Cooperative Lewis Acid‐1,2,3‐Triazolium‐Aryloxide Catalysis: Pyrazolone Addition to Nitroolefins as Entry to Diaminoamides

• Published in: Angewandte Chemie International Edition 2023-09, Vol.62 (36), p.e202307317-n/a
• Main Authors: Wanner, Daniel M., Becker, Patrick M., Suhr, Simon, Wannenmacher, Nick, Ziegler, Slava, Herrmann, Justin, Willig, Felix, Gabler, Julia, Jangid, Khushbu, Schmid, Juliane, Hans, Andreas C., Frey, Wolfgang, Sarkar, Biprajit, Kästner, Johannes, Peters, René
• Format: Article
• Language: English
• Subjects: 1,4-Additions; Asymmetric synthesis; Camptothecin; Cancer therapies; Catalysis; Catalysts; Confinement; Copper(II); Density Functional Theory; DNA biosynthesis; Hydrogen Bonding; Lewis acid; Mode of action; Pyrazolones; Stereoselectivity; Synthesis
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202307317

Pyrazolones represent an important structural motif in active pharmaceutical ingredients. Their asymmetric synthesis is thus widely studied. Still, a generally highly enantio‐ and diastereoselective 1,4‐addition to nitroolefins providing products with adjacent stereocenters is elusive. In this article, a new polyfunctional CuII‐1,2,3‐triazolium‐aryloxide catalyst is presented which enables this reaction type with high stereocontrol. DFT studies revealed that the triazolium stabilizes the transition state by hydrogen bonding between C(5)−H and the nitroolefin and verify a cooperative mode of activation. Moreover, they show that the catalyst adopts a rigid chiral cage/pore structure by intramolecular hydrogen bonding, by which stereocontrol is achieved. Control catalyst systems confirm the crucial role of the triazolium, aryloxide and CuII, requiring a sophisticated structural orchestration for high efficiency. The addition products were used to form pyrazolidinones by chemoselective C=N reduction. These heterocycles are shown to be valuable precursors toward β,γ’‐diaminoamides by chemoselective nitro and N−N bond reductions. Morphological profiling using the Cell painting assay identified biological activities for the pyrazolidinones and suggest modulation of DNA synthesis as a potential mode of action. One product showed biological similarity to Camptothecin, a lead structure for cancer therapy. Pyrazolones represent an important structural motif in active pharmaceutical ingredients. A polyfunctional CuII‐1,2,3‐triazolium‐aryloxide catalyst which enables their addition to nitroolefins with high enantio‐ and diastereocontrol is presented. DFT studies show that the catalyst adopts a rigid chiral cage structure by intramolecular hydrogen bonding. The products were used to form bioactive compounds, pyrazolidinones and β,γ’‐diaminoamides.