Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China.
College of Materials Science &Engineering, Taiyuan University of Technology, Shanxi 030024, China.
Nat Commun. 2016 Dec 22;7:13852. 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.
中到大环桥环是天然产物和治疗剂中具有吸引力的结构基序。由于这些环系的不利熵和/或焓因子，它们的有效构建仍然是一个艰巨的挑战。为了解决这个问题，我们在此公开了一种基于自由基的方法，用于多样性导向合成各种苯并稠合的碳和杂原子含 8-11(14)-成员的酮库。该策略涉及通过自由基叠氮化、三氟甲基化、膦酰化、磺酰化或未活化烯烃的全氟烷基化引发的 1,4-或 1,5-芳基迁移，然后进行分子内环扩张。该方法作为一种高度灵活的构建工具，用于构建 37 个具有挑战性的中到大环和大环环支架，包括具有各种功能和骨架的桥环，这一点得到了突出强调。在初步的生物学研究中，其中一些产物对癌细胞或人胚肾系衍生物显示出强烈的抑制活性。通过对照实验和 DFT 计算研究了这种新策略的机制。
