J. Am. Chem. SOC.: asymmetric total synthesis of natural products hippolachnin A and gracioethers

On January 25, 2018, Tang Yefeng's research group, School of pharmacy, Tsinghua University, published online on J am Chem SOC, "enantioselective total syntheses of (+ - hippolachnin a, (+) - gracioether a of natural products hippolachnin A and gracioethers a, e and F", (-) - gracioether E and (-) - gracioether f) research papers, reported the latest research results in the field of natural product synthesis In 2013, Professor Lin Houwen's research group of Shanghai Jiaotong University School of Medicine found the natural product hippolachnin a from a sponge in the South China Sea The compound has a novel 5-5-4 tricyclic framework, which contains several consecutive chiral centers, and is quite challenging to synthesize The results showed that hippolachnin a had significant inhibitory activity (MIC = 0.41 μ m) against a variety of fungi, including Cryptococcus neoformans, Trichophyton rubrum, and Microsporum gypseum, which was similar to those of ketoconazole and voriconazole In addition, the compound has potential applications in the treatment of renal fibrosis, rhinositis and chronic heart failure Hippolachnin A and its homologues have attracted the interest of many synthetic chemists due to their novel chemical structures and important biological functions, and become one of the star molecules in the field of marine natural products research in recent years However, there are still many unsolved problems in the synthesis of these molecules For example, most of the reported total synthesis work is about the synthesis of racemates, and there is no asymmetric synthesis route Secondly, the existing route is only suitable for a specific target molecule, and does not have synthesis diversity In addition, the biomimetic synthesis of these molecules has not been realized In this study, based on the inspiration of biogenic synthesis and rational synthesis design, the author developed a simple, efficient and universal asymmetric synthesis strategy, and realized the cluster synthesis of (+ - hippolachnin A and its homologous compounds (+ - gracioether a, (-) - gracioether E and (-) - gracioetherf The highlights of this work include: 1) a key intermediate was obtained by asymmetric 1,4-addition reaction catalyzed by organic small molecules, and with this intermediate as the center, multiple natural products with different skeletons of the family were synthesized by "bifurcating" synthesis strategy; 2) natural product (+ - hippolachnin was realized by light promoted [2 + 2] - cycloaddition reaction as the key step The first full biomimetic synthesis of a confirmed the biogenic synthesis pathway of the molecule; 3) a novel synthesis methodology was developed, i.e., the hydrogen atom transfer (HAT) - induced form of vinyl cyclobutane and oxygen [2 + 2 + 2] - cycloaddition reaction, which efficiently constructed the core skeleton containing peroxide bond in (+ - gracioether a Compared with previous work, this study has significantly improved the synthesis efficiency, diversity and asymmetric selectivity At present, tangyefeng research group is working closely with other research groups to study the biological activity and mechanism of such natural products Cluster synthesis of (-) - hippolachnina and (+) - gracioethers (source: J am Chem SOC.) the research work was completed by Tang Yefeng research group, School of pharmacy, Tsinghua University and Dieter Enders, Professor of Aachen University of technology, Germany Tang Yefeng group is responsible for the overall synthesis strategy design, the total synthesis of all target molecules and the writing of research papers, etc Professor Dieter Enders group has completed one of the key reactions, namely the asymmetric 1,4-addition reaction catalyzed by organic small molecules Researcher Tang Yefeng is the main corresponding author of the paper (Tsinghua University is the first completion unit), Professor Dieter Enders is the co corresponding author, and Li Qingong, a 2014 doctoral student in the school of pharmacy, and Dr Zhao Kun from Aachen University of technology in Germany are the co authors of the paper Paper link: http://pubs.acs.org/doi/10.1021/jacs.7b1293 brief introduction of researcher Tang Yefeng: http:// researcher Tang Yefeng