Xu Jing group of South University of science and technology: Total Synthesis of daphaldhamine B

The alkaloids from photiniaceae, which are widely distributed in China, New Guinea and Japan, are highly complex and diverse in structure and bioactivity They have attracted the attention of numerous synthetic chemists for a long time Since professor Heathcock's classic bionic synthesis, famous scientific research groups at home and abroad, such as carreira, Li Ang, Fukuyama, Smith, hanesian, Zhai Hongbin, Dixon, Qiu fayang, Gao juehu, Sarpong, etc., as well as the Xu Jing research group of the University of South Science and technology, have successively completed the total synthesis of more than 20 biological alkali molecules of Photinia Hupi Recently, Professor Xu Jing's research group of South University of science and technology successfully completed the asymmetric synthesis of dapholdhamine B and its lactone derivatives by 21 step linear route for the first time It is also the first synthetic natural product of azaadamantane The results were published in J am Chem SOC (DOI: 10.1021 / JACS 9b05641) Prof Xu Jing's research group is mainly concerned with the synthesis of complex natural products, natural products and small molecule pharmaceutical chemistry At present, the research group has completed the total synthesis of several complex diterpenoids, sesquiterpenes, indole alkaloids and Machilus hupehensis alkaloids, such as phaseic acid, strychnofoline, astralatol, astralatene, atropurpuran, himalensine a, daphaldhamine B, etc., and has also completed the total synthesis of these alkaloids in nature Rev Chem., J am Chem SOC., angel Chem Int ed, Nat Prod Rep and other world-class chemical journals published many papers At present, the research group has 3 postdoctoral students, 3 doctoral students, 5 Master students and 3 research assistants The research group is looking for postdoctoral and research assistant of organic synthesis (homepage of the research group: http://factory.sustc.edu.cn/? TagID = Xuj) Professor Xu Jing, researcher, associate professor and independent project leader of Department of chemistry, South University of science and technology Double Professor, Shenzhen grabs Research Institute, South University of science and technology Graduated from Nanchang University in 2000 In 2004, he graduated from Tongji University with a master's degree and then joined Wuxi apptec as a researcher 2005-2009 Ph.D in Leipzig University, Germany From 2009 to 2013, he worked as a postdoctoral researcher at the University of California, San Diego (UCSD) In April 2014, he joined the Chemistry Department of South University of science and technology to carry out independent research In the same year, he was selected into the "peacock program" of Shenzhen overseas high-level talents In 2015, it was selected into the national "youth millennium plan" In 2016, he was selected as a core member of "peacock team" in Shenzhen Leading scientific research achievements: dapholdhamine B, a total synthetic alkaloid of pholidhamine B, is isolated from pholidhamine B, which is widely distributed in China, New Guinea, Japan and other places, and has a highly complex and variable ring skeleton structure According to the theory of traditional Chinese medicine, photiniaceae plants, such as jiaorang wood, niuerfeng, and Hupi Nan, have the functions of clearing away heat and detoxification, promoting blood circulation and removing blood stasis, cowardly wind and relieving pain, and treating furuncle and swelling toxin Modern scientific research has also found that some alkaloids of Photinia hupehensis have important activities of anti-cancer, anti HIV, neurotrophic and so on The complex and diverse chemical skeleton structure and good biological activity of alkaloids from Photinia hupehensis have attracted the attention of numerous synthetic chemists for a long time Since professor Heathcock's classic highly efficient biomimetic synthesis, famous scientific research groups at home and abroad, such as carreira, Li Ang, Fukuyama, Smith, hanesian, Zhai Hongbin, Dixon, Qiu fayang, Gao embohu, Sarpong, and Xu Jing research group of South University of science and technology, have successively completed more than 20 wonderful total synthesis of alkaloid molecules of Phoebe, as shown in Figure 1 (chem Rev 2017, 117 , 4104; Angew Chem Int Ed 2018 , 57 , 952; J Am Chem Soc 2018 , 140 , 4227; Angew Chem Int.Ed 2018 , 57 , 947; Angew Chem Int.Ed 2019 , 58 , 5754; Angew Chem Int Ed 2019 , 58 ,7390; Org Lett 2019 , 21 , 3741; J Am Chem Soc 2019 , 141 , 8431 ） 。 