Asymmetric synthesis of Cyclopentanone containing β - indole chiral quaternary carbon center by Yang Xiaoyu group of Shanghai University of science and technology

Lead indole skeleton is widely found in natural products and pharmaceutical chemical molecules, and more than 10000 indole derivatives have been confirmed to have physiological activities, and many have been used in clinical The synthesis of chiral indole derivatives has always been an important topic in organic synthesis and pharmaceutical chemistry, among which the asymmetric addition of indole to β - substituted cyclopentenone is still a difficulty in this field due to its inherent large steric hindrance Recently, Yang Xiaoyu's research group of School of material science and technology of Shanghai University of science and technology has realized the enantioselective synthesis of β - alkyl - β - indolecyclopentadone and β - alkyl - β - indolecyclopentadiamide containing quaternary carbon chiral center through chiral phosphoric acid catalysis Relevant research results were published in org Lett (DOI: 10.1021/acs.orglett.9b00963) Professor Yang Xiaoyu's cutting-edge scientific research achievements: the asymmetric synthesis of indole derivatives containing β - indole chiral quaternary carbon center cyclopentanone is one of the most advantageous heterocyclic compounds in pharmaceutical chemistry, as well as a natural product with physiological activity and an important component of material science Therefore, the synthesis of indole derivatives has been an important research topic in organic chemistry and pharmaceutical chemistry for a long time, so it is of great significance to develop new asymmetric synthesis methods of chiral indole derivatives Direct enantioselective functionalization of indole is a simple and efficient method to obtain chiral indole derivatives In the past two decades, researchers have developed a large number of asymmetric catalytic functionalization of indole, among which asymmetric Friedel crafts alkylation is one of the most effective methods At present, a large number of asymmetric catalytic addition reactions of indole with various electrophilic reagents have been developed, such as activated olefins, carbonyl compounds and imines However, due to the inherent steric hindrance, indole is very challenging for β, β - disubstituted activated olefins with high enantioselective 1,4-addition to construct indole derivatives containing quaternary carbon chiral centers Recently, scientists have developed some ingenious methods to catalyze the Friedel crafts alkylation of indole by using β, β - disubstituted activated olefins to construct chiral quaternary carbon centers However, these substrates need two electron absorbing groups to activate olefins (Fig 1, a) For these reasons, there are few reports on the construction of quaternary carbon chiral centers by the conjugation of indole with cyclic electron deficient alkenes Up to now, only one case has been reported to achieve asymmetric conjugation addition of indole to β - substituted cyclohexanone under high pressure using chiral primary amine catalyst, but only 74:24 E.R product has been obtained (Fig 1, b) In addition, due to the low reactivity of cyclopentenone and the challenge of chiral control in the process of its conjugation, there are no reports of enantioselective addition of β - substituted cyclopentenone by indole Moreover, the racemic form of the reaction has been developed only recently, and only 37% yield can be obtained, which fully proves the low reactivity of β - substituted cyclopentenone in the conjugated addition reaction with indole (Fig 1, c) It is well known that chiral phosphoric acid catalyst has good activation ability and stereoselectivity control ability for imine substrates Inspired by this, β - substituted cyclopentenone was converted into corresponding β - substituted cyclopentene imine The asymmetric conjugation addition reaction of indole to β - substituted cyclopentene imine was realized under the catalysis of chiral phosphoric acid After in-situ hydrolysis or reduction reaction, β - alkyl - β - indole cyclopentenone or β - alkyl - β - cyclopentenone containing quaternary carbon chiral center could be obtained with high enantioselectivity- Indole cyclopentamide product (Fig 1, d) Fig 1 the indole derivatives (source: org Lett.) containing quaternary carbon chiral center were constructed by asymmetric Friedel crafts alkylation After the detailed optimization of reaction conditions, the 1-Naphthalene substituted phosphoric acid catalyst (15 mol%), toluene, - 38 ℃ and 4 Å zeolite based on the binaphthol framework were used as the optimal conditions After hydrolysis by alumina, β - alkyl - β - indole cyclopentanone derivatives were obtained with high enantioselectivity Under this condition, the author investigated the application scope of the method As shown in Figure 2, different substituents at C5 and C6 positions of indole can be well compatible No matter it is an electrically neutral methyl group, an electron donor methoxy group or an electron acceptor halogen atom (F, Cl, BR) can obtain the product with high enantioselectivity In addition, it is worth mentioning that c-6-coome Almost enantiomeric pure products (99.5:0.5e R.) can be obtained by the reaction of substituted indoles In addition, the author also tried 2,4,7-substituted indoles, but did not get good experimental results The authors have also tried to use the β - substituted (ethyl, allyl) cyclopentene imine and β - methylcyclohexene imine substrates However, due to the steric hindrance, the corresponding products can only be obtained at room temperature with medium enantioselectivity and yield Fig 2 The substrate range of β - alkyl - β - indolecyclopentadone (source: org Lett.) β - indolecyclopentadine is a kind of conformationally restricted hyperchromic amine derivatives Due to its excellent selective serum reabsorption inhibitor (SSRIs) activity, many research interests are attracted, among which (1s, 3R) - 5-cn derivatives have ten times higher activity than straight chain hyperchromic amines (Fig 3 ) However, the physiological activity of β - alkyl - β - indolecyclopentadine analogues with quaternary carbon chiral centers has never been reported, which may be due to the lack of chiral synthesis methods of these indole derivatives In this paper, l-selectride was used as a reductant to reduce the adduct of indole and cyclopenteneimide in situ at - 78 ℃, and β - alkyl - β - indole cyclopentamide containing quaternary carbon chiral center was obtained with high enantioselectivity and good non enantioselectivity Fig 3 Substrate range of β - alkyl - β - indolylcyclopentylamide (source: org Lett.) in order to prove the potential application of this method, the author also carried out the conversion research of chiral products (Fig 4) At - 78 ℃, the stereoselective reduction of carbonyl group in product 3A was carried out by using l-selectride, and 3a was converted into Cyclopentanol derivatives with 85:15 Dr equivalent, and the enantioselectivity remained unchanged In addition, the p-methoxybenzenesulfonyl group on the product 4A can also be removed by SMI 2, and the chiral β - alkyl - β - indolecyclopentadine derivatives can be obtained in nearly equivalent conversion yield Figure 4 Derivatization of chiral products (source: org Lett.) summary, the author reported a method for the construction of indole derivatives containing quaternary carbon chiral centers by asymmetric Friedel Crafts reaction of indole with β - substituted cyclopenteneimide catalyzed by chiral phosphoric acid The chiral addition products can be converted into β - alkyl - β - indole cyclopentanone or β - alkyl - β - indole cyclopentamide by one pot hydrolysis or reduction It is expected that the strategy can be further applied to other challenging asymmetric conjugate addition reactions Professor Yang Xiaoyu's doctoral student Liu Wei is the first author of the research The work was supported by the "Youth Program" of the thousand talents program, the National Natural Science Foundation of China, the Shanghai Pujiang talent program and the Shanghai University of science and technology The results were published in org Lett (DOI: 10.1021/acs.orglett.9b00963) Review of previous reports: Professor Yang Xiaoyu, Shanghai University of science and technology research group: the regional selectivity and enantioselective synthesis of β - indolecyclopentadiamide People and scientific research are getting more and more attention in the economic life Today, 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.