Research group of Professor Sun Jianwei, Hong Kong University of science and technology: organic catalytic asymmetric functionalization of indole inactive SP3 hydrocarbon bond

The introduction of nitrogen-containing heterocycles is widespread in drug molecules, and the asymmetric functionalization of α - alkylazaarenes can be used to enhance the molecular diversity and biological activity of nitrogen-containing heterocycles Traditionally, the asymmetric functionalization of α - alkylazaarenes usually depends on the deprotonation under the action of strong bases, or the use of aromatic hydrocarbons (such as pyridine and quinoline) with relative electron deficiency and aromatic hydrocarbons with electron absorption substitution to reduce the pKa of the reaction site However, asymmetric functionalization of a-alkylazaarenes under non alkaline conditions has not been reported Recently, Professor Sun Jianwei's research group of Hong Kong University of science and technology started from the inactive 2-alkyl indole and used trifluoroacetate as electrophilic reagent to realize the asymmetric functionalization of indole's inactive SP 3 hydrocarbon bond Relevant results were published online in angew Chem Int ed (DOI: 10.1002 / anie 201909397) Prof sun Jianwei's research group is mainly engaged in the research of organic synthesis methodology Since 2010 Since its establishment in, systematic and in-depth studies have been carried out in the fields of asymmetric catalysis of small organic molecules, Lewis acid catalysis and asymmetric nucleophilic catalysis Meanwhile, challenging problems in organic synthesis, such as the construction of mesolide and lactam, and the selective conversion of electron rich alkynes, have also been studied From a new perspective, new ideas and strategies have been explored Finally, a unique solution is realized The research group has published more than 60 papers in internationally renowned academic journals, including J am Chem SOC., angel Chem Int ed., NAT Commun., chem Rev And other internationally renowned journals At present, the research group has 4 postdoctoral students, 6 doctoral students, 2 master students and 2 visiting scholars Introduction to Professor Sun Jianwei, professor and project leader of the Department of chemistry, Hong Kong University of science and technology Sun Jianwei received his bachelor's degree and master's degree in Chemistry Department of Nanjing University in 2001 and 2004 respectively, and his doctor's degree was obtained at the University of Chicago in 2008, and he carried out postdoctoral research at MIT from 2008 to 2010 Since 2010, he has been employed in the Department of chemistry, Hong Kong University of science and technology He has successively served as assistant professor and associate professor, and was promoted to Professor in 2019 He has won a number of academic honors, including Hong Kong Outstanding Young Scholars award, Asian core program leadership award, thiemechemistry Journal Award, emerging investigator (Chemical Communications) and innovation award of new and completed China chemistry He was invited to give a personal interview report in German Journal of Applied Chemistry and was also a member of the founding Committee of the Youth Committee of the Chinese chemical society Leading scientific research achievements: the asymmetric functionalization of indole with non activated SP 3 hydrocarbon bond catalyzed by organic catalyst indole compounds widely exist in drug molecules, natural products and other bioactive molecules Based on the charge rich properties of indole molecules, the asymmetric functional group reaction of indole usually takes place at 2,3 position, that is, Friedel Crafts reaction In addition, at present, the asymmetric functionalization of α - alkylazaarenes usually depends on the deprotonation under the action of strong base, or the aromatics with relative electron deficient and electron absorbing substituent are used The conditions of these methods are harsh and the range of substrate application is narrow Therefore, it is of great challenge and significance to develop asymmetric functionalization of indole inactive SP 3 (Fig 1) Fig 1 Asymmetric functionalization of indole and other α - aza arenes (source: angelw Chem Int ed.) according to the mechanism of the functionalization of α - alkylaza arenes catalyzed by Lewis acid / Bronsted acid, the author believes that 2-alkylindole may undergo isomerization / dearomatization under the action of Bronsted acid to obtain intermediate I And then, the intermediate II is formed by the tautomerization of enamine, and then the intermediate III is obtained by stereoselective addition reaction with electrophilic reagent under the action of Bronsted acid Finally, the expected product is obtained through isomerization / aromatization (Fig 2) However, there are many challenges in the course of this reaction: (1) although Brownstein acid catalyst can reduce the energy barrier, the dearomatization of indole is not easy to occur; (2) there may be multi-step reversible reaction in the reaction, which increases the difficulty of chiral control; (3) There may be a competitive reaction between Bronsted acid catalyst and electrophilic reagent, which makes the reaction not get the expected product Figure 2 Proposed reaction mechanism of chiral Bronsted acid (source: angelw Chem Int ed.) by 2, A series of chiral Bronsted acid and Bronsted base catalysts were screened with 3-dimethylindole 1A as the substrate and ethyl trifluoropyruvate 2A as the electrophilic reagent It was found that only when the thiourea / urea catalyst developed by Jacobsen was used, the average Er value could be obtained It is worth mentioning that there is a considerable degree of background reaction in this reaction Under the same reaction conditions, the yield of background reaction reaches 33%, which further increases the difficulty of chiral control The author further optimized the reaction conditions such as solvent, concentration, temperature and additive, and finally got 95% NMR yield and 91:9 Er value After simple recrystallization, the yield of the product can reach 81% and the ER value of 98:2, which has no great influence on the yield of the product Next, the author investigated the substrate application range of the reaction The substituted indoles, such as halogen