Acta Chimica Sinica ›› 2014, Vol. 72 ›› Issue (7): 862-866.DOI: 10.6023/A14040294 Previous Articles     Next Articles

Special Issue: 不对称催化与合成



周容, 肖微, 尹祥, 詹固, 陈应春   

  1. 四川大学华西药学院 靶向药物与释药系统教育部重点实验室 成都 610041
  • 投稿日期:2014-04-18 发布日期:2014-05-06
  • 通讯作者: 陈应春
  • 基金资助:

Diastereo- and Enantioselective [4+2] Cycloadditions of Cyclic Enones with Cyclic 1-Azadienes

Zhou Rong, Xiao Wei, Yin Xiang, Zhan Gu, Chen Yingchun   

  1. Key Laboratory of Drug-Targeting and Drug Delivery Systems of the Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041
  • Received:2014-04-18 Published:2014-05-06
  • Supported by:
    Project supported by the National Natural Science Foundation of China (Nos. 21125206 and 21372160) and 973 Program (No. 2010CB833300).

Asymmetric aminocatalysis provides versatile tools for the stereoselective functionalizations of cyclic enone substrates at various sites. Recently, we developed an unusual [5+3] formal cycloaddition reaction of β-substituted 2-cyclopentenones or simple 2-cyclohexenone with bis(electrophilic) 1-azadienes, 3-vinyl-1,2-benzoisothiazole-1,1-dioxides, through α'-regioselective Michael addition followed by γ-regioselective intramolecular Mannich reaction via cascade cross-conjugated dienamine-endo-dienamine catalysis of a chiral primary amine. However, a completely different reaction pathway was disclosed when other type of cyclic enones, such as β-substituted 2-cyclohexenones or simple 2-cyclopentenone, were used under the similar aminocatalytic conditions. In this case, the same 1-azadiene partners act as electron-deficient dienophiles, and α',β-regioselective [4+2] cycloadditions occurred via cross-conjugated dienamine catalysis, giving bridged [2.2.2] octane or [2.2.1] heptane architectures with densely adorned functionalities. After systematically screening a number of reaction parameters, such as catalyst, acid additive and solvent, we can successfully realize the diastereodivergence in the above mentioned [4+2] cycloadditions. The endo-selective cycloadducts were efficiently obtained in moderate to excellent stereoselectivity (5:1~>19:1 dr, 86%~98% ee) in toluene at 50 ℃, by employing a (R,R)-1,2- diphenylethanediamine derived bifunctional primary amine catalyst with a benzothiadiazine-1,1-dioxide group as hydrogen bonding donor and in combination of benzoic acid. Even exclusive endo-selectivity (>19:1 dr) was consistently observed in the reactions of simple 2-cyclopentenone. A combination of 9-amino-9-deoxyepiquinidine and salicylic acid also produced the endo-selective cycloadduct but with slightly lower diastereoselectivity. In contrast, the diastereoselective [4+2] cycloadditions of β-substituted 2-cyclohexenones and 3-vinyl-1,2-benzoisothiazole-1,1-dioxides could be pleasingly switched by using 6'-OH-9-amino-9-deoxyepiquinidine and benzoic acid in PhCF3 at 50 ℃, providing the exo-selective cycloadducts with good results in terms of diastereo- and enantioselectivity (4:1~>19:1 dr, 83%~95% ee). 6'-OH-9-amino- 9-deoxyepiquinine could afford the exo-cycloadducts with an opposite configuration, but with less satisfactory stereoselectivity (3 examples, 5:1~9:1 dr, 62%~71% ee). Moreover, the analogous 4-styryl-1,2,3-benzoxathiazine-2,2-dioxide could be smoothly utilized as the dienophilic partner, which further enriched the functionalities of the [4+2] cycloadducts.

Key words: aminocatalysis, [4+2] cycloaddition, enantioselectivity, diastereoselectivity, diastereodivergence, cyclic enones, 1-azadienes