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

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.

• Publication year

  2016

• Venue

  Nature Communications

• Publication date

  2016-12-22

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1038/ncomms13852PMID 28004746PMCID 5192181
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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