Chen Gong, Professor of Nankai University, research group: heteroisomerization of third-order carbon centers based on the activation of free radical C (SP3) - H bonds

Epimerization is an important means to change the stereochemical structure of organic molecules It has been widely used in organic synthesis and enzyme catalyzed biosynthesis through the cleavage of C-H bonds with certain acidity (such as C-H at the α position of carbonyl compounds) In contrast, the differential isomerization of C (SP 3) - H third-order carbon with nonacidity is a great challenge, and there is basically no practical method at present Recently, the team of Professor Chen Gong of Nankai University used bin 3 and H 2O as additives to realize the isomerization of the third-order carbon center with non acid C (SP 3) - H bond under mild conditions for the first time through the reversible free radical breaking of the non activated C (SP 3) - H bond The isomerization reaction takes place efficiently and selectively on the inert third-order C-H bonds of various cycloalkanes, which provides a powerful strategy for the chiral inversion of the third-order carbon stereocenters that are difficult to be solved by traditional methods (j.am.chem.soc 2018, 140, 9678) A brief introduction to the research group of Professor Chen Gong based on the differential isomerization of the third-order carbon chiral center activated by the free radical C (SP 3) - H bond (source: J am Chem SOC 2018, 140, 9678) Professor Chen Gong of Nankai University was established in September 2014 and is affiliated to the National Key Laboratory of elemental organic chemistry of Nankai University At present, the research group has one professor, one special researcher, two postdoctoral teachers, seven doctoral students and seven master students At present, Professor Chen Gong's research group is mainly engaged in the organic synthesis and chemical biology of complex glycopeptides In view of the difficulties in the synthesis of complex glycopeptides, they have developed a series of transition metal catalyzed functionalization reactions of hydrocarbon bonds and free radical reactions mediated by high valent iodine, which have realized the efficient synthesis and modification of unnatural amino acids and complex peptide skeletons At present, the research group has published 59 papers in NAT Chem., J am Chem SOC., angel Chem Int ed and other international chemical journals, and he cited them for more than 2000 times Prof Chen Gong, Professor of Nankai University, doctoral supervisor In 1998, he graduated from the Department of chemistry of Nanjing University, and in 2004, he received his Ph.D in bioorganic chemistry from the Department of chemistry of Columbia University In 2005-2008, he worked in Sloan Caitlin cancer research center of the United States as a postdoctoral researcher Since 2008, he has independently carried out teaching and research work in the Department of chemistry, Pennsylvania State University, and obtained tenure in 2014 Since 2015, he has worked full-time in the State Key Laboratory of elemental organic chemistry of Nankai University as a professor and doctoral supervisor Since his independent work, Professor Chen Gong has successively obtained us-nsf career award, Thieme Chemistry Journal Award, Amgen Young Investigator Award, ACP collectionship, outstanding young professor award of Sino American Chinese Association of professors of chemistry and chemical biology, biomedical Kant scholars award, overseas Chinese community contribution award of Chinese Federation of overseas Chinese, etc.; young scholars selected into "Yangtze River scholars Award Program" of the Ministry of education, and "young and middle-aged leading talents of science and technology innovation" of the Ministry of science and technology; and in 2018 He was supported by the National Natural Science Foundation of China Research achievements: in recent years, Professor Chen Gong's research group of Nankai University has carried out a series of research work on the functionalization of hydrocarbon bond mediated by cyclic trivalent iodine reagent In 2016, the team used tripyridine ruthenium dichloride as photosensitizer and trivalent iodazide (bin 3 reagent, 1) as azide source under visible light to realize the next methyl azide reaction with high selectivity at room temperature The reaction process can be successfully controlled by adding halides such as lithium chloride or tetrabutylammonium bromide to obtain selective chlorination or bromination products (Fig 1) Figure 1 Visible light promotes the hydrogen bond azide and halogenation reaction (source: chem SCI 2016, 7, 2679) In 2017, the team used trivalent iodine oxidizer (pfbi-oh or bi-oh), also under the catalysis of visible light and photosensitizer, selectively activated the C (SP 3) - H