Professor Yang Hua group of Central South University: explanation and regulation of stereospecific reverse reaction in asymmetric organic catalytic condensation of indigo with cyclohexanone

The rapid development of asymmetric catalysis provides many powerful means for the synthesis of pharmaceutical intermediates and natural products For a long time, the focus of this field has been on the development and application of new catalytic systems Therefore, relevant reports have made a detailed description of the application of corresponding catalytic systems in methodology and the influencing factors of stereoselectivity At present, the factors that affect the stereoselectivity of catalytic system are mainly solvent, temperature, concentration, additive and so on Recently, the research group of Professor Yang Hua of Central South University took the influence of reverse reaction on enantioselectivity as an index for the first time, which successfully overcame the adverse effect of stereospecific reverse aldol condensation on stereoselectivity, and provided a new strategy for improving the chiral control ability of catalytic system in asymmetric synthesis The results were published in org Lett (DOI: 10.1021 / ACS Orglett 8b03292) Brief introduction of the research group of Professor Yang Hua the research direction of the research group of Professor Yang Hua mainly focuses on the design and synthesis of organic small molecule catalyst and its application in asymmetric synthesis, as well as the research on the synergistic catalysis system of photo oxidation-reduction catalysis and organic catalysis In recent years, our group has successfully synthesized a series of spiro-epoxidized indoles with potential biological activity by using organic small molecule catalysis and photo oxidation-reduction catalysis By monitoring the change of enantiomeric excess value in asymmetric catalytic reaction, they revealed a series of rules Under the same catalytic system, they obtained two enantiomers of coumarin derivatives with high enantioselectivity, and successfully suppressed the negative effect of stereospecific reverse aldol condensation on enantioselectivity Professor Yang Hua's cutting-edge scientific research achievements: explanation and regulation of stereospecific reverse reaction in asymmetric organic catalytic condensation of indigo and cyclohexanone aldol It provides many alternative means for asymmetric synthesis of chiral drugs and natural products In the past studies of asymmetric synthesis, the synthesis of new catalysts and the factors affecting the chiral control ability of catalysts are the main focus in this field The research on the influencing factors of stereoselectivity mainly focuses on the external factors such as solvent, temperature, concentration, additive, etc However, there are few reports on the influence of the nature of the reaction itself on stereoselectivity, and there is lack of research on the essential reasons Based on the above reasons, the author designed and synthesized the pyroglutamate Cyclohexanediamine bifunctional organic catalyst, and applied it to the asymmetric aldol condensation of indigo In the study of substrate tolerance, the author found that both substrates with electron withdrawing substituents and with electron supplying substituents obtained extremely poor enantioselectivity under the optimal conditions selected by the model reaction (Fig 1) Fig 1 Design of catalyst and its performance in substrate expansion (source: org Lett.) based on the abnormal performance of the catalyst system in substrate expansion, the author repeated the model reaction under the optimal conditions, and found that the enantioselectivity obtained by each repetition was different Therefore, it is reasonable to assume that the enantioselectivity of the reaction in this catalytic system changes with time Then, the author monitored the EE value in the reaction process under the optimal conditions, and found that the EE value gradually decreased from 96% to 87% in the reaction process Subsequently, the solvent was changed under the same condition for monitoring experiment, and the same experimental phenomenon was found by the author (Fig 2a) On this basis, the author also found that the higher the concentration of the reaction system, the lower the EE value will also increase significantly (Fig 2b) As we all know, aldol condensation is a reversible reaction However, as long as the catalyst performance remains unchanged, the reverse reaction will not have such a strong impact on the final enantioselectivity If it is necessary to study whether the chiral control ability of the catalytic system is stable in the reaction process, it is necessary to determine whether the EE value of the product changes in the reaction process Therefore, the model reaction product with high optical purity was mixed with catalyst, and the EE value of the product was monitored The experimental results show that the EE value of the product in the mixed system decreases with time and has a certain upward trend (Fig 2C) Therefore, it is necessary to focus on the effect of product and catalyst to explore the essential reason for the decrease of EE value with time Subsequently, the author monitored the reaction process of substrates with different substituents, and found that the EE value decreased with time (Fig 2D) In the reaction of 5-fluoroindigo, the EE value turned to - 25%, which also explains why the substrates in Figure 1 show great differences under the same reaction conditions Fig 2 Monitoring of EE value change process (source: org Lett.) further, the author found that the molecular ion peak of intermediate produced by the combination of product and catalyst appeared in the high-resolution mass spectrum, and the sub ion peak of raw material appeared This indicates that the product undergoes an inverse reaction under the action of catalyst In the NMR spectrum of the mixture, it is found that the peaks and chemical shifts of the active protons of the catalyst and the product have changed obviously It is reasonable to infer that the reaction of the product and catalyst is reversible through hydrogen bond If the catalyst has no chiral recognition for the product, the EE value after the reverse reaction should remain unchanged Therefore, the reverse reaction in this system should be stereospecific In order to verify this assumption, the enantiomers of the catalysts and the products were synthesized Then, the monitoring experiment as shown in Fig 2C is carried out, and the experimental results of the mixture of catalyst and product enantiomers are highly consistent with FIG 2C Then, the cross experiments of catalyst and product, catalyst and product were carried out The results showed that the EE values of the products in the two mixtures did not change with time (Fig 3) It can be proved that the catalyst can specifically recognize the dominant enantiomers of the products produced by its chirality control and catalyze its reverse reaction In the process of the reaction, the dominant enantiomers decompose, while the other enantiomers accumulate, which leads to the decrease of EE value Figure 3 Cross experiment and Mechanism Study (source: org Lett.) from mechanism study, it can be seen that the EE value of the reaction product can be greatly increased by inhibiting the reverse reaction (Figure 3, bottom) In combination with the monitoring in Fig 2, THF with a relatively slow reduction in EE value was reacted with cyclohexanone, which can inhibit the reverse reaction, as a mixed solvent, and the EE value of each product shown in Fig 1 was successfully increased (Fig 4) The feedback information of this result also verifies the rationality of the mechanism shown in Fig 3, that is, the decrease of EE value with time in the reaction process is determined by the nature of the reaction itself, independent of the chiral control ability of the catalyst Figure 4 Enhancement of enantioselectivity (source: org Lett.) was recently published in org Lett (DOI: 10.1021 / ACS Orglett 8b03292) The first author of this paper is Wang Jing, a doctoral student in the school of chemistry and chemical engineering of Central South University, and the corresponding authors are Professor Yang Hua, Professor Chen Xiaoqing and associate professor Xiang Fuyue The above research work was supported by the Ministry of science and technology, the National Natural Science Foundation of China, and the natural science foundation of Hunan Province Wang Jing (left, first work); Deng Zhixiong (right, second work) review of previous reports: CBG information interview with Professor Yang Hua of Central South University 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, chembeangoapp, chembeango official microblog, CBG wechat subscription number and other platforms jointly launch the column of "people and scientific research", approach the domestic representative research group, pay attention to their research, listen to their stories, record their demeanor, and explore their scientific research spirit.