Li Wenjun of Qingdao University and Li Pengfei of South University of science and technology

The long-distance stereoscopic control of lead organic catalysis is a synthesis strategy to construct stereoscopic center from the reaction functional group At present, how to control the regioselectivity and stereoselectivity of these reactions is a great challenge In recent years, asymmetric 1,6-conjugated addition reactions catalyzed by organic catalysts in this field have attracted extensive attention and achieved remarkable results Although the electrons of the guiding group can be delocalized in the conjugated system to maintain the reaction activity of the conjugated system, the reports of asymmetric 1,8-conjugation addition catalyzed by organic catalysts are very limited Compared with asymmetric 1,6-conjugate addition reaction, asymmetric 1,8-conjugate addition reaction is more challenging, and the research in this field is still in its infancy Recently, on the basis of previous work (chem Asian J 2018, 13, 2350-2359), Li Wenjun research group of School of pharmacy, Qingdao University and Li Pengfei research group of South University of science and technology have made a series of breakthroughs in the field of remote stereoscopic control of organic catalysis, realizing the asymmetric 1,6-addition reaction of methylene quinone and acridolide (org Lett 2018, 20, 1142-1145), asymmetric [4 + 3] cycloaddition with unsaturated aldehydes (adv synth Catalyst 2018, 360, 2460-2464), asymmetric 1,8-conjugate addition of propargylic p-methylenequinone with thiazolone and acridolide (org Lett 2019, 21, 503-507), asymmetric 1,8-conjugate addition of propargylic p-methyleneazaquinone with thiazolone (org Lett 2019 , 21 , 7415-7419 ）。 The regioselectivity and stereoselectivity of these reactions are very good, especially the asymmetric 1,8-conjugation provides a simple and effective method for the construction of the chiral centers of four substituted carbon atoms with heteroatoms and the framework of axially chiral four substituted dienes Li Wenjun task group Li Wenjun task group was founded in 2015, relying on the school of pharmacy, Qingdao University There are 11 postgraduate students in the research group The research directions include: 1) organic synthesis chemistry: developing high selectivity, high efficiency, economy and environment-friendly synthesis methodology; 2) pharmaceutical synthesis chemistry: using organic catalysis to synthesize active drug molecules and carry out activity research; 3) process chemistry: Research on new synthesis methods and process chemistry development of chiral drugs and intermediates and natural drugs Li Wenjun, Ph.D., distinguished professor of Qingdao University, young expert of Taishan scholar, Shandong Youqing In 2006, he graduated from Zhengzhou University, and in 2011, he graduated from East China University of science and technology From January 2012 to July 2015, he was engaged in post doctoral research at National University of Singapore and Tsinghua University respectively During his doctoral and post doctoral period, he mainly engaged in the field of organic small molecule catalysis In July 2015, Dr Li Wenjun joined Qingdao University with high-level talents He is currently the team leader of "asymmetric catalysis and drug synthesis" in the school of pharmacy of Qingdao University So far, Dr Li Wenjun has been working in the world famous magazine angelw Chem Int ed., chem Commun., green chem., acsacatal, Org Lett Et al Published more than 40 SCI papers, of which 39 were the first author and corresponding author, 2 were highly cited, several were highlighted by angelw Chem Int ed and synfacts as highlight work or introduced as cover article, and 4 national invention patents have been authorized At present, as the project leader, he presides over the National Natural Science Foundation, Shandong Provincial Excellent Youth Fund and Qingdao University Distinguished Professor start-up fund Brief introduction of Li Pengfei's research group Li Pengfei's research group was established in January 2012 The research group is committed to the research fields of asymmetric catalysis and chemical biology: 1) building a three-dimensional Center for asymmetric organic catalytic addition reaction, which is embodied in the research and development and application of new organic catalysts and strategic synthesis of high value-added chemicals; 2 ）The research of chemical biology focuses on the development of protein labeling technology and multifunctional probes Li Pengfei, Ph.D., associate professor (researcher) of Chemistry Department of South University of science and technology, Shenzhen overseas high-level "peacock plan" talents (class B), Shenzhen "reserve level" talents, Shenzhen Nanshan District navigation talents (class B); in 2009, Dalian Institute of Chemical Physics, Chinese Academy of Sciences received a doctorate in organic chemistry From 2009 to 2011, he successively engaged in postdoctoral research at Hong Kong Polytechnic University and Hong Kong Baptist University Since 2012, he has been an assistant professor (associate researcher) in the Department of chemistry, South University of science and technology, and has set up an organic biomimetic catalysis research group to independently carry out research work In August 2019, he was promoted to associate professor (researcher) Since he joined Southern University of science and technology, Li Pengfei has published more than 40 papers in PNAS, org Lett And other journals as a corresponding author, including 7 cover articles, 2 highly cited articles, more than 1000 citations in total, h-index 19 He has successively presided over scientific research projects such as the National Natural Science Foundation and the basic research of Shenzhen Science and technology innovation Commission Cutting edge scientific research achievements: the construction of remote control stereo center of asymmetric organic catalysis provides convenience for the remote functionalization of guiding group, and is the difficulty and hot spot in the field of asymmetric catalysis Recently, Li Wenjun group of Qingdao University and Li Pengfei group of South University of science and