化学学报 ›› 2022, Vol. 80 ›› Issue (3): 277-281.DOI: 10.6023/A21120588 上一篇    下一篇

研究论文

铑催化吲哚C(4)—H选择性活化构建氮杂-螺[4,5]吲哚骨架

王孟孟a, 张俊b, 王慧颖a, 马彪b,*(), 戴辉雄a,b,c,*()   

  1. a 南京中医药大学 新中药学院 南京 210023
    b 中国科学院大学 中国科学院上海药物研究所 中国科学院受体结构与功能重点实验室 上海 201203
    c 国科大杭州高等研究院药物科学与技术学院 杭州 310024
  • 投稿日期:2021-12-27 发布日期:2022-01-30
  • 通讯作者: 马彪, 戴辉雄
  • 作者简介:
    共同第一作者
    庆祝中国科学院青年创新促进会十年华诞.
  • 基金资助:
    国家自然科学基金(22001258); 国家自然科学基金(21920102003); 中国科学院青年创新促进会(2018293); 上海市科学技术委员会(17JC1405000); 上海市科学技术委员会(21ZR1475400); 上海市科学技术委员会(18431907100); 上海市学术/技术带头人计划(19XD1424600)

Construction of Aza-spiro[4,5]indole Scaffolds via Rhodium-Catalyzed Regioselective C(4)—H Activation of Indole

Mengmeng Wanga, Jun Zhangb, Huiying Wanga, Biao Mab(), Hui-Xiong Daia,b,c()   

  1. a School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023
    b Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai 201203
    c School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024
  • Received:2021-12-27 Published:2022-01-30
  • Contact: Biao Ma, Hui-Xiong Dai
  • About author:
    These authors contributed equally to this work
    Dedicated to the 10th anniversary of the Youth Innovation Promotion Association, CAS.
  • Supported by:
    National Natural Science Foundation of China(22001258); National Natural Science Foundation of China(21920102003); Youth Innovation Promotion Association CAS(2018293); Science and Technology Commission of Shanghai Municipality(17JC1405000); Science and Technology Commission of Shanghai Municipality(21ZR1475400); Science and Technology Commission of Shanghai Municipality(18431907100); Program of Shanghai Academic Research Leader(19XD1424600)

螺环吲哚是天然产物和药物化学中的一类重要骨架, 通过导向基团导向的C—H键活化反应已经成为构建螺环吲哚的重要方法. 目前在吲哚的吡咯片段上引入螺环结构已经比较成熟, 然而在吲哚的苯环片段上引入螺环还存在挑战. 以过渡金属铑催化, 选择性地活化吲哚C(4)—H键, 高效构建了氮杂-螺[4,5]吲哚骨架.

关键词: 螺环吲哚, C(4)—H键活化, 铑催化

Indole skeletons are widely used in drug research and development as a “privileged structure”, while spirocyclic scaffold as a common structural unit, usually plays an important role in the bioactivity and physicochemical properties of molecule skeletons. Hence, spiroindoles which incorporate both indole and spirocycle units have great significance and widespread applications in pharmaceutical field, and substantial progress has been made in the field for their construction and modification. C—H Activation via directing group's assistance has emerged as a powerful approach in the field of organic synthesis. To date, various 2- and 3-indolyl-tethered aza-spiro-centres via C—H activation have been successfully achieved. However, due to the inherent reactivity of the pyrrole side of the indole, introduction of spiro-containing systems onto the benzenoid core of indole still remains challenging. Here, by installing an appropriate directing group onto the C(3) position of indole, a mild and efficient method of Rh(III)-catalyzed selectively C(4)—H activation/cyclization of indole with diazo compound was developed. As a result, a series of novel aza-spiro[4,5]indole derivatives were obtained in mild to excellent yields. The protocol showed excellent functional group tolerance. Gram-scale synthesis demonstrated the utility of this protocol, and further modification via click chemistry offered the novel scaffold as a versatile spiro linker. A general procedure for the synthesis of spiroindole derivatives is described as the following: to a solution of N-(pivaloyloxy)-indole- 3-carboxamide (0.1 mmol), [Cp*RhCl2]2 (1.6 mg, 2.5 mol%) and NaOAc (1.6 mg, 20 mol%) in CH3CN (1 mL) was added diazooxindole (0.12 mmol) under air. Then the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the resulting mixture was diluted with 25 mL of EtOAc, and filtered through a celite pad. Then the filtrate was concentrated under vacuum to give the crude product, which was purified via silica gel to obtain the corresponding spiroindole product.

Key words: indole spirocycle, C—H activation, Rh-catalyst