central chirality into indole carbon ring by organic catalysis (org Lett 2018, 20, 2190-2194) In view of the important applications of axial chirality compounds in asymmetric catalysis, active molecules and natural products, the team has made a breakthrough in introducing axial chirality into indole carbon ring (org Lett 2019, 21, 5219-5224), a new type of asymmetric catalyst with high catalytic activity, was synthesized on indole carbon ring by using chiral hydrogen bond catalysis for the first time Professor Xu Pengfei's cutting-edge scientific research achievements: the use of chiral hydrogen bond catalysis to introduce axial chirality into indole's carbon ring Among the chiral catalysts and ligands, 47% were axial chiral compounds However, all these axial chiral compounds rely on the inefficient chiral resolution at present, but the efficiency of chiral resolution is very limited (no more than 50%), and the need for stoichiometric resolution reagents Asymmetric catalysis is the most atom economical way to obtain chiral products from non chiral materials But because chemists pay more attention to the construction of central chirality, asymmetric catalysis has been paid less attention to the construction of axial chirality In the early stage, the research on Asymmetric Catalytic construction of axial chirality mainly focused on metal catalysis The development of axial chirality ligands prompted chemists to develop some strategies of transition metal catalytic construction of axial chirality compounds for the synthesis of new and more effective axial chirality ligands Compared with the mature metal catalysis, organic catalysis is like a rising star in the construction of axial chirality At present, chiral phosphoric acid catalysis has been widely used in the construction of axial chirality compounds, and the third-order amine hydrogen bond, chiral peptide, second-order amine, third-order amine and quaternary ammonium salt catalysis have also been successfully used in the construction of axial chirality However, there is no report on the construction of axial chirality in the field of chiral hydrogen bond catalysis, which is worthy of further research and development On the other hand, with the development of asymmetric catalysis, more and more axial chiral skeletons have been synthesized, and the development of organic catalysis to construct axial chiral skeletons has also enriched the types of axial chiral skeletons, such as: benzamide type, olefin type, etc Professor Xu Pengfei's research group (org Lett 2018, 20, 2190-2194) has realized the construction of central chirality on the indole carbon ring (Fig 1, a) Further in-depth thinking makes the author think boldly: can axial chirality be constructed on the indole carbon ring? Through literature review, the author found that in the reports of indole skeleton construction of axial chirality (angelw Chem Int ed 2017, 56, 116-121 and NAT Chem 2018, 10, 58-64), all of them were constructed at C-3 (Fig 1, b) The examples of axial chirality construction on carbon ring have not been reported Based on these assumptions and research, the author tries to find an effective strategy to construct axial chirality on indole carbon ring (Fig 1, c) Fig 1 At the beginning of the reaction design study (Fig 2), the author first selected 4-hydroxyindole as nucleophilic substrate, expecting to achieve the same effect in the previous work, which can realize the C-5 position of C-H In view of the characteristics of quinone and hydroxyindole, the author chose the third-order amine hydrogen bond catalyst Although the expected product can be obtained, unfortunately, the regioselectivity of the reaction is not good and the optical rotation of the final product is 0 The reason for this result may be that the C-6 position of indole is lack of steric hindrance group, the energy barrier of chiral axis rotation is low and it can rotate freely In order to increase the rotating energy barrier, 5-hydroxyindole was chosen as the raw material Fig 2 Preliminary reaction attempt The author tried again with 5-hydroxyindole 1a and aza-p-benzoquinone derivative 2A as template reaction substrate Using 20 mol% chiral hydrogen bond catalyst I as a bifunctional organic small molecule catalyst, the substrate 1a (0.15 mol) and 2A (0.1 mol) were mixed in 1 ml of dichloromethane (DCM) solution at - 20 ℃ After stirring for 12 hours, TLC monitoring showed that new compounds were formed (Fig 3, condition 1) The new compound was separated by column chromatography and identified by NMR and HPLC The new compound is the expected axial chiral product 3a The yield and stereoselectivity of the reaction are not very satisfactory, so the author then screened other types of catalysts, and finally found that thiourea (IV and x) derived from Cyclohexanediamine has the best catalytic effect (Fig 3, conditions 4 and 10) The most efficient chiral phosphoric acid catalyst (catalyst IX) previously reported could not promote the reaction By adjusting the solvent and reaction temperature, the author finally obtained the final axial chiral product with the yield of > 99% and the EE value of 97% (Fig 3, condition 18) Figure 3 Reaction condition screening After establishing the optimal conditions, the author has studied the universality of the reaction (Figure 4) For indole substrates, 1,4-hydroxyindole and 7-hydroxyindole are not suitable for the construction of axial chirality due to the effect of rotational steric hindrance, while 6-hydroxyindole is less nucleophilic and can not react Therefore, at present, this strategy can only construct axial chirality at C-5 position of indole; all