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

• Applicant: Professor Dr. Christoph Schneider
• Subject Area: Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2015 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 268823980

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.

• DFG Programme: Research Grants