Research group of Professor Ye Longwu of Xiamen University: asymmetric 6 π electrocyclization based on alkyne ether and isoxazole

Introduction 6 π electrocyclization is a very important kind of reaction for the construction of 5-7-membered cyclic compounds Because of its high stereoselectivity, high atom economy and other advantages, it has attracted great attention in recent years and has been widely used in the synthesis of natural products and bioactive molecules However, there are few reports about the catalytic asymmetric 6 π electrocyclization, especially the construction of chiral seven membered ring compounds by asymmetric 6 π electrocyclization (Fig 1) Recently, the research team of Professor Ye Longwu of Xiamen University has successfully realized the asymmetric [4 + 3] cycloaddition reaction of 6 π electrocyclization catalyzed by zinc, starting from the simple and easily available isoxazole and enyne ether, and constructed a series of chiral nitrogen-containing seven membered heterocyclic molecules The results were published online in angew Chem Int ed (DOI: 10.1002 / anie 201912534) Figure 1 Asymmetric 6 π electrocyclization (source: angelw Chem Int ed.) brief introduction of Professor Ye Longwu's research group The research group is currently committed to "selective control and diversity synthesis based on alkyne conversion" In this paper, through the strategies of guiding group and ring tension, we developed a series of homogeneous catalytic anti Markovian or formal anti Markovian addition reactions, realized the control of regioselectivity and stereoselectivity of alkyne reactions, provided a new synthesis method for the diversity synthesis of a series of functional heterocyclic molecules (with drug core framework), and successfully applied it to dozens of natural products Efficient and simple synthesis of compounds, bioactive molecules and drugs Through several years of exploration, the research team has obtained the following characteristic research results: 1) A series of new series reactions based on the oxidation, amination and cycloisomerization of alkynes substituted by heteroatoms such as alkyne amide were developed, which provided a new way for the diversity synthesis of a series of functional heterocycles; 2) a series of new series reactions based on the cycloisomerization of high propargyl amine were developed by using the cyclotension strategy to achieve the selective control A series of five member heterocyclic compounds with optical activity were synthesized by series reaction Since its establishment (2012 to now), the research group has published more than 60 papers of corresponding authors in international famous journals, including NAT Commun (2), J am Chem SOC (2), angel Chem Int ed (6), chem SCI (3), ACS catalyst (4), etc The corresponding author's papers have been cited for more than 200 times (h-index: 39), among which 6 are highly cited papers of ESI, 2 are single cited for more than 150 times; they have been repeatedly reported by the organizational chemistry portal website (7 times), synfacts (3 times), JACS homepage, synacts, chin J org Chem Etc as highlights, some articles have been selected as front Cover (5 times), frontispiece and hot paper Brief introduction to Professor Ye Longwu, professor and project leader of School of chemistry and chemical engineering, Xiamen University From 1999 to 2003, he studied in the Department of chemistry, Zhejiang University (Tutor: academician Ma Shengming), and from 2003 to 2008, he studied in Shanghai Institute of organic chemistry, Chinese Academy of Sciences (Tutor: academician Tang Yong) From 2008 to 2011, he successively worked in the Scripps Research Institute and the University of California, Santa Barbara (UCSB) as a postdoctoral researcher In 2011, he was sponsored by Jiageng chemical platform of Xiamen University to work in school of chemistry and chemical engineering of Xiamen University He has won the first prize of "Tian Zhaowu interdisciplinary Award" of Xiamen University, etc., including Fujian science foundation for Distinguished Young Scholars (2015), National Natural Science Foundation "excellent young scholars fund" (2016), Thieme Chemistry Journals Award (2016), Ministry of education young Yangtze scholars (201 7), Fujian young top talents (201 7) For two consecutive years (2017 and 2018), he has been selected as the top 1% highly cited Chinese author of the Royal Society of chemistry Cutting edge scientific research achievements: Based on the asymmetric 6 π electrocyclization reaction of alkyne ether and isoxazole, ye Longwu research group first reported the reaction between isoxazole and alkyne, and successively realized the related formal [3 + 2] and [5 + 2] cycloaddition reactions (chem SCI 2015, 6, 1265; Angel Chem Int ed 2017, 56, 605) After the publication of this work, more than 10 research groups at home and abroad have paid extensive attention to it, and developed dozens of efficient cyclization reactions of isoxazole and alkyne In particular, isoxazole is considered to be a kind of universal reagent of alkyne nitrogen oxygen double functionalization, which can be applied to the efficient construction of various nitrogen heterocycles However, these reactions are mainly catalyzed by noble metals (AU and PT), and there is no asymmetric catalytic reaction between isoxazole and alkynes The asymmetric [4 + 3] cycloaddition of 6 π electrocyclization catalyzed by cheap metal zinc was successfully realized by using alkyne ether with high activity as the substrate, and a series of chiral 2H azepine molecules were constructed Based on the previous work of the research group, the author first tried a series of cheap Lewis acid catalysts and Br? Nsted Acid Catalysts, and found that only zinc catalyst can