Research group of Professor Ye Longwu of Xiamen University: stereoselective synthesis of mesolactam by [1,3] - rearrangement series reaction based on alkynamide

Lead rearrangement is widely used in organic synthesis chemistry because of its high bonding efficiency and high atom economy [3,3] - rearrangement often goes through chair transition state and has high stereospecificity, which has been widely studied However, the [1,3] - rearrangement reaction often involves ion pair intermediates, and the stereospecific [1,3] - rearrangement has always been very challenging, with few relevant reports (Fig 1) Recently, the research group of Professor Ye Longwu of Xiamen University successfully realized the stereoselective synthesis of a series of cyclolactams through the series reaction of alkynamide oxidation / [1,3] - rearrangement catalyzed by nonmetallic br ø nsted Acid Relevant results were published online in nature communications (DOI: 10.1038/s41467-019-11245-2) Figure 1 Comparison of [3,3] - rearrangement and [1,3] - rearrangement (source: Nat Commun.) brief introduction to Professor Ye Longwu's research group, the research group has been committed to the selective control of alkyne conversion and the synthesis of heterocyclic structural diversity In this paper, through the strategy of directing group and ring tension, we developed a series of anti Markovian addition reactions based on anti Markovian or formalism, realized the regioselectivity control of alkyne reaction, 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, bioactive molecules and Efficient and simple synthesis of drugs Since its establishment (2012 to now), the research group has published more than 50 papers of corresponding authors in international famous journals, including 15 if > 9.5 papers of NAT Commun., J am Chem SOC., angel Chem Int ed., chem SCI., ACS catalyst And 18 If > 6 papers of greenchem., chem Commun., org Lett The corresponding author's papers have been cited for more than 1600 times (h-index: 37 http:// of which 6 are highly cited ESI papers, 2 research papers have been cited for more than 140 times, and 1 research paper has been selected as the top 1% highly cited articles of Royal Society of chemistry in 2017 (2015-2016) Brief introduction to Professor Ye Longwu, professor and project leader of School of chemistry and chemical engineering, Xiamen University Graduated from Zhejiang University in 2003 From 2003 to 2008, he studied in the State Key Laboratory of metal organic, Shanghai Institute of organic science, Chinese Academy of Sciences, under the guidance of academician Tang Yong From 2008 to 2011, he 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 was awarded the first prize of "Tian Zhaowu interdisciplinary interdisciplinary Award" of Xiamen University (2019) and so on Leading scientific research achievements: Based on the stereoselective synthesis of [1,3] - rearrangement series reaction of alkynamides, cyclolactams are widely found in natural products and bioactive molecules However, due to the hindrance of entropy and enthalpy in the process of cyclization, the construction of this kind of meso lactam has always been a challenge in organic synthesis chemistry At present, only limited methods such as precious metal catalyzed cycloaddition reaction can be used to construct meso - cyclolactams Inspired by the previous work of our research group on alkyne oxidation / [3,3] - rearrangement series reaction (angel Chem Int ed 2017, 56, 4015; chem SCI 2019, 10, 3123), the author has realized alkyne oxidation catalyzed by nonmetallic br / nsted Acid Using the special reaction characteristics of alkyne amide, 3] - rearrangement series reaction, and a series of functional mesocyclic lactam compounds have been successfully constructed by using such reaction (Fig 2) Fig 2 A series of typical gold catalysts and Lewis acid catalysts were first tried in the series reaction of alkynamide alkane oxidation / [1,3] - rearrangement catalyzed by br ø nsted Acid (source: Nat Commun) It was found that the reaction could be carried out under most catalyst conditions, and the product of octagonal cyclolactam was obtained in medium yield It is found that the equivalent of HOTf catalyst plays a key role in the reaction yield through the screening of Br? Nsted Acid Catalyst Finally, the optimal equivalent of HOTf catalyst for the oxidation / [1,3] - rearrangement of alkynamide alkane is 0.5 mol% Through the study of the universality of the substrate, it is found that the series reaction substrate has a wide range of application and high yield, and various types of benzo [D] acrinone octagonal cyclolactam products can be obtained (Fig 3) Figure 3 Study on the universality of substrates: synthesis of benzooctacyclolactam (source: Nat Commun) Based on the above-mentioned substrates, the author synthesized a series of allyl alcohol alkynamide substrates It