Liu Yankai, associate professor of Ocean University of China: asymmetric organic catalytic series reaction of cyclic hemiacetals with complex structure and functional Nitroalkenes to synthesize multiple heterocycles

The structure of the lead containing chiral cyclic acetals is the basic skeleton of many natural products and drug molecules Many of these compounds show good biological activity, so it attracts many chemical researchers to engage in the synthesis of similar skeleton Recently, the research group of Liu Yankai, associate professor of Ocean University of China, has used the strategy of asymmetric organic catalytic series reaction (aocp) to construct two separable epimers with quaternary carbon chiral center cyclic acetal structure with high stereoselectivity, and modified and transformed the intermediates and products with various structures (DOI: 10.1021 / ACS Orglett 8b01386) Liu Yankai, associate professor of Ocean University of China He was an associate professor of Southwest Jiaotong University from 2012 to 2013, and has been an associate professor of Ocean University of China since 2013 Liu Yankai, associate professor, presided over and participated in a number of research topics such as NSFC and the second level of "talents" of Ocean University of China In the past few years, he has carried out in-depth research on the reactions catalyzed by carbene, chiral bifunctional thiourea and chiral amines, J More than 30 research results have been published in high-level international SCI journals such as am Chem SOC And org Lett Leading scientific research achievements: heterocyclic compounds with asymmetric structure and stereo diversity, containing chiral cyclic acetals, widely exist in active natural products and drug molecules, and these compounds are often used as important synthesis precursors in organic synthesis Direct structural modification of cyclic acetals or hemiacetals is the most simple and efficient way to synthesize these heterocyclic compounds Liu Yankai, associate professor of Ocean University of China, has long been committed to the application of asymmetric catalysis in the synthesis of heteropolycyclic compounds The team's previous research found that hemiacetals have unique properties that general aldehydes do not have in asymmetric synthesis of heterocyclic compounds Hemiacetals (amines) can be obtained by reduction of lactones or lactams Hemiacetals (amines) and corresponding hydroxy (amino) aldehydes exist in a state of equilibrium After ring opening, hydroxy (amino) aldehydes can be modified at the α position by catalysis of organic small molecular catalysts After ring closing, hemiacetals (amines) can be simply oxidized to obtain α Asymmetric modified lactones and lactams (org Lett., 2015, 17, 2022-2025; org Lett., 2015, 17, 3794-3797; org BIOMOL Chem., 2016, 14, 6316-6327) Then, the team introduced a modified group containing different electrical functional groups at the α position of hemiacetal, and utilized the hydroxy (amine) nucleophilic (org Lett., 2016, 18, 864-867; org Chem Front., 2017, 4, 2358-2363; org BIOMOL Chem., 2017, 15, 1407-1417), and the electrophilic properties of oxyonium salt after dehydration under the acid condition of semicolon (aldehyde) (amine) (org Lett., 2018, 20, 1630-1633; J org Chem., 2017, 82, 4774-4783; J.Org Chem., 2017, 82, 10450-10 460; org BIOMOL Chem., 2016, 14, 2444-2453), a series of polycyclic acetals (amines) and ketals were synthesized By using the strategy of opening and closing the ring, our group has opened a new way for the synthesis of unsymmetrical substituted heterocycles and heteropolycyclic compounds It has been a challenge in organic synthesis to construct a highly stereoselective quaternary carbon chiral center Based on the previous research results, the research team found that the low-cost column chromatography can quickly separate two differential isomers containing acetal groups Therefore, column chromatography is a potential method for the synthesis of quaternary carbon chiral centers Therefore, racemic hemiacetals containing a quaternary carbon chiral center are used as the reaction substrate, and each hemiacetal substrate can achieve a yield of more than 800 mg through two-step reaction In addition, compared with the common β - substituted Nitroalkenes, the research group selected the functional Nitroalkenes containing acetals as Michael receptors, and constructed the structural units containing chiral cyclic acetals through asymmetric organic catalytic series reaction Figure 1 Upgraded hemiacetals and Nitroalkenes (source: org Lett.) according to the above design strategy, the author developed a new method to synthesize complex multi heterocyclic compounds by asymmetric organic catalytic series reaction In the reaction, α, α - diphenylproline trimethylsilyl ether (20 mol%) was used as catalyst and benzoic acid (20 mol%) as additive Two key semi acetal intermediates (6a, 6'a) which can be separated can be obtained by relatively complex reaction of initial semi acetal (±) 3a and functional nitroalkene 4 A series of enantiomeric isomers (7a, 7'a) containing chiral cyclic acetals were obtained by series reaction with high enantioselectivity (more than 99% ee) Fig 2 Two differential isomers 7a and 7'a (source: org Lett.) were obtained by series reaction The reaction has good substrate adaptability A variety of substituted semiacetal substrates (±) - 3, including alkynyl, alkenyl, ester and semiacetal, can be used in this reaction The products can be separated by column chromatography, and two stereoselective isomers can be obtained Fig 3 The results of substrate adaptability experiment (source: org Lett.) later, the author selected the product 7'm for further synthesis and transformation to show the application of this method in synthesis Under the condition of BF 3 · et 2O, 7'm reacts with PHSH and tmscn respectively to obtain 8 and 10 containing bicyclic acetals The sulfur atom in compound 8 can be oxidized to sulfone 9 by m-CPBA The product 7'm formed lactone compound 11 under the action of BF 3 · et 2O and m-CPBA, and then in the presence of triethylamine, a dicyclolactone compound 12 containing double bonds outside the ring was obtained In addition, 7'm nitroalkyls can be converted into cyano containing compounds 13 and amide containing compounds 14 by series reaction under mild conditions Finally, 7'm reacts with ethyl acrylate to form compound 15, which is reduced by nitro group to form lactam 16 Fig 4 Synthesis and transformation of 7'm (source: org Lett.) Michael addition products 6 and 6 'intermediates can also be further derived 6'a can be oxidized by DESs Martin oxidant to generate corresponding monocyclic lactone compound 17, which reacts with indole to generate compound 18 under the action of BF 3 · et 2O Under the action of aqueous acetone and p-toluenesulfonic acid, 6'm can form a bicyclic hemiacetal compound 19 The compound 20 can be obtained by hosomi Sakurai reaction under the catalysis of BF 3 · et 2O, and the compound 21 can be obtained by ET 3 SIH reduction under the catalysis of BF 3 · et 2O Fig 5 Synthesis and transformation of 6'a and 6'm (source: org Lett.) in summary, Liu Yankai's research group prepared a series of relatively complex cyclic semiacetals with racemic quaternary carbon chiral centers by a simple method Then, two stereoselective isomers with high stereoselectivity were synthesized by the reaction of the hemiacetals and the functionalized Nitroalkenes The process is simple and suitable for a variety of substituted cyclic hemiacetals In addition, when the scale of the reaction was enlarged to 8 mmol, there was no effect on the yield and stereoselectivity At last, the intermediate and product were modified and transformed The results were recently published in organic letters (DOI: 10.1021 / ACS Orglett 8b01386) The first author of the paper is Pei Junping, a master of Ocean University of China Liu Yankai, associate professor of Ocean University of China research team: organic catalytic asymmetric synthesis of heterocyclic compounds with structure and stereodiversity 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 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.