catalyze this kind of reaction After further optimization of the conditions, the optimal reaction conditions were determined Several typical gold catalysts can also catalyze the reaction, but the yield is low Next, the substrate universality of the racemic reaction between alkyne ether and isoxazole was studied It was found that this kind of [4 + 3] cycloaddition reaction substrate has a wide range of application and good functional group tolerance When the R 2 substituent on isoxazole is alkyl, a series of 2 h-azepine products with seven membered rings were obtained with the medium to excellent yield and high enantioselectivity (Figure 2) Figure 2 Substrate universality study: synthesis of 2 h-azepine (source: angel Chem Int ed.) When R 2 substituent on isoxazole is aryl, another seven membered nitrogen-containing heterocycle: 4 h-azepine can be selectively obtained The reaction also showed good substrate universality (Fig 3) Figure 3 Study on the universality of substrates: synthesis of 4 h-azepine (source: angel Chem Int ed.) after the completion of the synthesis of racemic products, the author realized the asymmetric synthesis of 6 π electrocyclization by adding chiral ligands The chiral bis (oxazoline) with high steric hindrance was selected as the optimal ligand Subsequently, the author studied the substrate universality of the asymmetric 6 π electrocyclization reaction, and found that the reaction also showed good substrate universality, and can obtain high enantioselectivity of chiral 2H azepine molecule in medium to good yield (Fig 4) Figure 4 Substrate universality study: synthesis of chiral 2H azepine (source: angel Chem Int ed.) in order to further prove the potential application value of the reaction, the author carried out a series of product derivatization for the chiral 2H azepine molecule, including oxidation, reduction, halogenation, hydrolysis reaction, etc (Figure 5) It is worth mentioning that the enantioselectivity of the chiral 2H azepine molecule can be basically well preserved after further conversion Figure 5 Product derivatization (source: angelw Chem Int ed.) based on the previous work of the research group, the author proposed the mechanism of the reaction combining with the calculation of density functional theory (DFT) (Figure 6) Firstly, the zinc catalyst activates the triple bond of alkyne ether, and then receives the attack of nitrogen atom on isoxazole to obtain alkenyl zinc intermediate B The results show that the intermediate C1 or C2 with double bond of Z configuration is more stable in thermodynamics than C2 with double bond of e configuration The intermediate C1 undergoes a stereospecific 6 π cyclization to obtain the trans seven membered ring intermediate D1, which undergoes the transition state ts-d1 and the activation energy is 12.1 kcal / mol The results show that the trans-7-membered ring intermediate D1 is more thermodynamically advantageous than the cis-1 Finally, the final 2 h-azepine compound 3A was obtained by proton elimination and demetallization It is worth noting that the formation of 4 h-azepine compound 4AA is not good in thermodynamics At the same time, the author proposed other possible cyclization paths for intermediate C1, such as 4 π electric cyclization through transition state ts-d2, 6 π electric cyclization through transition state ts-d3 and 8 π electric cyclization through transition state ts-d4, with corresponding energy barriers of 15.5, 11.6 and 29.7 kcal / mol, it can be found that the energy barriers of 4 π electric cyclization and 8 π oxygen heterocyclization are higher than that of 6 π electric cyclization (12.1 kcal / mol), which are disadvantageous in dynamics Although the energy barrier of 6 π electro cyclization is slightly lower than that of 6 π electro cyclization, the transition state ts-d3 is a highly reversible process, so the intermediate C1 will undergo normal 6 π electro cyclization to obtain 2H azepine compound, which is consistent with the experimental results Figure 6 Reaction mechanism (source: angelw Chem Int ed.) To sum up, the author uses alkyne ether, a kind of relatively activated alkyne, to realize the asymmetric [4 + 3] cycloaddition reaction after 6 π electrocyclization catalyzed by cheap metal zinc, and constructs a series of chiral nitrogen-containing seven membered heterocyclones, and realizes the asymmetric catalysis of isoxazole and alkyne for the first time, The asymmetric catalysis based on alkyne ether compounds was realized for the first time, and the reaction was the first reported asymmetric 6 π electrocyclization reaction applied to the synthesis of seven membered rings The mechanism of this kind of reaction is well explained by DFT calculation, especially the origin of regioselectivity and stereoselectivity control The research work is mainly completed by Zhu Xinqi, a 2017 level doctoral student of Professor Ye Longwu's research group, and assisted by other graduate and undergraduate students of the research group The theoretical calculation was completed by Deng Chao, associate professor of Nanjing Agricultural University The research work was supported by the National Natural Science Foundation of China (21622204 and 21772161), the president's fund of Xiamen University (20720180036), the National Basic Science Talent Training Fund (j1310024), and the Yangtze River scholars and innovation team development plan of the Ministry of education Nowadays, people and scientific research have been paid more and more attention in the 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 website, chembeangoapp, chembeango official micro blog, CBG information wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the representative research groups in China, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.