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

邻苯二酚亚甲基是一类寿命短、活性高的亚烷基环己二烯酮类化合物，在芳构化反应中可通过共轭加成和环加成反应转化为苯酚。在第一个资助期，我们已经能够为广泛的反应展示，邻羟基苯甲醇可以很容易地生成磷酸结合的手性邻苯二酚亚胺，并用富含烯醇的亲核剂和相关的亲核剂处理，通过双功能活化提供具有良好对映体选择性的苯环氧杂环。在下一个资助期，我们打算不仅充分挖掘邻醌甲基化合物的潜力，而且还开发相应的邻醌甲基亚胺的潜力。我们打算将这些反应发展成广泛适用的过程，用于灵活和高度立体选择性地合成苯环氧和氮杂环。在这方面，计划了两个在概念上远远超出以前工作的主要分专题：第一，制定合作-协同催化战略，允许将磷酸催化与胺催化相结合用于邻苯二酚甲基的反应。这种战略应使在单催化条件下不可行的转化和使用催化生成的烯胺和二胺成为可能。在与邻苯二酚亚胺的反应中，我们将以高对映选择性的方式合成具有浓密官能化和高取代度的色满。其次，我们打算研究邻苯二酚甲基亚胺的分子内、对映选择性环加成反应，以获得类似生物碱的结构，如苯环化的吲哚和喹啉。这种策略目前在对映体选择性方面尚无先例，并将在合成邻苯二酚甲基亚胺方面取得重大的概念性进展。在初步工作中，我们已经能够证明原则，现在打算将这一战略发展成一种强有力的一般方法。此外，我们打算研究不同的对核亲核试剂和杂核亲核试剂与邻苯二酚甲亚胺的分子内共轭加成反应，以获得多取代和高官能化的四氢喹啉、苯并氮卓和苯二氮卓类化合物。

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.