atoms (such as fluorine, chlorine, bromine), alkyl groups (such as methyl, isopropyl), borates, silicates, trifluoromethylsulfonates, trifluoromethylethers and silicones, can participate in the reaction well 2-benzyl and ethyl substituted indoles also showed good enantioselectivity and non enantioselectivity In addition, the indole substrate with amino groups at the end of 1 m undergoes both imine formation and intermolecular C-C bond formation, resulting in a product of 3 Ma Methyl trifluoropyruvate is also a suitable electrophilic reagent In order to illustrate the practicability of the reaction, the author also tried the gram scale reaction, and the yield and enantioselectivity are still very good after the reaction amplification (Fig 3) Figure 3 Application scope of substrate (source: angelw Chem Int ed.) in order to explore the mechanism of the reaction, the author carried out a series of deuterium experiments and control experiments It was found that only when electrophilic reagent was added, deuterium atom could be detected at the α position of the product and indole raw material (Figure 4) This shows that electrophilic reagent not only acts as reactant, but also has activation effect in the reaction However, the mechanism envisaged in Figure 2 may not be correct, because electrophilic reagent is not involved in the formation of intermediate of enamine Adding the catalytic amount of trifluoropyruvate, there is still no deuterium atom in the α position of the recovered indole material, which eliminates the possibility that the residual acid in trifluoropyruvate can promote the background reaction Figure 4 Deuterium generation experiment and control experiment (source: angelw Chem Int ed.) based on this, the author proposed a more reasonable reaction mechanism First, under the action of Bronsted acid, indole reacts with electrophilic reagent to obtain the intermediate IV of dearylation; then, the enamine is tautomerized to obtain the intermediate V; then, it reacts with another electrophilic reagent to obtain the intermediate VI; finally, the electrophilic reagent at position 3 is eliminated, and then the final product is obtained by aromatization (Fig 5) The reaction mechanism is supported by DFT calculation The results showed that: (1) the rate determining step was different from the enantioselectivity determining step; (2) under the standard conditions (the interaction of chiral urea and racemic phosphoric acid), the electrophilic reagent first reacted at 3-position and then isomerized with enamine, all of which had lower energy than the process of 3-position protonation; (3) The addition of racemic phosphoric acid can significantly reduce the energy barrier of the whole reaction and accelerate the reaction, which may be due to its stable effect on the reaction intermediates Figure 5 Reaction mechanism (source: angelw Chem Int ed.) the kinetic experiment of electrophilic reagent shows that it is first-class (Figure 6); monitoring the reaction process shows that the reaction rate under standard conditions is significantly higher than the background reaction, which is also the basis of the control of enantioselectivity In addition, 2,6-di-tert-butylpyridine and trifluoropyruvic acid were added to the background reaction, which had no effect on the background reaction rate, further excluding the speculation that the residual acid in trifluoroacetate caused the background reaction (Fig 7) Figure 6 Electrophilic first-order kinetics (source: angelw Chem Int ed.) Figure 7 Reaction monitoring: (a) background reaction; (b) background reaction + 2, 6-di-tert-butylpyridine (1 equivalent); (c) background reaction + trifluoropyruvate (5 mol%); (d) standard conditions (source: angelw Chem Int ed.) N-methyl protected indole substrate reaction rate and enantioselectivity are greatly reduced, indicating that indole N-H plays an important role in the reaction (EQ 1) The cross experiment (EQ 2) and deuterium experiment (EQ 3) confirmed that the formation of C-C into an irreversible step, which are consistent with the experimental phenomena and the proposed experimental mechanism (source: angelw Chem Int ed.) at last, the product was derivatized to further illustrate the practicability of the method The product 3AA was reduced to 1,2-diol containing chiral trifluoromethyl center by aluminum lithium hydride; the product 3AA was intramolecular cyclized under the action of DMAP to obtain polycyclic lactam; under the action of DMAP, the product 3AA reacted with carbonyl diimidazole to obtain polycyclic carbamate In the above transformation, the ER value remains unchanged (Figure 8) Fig 8 Product derivatization (source: angelw Chem Int ed.) in summary, the author has realized the asymmetric functionalization of the organic catalyzed non activated indole SP 3 hydrocarbon bond This method does not need to use activated substrate, the reaction conditions are mild and the product selectivity is good, so it has the potential of further application in organic synthesis The research work was completed by postdoctoral Ma Dengke, the theoretical calculation part was completed by doctoral student Zhang Zhihan, and the corresponding authors were Professor Sun Jianwei and Professor Lin Zhenyang, Department of chemistry, Hong Kong University of science and technology The research work was supported by Hong Kong research funding Committee (16302617163041515630231816311616) and Shenzhen Science and Technology Innovation Committee (jcyj20160229205441091) Nowadays, people and scientific research have been paid more and more attention in the economic life China has ushered in the "node of science and technology explosion" Behind the progress of science and technology is the work of countless scientists In the field of chemistry, in the context of the pursuit of innovation driven, international cooperation has been strengthened, the influence of Returned Scholars in the field of R & D has become increasingly prominent, and many excellent research groups have emerged in China For this reason, CBG information adopts the 1 + X reporting mechanism CBG information website, chembeangoapp, chembeango official microblog, CBG information wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the representative research groups in China, pay attention to their research, listen to their stories and record their styles