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

邻醌甲基化物是一种短寿命、高反应活性的亚烷基环己二烯酮，其原位生成，并在重排反应下通过共轭加成和环加成反应转化为苯酚。在第一个资助期内，我们已经能够证明磷酸结合的广泛反应，手性邻醌甲基化物可以很容易地从邻羟基苄醇生成，并与烯醇式和相关的亲核试剂处理，通过双官能活化提供具有优异对映选择性的苯环化氧杂环。在下一个资助期内，我们打算不仅充分利用邻-醌甲基化物，而且还包括相应的邻醌甲基化物亚胺。我们打算将这些反应发展成广泛适用的方法，用于灵活和高度立体选择性合成苯并环化的氧和氮杂环。在这方面，两个主要的子课题计划远远超出了以前的工作概念：第一，合作-协同催化策略的发展，这使得磷酸催化与胺催化的反应中的邻醌甲基化物的组合。这样的策略应能够实现在单催化条件下不可行的转化以及使用催化产生的烯胺和二烯胺。密集功能化和高度取代的苯并二氢吡喃是在一个高度对映选择性的方式在与邻醌methides.Second反应中合成的，我们打算研究分子内，邻醌甲基亚胺的对映选择性环加成反应，以获得类似的结构，如benzoannulated indolizidines和quinolizidines。这种策略目前在对映选择性方式中没有先例，并且将构成邻醌甲基亚胺合成潜力的重要概念性进展。在初步的工作中，我们已经能够实现原理的证明，现在打算把这个策略发展成一个强大的通用方法。此外，我们打算研究各种p-亲核试剂和杂亲核试剂对邻醌甲基亚胺的分子内共轭加成，以获得多取代和高度官能化的四氢喹啉，苯并氮杂卓和苯并二氮杂卓。

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.