School of Physical Science and Technology (SPST) Professor Yang Xiaoyu’s research group has developed a novel method for chiral indole derivatives synthesis through chiral anion catalysis. Their work, 'Regioselective and Enantioselective Synthesis of β-Indolyl Cyclopentenamides by Chiral Anion Catalysis' was recently published in Angewandte Chemie International Edition, a top chemical journal.
Indole derivatives are one of the most privileged heterocyclic compounds in pharmaceutical chemistry, and over ten thousand biological active indole derivatives have been identified to date. Meanwhile, they also represent a common moiety in various bioactive alkaloids natural products, as well as in material science. Enamides are likewise a valuable class of compound because of their wide application in the construction of heterocycles and chiral amines as well as their presence in some natural products. Therefore, the asymmetric functionalization of indoles to provide products which incorporate an enamide functional handle would provide valuable chiral building blocks for the synthetic community, which would have wide applications in both medicinal chemistry and total synthesis of natural products. Among various indole substituted enamides, we are particularly interested in β-indolyl cyclopentenamides because of their potent pharmaceutically activities and the lack of a versatile method for their high efficient asymmetric synthesis.
In this study, the researcher developed regioselective and enantioselective synthesis of β-indolyl cyclopentenamides, a versatile chiral building block, by asymmetric addition of indoles to α,β-unsaturated iminium intermediates through chiral anion catalysis. Key to the success of this methodology is the generation of a chiral anion-paired ketone-type α,β-unsaturated iminium intermediate from α-hydroxyl enamides. Preliminary mechanistic studies and DFT calculations (in collaboration with Professor Peng at Nankai University) are consistent with a mechanism involving multiple, concurrent pathways for isomerization of the initially formed azaallylcation to the key α,β-unsaturated iminium intermediate, all mediated by the phosphoric acid catalyst.
Dr. Subramani Rajkumar (post-doc) and Wang Jiawen (third-year PhD student) are co-first authors of this paper. Wang Donglei, Ye Xueqian (second-year MSc student) and Li Xuejiao (a senior undergraduate student) are co-authors of this paper. ShanghaiTech University is the first responsible institution. This work was supported by start-up funding from ShanghaiTech University, the “Thousand Talents Plan” Youth program, Shanghai Pujiang Program and National Natural Science Foundation of China. The DFT calculation work was finished by Professor Peng Qian and colleagues at Nankai University.
Novel asymmetric synthesis of chiral indole derivative through chiral anion catalysis