Inter- und intramolecular, phosphoric acid-catalyzed reactions of in situ-generated ortho-quinone methides and ortho-quinone methide imines towards the enantioselective synthesis of benzoannulated oxygen and nitrogen heterocycles

原位生成的邻醌甲基化物和邻醌甲基化物亚胺的分子间和分子内磷酸催化反应，用于对映选择性合成苯环氧和氮杂环

• 批准号: 268823980
• 负责人: Professor Dr. Christoph Schneider
• 金额: --
• 依托单位: Institut für Organische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/268823980?language=en
• 关键词: Inter; und; intramolecular; phosphoric; acid

Ortho-quinone methides are shortlived, highly reactive alkylidene cyclohexadienones, which are generated in situ and are converted into phenols via conjugate addition and cycloaddition reactions under rearomatization. In the first funding period we have been able to show for a broad range of reactions that phosphoric acid-bound, chiral ortho-quinone methides can be easily generated from ortho-hydroxyl benzyl alcohols and treated with enolrich and related nucleophiles to furnish benzoannulated oxygen heterocycles with excellent enantioselectivity through bifunctional activation.In the next funding period we intend to exploit the full potential not only of the ortho-quinone methides but also of the corresponding ortho-quinone methide imines. We intend to develop these reactions into broadly applicable processes for the flexible and highly stereoselective synthesis of benzoannulated oxygen and nitrogen heterocycles. In that respect two main subtopics are planned which go far beyond the previous work conceptually: First, the development of a cooperative-synergistic catalysis strategy, which allows for the combination of phosphoric acid catalysis with amine catalysis in reactions of ortho-quinone methides. Such a strategy shall enable transformations not feasible under monocatalytic conditions and the use of catalytically generated enamines and dienamines. Densely functionalized and highly substituted chromans are to be synthesized in a highly enantioselective manner in reactions with ortho-quinone methides.Second, we intend to study intramolecular, enantioselective cycloadditions of ortho-quinone methide imines in order to access alkaloid-like structures such as benzoannulated indolizidines and quinolizidines. Such a strategy is currently without precedence in an enantioselective fashion and would constitute a significant conceptual advance of the synthetic potential of ortho-quinone methide imines. In preliminary work we have been able to achieve a proof of principle and intend now to develop this strategy into a powerful general method. Furthermore, we intend to study intramolecular conjugate additions of various p-nucleophiles and heteronucleophiles toward ortho-quinone methide imines in order to access polysubstituted and highly functionalized tetrahydroquinolines, benzoazepines, and benzodiazepines.

邻醌类化合物是一种寿命短、活性高的烷基烯环己二烯类化合物，在原位生成后通过共轭加成和环加成反应在重芳构化下转化为酚类化合物。在第一个资助期，我们已经能够证明，在广泛的反应中，磷酸结合的手性邻醌方法可以很容易地从邻羟基苯甲醇中生成，并与烯醇和相关的亲核试剂一起处理，通过双功能活化提供具有优异对映选择性的苯并环氧杂环。在下一个筹资期内，我们打算不仅充分挖掘对醌类方法的潜力，而且充分挖掘相应的对醌类甲基亚胺的潜力。我们打算将这些反应发展成广泛适用的工艺，用于柔性和高度立体选择性合成苯并环氧和氮杂环。在这方面，计划了两个主要的子主题，它们在概念上远远超出了以前的工作：首先，开发一种协同-协同催化策略，该策略允许在邻醌方法的反应中磷酸催化与胺催化的结合。这种策略将使在单催化条件下无法实现的转化和使用催化生成的胺和二胺。密集功能化和高度取代的染色质在与邻醌的反应中以高度对映选择性的方式合成。其次，我们打算研究分子内对映选择性的邻醌甲基亚胺环加成，以获得类生物碱结构，如苯并环吲哚嘧啶和喹啉嘧啶。这种策略目前在对映选择性方面还没有先例，它将构成对邻醌甲酰亚胺合成潜力的重大概念进步。在初步工作中，我们已经能够实现原理证明，现在打算将这一战略发展成为一种强大的一般方法。此外，我们打算研究各种对亲核试剂和杂核试剂对邻醌甲基亚胺的分子内共轭加成，以获得多取代和高功能化的四氢喹啉类、苯并氮卓类和苯二氮卓类药物。

项目成果

Cooperative Photoinduced/Brønsted Acid Catalyzed Cycloaddition of Transient Thioaldehydes and ortho-Quinone Methides toward a Synthesis of Benzo[e][1,3]oxathiines.

光诱导/布朗斯台德酸催化瞬时硫醛和邻醌甲基化物的环加成反应合成苯并[e][1,3]氧噻啶

• DOI: 10.1021/acs.orglett.1c00588
• 发表时间: 2021
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: F. Sachse;C. Schneider
• 通讯作者: C. Schneider

Unravelling the configuration of transient ortho-quinone methides by combining microfluidics with gas phase vibrational spectroscopy.

将微流体与气相振动光谱相结合，揭示瞬态邻醌方法的结构

• DOI: 10.1039/c9cp06435d
• 发表时间: 2020
• 期刊: Physical chemistry chemical physics : PCCP
• 作者: M. Mayer;M. Pahl;M. Spanka;M. Grellmann;M. Sickert;C. Schneider;K. Asmis;D. Belder
• 通讯作者: D. Belder

Phosphoric Acid Catalyzed Aldehyde Addition to in Situ Generated o-Quinone Methides: An Enantio- and Diastereoselective Entry toward cis-3,4-Diaryl Dihydrocoumarins.

• DOI: 10.1021/acs.orglett.8b01865
• 发表时间: 2018-08
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Matthias Spanka;C. Schneider

Phosphoric Acid Catalyzed [4 + 1]-Cycloannulation Reaction of ortho-Quinone Methides and Diazoketones: Catalytic, Enantioselective Access toward cis-2,3-Dihydrobenzofurans.

• DOI: 10.1021/acs.orglett.8b03311
• 发表时间: 2018-11
• 期刊: Organic letters
• 影响因子: 5.2
• 作者: Arun Suneja;C. Schneider