手性磷酸催化的C（3）-取代吲哚和甲基乙烯基酮不对称串联反应

doi:10.6023/A14060497

化学学报 ›› 2014, Vol. 72 ›› Issue (9): 1001-1004.DOI: 10.6023/A14060497 上一篇下一篇

研究通讯

手性磷酸催化的C（3）-取代吲哚和甲基乙烯基酮不对称串联反应

段德河^a,b, 殷勤^a, 王守国^a, 顾庆^a, 游书力^a,c

a 中国科学院上海有机化学研究所金属有机化学国家重点实验室上海 200032;
b 康龙化成(西安)新药技术有限公司西安 710018;
c 天津化学化工协同创新中心天津 300072

投稿日期:2014-06-30 发布日期:2014-08-27
通讯作者: 游书力 E-mail:slyou@sioc.ac.cn
基金资助:
项目受科技部973计划（No. 2010CB833300）、国家自然科学基金（Nos. 21025209，21121062，21272253，21332009）和中国科学院资助

Chiral Phosphoric Acid-Catalyzed Asymmetric Cascade Reaction of C(3) Substituted Indoles and Methyl Vinyl Ketone

Duan Dehe^a,b, Yin Qin^a, Wang Shouguo^a, Gu Qing^a, You Shuli^a,c

a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032;
b Pharmaron (Xi'an) Co. Ltd. Xi'an, 710018,
c Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072

Received:2014-06-30 Published:2014-08-27
Supported by:
Project supported by the National Basic Research Program of China (973 Program, No. 2010CB833300), the National Natural Science Foundation of China (Nos. 21025209, 21121062, 21272253, 21332009) and the Chinese Academy of Sciences.

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摘要/Abstract

3位含有季碳手性中心的吲哚啉并环化合物是一类非常重要的化合物, 广泛存在于各种天然产物和具有生物活性的分子中. 化学家们发展了多种有效的途径来合成这类化合物. 其中以方便易得的吲哚衍生物为起始原料, 利用不对称去芳构化\环化串联的方法最为简单高效, 但多数工作都是从色胺或色醇衍生物出发, 合成二氢吡咯并吲哚啉或二氢呋喃并吲哚啉化合物. 因此, 发展其他类型的吲哚衍生物的不对称去芳构化\环化反应显得非常有必要. 作者课题组发展了手性磷酸催化的吲哚衍生物与甲基乙烯基酮的不对称Michael加成\环化串联反应. 以5 mol% (R)-SPINOL为骨架的手性磷酸(R)-4c为催化剂, 以中等到良好的收率和优秀的对映选择性构建了一系列手性吲哚[2,3-b]并氢化喹啉化合物, 而且该催化体系对于克级规模反应同样能够获得很好的结果.

关键词: 手性磷酸, 不对称去芳构化, 吲哚, 串联反应

Fused indolines bearing a chiral quaternary carbon center at the C(3) position represent very important moieties widely existed in natural products and biologically active compounds. Various approaches to access these important scaffolds have been developed. Among them, asymmetric dearomatization\cyclization cascade reaction is the most concise and effective method by using indole derivatives as starting material. However, the documented reports mainly employed tryptamine or tryptophol derivatives, providing indoline products, such as pyrroloindolines or furoindolines. Therefore, the development of other type of indole derivatives allowing structural diversity is highly desirable. In this paper, an efficient asymmetric Michael addition\cyclization cascade reaction of indole derivatives with methyl vinyl ketone (MVK) was developed. After screening various phosphoric acids in the reaction of indole derivative (1a) with MVK, this cascade reaction delivered the dearomative product (2a) in 77% yield and 95% enantiomeric excess in the presence of (R)-SPINOL-derived chiral phosphoric acid (R)-4c with 5 Å molecular sieves as additive in CHCl₃ at room temperature. Under the optimized reaction conditions, a wide range of substituted indole derivatives bearing both electron-donating and electron-withdrawing groups have been tested. In all cases, the cascade dearomatization reaction proceeded smoothly to afford their corresponding indolo[2,3-b]quinoline products in moderate to good yields and excellent enantioselectivity. The absolute configuration of the products was then determined as (5aR,10bR) by an X-ray crystallographic analysis of a single crystal of enantiopure 2m. Moreover, this catalytic system was also feasible in a gram-scale reaction without erosion of enantiomeric excess. 1.25 g of product 2a can be prepared under the identical conditions in 91% yield and 93% ee.

Key words: chiral phosphoric acid, asymmetric dearomatization, indole, cascade reaction

引用此文

段德河, 殷勤, 王守国, 顾庆, 游书力. 手性磷酸催化的C（3）-取代吲哚和甲基乙烯基酮不对称串联反应[J]. 化学学报, 2014, 72(9): 1001-1004.

Duan Dehe, Yin Qin, Wang Shouguo, Gu Qing, You Shuli. Chiral Phosphoric Acid-Catalyzed Asymmetric Cascade Reaction of C(3) Substituted Indoles and Methyl Vinyl Ketone[J]. Acta Chim. Sinica, 2014, 72(9): 1001-1004.

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手性磷酸催化的C（3）-取代吲哚和甲基乙烯基酮不对称串联反应

Chiral Phosphoric Acid-Catalyzed Asymmetric Cascade Reaction of C(3) Substituted Indoles and Methyl Vinyl Ketone

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