was found that no [3,3] - rearrangement products were observed in this reaction system, only [1,3] - rearrangement products were observed Furthermore, they successfully applied the series reaction to the synthesis of benzo-9-membered and heterocyclo-8-membered cyclolactams (Fig 4) Fig 4 After the racemization of other types of octagonal and nine membered cyclolactams (source: Nat Commun.) obtained satisfactory results, the author realized the asymmetric alkoxylation / [1,3] - rearrangement series reaction catalyzed by chiral br / nsted Acid Using the desymmetry strategy The preliminary study of substrate universality found that the reaction has good functional group tolerance, which will lay a foundation for the further study on the asymmetric reaction of alkynamide by the research group (Fig 5) Figure 5 Substrate universality study: synthesis of chiral benzooctacyclolactam (source: Nat Commun.) in order to further prove the potential application value of the reaction, the author conducted gram scale amplification and product derivation for the reaction, including SMI 2 deprotection, methylation, oxidation, etc (Figure 6) In addition, they tested the bioactivity of the synthesized products, and found that most of the compounds have certain anticancer activity Figure 6 Gram scale reaction and product derivatization (source: Nat Commun.) based on a series of mechanism experiments and theoretical calculations, the author proposed the mechanism of the reaction (Figure 7) Firstly, under the activation of HOTf, alkynamide 1a is transformed into diene imine positive ion intermediate a, and then it receives the attack of intramolecular hydroxyl to obtain the octane cycloalkenyl ether intermediate B with double bond of single e formula On the basis of intermediate B, the key intermediate 6A was obtained by leaving a molecule of HOTf, and the catalyst was regenerated Finally, the intermediate 6A undergoes the rearrangement of [1,3] o-to-c under heating conditions to obtain CIS benzo [D] acrinone product 2A When the chiral Br? Nsted Acid is used as catalyst, the kinetic resolution of the chiral control step occurs in the first stage of alkoxylation The coordination model may be as follows: firstly, the protons of the chiral br ø nsted Acid are given to activate the alkynamide to obtain the intermediate a ', and the negative ion a * - of the chiral br ø nsted Acid is complexed with the intramolecular Oh in the form of hydrogen bond, respectively, and interacts with the N + ion in the form of positive and negative ion pairs This is equivalent to the formation of a large intramolecular rigid complex, which can well control the chirality of the intermediate 6a of alkoxylation, and finally control the enantioselectivity of the target product In order to further study the non enantioselective control of [1,3] o-to-c rearrangement process, the DFT theoretical calculation has been carried out The rearrangement of (R) - 6A intermediates shows that the transition states of C-O bond breaking in the formation of two kinds of enantiomeric rearrangement products are TS ￣ CIS and TS ￣ trans, respectively At the same time, the energy of transition state TS CIS experienced by the target CIS product 2a is 9.7 kcal / mol lower than that experienced by the trans product 2A trans The results show that the enantioselectivity of the products is controlled by kinetic factors Fig 7 Reaction mechanism (source: Nat Commun.) to sum up, the author has realized the series reaction of alkoxylation / [1,3] - rearrangement catalyzed by nonmetallic br ø nsted Acid by using alkyne amide as an activated alkyne, and constructed a series of functional cyclolactams In addition, a series of chiral mesocyclic lactams were synthesized by parallel kinetic resolution strategy catalyzed by chiral Br? Nsted Acid The final product derivatization and biological activity test lay the foundation for the further application of this kind of reaction The research work was mainly completed by Zhou Bo, a 2016 level doctoral student of Ye Longwu research group, with the assistance of other graduate and undergraduate students of the research group The chiral spirocyclic phosphinamide catalyst used in the experiment was provided by academician Zhou Qilin and Professor Zhu shoufei of Nankai University, and the theoretical calculation was completed by Professor Peng Qian of Nankai University Special thanks to Professor Deng Xianming's research group for their help in biological activity test and Professor Zheng Nanfeng's research group in single crystal analysis The research work was supported by NSFC (21772161, 21622204, 21625204, 21702109, 21890722), President's fund of Xiamen University (20720180036), National Basic Science Talent Training Fund (j1310024), Changjiang Scholars and innovation team development plan of the Ministry of education, etc 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