Radical aryl migration enables diversity-oriented synthesis of structurally diverse medium/macro- or bridged-rings

• Published in: Nature communications Vol. 7; no. 1; p. 13852
• Main Authors: Li, Lei, Li, Zhong-Liang, Wang, Fu-Li, Guo, Zhen, Cheng, Yong-Feng, Wang, Na, Dong, Xiao-Wu, Fang, Chao, Liu, Jingjiang, Hou, Chunhui, Tan, Bin, Liu, Xin-Yuan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.12.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 639/638/403/933; 639/638/403/935; 639/638/549/2132; Alcohol; Alkenes; Alkenes - chemistry; Bridged-Ring Compounds - chemical synthesis; Bridged-Ring Compounds - chemistry; Bridged-Ring Compounds - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; Chemistry Techniques, Synthetic - methods; HEK293 Cells; Humanities and Social Sciences; Humans; Ketones - chemical synthesis; Ketones - chemistry; Ketones - pharmacology; Libraries; Macrocyclic Compounds - chemical synthesis; Macrocyclic Compounds - chemistry; Macrocyclic Compounds - pharmacology; Models, Chemical; Molecular Structure; multidisciplinary; Science; Science (multidisciplinary); Thermodynamics; China
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13852

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. Medium-sized ring systems are common in natural products, however their synthesis is challenging, largely due to entropic factors. Here the authors report a radical-based method for the synthesis of medium to large functionalized, carbon or heterocyclic scaffolds.