Professor Xie Weiqing's research group of northwest agricultural and Forestry University: efficient asymmetric tandem Michael addition of tryptamine derived indole oxide and alkynone and its application in total synthesis of Logan alkaloids

The structure units of pyrrolidine oxyindole are widely found in various monoterpene indole alkaloids and drug molecules At present, there are many reports on the synthesis of the skeleton However, how to achieve efficient asymmetric synthesis of the skeleton is still very challenging Recently, the research group of Xie Weiqing, Professor of northwest agricultural and Forestry University of science and technology, has made a breakthrough in this field, successfully realized the asymmetric tandem Michael addition reaction of tryptamine derived indole and alkynone, and applied this method to the efficient asymmetric synthesis of (- - tubifoline, (-) - tubifolidine, (-) - dehydrotubifoline A brief introduction to the research group of Professor Xie Weiqing on the highly efficient asymmetric total synthesis of alkaloids (- - tubifoline, (-) - tubifolidine, (-) - dehydrotubifoline (source: angelw Chem Int ed.) Professor Xie Weiqing's research group was established in June 2015 At present, there are 1 postdoctoral, 5 doctoral, 5 Master's and 4-6 undergraduates who have been doing scientific research in the research group for a long time At present, the main research directions of the research group are: 1 Asymmetric catalytic reaction and its application in the total synthesis of natural products; 2 The synthesis of natural products with important physiological complex activities; 3 Chemical biology research based on natural products Brief introduction to Professor Xie Weiqing, professor and doctoral supervisor of northwest agricultural and Forestry University, winner of National Natural Science Foundation Outstanding Youth Fund (2017), and winner of Shaanxi Youth "hundred talents plan" Graduated from Lanzhou University in 2002 with a Bachelor of Science degree In 2007, he received his Ph.D from Shanghai Institute of organic chemistry, Chinese Academy of Sciences, and studied with Ma DA as a researcher After graduation, he stayed in Shanghai Institute of organic chemistry, Chinese Academy of Sciences as an assistant researcher In 2009, he went to Southwest Medical Center to carry out postdoctoral research In 2011, he returned to Shanghai Institute of organic chemistry, Chinese Academy of Sciences as an associate researcher In 2015, he was introduced to northwest agricultural and Forestry University as a young talent and served as a professor and doctoral supervisor More than 20 papers have been published in international academic journals included in SCI, such as J am Chem SOC., angelw Chem Int ed., org Lett., chem Commun Leading scientific research achievements: Michael addition of tryptamine derived oxidized indole and alkyne ketone in highly efficient asymmetric series and its application in the total synthesis of Logan alkaloids monoterpene indole alkaloids widely exist in nature, with multi ring skeleton structure, and show a variety of physiological activities, which is an important source of drug development The structure units of pyrrolidine oxyindole are widely found in various monoterpene indole alkaloids and drug molecules At present, there are many reports on the synthesis of the skeleton Among the monoterpenoid indole alkaloids, Logan alkaloids are based on cyclohexane and pyrrolidine, and have a characteristic bridge ring (D-ring) Since Woodward completed the synthesis of strychnine, a natural product of Logan, the exploration of new methods and strategies for the synthesis of such natural products has never stopped Although tetrahydropyrrole oxyindole contains a, B and C rings of Logan alkaloids and the core skeleton of natural products of oxyindole, the application of this structural unit in the total synthesis of Logan alkaloids has not been reported Figure 1: natural products with tetrahydropyrrole spiro indole skeleton and total synthesis of Logan alkaloids by asymmetric tandem Michael addition (source: angelw Chem, In Ed.) inspired by the reported series Michael addition reaction and the Michael addition reaction of indole oxide, Professor Xie Weiqing's research team realized the asymmetric series Michael addition reaction of indole oxide 2 and alkyne ketone 3 by using the SC (OTF) 3-chiral diazoamide catalytic system developed by Professor Feng Xiaoming of Sichuan University, and successfully applied the method to Logan alkaloids (-) - tubifoline, (-) - tubifoldine, (-) - dehydrotubifoline, in highly efficient asymmetric total synthesis Figure 2: selection of reaction conditions (source: angelw Chem., int ed.) Firstly, the author selected ligands, bases and solvents of the reaction with 2a and 3a as model substrates, and finally determined the optimal conditions with L1 as ligand, 1,2-dichloroethane as solvent and Na 2CO 3 as base Figure 3: indole oxide substrate development (source: angelw Chem, In Ed.) later, the author investigated the applicability of the substrate and found that indole 2 oxide The protecting group of intermediate primary amines is very important for the series reaction When using sulfonyl protecting group, the target product can be obtained with good enantioselectivity; but when using carbamate protecting group, only the indole oxide addition product can be obtained, which may be caused by the reduction of nucleophilic property of nitrogen By changing the substituents on the benzene ring, it is found that both the electron acceptor and the electron donor have good enantioselectivity However, the enantioselectivity of the C-7 site is not ideal, whether it is an electron acceptor or a electron acceptor Figure 4: alkynone substrate development (source: angelw Chem, In addition, different alkynes were used to study the reaction It was found that the alkynes, whether directly connected or branched, can be obtained with good enantioselectivity, and some functional substrates, such as alkenyl, halogen, TBS protected hydroxyl, ester and acetal, have good tolerance It also provides more possibilities for later application The enantioselectivity of arylalkyne ketone decreased slightly Fig 5: asymmetric total synthesis of Logan alkaloids (source: angelw Chem Int ed.) in order to explore the practicability of this reaction in the asymmetric total synthesis of indole alkaloids of Logan, the author used this series reaction as the key step, and completed the efficient asymmetric total synthesis of (- - tubifoline, (-) - tubifolidine, (-) - dehydrotubifoline through only 10-11 steps In the synthesis process, the double activation strategy was adopted to solve the racemization problem of the indole compound oxidized by tetrahydropyrrole The E-ring was constructed by intramolecular condensation The bridge ring D was constructed by intramolecular allylation promoted by SnCl4, and the racemization caused by intramolecular reverse Mannich reaction was avoided This is the first time to complete the asymmetric total synthesis of indole alkaloids from Logan through the oxidation of indole compounds by pyrrolidine, which provides a new way for the total synthesis of monoterpene indole alkaloids The research results were published in angelw Chem Int ed., and he Weigang, Ph.D., Hu Jiadong, and Wang Pengyan, M.D., were the co authors of the paper The research work was supported by the National Natural Science Foundation of China, northwest agricultural and Forestry University of science and technology, and the National Key Laboratory of life organic chemistry Related paper link: http://onlinelibrary.willey.com/doi/10.1002/anie.201800567/full Professor Xie Weiqing's research group homepage: http://www.xiegroup.icoc.cc/ about people and scientific research are increasingly valued in economic life today, China 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, chembeango app, 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.