Liu Yankai, associate professor of Ocean University of China: asymmetric organic catalytic synthesis of benzo bridged or spiro bridged compounds containing chiral acetaldehyde amines

The bridged ring or spiro bridged ring skeleton with benzoacetamide structure is widely found in the bioactive natural products and drugs Although there are many reports on the synthesis of these two kinds of skeletons, the products are racemates, but there is no report on the asymmetric catalytic synthesis of these two kinds of acetaldehyde amines Recently, Liu Yankai group, School of medicine, Ocean University of China reported a series reaction with o-hydroxycinnamaldehyde and cyclic sulfonimide as substrates, which can successfully construct the above two kinds of bridge ring or spiral bridge ring skeleton containing benzoacetamide structure with good yield and high stereoselectivity The results were recently published in the organizational letters (DOI: 10.1021 / ACS Orglett 9b01874) Liu Yankai, associate professor, Research Group Introduction Liu Yankai, associate professor of Ocean University of China, was founded in September 2013 At present, the research group mainly studies the application of cyclic hemiacetal and hemiacetal amine substrates in asymmetric organic catalytic reactions Using the special properties of semiacetal (amine) on-off tautomerism and multi reactive active sites, a variety of paracyclic, bridged and spiro compounds containing acetal or acetal amine structures have been successfully synthesized by organic / metal catalysis A series of research results have been published (org Lett 2015, 17, 3794; org Lett 2015, 17, 2022; org Lett 2016, 18, 864; org Chem Front 2017 , 4 , 2358; Adv Syn Catal 2017 , 359 , 4260; Org Lett 2018 , 20 , 1630; Org Lett 2018 , 20 , 3609; Org Lett 2018 , 20 , 6682; Org Lett 2019 , 21 , 190; Org Chem Front 2019 , 6 , 1972 ） 。 Liu Yankai, Ph.D., associate professor, received his Ph.D degree from Sichuan University in July 2010, under the guidance of Professor Chen Yingchun (outstanding youth) Main research interests: asymmetric synthesis catalyzed by small chiral organic molecules and synthesis of chiral drugs In 2009, as an exchange student, a 4-month chiral asymmetric catalysis study was carried out in Prof a berkesel research group, University of Cologne, Germany In 2011, he won Marie Curie fellowship, the most famous scholarship in the European Union, and conducted postdoctoral research under the guidance of Prof P melchiorre, Institute of Chemical Research of Catalonia (iciq) in Spain Leading scientific research achievements: asymmetric organic catalytic synthesis of benzo bridged ring or spiro bridged ring compounds containing chiral acetaldehyde amine structure, or spiro bridged ring skeleton containing benzo acetaldehyde amine structure, widely exists in natural products and drugs with biological activities Surprisingly, the previously reported methods have been used to synthesize racemates, but the asymmetric catalytic synthesis of these two acetaldehyde amines has not been reported The research team found that the Michael addition reaction of o-hydroxycinnamaldehyde after being activated by imine salt can generate 4-substituted chroman-2-ol intermediate, which is very suitable for the construction of acetals containing bridge ring structure (Figure 1) Fig 1 The skeleton structure of benzoacetamide and previous work (source: org Lett.) based on this, the author speculated that the cyclic imine 4A derived from saccharin could react with o-hydroxycinnamaldehyde 1A via imine salt to form a key intermediate, which contains one nucleophilic reaction site (phenol hydroxyl) and two electrophilic reaction sites (one aldehyde carbonyl and one imine) Therefore, the intermediate can participate in two different reaction processes, and generate different bridged or spiro bridged ring structures through oxidation or acid catalyzed ring closing (Fig 2) Fig 2 Synthesis strategy design (source: org Lett.) however, due to the fact that the active intermediate has multiple reaction sites, compounds 1a and 4A generate an inseparable mixture of isomers after 3 catalysis Under the condition of oxidation, the mixture only produced 6a of path a product, but no 9A of path B product Under the condition of acid, it could produce 7a of path a product and 8A of path B product It has been found that spiro bridged compound 7a is not stable under acidic conditions and will slowly convert to bridged compound 8A (Fig 3) Figure 3 Diversity of reactions for 1a and 4a (source: org Lett.) the authors then extended the substrate for this reaction (Figure 4) The results showed that the reaction had good substrate adaptability and showed high stereoselectivity In addition to o-hydroxycinnamaldehyde, o-aminocinnamaldehyde is also suitable for the reaction Fig 4.1 and the reaction substrate expansion of the five membered ring imine 4 (source: org Lett.) however, the author further found that the size of the ring system of the ring imine has a great influence on the reaction process Only the intermediate of path B was obtained, which can be separated and identified Further oxidation or acid catalyzed ring closing reaction can respectively obtain 4-substituted chroman-2-one derivative 12a and bridge ring compound 13A (Fig 5) Fig 5 1a and 10A reaction diversity (source: org Lett.) the author then expanded the substrate for the reaction of hexameric imine with o-hydroxycinnamaldehyde (Fig 6), and the results were satisfactory for various types of substituted substrates Fig 6.1a reaction substrate development (source: org Lett.) of hexameric imine 10 In the study of synthesis and transformation of product 13, the enamine part of the product structure can be oxidized and broken by m-CPBA to produce two different heterocyclic products (Fig 7) The type of product depends on the electrical properties and position of the substituents on the aromatic ring of hexamer imines When the substituent is h or F, only product 14 is produced, while the methyl substituent is produced at the same time, and only product 15 is obtained when the ortho and para position of the imine group are connected with the strong power supply group methoxy Fig 7 Oxidation conversion of compound 13 (source: org Lett.) the mixture of reaction intermediates of compounds 1a and 4A cannot be oxidized to form 4-substituted chroman-2-one derivative 9a, which can be obtained by ring opening isomerization of 6A in acid condition (Fig 8) Fig 8.6a was transformed into 9A in acid condition (source: org Lett.) summary The author developed an efficient organic catalytic series reaction, using the characteristics of o-hydroxycinnamaldehyde and cyclic sulfonimide multi reaction sites, successfully constructed the bridge ring or spiral bridge ring skeleton of chiral benzoacetamide structure The developed reaction substrate has wide application range and high stereoselectivity The results were recently published in the organizational letters (DOI: 10.1021 / ACS Orglett 9b01874) Review of previous reports: research group of Liu Yankai, associate professor of Ocean University of China: diversified synthesis of bridged compounds containing chiral acetals; research group of Liu Yankai, associate professor of Ocean University of China: asymmetric synthesis of spiro bridged and spiro fused heterocyclic compounds containing chroman, indole and oxindole structures Liu Yankai, associate professor of Ocean University of China Research Group: asymmetric organic catalytic series reaction of cyclic hemiacetals with complex structure and functional Nitroalkenes to synthesize multiple heterocycles Today, science and technology elements are increasingly valued in economic life, 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 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