Song Qiuling research group of Fuzhou University / Huaqiao University: new chiral "br ø nsted Acid" for asymmetric reduction of 2-arylindole

In the field of asymmetric chemistry, chiral br ø nsted Acid has become a powerful assistant for chemists because of its high reactivity and selectivity Although great progress has been made in the research of chiral br ø nsted Acid, there is still a great need to develop new chiral br ø nsted Acid Recently, song Qiuling, a Key Laboratory of organic synthesis and function, Fuzhou University, has cleverly used chiral phosphoric acid, catbh and water to construct a new type of chiral strong Br? Nsted Acid, and asymmetric reduction of 2-arylindole has been realized with good yield and excellent stereoselectivity (up to 96% ee) Relevant research work was published in the recent angelw Chem Int ed (DOI: 10.1002 / anie 201913656) Recently, song Qiuling, a Key Laboratory of organic synthesis and function, Fuzhou University, designed a new type of chiral Br? Nsted Acid in situ, which can be produced by the chiral boron phosphate activated water with Lewis acid property, and worked with Yu Peiyuan, a teacher from South University of science and technology, to calculate it theoretically It is confirmed that the process is feasible in thermodynamics By means of low temperature NMR, the author confirmed the production of a new Br? Nsted Acid At the same time, it was found that BR ø nsted Acid was stronger than TsOH acid (Fig 1) Further DFT calculation shows that the new chiral Br? Nsted Acid can activate 2-phenylindole to form an imine Intermediate 4, which has only a small reaction energy barrier (7.7 kcal / mol) Figure 1 The framework of chiral indoline designed by "br ø nsted Acid" (source: angelw Chem Int ed.) widely exists in drugs and natural products, which has been the focus of synthetic chemists and pharmaceutical chemists Asymmetric reduction of indole is the most direct way to synthesize chiral indoline, but unprotected 2-arylindole is a kind of compounds with great challenge in asymmetric reduction The asymmetric reduction of unprotected 2-arylindole was realized by this new chiral br ø nsted Acid (Fig 2) Fig 2 The new chiral "br ø nsted Acid" helps asymmetric reduction of 2-arylindole (source: angel Chem Int ed.) the author first optimized the conditions with 2-phenylindole as the substrate, and found that the addition of water can greatly promote the reaction Then the author screened the chiral phosphoric acid, and finally achieved high yield (8 8 %) and high stereoselectivity (91% ee) In order to investigate the substrate application scope of this method, the authors investigated a series of 2-arylindole substrates with different groups (Fig 3) It can be seen that in this catalytic system, 2-arylindoles with electron absorbing or electron donating functional groups have good enantioselectivity (83% - 96% ee) Fig 3.2 - arylindole substrate expansion (source: angel Chem Int ed.) surprisingly, through further screening, the author found that large steric hindrance 2-alkylindole can also obtain the corresponding product with high yield stereoselectivity under the system conditions (Fig 4) Figure 4.2 - alkylindole substrate expansion (source: angelw Chem Int ed.), and then in the gram reaction (Figure 5), the reaction can still obtain the corresponding products with high yield and high stereoselectivity, and more derivatization has been done for the products to fully show the practicability of the reaction Figure 5 Synthesis application (source: angelw Chem Int ed.) finally, the author made a preliminary exploration on the mechanism Deuterium experiment also proves that water plays a key role in this process, but when h on N is replaced by methyl, chirality control cannot be achieved (Fig 6) In order to further study the conversion mechanism and stereoselectivity of the reaction, the author calculated DFT with catalyst CP7, evaluated several possible pathways and determined the lowest energy pathway (Figure 7) Fig 6 Mechanism experiment (source: angelw Chem Int ed.) Fig 7 DTF calculation (source: angelw Chem Int ed.) to sum up, the author generated a new kind of product through water, catechol borane and chiral phosphoric acid Br? Nsted Acid was used to asymmetric reduce a series of indoles at atmospheric pressure The above work was strongly supported by NSFC (21772046, 21931013), etc.