Wanner, Daniel M.Becker, Patrick M.Suhr, SimonWannenmacher, NickZiegler, SlavaHerrmann, JustinWillig, FelixGabler, JuliaJangid, KhushbuSchmid, JulianeHans, Andreas C.Frey, WolfgangSarkar, BiprajitKästner, JohannesPeters, René2023-11-082023-11-0820231433-78511521-3773187050514Xhttp://nbn-resolving.de/urn:nbn:de:bsz:93-opus-ds-137464http://elib.uni-stuttgart.de/handle/11682/13746http://dx.doi.org/10.18419/opus-13727Pyrazolones 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.eninfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc/4.0/540article2023-10-10