New Application of the Organocatalyzed House-Meinwald Rearrangement - Facile Synthesis of Aldehydes

This thesis explores the organocatalytic House–Meinwald rearrangement as a versatile strategy for the efficient synthesis of aldehydes, their subsequent transformation into various functional groups and provides access to prepare active pharmaceutical ingredients. In both projects, we employ disulfonimides as carefully tunable organocatalysts and demonstrate their application enabling highly selective and efficient formation of carbonyl compounds under mild conditions.
In the first part, we present a new method for the organocatalyzed, chemoselective, and stereospecific House-Meinwald rearrangement of trisubstituted epoxides, a particularly challenging substrate class due to competing reaction pathways. By using simple perfluorinated disulfonimides as catalysts we achieve the epoxide rearrangement under mild conditions and with low catalyst loadings. We efficiently synthesize α-quaternary aldehydes, which are traditionally difficult to access. Using enantioenriched epoxides we demonstrate the rearrangement proceeding in a stereospecific manner and with a fully preservation of the stereochemical information. This high level of stereochemical control highlights the potential of our method for its application in natural product synthesis and construction of complex molecules bearing quaternary carbons.
In the second part, we utilize bis(trifluoromethane)sulfonimide as an organocatalyst in the House-Meinwald rearrangement of terminal epoxides to synthesize various aldehydes. Previous approaches used such substrates in one-pot procedures in combination with subsequent reductions to avoid side reaction after formation of the target aldehydes. Therefore, it is a key achievement of our strategy to access various aldehydes in excellent yields utilizing low catalyst loadings and mild reaction conditions, while achieving a broad functional group tolerance across both alkyl- and aryl-substituted substrates. In addition, we transfer the aldehydes into various functional groups such as alcohols, amines, and carboxylic acid, demonstrating the versatility of our method. To highlight the practicality and scalability of our procedure we synthesize ibuprofen in a three-step synthesis starting from commercially available starting material and with a high overall yield of 90%. In comparison to the industrial ibuprofen synthesis, our protocol avoids the usage of catalysts based on heavy metals such as palladium and proceeds under slightly elevated temperature of 55 °C.
Overall, we demonstrate the versatility of organocatalytic strategies for epoxide rearrangements by firstly expanding the scope toward highly substituted substrates (project 1) and secondly by emphasizing practical applicability (project 2). Through both contributions, we show that organocatalysis effectively overcomes longstanding challenges associated with the House–Meinwald rearrangement and provides valuable tools for modern synthetic chemistry.