通过不对称多组分反应高效构建手性磺酰胺类化合物

doi:10.6023/A18060228

摘要/Abstract

手性磺酰胺类化合物在新型药物方面研究中占据越来越重要的地位.我们成功地实现了磺酰胺、芳基重氮乙酸酯以及亚胺的不对称三组分反应.此反应给出了高达85%产率，以及优异的非对映选择性（d.r.>20：1）和对映选择性（最高可达99%ee），为高效构建具有两个手性碳的光学纯磺酰胺类化合物提供了一种快速合成方法.我们将反应放大到了克级规模，并对三组分产物进一步衍生得到一种具有三个手性中心的光学纯含亚砜亚胺骨架的五元环化合物.反应的选择性通过过渡金属与手性磷酸协同催化控制.

关键词: 磺酰胺, 不对称多组分反应, 铵基叶立德, 协同催化, 亚砜亚胺

Sulfonamide is a key structural unit of several groups of vitally synthetic drugs that have been extensively used as antimicrobials, antiretroviral drugs and anticancer agents. In particular, enantiomerically pure sulfonamides represent a rapidly-increasing important substance in new drug discovery due to their unique pharmacological properties. Thus, developing asymmetric synthetic methods involving rapid and highly efficient construction of these compounds is extremely important and highly demanded for medicinal chemists. In our laboratory, we have reported a serial of asymmetric multicomponent reactions via trapping reactive ammonium ylides generated from amines and diazo compounds in the presence of transition metal complexes and chiral phosphoric acids. In this work, an asymmetric three-component reaction of sulfonamides, diazo compounds and imines cooperatively catalyzed by Rh₂(OAc)₄ and chiral phosphoric acids was reported. This Rh₂(OAc)₄ and chiral phosphoric acids cooperatively catalyzed three-component reaction of sulfonamides, diazo compounds and imines accomplished with satisfying yields (up to 85%), high diastereoselectivity (>20:1) and excellent enantioselectivity (up to 99% ee), thus providing a rapid access to synthesize enantiomerically enriched sulfonamides bearing two adjacent chiral carbons. Furthermore, this newly developed three-component reaction was carried out on a gram-scale with a lower catalyst loading and without impacting the yield, diastereoselectivity and enantioselectivity. Finally, we explored the further transformation of obtained three-component reaction products:1) treatment of 5aaa with LiAlH₄ under 0℃ in THF for 8.0 h gave the corresponding alcohol derivative 6 in 82% yield without changing the diastereoselectivity and enantioselectivity (0.20 mmol scale); 2) treatment of 5aaa with triphosgene and triethylamine under 0℃ in DCM for 1.0 h, gave five-membered heterocyclic sulfoximine derivative 7 bearing three adjacent chiral atoms (2 carbons and 1 sulfur) in 80% yield with perfect diastereoselectivity (>20:1) and remained enantioselectivity (0.20 mmol scale).

Key words: sulfonamides, asymmetric multicomponent reactions, ammonium ylides, cooperative catalysis, sulfoximines

引用此文

余思凡, 傅祥, 刘耿鑫, 邱晃, 胡文浩. 通过不对称多组分反应高效构建手性磺酰胺类化合物[J]. 化学学报, 2018, 76(11): 895-900.

Yu Sifan, Fu Xiang, Liu Gengxin, Qiu Huang, Hu Wenhao. Efficient and Facile Synthesis of Chiral Sulfonamides via Asymmetric Multicomponent Reactions[J]. Acta Chim. Sinica, 2018, 76(11): 895-900.

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