The research group of Tang Yong, academician of Shanghai Institute of organic chemistry, has made important progress in the study of structural diversity and asymmetric synthesis of benzofuran indoline

The author of this paper: sunewang R Wang / wangrixin benzofuran indoline is widely found in the core skeletons of some natural products, among which the most representative molecule is the toxin diazonamide a isolated from marine animals named ascidians, which has a strong growth inhibition effect on a variety of human cancer cells through its unique mode of action Therefore, the construction of benzofuran indoline skeleton has been widely concerned by synthetic chemists The framework is usually synthesized by the cyclization of 3 - (2-hydroxyphenyl) indoleamine salt intermediates, among which the most direct and efficient is the dearylation cyclization of indole However, the asymmetric synthesis of benzofuran indoline is rarely reported For example, in 2014, Zhang Xiaomei and other researchers from Chengdu Institute of organic chemistry, Chinese Academy of Sciences reported the highly enantioselective [3 + 2] cyclization of indole and benzoquinone imine catalyzed by chiral phosphoric acid to synthesize chiral benzofuran indoline (angelw Chem Int ed 2014, 53, 10471) It should be pointed out that in the catalytic asymmetric dearomatization of indole (cadA), it is usually necessary to introduce substituents at the 3-position of indole to prevent the product from re aromatization, which is the case in the above research work of Zhang Xiaomei and other researchers However, considering the structural diversity of the small molecular library needed for drug screening, the asymmetric synthesis of 3-position benzofuran indoline without substituents is also very important At the same time, it puts forward higher requirements for the regulation of chemical reactions, so it has certain challenges The research group of Tang Yong, academician of Shanghai Institute of organic chemistry, Chinese Academy of Sciences, has successfully developed a series of asymmetric conversion methods of indole, such as the Friedel crafts alkylation of indole and alkylmalonates (j.am.chem.soc 2002, 124, 9030) or [2 + 2 + 2] tandem cyclization (angel Chem Int ed 2017, 56, 6942); cyclization of indole with cyclopropane and cyclobutane (J am Chem SOC 2013, 135, 7851; angelw Chem Int ed 2017, 56, 3055) Recently, the research group has made new important progress in this field: using copper (II) catalyzed [3 + 2] cyclization of indole and p-diphenylquinone, the same catalyst has been used for asymmetric catalytic synthesis of benzofuran indoline derived from 3-unsubstituted and 3-substituted indole for the first time In this reaction, the ester group on p-diphenylquinone is not only beneficial to the coordination between the substrate and the chiral catalyst, but also increases its electrophilicity Fig 1 the structural diversity and asymmetric synthesis sources of benzoindoline based on the side arm strategy: angelw Chem Int ed during the detailed optimization of reaction conditions, they found that the water content in the reaction system had little effect on the enantioselectivity of the product, but had a great fluctuation on its yield In the end, the research group successfully solved the problem of repeatability by using copper hydrate (II) salt side arm modified dioxazoline (sabox) complex as catalyst and combining with active molecular sieve to form dynamic regulation of water content It is worth noting that this seemingly contradictory approach is rare The reaction substrate has wide adaptability, strong functional group compatibility and excellent enantioselectivity It was also found that the change of the substituent electrical properties of indole n could regulate the activity of indole, and expand the substituent and structural diversity of the reaction products At the same time, the reaction can be magnified, and only 0.5mol% catalyst is needed for the gram scale reaction to obtain the same high enantioselectivity, with good yield Fig 2 synthesis source of chiral catalyst containing crystal water: angelw Chem Int ed Fig 3 3 - substrate range of non substituted indole (TS = p-toluenesulfonyl; BOC = t-butoxycarbonyl CBZ = benzyloxycarbonyl; BZ = benzoyl; MDB = 3, 4-dimethoxybenzenesulfonyl) source: angelw Chem Int ed Fig 43 - substituent range of indole (MBS = p-methoxybenzenesulfonyl) source: angelw Chem Int ed The research results are published in angelw Chem Int ed (DOI: 10.1002 / anie 201800733), the first author is Dr Liu qiongjie; assistant researcher Wang Rixin is the co corresponding author The research work has been greatly supported by NSFC and the State Key Laboratory of organometallic chemistry of Chinese Academy of Sciences Corresponding author: academician Tang Yong