Synthesis of seven quebracho indole alkaloids using "antenna ligands" in 7-10 steps, including three first-ever asymmetric syntheses

Professor Lijia Wang's group at East China Normal University, in collaboration with Academician Yong Tang of the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, developed a nickel (II)-catalyzed asymmetric [2+2] cyclobutanization reaction. By introducing a flexible "antenna" structure into the traditional chiral BOX ligand, they successfully achieved efficient asymmetric cyclobutanization of indole-derived heterocyclic enamines with methylene malonates. Based on this method, the team completed a concise asymmetric synthesis of seven quebracho indole alkaloids with a total yield of 29%-39% in just 7-10 steps (the longest linear step). Among them, (-)-eburine, (-)-eburcine, and (-)-minovine were achieved for the first time in asymmetric total synthesis, providing a new path for the efficient preparation of complex alkaloids. The article was published as an open access research article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background:
Natural products containing a spiroindoline skeleton have long garnered significant attention, with their well-established physiological activities. Alkaloids from the genera Strychnos nux vomica, Quebracho chinensis, and Malagasy have shown promising potential in anticancer, antimalarial, central nervous system regulation, and combating multidrug resistance. However, the synthetic nature of these natural products faces challenges due to their complex structures, diverse stereoconfigurations, and difficult selectivity control. Therefore, developing simple, efficient, and precise total synthetic strategies based on inexpensive and readily available raw materials is crucial for their synthesis. Professor Wang Lijia's team at East China Normal University, leveraging the structural characteristics of monoterpene indole alkaloids containing a spiroindoline skeleton, proposed a "push-pull electron butane stereoselective ring-opening/cyclization" strategy. In collaboration with Academician Tang Yong of the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, they developed [2+2+2] and [4+2]  cyclization reactions based on tryptamine derivatives , enabling the one-step construction of the spiroindoline skeleton. Mechanistic studies clarified the principles governing stereoselectivity , enabling precise control. Based on this strategy , the team has completed the total synthesis of four alkaloids from the Malagasy family and the enantioselective synthesis of multiple natural products from the genus Quercus, laying the foundation for drug innovation from natural sources.

Highlights of this article:
As early as the 1980s, the reaction of methylene malonates with electron-rich olefins was developed, but when it comes to heteroatom-substituted olefins, especially important substrates such as indole-substituted cyclic alkenyl amides, the reaction often fails to achieve ideal yields, which directly limits its application in the synthesis of indole alkaloids. The team has long focused on this field and ultimately solved this problem through the innovative design of "antenna ligands." When traditional chiral BOX ligands are combined with nickel metal to catalyze reactions, the activity of heteroatom-substituted olefins may be unsatisfactory due to the influence of the heteroatom's easy coordination with the metal. The team introduced an "antenna" structure (such as an n-propyl chain) into the ligand bridging part, which not only did not affect the chiral control, but also solved the interference of heteroatoms in the substrate on the central metal, allowing the catalyst to maintain its activity - this design is the core of the success of this asymmetric reaction.

Under optimized conditions (Ni(OTf)₂ as catalyst, mesitylene as solvent, and reaction temperature of -20 °C), the reaction exhibited excellent performance: 1) the yield reached as high as 99%, achieving almost "quantitative conversion"; 2) the enantiomeric ratio (er) reached as high as 96:4, with precise chirality control; and 3) the substrate applicability was broad: electron-donating/electron-withdrawing substituents on the indole ring and different substituents on the nitrogen atom did not affect the reaction efficiency, and even substrates substituted with benzene rings or methyl groups could react smoothly.

Using this asymmetric catalytic method , the team was able to conveniently synthesize chiral cyclobutanes containing all-carbon quaternary carbons on a gram-scale. Starting from N -methyltryptamine, they enantioselectively constructed the complex pentacyclic structure of quebracho alkaloids via a three-step reaction. Building on this, the team developed highly efficient synthetic routes for seven quebracho alkaloids. This synthetic strategy has the following advantages: 1) The total synthesis steps are significantly shortened compared with the previously reported route: starting from commercial N -methyltryptamine, the target alkaloids can be obtained in 7-10 steps; 2) The asymmetric synthesis of three alkaloids, (-)-eburine, (-)-eburcine, and (-)-minovine, was reported for the first time; 3) Compared with the traditional route, the overall yield of alkaloids such as (-)-vincadifformine and (-)-tabersonine was significantly improved, among which the yield of (-)-kopsifoline D was increased by 27 times compared with the previous record (1.1%); more importantly, the new total synthetic route can synthesize these natural products at the gram level (examples of (-)-eburine and (-)-eburcine are given in the article).

Summary and Outlook:
In summary, this study sets a new benchmark for the efficiency of the total synthesis of complex indole alkaloids. It will facilitate further research on the biological activities of Quercus alkaloids and provide a key material foundation for the development of new drugs (such as those for anti-tumor and neurological diseases). Furthermore, the design of this "antenna ligand" offers a new direction for ligand optimization in asymmetric catalysis. This work was supported by the National Natural Science Foundation of China (No. 91956103) and the Fundamental Research Funds for the Central Universities. The related results have been published in CCS Chemistry.

Pengjuan Li of the Zhuang Changgong Institute of East China Normal University is the first author of the article, Pengcheng Yin of the Zhuang Changgong Institute of East China Normal University is the second author, and Professor Lijia Wang and Academician Yong Tang are co-corresponding authors.

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About the journal: CCS Chemistry is the Chinese Chemical Society’s flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem.

About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman’s Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/.