substituted 5-hydroxyindole can react smoothly, and obtain corresponding axial chirality products with good yield and enantioselectivity (Fig 4, 3a-3e), of which 2-methyl-5-hydroxyindole has the best reaction effect (Fig 4, 3C) When aza-p-benzoquinone derivative 2 has electron donor substituent, its activity is greatly reduced and the reaction can not take place smoothly When TS (p-methylbenzenesulfonyl) with hydrogen bond is replaced by MS (methylsulfonyl), the stereoselectivity of the reaction decreases (Fig 4, 3f), which may be due to the fact that the benzene ring in the benzenesulfonyl group can interact with the aromatic ring in the catalyst to form π - π, while the absence of the methylsulfonyl group will reduce the binding ability of the catalyst and the substrate When the substituents on the benzene sulfonyl group change, the reaction effect is still very good (Fig 4, 3g-3m) The only thing worth noting is that when there is an electron absorption substituent on the benzene ring, the reaction activity of the substrate will be reduced (4-nitro or 4-bromo cannot react normally), and higher reaction temperature is required (Fig 4, 3M) The expected axial chirality products can also be obtained from the substituted azo-p-benzoquinone, but the reaction effect is slightly poor (Fig 4, 3N and 3O) For substrate 2 with slightly poor reaction effect, replace 5-hydroxyindole with 2-methyl-5-hydroxyindole, and the reaction effect will be improved (Fig 4, 3p-3s) Fig 4 reaction substrate expansion In order to further investigate the reaction mechanism, the author first carried out NMR experiment (Fig 5) to explore the combination mode of catalyst and substrate Catalyst X and substrate 2 should have strong hydrogen bond effect After mixing 0.1 equivalent catalyst and substrate 2a, the NMR experiment was carried out from 1 H It is easy for the author to find that the characteristic peaks of catalyst almost disappear, and substrate 2a is partially converted into active complex (emerging signal), which fully shows that substrate 2 and catalyst can generate active intermediate through hydrogen bonding in the system Subsequently, the amount of catalyst was increased gradually The results show that with the increase of the amount of catalyst, the new signal will gradually increase, and the signal of the substrate will gradually weaken When 0.5 equivalent catalyst X and 1.0 equivalent substrate 2a are mixed for the NMR experiment, the experimental results show that all the characteristic peaks of catalyst and substrate disappear, and all of them are converted into new NMR signals, that is, the active products of the combination of the two The results show that the substrate 2 is closely bound to the chiral hydrogen bonded catalyst X in the ratio of 2:1 Fig 5 Study on reaction mechanism in the expected mechanism, 5-hydroxyindole does not react with catalyst, but through relevant NMR experiments, the author found that there is weak interaction between them When 5-hydroxyindole was mixed with catalyst x for NMR experiment, the author found that the chemical shift of hydrogen atom between hydroxyl and catalyst NH changed significantly (Fig 6) This shows that there is a weak interaction between the hydroxyl group in hydroxyindole and the sulfur atom in the catalyst Although it is not as tight as the binding of substrate 2 (the change of hydrogen spectrum is not as obvious as that of substrate 2a), it also plays a decisive role in the reaction Fig 6 study of reaction mechanism in order to verify the effect of hydroxyl, the author used 2- methoxyindole as substrate, and the results showed that the reaction did not occur (Fig 7, a), which showed that the weak interaction between hydroxyl and catalyst played an important role in the reaction At the same time, when 4-fluoro-5-hydroxyindole was used as the substrate (Fig 7, b), the product of C-6 or phenolic hydroxyl addition was not detected, which led the author to exclude another mechanism proposed by Xu Qinglong of China Pharmaceutical University (j.am.chem.soc 2016, 138, 5202 − 5205): the oxygen of phenolic hydroxyl reacted with imine first, and then passed [3, 3] Rearrangement to produce axial chiral products Fig 7 Control experiment Based on the above experimental results, the author proposes a possible reaction mechanism (Fig 8): the catalyst of one molecule can combine with the substrate 2a of two molecules through hydrogen bonding, and the sulfur carbonyl of the catalyst can combine with the hydroxyl in the substrate 1a to enhance C-4 Under the control of catalyst, asymmetric addition reaction takes place to form central chiral intermediate, and finally to form axial chiral product 3A through aromatization Figure 8 Speculated reaction mechanism The final product of this strategy is an axial chiral biphenyldiphenol containing indole skeleton The axial chiral diphenol has a very wide range of uses in asymmetric catalysis It can not only be used as a chiral ligand, but also as an organic catalyst directly In order to verify the potential of this chiral product as an asymmetric catalyst, product 3C was used to catalyze the asymmetric allylation of ketones (Fig 9) Surprisingly, axial chiral compound 3C shows excellent catalytic effect, and its control ability of catalytic activity and stereoselectivity is better than that of traditional chiral BINOL, and even the reaction effect is better than the optimal catalyst reported in the previous literature (j.am.chem.soc 2006, 128, 12660-12661) The experimental results show that the newly synthesized framework has great potential in asymmetric catalysis Figure 9 Application of axial chiral indole