Acta Chimica Sinica ›› 2013, Vol. 71 ›› Issue (06): 879-883.DOI: 10.6023/A13020217 Previous Articles     Next Articles


手性磷酸催化亚甲胺叶立德与吲哚-3-甲醇不对称[3+3]环加成反应: 一步构建多取代四氢-β-咔啉

黄建洲, 罗时玮, 龚流柱   

  1. 中国科学技术大学 合肥微尺度物质科学国家实验室和化学与材料科学学院 合肥 230025
  • 投稿日期:2013-03-11 发布日期:2013-05-02
  • 通讯作者: 罗时玮,;龚流柱,; Fax: 0086-0551-3606266;
  • 基金资助:

    项目受国家自然科学基金(No. 21072181)资助.

Chiral Brønsted Acid Catalyzed Stereoselective [3+3] Cycloaddition Reaction of Azomethine Ylide to Vinylimine Intermediates: Constructing Fully Functionalized Chiral Tetrahydro-β-Carboline

Huang Jianzhou, Luo Shiwei, Gong Liuzhu   

  1. Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China, Hefei 230026
  • Received:2013-03-11 Published:2013-05-02
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 21072181).

An asymmetric three-component formal [3+3] cycloaddition reaction of aldehyde, diethyl 2-aminomalonate and substituted indolyl alcohols, has been investigated with chiral BINOL-derived monophosphoric acids as catalysts. The active azomethine ylide intermediate can be readily formed from the condensation of aldehyde and diethyl 2-aminomalonate under the promotion of the chiral phosphoric acids and is thereby able to undergo nucleophilic addition reaction to electron-deficient carbon-carbon double bonds as reported previously in the multicomponent reactions. On the other hand, the indolyl alcohols are able to participate in a dehydration reaction in the presence of the phosphoric acids to generate transient vinyliminium intermediates, which are principally reactive toward nucleophiles. Thus, we envisioned that the two types of active intermediates could undergo an asymmetric formal [3+3] cycloaddition to stereoselectively produce functionalized tetrahydro-β-carbolines under the catalysis of the chiral phosphoric acids. Consequently, a variety of 3,3'-disubstituted BINOL-phosphoric acids were initially evaluated for the reaction. As a result, the 3,3'-bis(p-ClPh) BINOL-phosphoric acid proved to perform most successfully in non-polar solvents, such as toluene. This reaction actually provides a highly straightforward access to functionalized tetrahydro-β-carboline derivatives. A number of substituted indolyl alcohols bearing either electronically donating or withdrawing groups are well tolerated, affording highly functionalized tetrahydro-β-carbolines in high yields ranging from 70% to 91% and with excellent enantioselectivities of up to 93% ee. A representative procedure for the enantioselective formal [3+3] cycloaddition reaction is as following: After a mixture of p-nitrobenzaldehyde (0.06 mmol), diethyl 2-amino-malonate (0.05 mmol), 3 Å MS (100 mg) and chiral phosphoric acid (10 mol%) in toluene (1.0 mL) was stirred at the r.t. for 15 min, the substituted indolyl acohol (0.1 mmol) was added. After completion of the addition, the reaction mixture was stirred for additional 12 h at the same temperature. The reaction solution was filtrated and the residue was washed three times with ethyl acetate (5 mL×3). The combined organic solutions were evaporated under the reduced pressure to give corresponding crude products, which were purified by column chromatography on silica gel (eluent: light petroleum ether:ethyl acetate, V:V=3:1) to give analytically pure tetrahydro-β-carboline derivatives.

Key words: chiral phosphoric acid, azomethine ylide, [3+3] cycloaddition, tetrahydro-β-carboline, asymmetric catalysis