Acta Chim. Sinica ›› 2018, Vol. 76 ›› Issue (5): 382-386.DOI: 10.6023/A18040131 Previous Articles     Next Articles



周远春, 周志, 杜玮, 陈应春   

  1. 四川大学华西药学院 成都 610041
  • 投稿日期:2018-04-05 发布日期:2018-05-09
  • 通讯作者: 杜玮,;Tel.:0086-028-85502609;Fax:0086-028-85502609;陈应春,;
  • 基金资助:


Asymmetric Inverse-Electron-Demand Diels-Alder Reaction of 2-Pyrone and 2,5-Dienones via HOMO-Activation

Zhou Yuanchun, Zhou Zhi, Du Wei, Chen Yingchun   

  1. West China School of Pharmacy, Sichuan University, Chengdu 610041
  • Received:2018-04-05 Published:2018-05-09
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 21772126) and Sichuan University Distinguished Young Scientist Program (No. 2017SCU04A15).

The bicyclic lactones possess multiple reactive sites, and are usually employed as the key intermediates in the synthesis of natural products and bioactive substances. Among the methods for the construction of these chiral skeletons, the asymmetric Diels-Alder (DA) reaction with 2-pyrone substrates represents one of the most straightforward protocols, generally with high stereocontrol. However, in regard to the electron-deficient 2-pyrone substrates, the corresponding asymmetric DA reactions usually rely on LUMO-activation by chiral Lewis acids, suffering from relatively narrow substitutions and functional group limitations. As a result, the development of new activation modes for this type of DA reactions is in high demand. Here we report an asymmetric inverse-electron-demand Diels-Alder (IEDDA) reaction of 3-methoxycarbonyl-2-pyrone and cyclic 2,5-dienones in the presence of a primary amine derived from cinchona alkaloid, through the in situ generation of extended trienamine species. In this case, the remote δ,e-C=C bond of 2,5-dienone substrates is activated via a HOMO-raising strategy. A variety of bicyclic lactones with contiguous stereogenic centers were produced in moderate to good yields (46%~82%) with excellent diastereo-and enantioselectivity (>19:1 dr, 93%~99% ee). In addition, the cycloadduct underwent the ring-opening reaction with methanol, affording a cyclohexenol derivative with dense substitutions in an excellent yield with a retained ee value. Therefore, the current method supplies an efficient tool to construct chiral bicyclic lactones with high molecular complexity under mild aminocatalytic conditions, which might have potential application in organic synthesis and medicinal chemistry. A representative procedure for the asymmetric IEDDA reaction is as follows:3-Methoxycarbonyl-2-pyrone 1 (0.1 mmol), cyclic 2,5-dienone 2 (0.2 mmol), amine catalyst C2 (0.02 mmol) and acid A4 (0.04 mmol) were added into an oven-dried vial equipped with a magnetic stirbar. p-Xylene (1.0 mL) was added and the mixture was stirred at 60℃ and monitored by TLC. After completion, the residue was purified by flash chromatography on silica gel eluting with petroleum ether/ethyl acetate (8:1 to 4:1) to afford the product 3.

Key words: trienamine, asymmetric catalysis, inverse-electron-demand Diels-Alder, bicyclic lactones, HOMO-activation