Research group of you Shuli, Shanghai Institute of organic chemistry: asymmetric amination of α - naphthol catalyzed by chiral phosphoric acid / Michael addition series reaction

Source: the aromatic compounds of youshuli group are the basic materials widely used in organic chemistry The traditional conversion reactions based on aromatic compounds are mainly aromatic electrophilic / nucleophilic substitution reactions This kind of reaction can introduce various functional groups into the aromatic ring, but the aromaticity of the core of the aromatic ring is generally not affected In recent years, catalytic asymmetric dearomatization (cadA) has gradually become a new mode of aromatic transformation In the process of de aromatization, with the establishment of new chemical bonds and quaternary carbon centers, the aromaticity of the substrate is weakened or lost The de aromatization reaction provides a new way to rapidly construct complex multi ring molecules with three-dimensional structure from cheap and easily available planar molecules It has potential application value in natural product synthesis and pharmaceutical chemistry Naphthol is an important aromatic compound Because there are many potential C / O nucleophilic sites in naphthol, how to control the chemical and regioselectivity of the reaction and how to realize the asymmetric dearomatization of naphthol is a challenging task The usual strategy is to design intramolecular reactions, and regulate the selectivity of reactions by the restriction of cyclization The disadvantage is that the substrates are not easy to synthesize Therefore, it is very urgent to develop the intermolecular asymmetric dearomatization of naphthol, especially α - naphthol The research group of you Shuli, Shanghai Institute of organic chemistry, Chinese Academy of Sciences, has carried out systematic research on catalytic asymmetric dearomatization In the previous work, they found that azodicarboxylate can be used as a highly active electrophilic reagent in the asymmetric amination of β - naphthol catalyzed by chiral phosphoric acid (angelw Chem Int ed 2015, 54, 647; similar reactions catalyzed by chiral Lewis acid can be found in angelw Chem Int ed 2015, 54, 2356; chem EUR J 2015, 21, 17453) Inspired by this, the research team of youshuli designed a 4-position α - naphthol substrate containing nucleophilic side chain, and successfully realized its asymmetric amination / Michael addition series reaction with azodicarboxylate under the catalysis of chiral phosphoric acid (Fig 1) Relevant research results were published in NAT Commun (DOI: 10.1038/s41467-019-11109-9) Fig 1 chiral phosphoric acid catalyzed a-naphthol asymmetric amination and dearomatization / Michael addition series reaction (source: Nat Commin.) the reaction has good substrate universality (Fig 2): 6-7-positions of a-naphthol can link a variety of functional groups, 4- It can tolerate n, O and C nucleophiles on the side chain, and can produce the multi substituted benzocyclohexanones with continuous chiral center in excellent yield (up to 93%) and enantioselectivity (up to > 99% ee) under mild conditions The asymmetric amination / Michael addition series reaction can also be extended to more challenging 2,3-disubstituted phenol The amount of chiral phosphoric acid catalyst can be reduced to 0.1 mol% Further study found that the intermediate 6 can be obtained by the separation of 86% yield and 99% ee enantiomeric purity in 30 minutes quenching reaction under standard conditions (Fig 3) The intermediate is stable for several weeks at - 20 ° C, and it takes 24 hours to fully convert to the final product under standard reaction conditions (50 ° C) The results show that the asymmetric amination de aromatization step is a very rapid irreversible process in this reaction system, and the stereochemistry of the product is also determined in this step, while the Michael addition reaction of intermediate 6 is the decisive step of the whole reaction In addition, DFT was used to calculate the asymmetric amination process of α - naphthol and azodicarboxylate catalyzed by chiral phosphoric acid, and a model which can reasonably explain the formation of enantioselectivity was obtained (Fig 4) Fig 2 investigation of substrate range (source: Nat Commun.) Fig 3 separation of intermediate 6 (source: Nat Commun.) Fig 4 chiral induction model of asymmetric amination and de aromatization (source: Nat Commun.)- A series reaction of symmetrical amination and dearomatization / Michael addition of naphthol The reaction has good substrate universality and functional group compatibility, and can be used for the synthesis of poly substituted benzocyclohexanones with continuous chiral centers under mild conditions At the same time, the mechanism of the reaction was studied by theoretical calculation and control experiments The experimental part of the research work is jointly completed by Dr Xia zilei and Dr Xu Renqi, and the theoretical calculation part is completed by associate researcher Zheng Chao Researcher you Shuli and associate researcher Zheng Chao are the co correspondents of this paper The research was funded by the Ministry of science and technology, the National Natural Science Foundation, the Shanghai Municipal Science and Technology Commission and the Chinese Academy of Sciences Review of previous reports: research group of you Shuli, Shanghai Institute of organic Sciences: palladium catalyzed asymmetric isopentenylation and dearomatization of indole derivatives