Acta Chim. Sinica ›› 2017, Vol. 75 ›› Issue (10): 998-1002.DOI: 10.6023/A17060277 Previous Articles     Next Articles



石明林, 詹固, 杜玮, 陈应春   

  1. 四川大学华西药学院 成都 610041
  • 投稿日期:2017-06-26 发布日期:2017-09-04
  • 通讯作者: 杜玮,;陈应春,;
  • 基金资助:


Direct Asymmetric Aza-Vinylogous Mannich Reaction of Nitrones from Isatins and Ketimines

Shi Minglin, Zhan Gu, Du Wei, Chen Yingchun   

  1. West China School of Pharmacy, Sichuan University, Chengdu 610041, China
  • Received:2017-06-26 Published:2017-09-04
  • Supported by:

    Project supported by the National Natural Science Foundation of China (No. 21602143).

Direct asymmetric vinylogous Mannich reaction is an efficient and powerful method for the synthesis of δ-amino-α,β-unsaturated carbonyl compounds; however, the nucleophiles are generally limited to γ-butenolides and α,α-dicyanoolefins. Therefore, it is highly desirable to design new vinylogous nucleophiles and develop the related asymmetric reactions. Recently, we disclosed a new type of nitrones derived from isatins and N-benzyl hydroxylamines, which could easily generate nitrone ylide species in the presence of a tertiary amine, and undergo asymmetric formal[3+2] cycloadditions with α,β-unsaturated aldehydes via iminium ion catalysis of a chiral secondary amine. Subsequently, we found that such nitrone ylides could isomerize to more interesting aza-dienolate-type intermediates, and engage in direct stereoselective aza-vinylogous Michael reactions with nitroalkenes under the catalysis of a bifunctional thiourea-tertiary amine, delivering chiral nitrone derivatives with extended carbon skeletons without subsequent cyclization. In this case, the same type of nitrones are employed as nucleophilic precursors under the catalysis of a cinchona alkaloid-based thiourea substance, and effectively assembled with isatins-derived ketimines to accomplish the direct asymmetric aza-vinylogous-type Mannich reactions. A series of densely functionalized nitrones with vicinal tertiary-quaternary stereogenic centers are furnished in high yields (70%~97%) with good to excellent stereoselectivity (83%~99% ee, >19:1 dr). Moreover, subsequent[3+2] dipolar cycloaddition reactions between the chiral nitrones and activated alkenes can be realized in exclusive diastereoselectivity, producing complex spirocyclic indolenine architectures incorporating a hydrogenated isoxazole ring. These nitrones, as a new type of aza-vinylogous nucleophiles, may have a wide range of applications in asymmetric synthesis in the future. A representative procedure for the asymmetric aza-vinylogous-type Mannich reaction is as follows:nitrone 1 (0.1 mmol), ketimine 2 (0.11 mmol), catalyst C5 (0.01 or 0.02 mmol) are added into an oven-dried vial equipped with a magnetic stirbar. Xylene (1.0 mL) is added and the mixture is stirred at 50℃ and monitored by TLC. After completion, the residue is purified by flash column chromatography on silica gel eluting with petroleum ether/ethyl acetate (15:1 to 5:1) to afford the product 3.

Key words: asymmetric catalysis, organocatalysis, vinylogous Mannich reaction, nitrones, ketimines