Liu Yankai, associate professor of Ocean University of China: asymmetric synthesis of spiro bridged and spiro fused heterocyclic compounds including chroman, indole and oxindole

Lead pharmacophore combination strategy is a common method to find the active molecules of drugs As common pharmacophores, chroman, indole and oxindole structures are widely found in natural products and active molecules However, the synthesis of these three common pharmacophores, especially in the form of spiro bridged and spiro fused heterocycles, has never been reported Recently, the research group of Liu Yankai, associate professor of School of medicine, Ocean University of China, made a breakthrough in this field By using the strategy of substrate reactive transformation, the asymmetric synthesis of these two compounds was realized for the first time with high efficiency (org Lett 2018, 20, 6682) Liu Yankai, associate professor of Ocean University of China, founded in September 2013 At present, there are 1 assistant professor, 1 doctoral student and 8 master students in the research group The research group is mainly engaged in the research work of asymmetric synthesis and chiral drug synthesis catalyzed by small chiral organic molecules, and has long been committed to the application of hemiacetals (amines) in the synthesis of heteropolycyclic compounds The synthesis of chiral heteropolycyclic compounds (org Lett 2015, 17, 2022; org Lett 2015, 17, 3794; org Lett 2016, 18, 864; synthesis 2016, 48, 2581; org Biosol Chem., 2016, 14, 2444; org Biosol Chem., 2016, 14, 2444; org, 2016 , 14 , 6316; Org Biomol Chem , 2017 , 15 , 1407; J Org Chem 2017 , 82 , 4774; Org Chem Front , 2017 , 4 , 2358; J Org Chem 2017 , 82 , 10450; Adv Synth Catal 2017 , 359 , 4260; Org Lett 2018 , 20 , 3609 ）。 Liu Yankai, associate professor, leading edge scientific research achievements: asymmetric synthesis of chroman, indole, oxyindole containing spiro bridge ring and spiro fused heterocycle compounds chroman, indole and oxyindole as common skeletons widely exist in natural products And many compounds containing the skeleton have good biological activity, so it is called common pharmacophore Combinatorial chemistry is an important method to find the leading compounds in the development of new drugs By combining multiple pharmacophores in the same molecule, special biological activities are often obtained Although the asymmetric synthesis of the above two combinations of structures has been reported for many times (angel W chem., int ed 2011, 51, 1046; chem EUR J 2014, 20, 3415; Angel W chem., int ed 2015, 54, 5460; chem Commun 2015, 51, However, it has never been reported that the three skeletons of chroman, indole and oxindole are combined in the same chiral molecule in the form of spiro bridged ring and spiro bicyclic ring (Fig 1) Fig 1 Asymmetric synthesis methodology including chroman, indole and oxindole skeleton compounds (source: org Lett.) according to previous research results, the author designed the following two reaction routes (Fig 2): route a: the author took diindole derivative 2A as substrate, and o-hydroxycinnamaldehyde 1A as Michael The acceptor, catalyzed by secondary amine catalyst, can obtain β - substituted semiacetal Intermediate 4 It is suggested that the intermediate of onium salt can be obtained by dehydrogenation of 4 in acid condition, and the product 5 of spiro bridged ring can be obtained by intramolecular Friedel Crafts reaction at position 2 of indole Route B: the author takes the precursor 7a of substrate 2a in route a as the substrate, and uses its methoxyl leaving property to react with hemiacetal 6A under the action of secondary amine catalyst to obtain α substituted hemiacetal intermediate 8; 8 also dehydrogenated under acid conditions to obtain oxyonium salt intermediate, which further undergoes intramolecular Friedel Crafts reaction at 2 of indole The product 9 was obtained Figure 2 Synthesis route design (source: org Lett.) according to the above strategies, the author optimized the reaction conditions of the two reaction routes and finally determined the optimal conditions of the two routes Under the optimal conditions, the author first studied the substrate applicability of route a (Fig 3), and obtained a series of spiro bridged compounds with high enantioselectivity Then, the absolute configuration of the compound was determined by the single crystal of 5'i Fig 3 Asymmetric synthesis of spiro bridged compounds (source: org Lett.) under the optimal conditions, the author also studied the substrate applicability of route B (Fig 4), and obtained a series of spiro bridged compounds with high enantioselectivity Furthermore, the absolute configuration of the compound was determined by the single crystal of 5'c Fig 4 Asymmetric synthesis of spiro-bicycles (source: org Lett.) through further study, the author found that the corresponding spiro bridged products 11 and 11 'can also be obtained by the reaction with 3-pyrrole oxindole 10 as the substrate, and have excellent enantioselectivity (Fig 5a) Finally, the author further derived the intermediate and the product: starting from the product 5'a, it was reduced by LiAlH 4 to obtain the semiacetaldehyde amine intermediate 12; 12 under the action of p-TsOH, the ring extension reaction took place to obtain the seven element ring extension product 13 (Fig 5b) Starting from the product 9'a, after reduction by LiAlH 4, it undergoes an acid catalyzed ring expanding rearrangement reaction, and finally obtains carbazole derivative 15 (Fig 5C) Finally, starting from the intermediate 8'a, the hemiacetamide derivative 17 can also be obtained by reduction methyl protection (Fig 5d) Figure 5 Derivation of products and intermediates (source: org Lett.) Summary: Liu Yankai's research group designed and developed two asymmetric synthetic spiro bridge rings and Spiros by using the substrate reactivity transformation strategy- A series of compounds with the pharmacophore structure of chroman, indole and oxyindole were obtained by the method of bicyclic compounds with high enantioselectivity In addition, other special skeleton derivatives were obtained At present, the bioactivity test of products and derivatives is in progress The results were recently published in org Lett (DOI: 10.1021/acs.orglett 8b02731) Review of previous reports: research team of Liu Yankai, associate professor of Ocean University of China: asymmetric organic catalytic series reaction of cyclic semi acetals with complex structure and functional Nitroalkenes to synthesize heterocyclic compounds with multiple heterocycles 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.