bond of tertiary carbon and benzylidene methylene, and reacted with H 2O or acetonitrile to realize the C (SP 3) - H bond Hydroxylation and amidation of (Fig 2) Figure 2 Hydroxylation and amidation of hydrocarbon bonds (source: chem SCI 2017, 8, 7180) In these works, the author found that trivalent iodine reaction system can effectively break the alkyl hydrocarbon bonds at specific sites to generate carbon free radicals, and then generate functional group reaction If reversible fracture and reconstruction of hydrocarbon bond can be realized, it will be possible to change the stereoscopic configuration of carbon center and solve the problem of differential isomerization of non acid C (SP 3) - H bond Based on the hypothesis of differential isomerization, the team investigated a series of common hydrogen donors with CIS decalin as template substrate Finally, the author found that in the presence of bin 3 reagent 1, when H 2O was used as the cosolvent of EtOAc, the model reaction could obtain trans decalin, the target product of configuration transformation, with a yield of 97% GC (Fig 3, formula 1) After detailed control experiments, the author found that bin 3 reagent 1 reacts with water under standard reaction conditions to produce trivalent iodine compounds bi-oh and azido acid The reaction is reversible When the reaction reaches equilibrium, bi-oh and azido acid are the main components (Fig 3, reaction formula 2) Further verification experiments show that HN 3 is a hydrogen donor in the reaction, but it can't initiate this differential isomerization reaction by itself (Fig 3, formula 3) Fig 3 Mechanism verification experiment (source: J am Chem SOC 2018, 140, 9678) Based on the above experimental results, the author proposed the following possible reaction mechanism: first, bin 3 reagent 1 is split to produce azide free radical (n 3 ·) As a unique carrier of hydrogen atom, azido free radical N3 can not only efficiently capture the hydrogen atom of the third-order C (SP 3) - H bond in the substrate, but also react with the generated third-order carbon free radical intermediate in the form of HN 3 to return the hydrogen atom Thus, hydrogen atoms are transported back and forth between the free radical intermediates with configuration inversion, thus realizing the configuration transformation of compounds (Fig 4) The high selectivity of the isomerization is due to the fact that the average cleavage energy of HN 3 is 93.3 kcal / mol, which is similar to that of the inactive third-order hydrocarbon (the average cleavage energy of 2-cis and 2-trans third-order hydrocarbon is 93.3 and 96.1 kcal / mol, respectively), while the difference between HN 3 and the second-order hydrocarbon of cyclohexane is large (97.5 kcal / mol) The DFT calculation results of Professor Chen Gong and Professor Liu Peng of the University of Pittsburgh also support the feasibility of this mechanism Figure 4 Reaction mechanism (source: J am Chem SOC 2018, 140, 9678) then, the author investigated the substrate applicability of the reaction, and found that the reaction has a good substrate application range Isomerization reaction takes place on the inert third-order C-H bond of various cycloalkanes with high efficiency and selectivity, which can realize the reversible isomerization of the non acid third-order C (SP 3) - H bond in the single ring and double ring compounds, It is compatible with ketone, ester, amide and other protective groups (Fig 5) Figure 5 Applicability of reaction substrate (source: J am Chem SOC 2018, 140, 9678) in order to further prove the practicability of the scheme, the author also successfully achieved the configuration transformation of the target site in steroids containing multiple third-order carbon centers which are difficult to achieve by conventional methods (Fig 6), providing a fast and effective method for the synthesis of non enantiomers of steroids Figure 6 Epiisomerization of steroid skeleton (source: J am Chem SOC 2018, 140, 9678) conclusion: this method has successfully realized the epimerization of the unactivated third-order C-H bond of cycloalkanes, showing excellent reactivity and selectivity, providing a powerful strategy for the chiral inversion of the third-order carbon solid center which is difficult to be solved by traditional methods, and has a good application prospect in the configuration transformation of chiral natural products Wang Yaxin, a doctoral student in Professor Chen Gong's team, and Hu Xiafei, a master's student, are the first adults to complete the research The research was supported by NSFC and Nankai University Professor Liu Peng of University of Pittsburgh provided theoretical calculation support for the research The results were published in J am Chem SOC (DOI: 10.1021 / JACS 8b05753) 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.