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    Home > Research group of Professor Shi Feng of Jiangsu Normal University: a new strategy for the construction of axial chiral naphthalene indole framework

    Research group of Professor Shi Feng of Jiangsu Normal University: a new strategy for the construction of axial chiral naphthalene indole framework

    • Last Update: 2019-09-18
    • Source: Internet
    • Author: User
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    The chiral diaryl skeletons of the lead axis exist in many natural products, bioactive molecules and dominant chiral catalysts Indole is an important five membered heteroaromatic ring with unique properties It is of great significance to design and catalyze the asymmetric construction of an axial chiral diaryl framework containing indole parent nucleus In addition, the chirality of the framework with five heteroaromatic rings is characterized by low rotational energy barrier and weak conformational stability Therefore, the design of axial chiral diaryl skeleton containing indole parent nucleus and the construction of asymmetric catalysis have become a challenge in this field Recently, the research team of Professor Shi Feng of Jiangsu Normal University has developed a new method to construct the framework of axially chiral naphthalene indole, that is, to synthesize axially chiral naphthalene indole derivatives through the dynamic kinetic conversion reaction of racemic naphthalene indole (angel Chem Int ed 2019, DOI: 10.1002 / anie 201908279) Prof Shi Feng's research group was founded in 2013 The research group is mainly engaged in the catalytic asymmetric synthesis of chiral heterocyclic molecules, which provides an efficient method for the construction of complex and diverse chiral bioactive skeletons In recent years, the research group has been committed to the catalytic asymmetric construction of chiral heterocyclic skeleton containing indole mother nucleus (angelw Chem Int ed 2014, 53, 13912; angelw Chem Int ed 2015, 54, 5460; ACS catalyst 2017, 7, 6984; angelw Chem Int ed 2018, 57, 5398), a breakthrough has been made in the catalytic asymmetric construction of axial chiral diaryl skeleton containing indole parent nucleus (angelw Chem Int ed 2017, 56, 116; angelw Chem Int ed 2019, 58, 8703; angelw Chem Int ed 2019, DOI: 10.1002/anie.201908279) Prof Shi Feng is vice president and professor of School of chemistry and materials science, Jiangsu Normal University He obtained his master's degree from Jiangsu Normal University in 2004, studied for a doctorate jointly cultivated by Suzhou University and China University of science and technology from 2010 to 2013, and worked as a visiting scholar at Nanyang University of technology in Singapore from 2012 to 2013 He has been selected as the winner of Jiangsu outstanding youth fund, the academic and technical leader of middle-aged and young people of "333 high-level talents" in Jiangsu Province, the high-level talent of "six talent peaks" in Jiangsu Province, and the academic leader of middle-aged and young people of "Blue Project" in Jiangsu Province It is mainly engaged in the catalytic asymmetric synthesis of chiral heterocyclic molecules, which provides an efficient method for the construction of a complex and diverse framework of chiral Bioactive Heterocycles The corresponding authors published 115 academic papers in the authoritative SCI journals such as angelw Chem Int ed., ACS catalyst., org Lett., chem Commun., adv synth Catalyst., J org Chem., among which 9 papers were published in the journals with influence factors greater than 12.0 The published papers have been cited 5947 times, with personal h index of 40 The published papers include 6 papers with high ESI and 2 papers with hot ESI Apply for 5 invention patents with the first inventor and authorize 1 invention patent It has won the second prize of science and technology of Jiangsu Province, the second prize of natural science of the Ministry of education, Thieme Chemistry Journal Award, Asian core program leadership award and other awards Frontier research achievements: a new strategy for the construction of axially chiral naphthalene indole skeleton - racemic naphthalene indole involved in the dynamic kinetic conversion reaction - axially chiral diaryl skeleton exists in many natural products, bioactive molecules and dominant chiral catalysts, and the asymmetric construction of such skeleton has aroused the strong interest of chemists Among them, the rotational energy barrier and conformational stability of the framework of axial chiral heteroaromatic ring, especially the framework containing five heteroaromatic rings, are low Therefore, the catalytic asymmetric construction of this kind of skeleton has become a challenging problem in this research field (Figure 1) Fig 1 overview of research on asymmetric construction of axial chiral diaryl skeleton (source: angelw Chem Int ed.) indole is a kind of important five membered heteroaromatic ring with unique properties The axial chiral diaryl skeleton containing indole parent nucleus also shows good biological activity and catalytic activity (Fig 2a) Therefore, it is of great significance to design and catalyze the asymmetric construction of an axial chiral diaryl skeleton containing indole parent nucleus In 2017, the research team of Professor Shi Feng of Jiangsu Normal University realized the catalytic asymmetric construction of the axial chiral aryl indole skeleton through the asymmetric coupling reaction of 2-indole alcohol with naphthol or phenol (angelw Chem Int ed 2017, 56, 116) (Fig 2b) On the basis of this work, the research group continues to look for a new strategy to construct this kind of axial chiral skeleton Fig 2 application and construction strategy of naphthalene indole skeleton (source: angel Chem Int ed.) the author found that when there is no substituent at C2 position of indole in naphthalene indole derivatives, naphthalene ring and indole ring can rotate freely, and can not produce stable axial chirality Therefore, the author envisages that by the asymmetric addition reaction of racemic naphthalene indole with large steric electrophilic blocking agent, large steric blocking group is introduced into C2 position of naphthalene indole, so that naphthalene ring and indole ring can not rotate freely, so as to realize the dynamic kinetic transformation of racemic naphthalene