Li Junlong, Sichuan Institute of antibiotic industry, Chengdu University: asymmetric cyclization of α - halogenated carbonyl compounds

Introduction in recent years, structural biology, molecular pharmacology, precision medicine and other related new disciplines have developed vigorously, providing new opportunities for structural innovation and synthesis of chiral molecules in both diversity and scale At the same time, "green development", as one of the five development concepts in the new era, has become the theme of the times Organic small molecule catalysis has unique advantages such as mild reaction conditions, insensitivity to water and oxygen, environmental protection and so on It has become one of the important methods to obtain chiral molecules at present Together with enzyme catalysis and transition metal catalysis, it constitutes three pillars of asymmetric catalytic synthesis Since its establishment, Li Junlong research group of Sichuan Institute of antibiotic industry of Chengdu University has been committed to the study of asymmetric reactions of carbonyl compounds such as aldehydes and ketones activated by organic small molecules A series of chiral heterocyclic skeletons with potential application value have been constructed by using traditional catalytic systems such as secondary amines and N-heterocyclic carbenes (chem.commin.2016, 52, 10617; chem.commin.2017 , 53 , 6875; Adv Synth Catal 2018 , 360 , 229 ）。 At the same time, through the reasonable design of the structural modification and catalytic system of carbonyl compounds, the research group further explored the new activation strategy and application of small organic molecules Recently, based on the new strategy of activating aldehydes with tertiary amines, the team completed the asymmetric [4 + 2] cycloaddition reaction of α - haloaldehydes and unsaturated ketones, and constructed a series of heterocyclic frameworks with chiral halogenated quaternary carbon centers (angel Chem Int ed 2018, 57, 1913) Subsequently, the team used chiral thioether to catalyze the asymmetric [2 + 1] cyclization of α - bromoketone, amide and other compounds with electron deficient diene, and obtained a series of cyclopropane derivatives containing chiral quaternary carbon centers (org Lett 2018, 20, 3700) Li Junlong, born in 1986, is a distinguished researcher and master tutor of Sichuan Antibiotic Industry Research Institute of Chengdu University In 2013, he graduated from Sichuan University and studied under Professor Chen Yingchun, engaged in the research of asymmetric organic small molecule catalysis Subsequently, with the support of Humboldt scholarship, he went to the Institute of organic chemistry of the University of Minster in Germany for postdoctoral research and studied with the famous chemist, Professor Frank glorius, to continue his research work in the direction of asymmetric catalysis In May 2015, he joined Sichuan Antibiotic Industry Research Institute of Chengdu University to independently carry out scientific research work, mainly engaged in catalytic synthesis and Research on new synthesis routes of chiral drugs Since our independent work, we have continued to study all kinds of asymmetric catalytic cyclization reactions At the same time, we focus on the development of some new activation strategies for small organic molecules At present, as the first author or corresponding author, he has published a number of relevant research results in the international mainstream academic journals of chemistry such as angelw Chem Int ed., org Lett., chem Commun., adv synth Catalyst., RSC adv., and some of them have been commented by synfacts and other journals as highlights, and invited to further introduce them in synfacts column In addition, researcher Li Junlong applied for and authorized a number of Chinese invention patents A brief introduction of the leading scientific research achievements (1) asymmetric [4 + 2] cyclization of α - haloaldehydes catalyzed by organic small molecule br ø nsted base in many natural products and drug molecules with physiological activities, halogen atoms such as chlorine and bromine are often connected to the cyclic quaternary carbon center as a special functional group with a specific configuration Through the cyclization reaction of α - haloaldehydes, the halogenated quaternary carbon centers can be introduced at the same time as the efficient and convenient construction of the ring skeleton However, it is difficult to realize the direct asymmetric [4 + 2] cyclization of α - haloaldehydes due to the restriction of electronic and steric hindrance effects of halogen substituents (Fig 1) Therefore, the development of new strategies to activate aldehydes is undoubtedly the most direct and effective way to solve these problems Fig 1 It is difficult to realize the direct asymmetric [4 + 2] cyclization of α - haloaldehydes through the activation of enamine (source: angelw Chem Int ed.) Recently, Li Junlong's research group successfully broke through the limitation of the steric hindrance of α - haloaldehydes by using the enol activation model of aldehydes catalyzed by br / nsted base, and then asymmetric [4 + 2] occurs between α - haloaldehydes and electron deficient unsaturated ketones A series of heterocyclic skeletons containing chiral halogenated quaternary carbon centers were constructed in high yield and high stereoselectivity by cyclization reaction, and the conversion of chiral products into spiro skeletons was realized by "one pot method" This work provides an effective new method for asymmetric activation of aldehydes Figure 2 The asymmetric [4 + 2] cyclization of α - haloaldehydes and unsaturated ketones catalyzed by br ø nsted base (source: angelw Chem Int ed.) was recently published on angelwandte Chemie International Edition (angelw Chem Int ed 2018, 57, 1913) The research work is supported by the National Natural Science Foundation of China, Sichuan thousand talents plan, Chengdu Talent Chengdu floating plan and Chengdu University talent introduction special funds (2) asymmetric cyclopropane reaction of α - bromo with diene deficient catalyzed by thioether Since the Johnson Corey chaykovsky reaction was reported in 1961, many kinds of chiral sulfides with different skeleton and structure have been synthesized by chemists, which lays a solid foundation for the study of asymmetric synthesis chemistry in which thiofulide participates Among them, thioether catalysis has attracted extensive attention due to its advantages of atomic economy, environmental protection, high efficiency and moderate temperature However, due to the limitation of substrate activity, the corresponding method has been difficult to be fully developed and applied Therefore, it is still a challenge to realize the asymmetric cyclopropanization catalyzed by thioether Recently, Li Junlong's group reported the asymmetric cyclopropanation of electron deficient dicyanodiene catalyzed directly by chiral thioether Electron deficient dicyanodiene 1a and α - bromoacetophenone 2A were selected as model substrates Through the selection of solvent, catalyst, alkali, additive and concentration, it is found that under the action of NaHCO 3, with eucalyptus leaf thioether as catalyst and the reaction concentration raised to 2 m, the excellent regioselectivity, yield and stereoselectivity can be used to obtain the chiral product 4a of cyclopropane (Fig 3) Figure 3 The optimal condition of the reaction (source: org Lett.) then, the author examined the universality of the reaction The results showed that for the aryl substituted substrate, any site on the aromatic ring can be compatible with the electron acceptor or electron donor, and the reaction can achieve medium to excellent yield and excellent stereoselectivity Surprisingly, the catalytic system can also be compatible with different types of electron withdrawing substituents When the electron absorption group is amide, ester, nitrobenzene or even chromone, the reaction can take place smoothly, and the target product can be obtained with good yield and stereoselectivity (Fig 4) Figure 4 Investigation of the application scope of substrate (source: org Lett.) in order to demonstrate the application value of the synthesis method, the author not only demonstrated the high-efficiency and high selective gram scale reaction of 4A, but also carried out a series of transformations of cyclopropanized products Compound 4A can not only open ring and aromatize under the action of tetra (triphenylphosphine) palladium to obtain polysubstituted benzene 5, but also hydrolyze and remove malondionitrile smoothly under the action of triethylamine Then compound 6 is condensed with hydrazine hydrate to obtain nitrogen-containing heterocyclic compound 7 In addition, compound 6 can construct chiral quaternary carbon centers containing halogen through decarboxylation and halogenation reaction, while maintaining its optical activity well (Fig 5) Figure 5 Derivative transformation of the product (source: org Lett.) finally, by adjusting the amount of electron deficient dicyanodiene, the chemical selectivity and stereoselectivity of the reaction with 1,3-dibromoacetone are well controlled, and a series of valuable synthesis transformations are carried out on the basis of the product This method not only provides a necessary reference for the efficient construction of complex cyclopropane skeleton, but also injects new energy into the synthesis chemistry of thioyelide Figure 6 The reaction of electron deficient dicyanodiene with 1,3-dibromoacetone and the product diversity transformation (source: org Lett.) this achievement was recently published on organic letters (org Lett 2018, 20, 3700) This research work has been greatly supported by NSFC and other funds 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.