CHEMICAL SCIENCE

The new strategy enables divergent total synthesis of multiple indole alkaloids


Recently, Researcher Tang Yong of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and Professor Wang Lijia of East China Normal University jointly developed the stereoselectivity of indolene sulfonamide and methylene malonate[2+2+2]The tandem cyclization reaction realizes the divergent total synthesis of multiple Aspidosperma alkaloids.

On June 23, 2022, the study was published under the title “Allenamide Initiated Cascade.” [2+2+2] Annulation Enabling the Divergent Total Synthesis of (-)-Deoxoapodine, (-)-Kopsifoline D and (±)-Melotenine A” by Anglo. Chem. Int. Ed. Journals.

Zhao Liupeng, phD candidate of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, is the first author of the paper, And Tang Yong, researcher of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and Professor Wang Lijia of East China Normal University are the corresponding authors of the paper.

Polycyclic indoleline skeletons are widely present in natural products and pharmaceutical molecules with important biological activity, and such compounds have very important applications in synthetic chemistry, chemical biology, drug development and other fields. Due to its complex ring structure and multiple stereoscopic centers and seasonal carbon centers, the efficient synthesis of such structures has always been a hot topic in the field of synthetic chemistry. The joint research team of Tang Yong, researcher of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, and Professor Wang Lijia of East China Normal University have been committed to the efficient construction of stereoselectivity of polycyclic indoleline skeleton and its application in the total synthesis of natural products (J. Am. Chem. Soc. 2013, 135, 7851; J. Am. Chem. Soc. 2014, 136, 6900; Angew. Chem., Int. Ed. 2017, 56, 3055; Angew. Chem., Int. Ed. 2017, 56, 6942; ACS Catal. 2018, 8, 4991; Angew. Chem. Int. Ed. 2018, 57, 3810; Angew. Chem. Int. Ed. 2019, 58, 4345)。 In recent years, the team has developed tryptophan-derived alkenyl sulfonamides with alkyl malonates[2+2+2]The tandem cyclization reaction successfully realized the stereoselective construction of the four-ring indoleline skeleton with C/D cyclotransmis (Angew. Chem. Int. Ed. 2016, 55, 9224), this method was used in the divergent total synthesis of four Malagasy alkaloids (CCS Chem. 2022, Just Accepted. DOI: 0.31635/ccschem.022.202202069)。

Recently, the team has made a breakthrough in the stereoselective construction of the C/D cyclic cis-fused tetracyclic indoleline skeleton, developing the stereoselectivity of indolene sulfonamide participation[2+2+2]The tandem cyclization reaction realized the non-enantioselective control of the polyfunctional tetracyclic indoleline by introducing a dienoleyl unit in the substrate, efficiently constructed the core skeleton of Aspidosperma alkaloids, and completed the divergent total synthesis of natural products (-)-deoxoapodine, (-)-kopsifoline D and (±)-melotenine A by this method.

First, the authors took trimetamine-derived bienesulfonamide1aand dimethyl methylenemalonate2aFor the template substrate, tests were carried out under different reaction conditions. When examining different Lewis acids, it was found that when using indium trifluoromethanesulfonate, which is more acidic in Louis, the reaction can achieve a yield of 89% and a single diastere cis-transectivity.

Next, under optimized conditions, the authors studied the substrate range containing different substituents and multiple substitutes of dienylamine on the indole ring. The results showed that the reaction had good functional group tolerance, and the electron effect and steric hindrance effect of the substituent on indole had no significant effect on the stereoselective control and reactivity of the tandem cyclization reaction. For various substituted diazylamine substrates, such as cyclopropyl substituents, phenyl substituents and terminal bisubstituted alkenyl substrates, this reaction can occur smoothly, greatly enriching the diversity of polycyclic indoleline compounds. It is worth noting that the reaction is simple to operate, can be easily scaled up to more than 10 grams, and has good application potential.

This tandem cyclization reaction was successfully applied to the synthesis of white wood alkaloids. First, starting from the precursor of bienesulfonamide, the authors synthesized a double-substituted bisubstylamine derivative by isomerization of potassium tert-butanol, which was not separated and purified, and directly occurred under the catalysis of indium trifluoromethanesulfonate[2+2+2]The tandem cyclization reaction can obtain a tetracyclic indoleline compound at a reaction scale of >8 grams, and the key intermediate is realized by the Claisen rearrangement/olefin closed cyclic decomposition reaction from the tetracyclic indoleline12The gram-scale preparation, which was finally prepared by chiral HPLC splitting, realized the total synthesis of natural products (-)-deoxoapodine, (-)-kopsifoline D and its enantiomers, respectively, laying a foundation for further study of biological activity.

This methodology can efficiently and conveniently construct a tetracyclic indole compound containing four substituted double bonds, using which the authors have completed the total synthesis of natural product (±)-melotenine A. Derivative from trisubstituted pyrylamine1aaStarting from this, tetracyclic indole compounds can be replaced on a reaction scale of 7 grams3aaPreparation, and then from the tetracyclic indole product, by a few steps such as diesteryl removal / protective group conversion to achieve the key intermediate17The total synthesis of natural product (±)-melotenine A was completed by the Appel reaction/DBU elimination/closed loop recombination reaction.

In this work, the joint research team of Tang Yong, researcher of Shanghai Organic Institute and Professor Wang Lijia of East China Normal University, reported the stereoselectivity of Indolene sulfonamide and methylene malonate catalyzed by Louis acid[2+2+2]The tandem cyclization reaction realizes the efficient construction of a series of high-functional grouped polycyclic indole compounds and applies them to the divergent total synthesis of three indole alkaloids with important biological activity. This method has the characteristics of cheap and easy to obtain raw materials, mild reaction conditions, good substrate universality, and can efficiently realize the preparation of grams, which provides a new strategy and method for the construction of polycyclic indole compounds with diverse structures.

The research work has been funded by the National Natural Science Foundation of China (21772224, 91956103) and others. (Source: Science Network)

Related paper information:https://doi.org/10.1002/anie.202207360



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