technology have worked together to realize asymmetric 1,6-conjugated addition and 1,8-conjugated addition of methylenequinone and its derivatives, and constructed a series of complex chiral molecules with four substituted carbon atom chiral centers and three-dimensional centers of axially chiral four substituted dienes There are two vinyl ketene systems in the structure of p-methylenequinone, which is a nonaromatic cyclohexadiene structure This structure can resonate into the form of an aromatic dipole, giving unique reactivity to p-methylenequinone Taking the conjugated addition of p-methylenequinone and acrylic ester produced in situ as an example, the asymmetric 1,6-conjugated addition of p-methylenequinone to acrylic ester catalyzed by chiral phosphoric acid was realized through the selection of catalyst and optimization of reaction conditions, and a series of complex chiral skeletons with adjacent three and four substituted carbon atom chiral centers were constructed (Fig 1) The catalytic method provides an efficient synthesis strategy for chiral a, a-disubstituted-a-amino acid ester and B, b-diaryl-a-amino acid ester Fig 1 asymmetric 1,6-conjugated addition of p-methylenequinone by internal acridine (source: org Lett 2018, 20, 1142-1145) on this basis, the author modified the structure of methylene quinone on the substrate, introduced hydroxyl to the ortho position of aromatic ring, and realized the [4 + 3] - cyclization reaction of o-HYDROXYPHENYL substituted p-methylene quinone and enoldehyde derived from indigo catalyzed by chiral carbene It is assumed that the intermediate I of Breslow intermediate was obtained by the addition of enoldehyde derived from indigo to the chiral carbene catalyst The intermediate was further isomerized into the racemic azoluhomoenoate intermediate II, which was asymmetric to the o-HYDROXYPHENYL substituted p-methylquinone, 6-conjugated addition reaction, acyl azolium intermediate III was obtained; finally, the target product spirobenzoxy heteropinone derivatives were obtained by intramolecular esterification, and the catalyst was regenerated (Fig 2) The asymmetric synthesis strategy can be applied to a series of o-HYDROXYPHENYL substituted p-methylenequinones and olefin aldehyde substrates with various substituents It should be noted that in this kind of reactions, o-hydroxyphenyl-p-methylenequinone is used as a TETRAATOMIC synthesis fragment while olefinic aldehyde plays the role of a three carbon synthon This work is also the first report on the asymmetric [4 + 3] cyclization of o-hydroxyphenyl-p-methylenequinone The synthesis strategy constructs a variety of ε - endolipid compounds containing indole skeleton, which provides a new idea for the asymmetric synthesis of seven component endolipid (Fig 3) Fig 2 [4 + 3] cyclization mechanism of o-hydroxyphenyl-p-methylenequinone and olefinic aldehyde (source: adv synth Catalyst 2018, 360, 2460-2464) Fig 3 [4 + 3] cyclization of o-hydroxyphenyl-p-methylenequinone and olefinic aldehyde (source: adv synth Catalyst 2018, 360, 2460-2464) chiral tetrasubstituted diene skeleton has attracted the attention of chemists because of its widespread existence in natural products and functional materials At present, there are few reports on the synthesis of axially chiral tetrasubstituted diene On the basis of their previous work, the two research groups jointly published their research results on the remote control of organic catalysis to construct the adjacent hybrid tetrasubstituted carbon atom chiral center and the axial chiral tetrasubstituted diene skeleton The author further modified the methylenequinone by the reaction substrate, and in-situ formed the p-methylenequinone with alkynyl group from propargyl alcohol in acid condition In this kind of substrate, alkynyl group forms a new conjugation system with the original vinyl ketene, providing more reaction sites, i.e 1,8-conjugation addition reaction can take place to obtain tetrasubstituted dienes (Fig 4) Compared with asymmetric 1,6-conjugated addition, asymmetric 1,8-conjugated addition is more challenging It is necessary to control the regioselectivity and stereoselectivity of the reaction while overcoming the reactivity Fig 4 1,8-conjugated addition of methylenequinones (source: org Lett 2019, 21, 503-507) the author first discussed the 1,8-conjugated addition reaction between methylenequinones containing alkynyl group and thiazolidone generated in situ It is found that propargyl alcohol can be easily converted into the key intermediate, alkynyl p-methylenequinone, under the action of chiral phosphoric acid Through catalyst screening and optimization of reaction conditions, the author successfully realized the reaction of thiazolidone with propargyl alcohol to obtain 1,8-adducts with various structures; in particular, these products all contain adjacent sulfur heteroquaternary carbon chiral center and axially chiral tetrasubstituted diene skeleton (Fig 5) Fig 5 asymmetric 1,8-conjugated addition of thiazolidone to propargyl alcohol derivatives (source: org Lett 2019, 21, 503-507) it is gratifying that the substrate applicability of this catalytic system is very good; when using acrylic ester instead of thiazolidone as nucleophile, asymmetric 1, 8-conjugated addition can also be carried out smoothly, resulting in a series of 1,8-addition products containing the chiral centers of adjacent aza quaternary carbon and the framework of axially chiral tetrasubstituted diene (Fig 6) Fig 6 asymmetric 1,8-conjugated addition of propargylic acid derivatives by intra acrylic ester (source: org Lett 2019, 21, 503-507) On the basis of completing asymmetric 1,8-conjugated addition of methylenequinone derivatives, the author continues to challenge asymmetric 1,8-conjugated addition of methyleneazaquinone derivatives Compared with the reaction to the derivatives of methylenequinone, the reaction to the derivatives of methyleneazaquinone is more complex: the introduction of nitrogen atoms leads to the competitive reaction between the electron rich diene amine system and the electron deficient conjugate system (Fig 7) Fig 7 asymmetric 1,8-conjugate addition of methyleneazaquinone derivatives (source: org Lett 2019, 21