Acta Chimica Sinica ›› 2014, Vol. 72 ›› Issue (7): 830-835.DOI: 10.6023/A14040249 Previous Articles     Next Articles

Special Issue: 不对称催化与合成



李清华a, 黄蓉a, 王春江a,b   

  1. a 武汉大学 化学与分子科学学院 武汉 430072;
    b 南开大学 元素有机化学国家重点实验室 天津 300071
  • 投稿日期:2014-04-03 发布日期:2014-04-21
  • 通讯作者: 王春江
  • 基金资助:


Catalytic Asymmetric exo-Selective 1,3-Dipolar Cycloaddition of Azomethine Ylides and Ethyl Cyclopropylidene Acetate for Construction of 5-aza-Spiro[2,4]heptane Motif

Li Qinghuaa, Huang Ronga, Wang Chunjianga,b   

  1. a College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072;
    b State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071
  • Received:2014-04-03 Published:2014-04-21
  • Supported by:

    Project supported by National Basic Research Program of China (973 Program) (No. 2011CB808600), the National Natural Science Foundation of China (No. 21172176) and Hubei Province NSF (No. ZRZ0273).

A direct and facile access to highly functionalized 5-aza-spiro[2,4]heptane derivatives is developed via Cu(CH3CN)4BF4/DTBM-BIPHEP-catalyzed asymmetric exo-selective 1,3-dipolar cycloaddition of azomethine ylides with ethyl cyclopropylidene acetate for the first time. The Cu(CH3CN)4BF4/DTBM-BIPHEP complex was identified as the optimal catalyst for the exo-selectivity. The reaction was carried out smoothly with wide substrate scope, and electron-deficient, electron-neutral and electron-rich aryl substituted imino esters were all compatible with the reaction, affording the 5-aza-spiro[2,4]heptane adducts containing three tertiary stereogenic centers and one spiro quaternary center in moderate to good yield (53%~83%) with excellent diastereoselectivity (>98:2, dr) and high enantioselectivity (up to 99% ee). The less reactive alkyl substituted imino ester derived from butyraldehyde was also tolerated in this annulation. The absolute configuration of the cycloadduct was unequivocally determined to be (4R,6S,7S) by X-ray analysis of N-tosylated derivative of exo-3a. Based on the relative and absolute configuration of the exo-cycloadducts, we proposed that an exo approach of ethyl 2-cyclopropylidene acetate to the copper(I) complex occurred predominantly because of the disfavored steric repulsion generated in the endo approach between the substituents of ethyl 2-cyclopropylidene acetate and the large bulky aryl group on the phosphorus atom of the chiral ligand. The produced 5-aza-spiro[2,4]heptanes fragment is widely present in many bioactive carbapenems derivatives, HSR-903 and substituted oxazolidinones. The optically active compounds with different stereoselectivities show different biological activities, therefore, it is important to develop the atom economical method for the asymmetric synthesis ofbiologically active exo-selective 5-aza-spiro[2,4]heptane derivatives.

Key words: asymmetric catalysis, 1,3-dipolar cycloaddition, azomethine ylide, ethyl cyclopropylidene acetate, 5-aza-spiro[2,4]heptane