Acta Chim. Sinica ›› 2014, Vol. 72 ›› Issue (9): 1001-1004.DOI: 10.6023/A14060497 Previous Articles     Next Articles



段德河a,b, 殷勤a, 王守国a, 顾庆a, 游书力a,c   

  1. a 中国科学院上海有机化学研究所 金属有机化学国家重点实验室 上海 200032;
    b 康龙化成(西安)新药技术有限公司 西安 710018;
    c 天津化学化工协同创新中心 天津 300072
  • 投稿日期:2014-06-30 发布日期:2014-08-27
  • 通讯作者: 游书力
  • 基金资助:

    项目受科技部973计划(No. 2010CB833300)、国家自然科学基金(Nos. 21025209,21121062,21272253,21332009)和中国科学院资助

Chiral Phosphoric Acid-Catalyzed Asymmetric Cascade Reaction of C(3) Substituted Indoles and Methyl Vinyl Ketone

Duan Dehea,b, Yin Qina, Wang Shouguoa, Gu Qinga, You Shulia,c   

  1. a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032;
    b Pharmaron (Xi'an) Co. Ltd. Xi'an, 710018,
    c Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072
  • Received:2014-06-30 Published:2014-08-27
  • Supported by:

    Project supported by the National Basic Research Program of China (973 Program, No. 2010CB833300), the National Natural Science Foundation of China (Nos. 21025209, 21121062, 21272253, 21332009) and the Chinese Academy of Sciences.

Fused indolines bearing a chiral quaternary carbon center at the C(3) position represent very important moieties widely existed in natural products and biologically active compounds. Various approaches to access these important scaffolds have been developed. Among them, asymmetric dearomatization\cyclization cascade reaction is the most concise and effective method by using indole derivatives as starting material. However, the documented reports mainly employed tryptamine or tryptophol derivatives, providing indoline products, such as pyrroloindolines or furoindolines. Therefore, the development of other type of indole derivatives allowing structural diversity is highly desirable. In this paper, an efficient asymmetric Michael addition\cyclization cascade reaction of indole derivatives with methyl vinyl ketone (MVK) was developed. After screening various phosphoric acids in the reaction of indole derivative (1a) with MVK, this cascade reaction delivered the dearomative product (2a) in 77% yield and 95% enantiomeric excess in the presence of (R)-SPINOL-derived chiral phosphoric acid (R)-4c with 5 Å molecular sieves as additive in CHCl3 at room temperature. Under the optimized reaction conditions, a wide range of substituted indole derivatives bearing both electron-donating and electron-withdrawing groups have been tested. In all cases, the cascade dearomatization reaction proceeded smoothly to afford their corresponding indolo[2,3-b]quinoline products in moderate to good yields and excellent enantioselectivity. The absolute configuration of the products was then determined as (5aR,10bR) by an X-ray crystallographic analysis of a single crystal of enantiopure 2m. Moreover, this catalytic system was also feasible in a gram-scale reaction without erosion of enantiomeric excess. 1.25 g of product 2a can be prepared under the identical conditions in 91% yield and 93% ee.

Key words: chiral phosphoric acid, asymmetric dearomatization, indole, cascade reaction