Because of the high diversity of alkaloid skeletons, there are still many alkaloid families to be studied and explored Recently, Xu Jing's research group completed the asymmetric synthesis of daphaldhamine B for the first time It is also the first synthetic natural product of azaadamantane Fig 1 The skeleton of daphnezominea alkaloid and the chemical structure of daphnezomine a alkaloid (source: j.am Chem SOC.) daphyldhamine B is a daphnezominea type alkaloid (j.nat Prod) extracted from Daphniphyllum oldhamii in 2009 by Professor Hao Xiaojiang's research group 2009 , 72 , 1325 ）。 Dapholdhamine B has a unique structure of azaadamantane, eight chiral centers and three consecutive all substituted quaternary carbon centers The synthesis of dapholdhamine B is very challenging, and there is no report on the synthesis of alkaloids from Machilus hupehensis Recently, Xu Jing group completed the first and asymmetric total synthesis of daphaldhamine B in 21 steps As shown in Figure 2, the research of Xu Jing's research team started from the known compound 6 Through the asymmetric Robinson ring increasing reaction (synlett 2008, 2831) catalyzed by l-prolimide developed by academician Tu Yongqiang and Professor Zhang Fumin, diketone compound 5 was obtained, which was introduced into the first quaternary carbon chiral center in the molecule After the conversion of compound 5 to enol methyl ether, the nitrogen-containing side chain was introduced by intercalation Mannich reaction, and then the allyl group on the nitrogen atom was replaced with p-toluenesulfonyl protecting group to obtain compound 9 The steric hindrance brought by the side chain of the structure makes the introduction of methyl difficult Finally, the condition developed by Professor luche was used to successfully introduce methyl, thus the second quaternary carbon chiral center was constructed After that, the compound 10 was transformed into ketene 12 using oxidant 11 developed by Professor Mukaiyama After the final epoxidation and bromination, Suzuki coupling reaction introduced three carbon fragments, then removed PMB protection group through can oxidation, and obtained important intermediate 18 through intramolecular azamichael addition reaction, enol trifluoromethylsulfonate synthesis and double bond hydrogenation Figure 2 Synthesis of intermediate 18 Next, the carbonyl group in compound 18 is reduced and eliminated to obtain compound 19 Subsequently, the research group successfully obtained the tetracyclic intermediate 21 by using Huang Peiqiang, Professor of Xiamen University, to activate the ring increasing reaction of xanthamide (chin.j.chem 2019, 37, 315; chin J.Chem 2017, 35, 613; org Chem Front 2017, 4, 431; SCI Rep 2016, 6, 28801) The allyl alcohol compound 22 was obtained by overall reduction of 21 by pressurized hydrogenation and then oxidized to carboxylic acid Compound 23 was synthesized by the reaction of S N 2 ′ with carboxyl group as nucleophile under acid condition Then it was transformed into compound 24 by borohydride oxidation After the protection of TS was removed, the Appel reaction in the molecule took place to get compound 25 The azaadamantane skeleton of daphaldhamine B was successfully constructed, and its structure was confirmed by single crystal diffraction In the end, the first asymmetric synthesis of daphaldhamine B was completed by using reagent 26 to extend the carbon of compound 25 through HWE reaction and hydrolyze the thiol structure in one pot Because the natural product is an amino acid structure, its nuclear magnetic spectrum is very sensitive to pH value, so it can not be compared with the literature Therefore, the author transformed 1 into its lactone structure 29 in acid condition The first synthesis of daphaldhamine B was confirmed by the in-depth NMR analysis of 29 and the undoubted structure characterization of the last intermediate 25 Figure 3 Total synthesis of dapholdhamine B this synthesis uses efficient and novel strategies and methods, and still ensures the efficiency of the synthesis route in the face of complex molecules with considerable difficulty The study was recently published online in J am Chem SOC (DOI: 10.1021 / JACS 9b05641) The experimental part was completed by Guo Liandong, Hou Jieping, Tu Wentong, Zhang Yan, Zhang Yue and Chen louxi of Xu Jing's research group The research work was supported by the general fund of National Natural Science, Shenzhen development and Reform Commission, Shenzhen science and technology innovation Commission and Shenzhen glabus Research Institute Review of previous reports: Xu Jing group of South University of science and technology: 14 step synthesis of alkaloid (-) - himalensine a from Phoebe robusta People and scientific research are increasingly valued in economic life Today, 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.