indole, and finally construct naphthalene indole skeleton with stable axial chirality The author believes that there are three main problems to be solved in this process: (1) to find electrophilic reagents with large potential resistance and high activity; (2) to find a suitable catalytic system to control the stereoselectivity of the reaction; (3) when using racemic electrophilic reagents, to control the axial and central chirality of the reaction at the same time (Fig 3) Fig 3 a new strategy and a challenging problem for the construction of an axially chiral naphthalene indole framework (source: angelw Chem Int ed.) the authors believe that chiral phosphoric acid can activate naphthalene indole derivatives through hydrogen bonding, while azocarbonate and O-hydroxybenzyl alcohol, two large electrophilic blocking agents, can show high reactivity under the catalysis of chiral phosphoric acid Therefore, the author designed the asymmetric addition reaction of racemic naphthalene indole with azocarbonate and O-hydroxybenzyl alcohol under the catalysis of chiral phosphoric acid, hoping to realize the dynamic kinetic conversion of racemic naphthalene indole through this reaction, and to construct a stable axial chiral naphthalene indole skeleton When O-hydroxybenzyl alcohol is used as electrophilic reagent, the author assumes that O-hydroxybenzyl alcohol can form o-methylene benzoquinone intermediate under the action of chiral phosphoric acid, and accept the attack of naphthalene indole, so as to construct a more challenging naphthalene indole skeleton with axial and central chirality (Fig 4) Fig 4 project assumption (source: angelw Chem Int ed.) the author first tried the asymmetric addition reaction between racemic naphthalene indole and azocarbonate After the optimization of reaction conditions, the author investigated the application scope of the substrate, and found that naphthalene indole compounds and azocarbonate with different substituents can be applied to the reaction, and the axial chiral naphthalene indole derivatives can be obtained with high yield and high enantioselectivity (Fig 5) Fig 5 study on the application scope of racemic naphthalene indole and azo carbonate (source: angelw Chem Int ed.) subsequently, the author tried the catalytic asymmetric addition reaction of racemic naphthalene indole with O-hydroxybenzyl alcohol The substrate compatibility of the reaction is also very good When the substrate contains different substituents, good results can be obtained A series of naphthalene indole derivatives with both axial and central chirality can be obtained with high stereoselectivity (Fig 6) Fig 6 study on the substrate application range of racemic naphthalene indole and O-hydroxybenzyl alcohol (source: angelw Chem Int ed.) After the completion of the substrate application range study, the author studied the activation mode of catalyst on the substrate in the reaction through control experiment (Fig 7) The results show that the NH group of racemic naphthalene indole, the ester group of azocarbonate and the phenolic hydroxyl group of O-hydroxybenzyl alcohol form hydrogen bond with phosphoric acid, which plays an important role in the activation of the substrate and the stereoselectivity control of the reaction Fig 7 the control experiment of catalyst on the activation mode of substrate (source: angelw Chem Int ed.) according to the experimental results, the author reasonably speculated on the reaction mechanism and the activation mode of catalyst (Fig 8) In these two reactions, chiral phosphoric acid activated naphthalene indole reactant with its configuration matching, and asymmetric addition reaction took place rapidly Another configuration of naphthalene indole reactant does not match with the configuration of chiral phosphoric acid, so the speed of addition reaction is very slow Naphthalene indole of this configuration can be converted into naphthalene indole reactant matching with the configuration of chiral phosphoric acid through racemization process, thus realizing the dynamic dynamic conversion of racemic naphthalene indole reactant and obtaining naphthalene with stable axial chirality- Indole derivatives 3 and 9 Fig 8 possible reaction process (source: angelw Chem Int ed.) in order to prove the practicability of the reaction, the author also conducted a large number of experiments (Fig 9a-c) The application of the product was also studied in detail The product 9 can be converted into a new triarylphosphonate catalyst with both axial and central chirality by derivatization (Fig 9F) The catalyst shows good catalytic activity in the asymmetric cyclization of MBH ester and o-methylbenzoquinone (Fig 9g) In addition, the author also screened the cytotoxic activity of some axial chiral naphthalene indole products and found that product 3AA had high cytotoxic activity on MCF-7 tumor cells (Fig 9) Fig 9 In order to further study the stability of the axial chiral naphthalene indole skeleton, the authors calculated the rotation energy barriers of naphthalene indole skeleton at different positions The results show that the reason for the rapid racemization of naphthalene indole reactants at room temperature is that their rotational energy barriers are low (less than 24 kcal / mol), while the axial chirality of naphthalene indole products 3 and 9 at room temperature is stable because they have relatively high rotational energy barriers (30.1 kcal / mol-46.3 kcal / mol) By testing the racemization temperature of two kinds of naphthalene indole products, the author found that the product 9aa could still maintain stable axial chirality when stirred at 120 ℃ for 24 hours, which provided the possibility for the further development of this kind of framework into a new type of chiral catalyst At the same time, the experimental results show that the rotational energy barrier of product 9aa is higher than 3BB, which is consistent with the calculation results (FIG 10) Fig 10 calculation of rotational energy barrier and racemization experiment of naphthalene indole derivatives (source: angelw Chem Int ed.) To sum up, the research group developed a new strategy to construct an axial chiral naphthalene indole framework, that is, under the catalysis of chiral phosphoric acid, by racemizing naphthalene- Asymmetric addition reaction of indole with azo carbonate and O-hydroxybenzyl alcohol
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