化学学报 ›› 2012, Vol. 70 ›› Issue (16): 1682-1685.DOI: 10.6023/A12070444 上一篇    下一篇

研究通讯

靛红Morita-Baylis-Hillman碳酸酯与环状N-磺酰亚胺的不对称烯丙基烷基化反应研究

孙峋皓, 彭景, 张叔阳, 周清清, 董琳, 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
  • 收稿日期:2012-07-19 出版日期:2012-08-28 发布日期:2012-08-15
  • 通讯作者: 陈应春 E-mail:ycchenhuaxi@yahoo.com.cn
  • 基金资助:
    项目受国家自然科学基金(Nos. 21125206, 21021001)资助.

Asymmetric Allylic Alkylation of Cyclic N-Sulfonylimines with Morita-Baylis-Hillman Carbonates of Isatins

Sun Xunhao, Peng Jing, Zhang Shuyang, Zhou Qingqing, Dong Lin, 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, China
  • Received:2012-07-19 Online:2012-08-28 Published:2012-08-15
  • Supported by:
    Project supported by the National Natural Science Foundation of China (Nos. 21125206, 21021001).

本课题组近年来发展的通过路易斯碱催化靛红Morita-Baylis-Hillman(MBH)碳酸酯的烯丙基烷基化反应是合成光学纯3,3-二取代2-氧化吲哚化合物的一种有效方法. 在此基础上, 本文研究了手性叔胺催化靛红MBH碳酸酯与环状N-磺酰亚胺的不对称烯丙基烷基化反应, 通过亲电反应途径以较高的立体选择性(达86% ee, dr>95∶5)和高收率(达96%)合成C-3位含季碳手性中心的多官能团氧化吲哚产物. 通过简单的转化可以得到含多个手性中心的2-吲哚酮-3,4'-哌啶环类骨架, 这为进一步合成生理活性物质研究奠定了基础.

关键词: 不对称有机催化, 烯丙基烷基化, Morita-Baylis-Hillman碳酸酯, 环状N-磺酰亚胺, 2-氧化吲哚, 季碳手性中心, 2-吲哚酮-3,4'-哌啶环

Enantiomerically pure 3,3-disubstituted 2-oxindoles are important building blocks for the synthesis of diverse oxindoles which are the core structure of many natural products and biologically active compounds. A number of asymmetric reactions to access such chiral materials have been reported over the past years, most of which rely on the application of nucleophilic 3-subsituted oxindoles. Although these methods have been proved to be useful, some challenging issues still remain in terms of efficiency, stereoselectivity and substrate scope. On the other hand, recently, we have developed some highly stereoselective allylic alkylation reactions with Morita-Baylis-Hillman (MBH) carbonates of isatins and diverse nucleophiles, to produce 3,3-disubstituted oxindoles under the catalysis of metal-free Lewis basic tertiary amines. In this work, the first asymmetric assembly of MBH carbonates of isatins and cyclic N-sulfonylimines is reported. An array of tertiary amine catalysts derived from β-isocupreidine (β-ICD) and a variety of reaction parameters have been systematically investigated, and the optimized conditions were determined to run the reaction at -20 ℃ using PhCF3 as the solvent, 4 Å MS as the additive, in the presence of 10 mol% of amine catalyst 1h. A number of MBH carbonates 2 derived from diversely substituted isatins and cyclic N-sulfonylimines 3 could be well tolerated under the established catalytic conditions, providing an alternative electrophilic pathway to access multifunctional oxindoles bearing adjacent quaternary and tertiary stereogenic centers (up to 86% ee, dr>95∶5) in high yield (up to 96%). Moreover, the thus obtained chiral 3,3-disubstituted 2-oxindole could be used for the synthesis of complex spirocyclic 2-oxindole-3,4'-piperidine product. In this case, the chemoselective reduction of imine group of allylic alkylation product 4a has been realized by using NaBH4 as the reducing reagent at -20 ℃. A following intramolecular aza-Michael addition reaction gave a 2-oxindole-3,4'-piperidine product 6 in a moderate yield.

Key words: asymmetric organocatalysis, allylic alkylation, Morita-Baylis-Hillman carbonates, cyclic N-sulfonylimines, 2-oxindoles, quaternary chiral centre, 2-oxindole-3,4'-piperidine