title: Radical aryl migration enables diversity-oriented synthesis of structurally diverse medium/macro- or bridged-rings.
abstract: Medium-sized and medium-bridged rings are attractive structural motifs in natural products and therapeutic agents. Due to the unfavourable entropic and/or enthalpic factors with these ring systems, their efficient construction remains a formidable challenge. To address this problem, we herein disclose a radical-based approach for diversity-oriented synthesis of various benzannulated carbon- and heteroatom-containing 8-11(14)-membered ketone libraries. This strategy involves 1,4- or 1,5-aryl migration triggered by radical azidation, trifluoromethylation, phosphonylation, sulfonylation, or perfluoroalkylation of unactivated alkenes followed by intramolecular ring expansion. Demonstration of this method as a highly flexible tool for the construction of 37 synthetically challenging medium-sized and macrocyclic ring scaffolds including bridged rings with diverse functionalities and skeletons is highlighted. Some of these products showed potent inhibitory activity against the cancer cell or derivative of human embryonic kidney line in preliminary biological studies. The mechanism of this novel strategy is investigated by control experiments and DFT calculations.
authors.affiliation: Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China.
authors.forename: Zhong-Liang
authors.initials: ZL
authors.lastname: Li
authors.affiliation: Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China.
authors.forename: Fu-Li
authors.initials: FL
authors.lastname: Wang
authors.affiliation: College of Materials Science &Engineering, Taiyuan University of Technology, Shanxi 030024, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China.
authors.forename: Yong-Feng
authors.initials: YF
authors.lastname: Cheng
authors.affiliation: College of Materials Science &Engineering, Taiyuan University of Technology, Shanxi 030024, China.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xiao-Wu
authors.initials: XW
authors.lastname: Dong
authors.affiliation: Department of Biology, South University of Science and Technology of China, Shenzhen 518055, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Fang
authors.affiliation: Department of Biology, South University of Science and Technology of China, Shenzhen 518055, China.
authors.forename: Jingjiang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Biology, South University of Science and Technology of China, Shenzhen 518055, China.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Hou
authors.affiliation: Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Tan
authors.affiliation: Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China.
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Liu
mesh_terms: D000475:Alkenes / Q000737:chemistry; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D057809:HEK293 Cells; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D015394:Molecular Structure; D013816:Thermodynamics
chemical_list: D000475:Alkenes; D001952:Bridged-Ring Compounds; D007659:Ketones; D047028:Macrocyclic Compounds