Mechanistic Insights into NHC/Cu Catalyzed Asymmetric Synthesis of Spirooxindole: Origins of Enantioselectivity and Diastereoselectivity

IF 4.7 1区 化学 Q1 CHEMISTRY, ORGANIC
Lili Zhao, Qin Ma, Shuqi Zhang, Qingshuang Zhang, Xing Yang, Lei Qin
{"title":"Mechanistic Insights into NHC/Cu Catalyzed Asymmetric Synthesis of Spirooxindole: Origins of Enantioselectivity and Diastereoselectivity","authors":"Lili Zhao, Qin Ma, Shuqi Zhang, Qingshuang Zhang, Xing Yang, Lei Qin","doi":"10.1039/d5qo01235j","DOIUrl":null,"url":null,"abstract":"Density Functional Theory (DFT) calculations were conducted to elucidate the mechanism of NHC/Cu catalyzed enantioselective annulation between isatin-derived enals and ethynyl carbonates, enabling the asymmetric synthesis of spirooxindole δ-lactones with vicinal all-carbon quaternary stereocenters. The catalytic process involves four key stages: (i) generation of azolium homoenolate intermediate IM3 via NHC-mediated nucleophilic addition to enal 1a; (ii) [Cu]-catalyzed decarboxylation of ethynyl carbonate 2a to afford the copper-alkynyl intermediate IM7; (iii) stereoselective C-C bond formation between IM3 and IM7, followed by a two-water-mediated enol-keto tautomerization yielding the ketone intermediate IM10; and (iv) NEt3-promoted deprotonation, intramolecular cyclization, and proton transfer affording product spirooxindole δ-lactone 3a. Notably, both the enantio-and diastereoselectivity-determining step and the rate-determining step occur in Stage III. Further DIAS and QTAIM analyses of four stereoisomeric transition states identify TS5(S,R) as the most favorable, exhibiting the lowest free energy barrier and multiple stabilizing non-covalent interactions (C-H⋯π, C-H⋯O, C-F⋯π, and Cu⋯H), rationalizing the observed high stereoselectivity. Water molecules are shown to play a crucial role in lowering the barrier of the rate-determining step by enhancing electrostatic, orbital, and dispersion interactions. This study not only deepens the mechanistic understanding of cooperative NHC/Cu catalysis but also provides valuable theoretical guidance for rational designing next-generation asymmetric annulation reactions.","PeriodicalId":97,"journal":{"name":"Organic Chemistry Frontiers","volume":"4 1","pages":""},"PeriodicalIF":4.7000,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Chemistry Frontiers","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1039/d5qo01235j","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, ORGANIC","Score":null,"Total":0}
引用次数: 0

Abstract

Density Functional Theory (DFT) calculations were conducted to elucidate the mechanism of NHC/Cu catalyzed enantioselective annulation between isatin-derived enals and ethynyl carbonates, enabling the asymmetric synthesis of spirooxindole δ-lactones with vicinal all-carbon quaternary stereocenters. The catalytic process involves four key stages: (i) generation of azolium homoenolate intermediate IM3 via NHC-mediated nucleophilic addition to enal 1a; (ii) [Cu]-catalyzed decarboxylation of ethynyl carbonate 2a to afford the copper-alkynyl intermediate IM7; (iii) stereoselective C-C bond formation between IM3 and IM7, followed by a two-water-mediated enol-keto tautomerization yielding the ketone intermediate IM10; and (iv) NEt3-promoted deprotonation, intramolecular cyclization, and proton transfer affording product spirooxindole δ-lactone 3a. Notably, both the enantio-and diastereoselectivity-determining step and the rate-determining step occur in Stage III. Further DIAS and QTAIM analyses of four stereoisomeric transition states identify TS5(S,R) as the most favorable, exhibiting the lowest free energy barrier and multiple stabilizing non-covalent interactions (C-H⋯π, C-H⋯O, C-F⋯π, and Cu⋯H), rationalizing the observed high stereoselectivity. Water molecules are shown to play a crucial role in lowering the barrier of the rate-determining step by enhancing electrostatic, orbital, and dispersion interactions. This study not only deepens the mechanistic understanding of cooperative NHC/Cu catalysis but also provides valuable theoretical guidance for rational designing next-generation asymmetric annulation reactions.
NHC/Cu催化不对称合成螺菌吲哚的机理:对映选择性和非对映选择性的起源
采用密度泛函理论(DFT)分析了NHC/Cu催化异黄酮衍生的烯醛和碳酸乙酯之间的对映选择性环化反应机理,从而实现了邻全碳季立体中心的螺嘧哚δ-内酯的不对称合成。催化过程包括四个关键阶段:(i)通过nhc介导的烯醛1a亲核加成生成azolium homoenolate中间体IM3;(ii) [Cu]催化碳酸乙酯2a脱羧得到铜-炔基中间体IM7;(iii)在IM3和IM7之间形成立体选择性C-C键,随后发生双水介导的烯醇-酮异构反应,生成酮中间体IM10;(iv) net3促进去质子化、分子内环化和质子转移,生成螺烷吲哚δ-内酯3a。值得注意的是,对映体和非对映体选择性决定步骤和速率决定步骤都发生在第三阶段。进一步的DIAS和QTAIM分析发现,TS5(S,R)是最有利的,表现出最低的自由能势垒和多种稳定的非共价相互作用(C-H⋯π, C-H⋯O, C-F⋯π和Cu⋯H),合理化了观察到的高立体选择性。水分子通过增强静电、轨道和色散相互作用,在降低速率决定步骤的势垒方面起着至关重要的作用。该研究不仅加深了对NHC/Cu协同催化机理的认识,而且为合理设计下一代不对称环化反应提供了有价值的理论指导。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Organic Chemistry Frontiers
Organic Chemistry Frontiers CHEMISTRY, ORGANIC-
CiteScore
7.90
自引率
11.10%
发文量
686
审稿时长
1 months
期刊介绍: Organic Chemistry Frontiers is an esteemed journal that publishes high-quality research across the field of organic chemistry. It places a significant emphasis on studies that contribute substantially to the field by introducing new or significantly improved protocols and methodologies. The journal covers a wide array of topics which include, but are not limited to, organic synthesis, the development of synthetic methodologies, catalysis, natural products, functional organic materials, supramolecular and macromolecular chemistry, as well as physical and computational organic chemistry.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信