Çok fonksiyonlu organokatalizörlerin etki şeklinin incelenmesi

Quantum mechanical calculations have successfully uncovered organocatalytic reaction mechanisms and explained their outcomes. However, understanding the mode of action of complex multifunctional organocatalysts remains challenging due to their numerous conformational degrees of freedom. This work presents a computational protocol called CIPOC (Computational Identification of Potential (Organo)Catalysts) that combines quantum mechanical calculations and drug design tools to address the challenges of exploring the mode of action and active conformations of complex multifunctional organocatalysts. CIPOC was applied (1) to discover novel chiral catalytic structures for the catalysis of the asymmetric conjugate addition reaction of dimethyl malonate to trans-(β)- nitrostyrene, which is particularly noteworthy to access gamma-aminobutyric acid (GABA) close analogs, (2) to uncover the mode of action of dimeric quinidine in the reaction of oxindole with nitrosobenzene that yielded unexpectedly aminooxylation products. We discovered a novel 2-aminoDMAP/urea catalyst, which catalyzed the reaction of dimethyl malonate to trans-(β)-nitrostyrene eight-fold faster than Takemoto's catalyst, previously the best-known catalyst for this transformation. We showed that quinidine dimer binds nitrosobenzene through its protonated amine, while both hydroxyl groups in the catalyst structure interact with the substrates and orient the enolate resulting in a concerted addition- proton transfer pathway. Additionally, both studies revealed the importance of catalyst distortion in determining the catalytic activity, highlighting the extraordinary performance of urea-based catalysts compared to their thiourea analogs, despite their lower acidity. The impact of catalysts on the mechanism and selectivity has been thoroughly investigated and explained. The essential interactions and binding preferences of catalysts in critical transition states have been explored, and the factors that influence the stereoselectivity of the reaction have been clarified. This work presents a new perspective on the challenges of exploring the mode of action and active conformations of complex multifunctional organocatalysts. As a future work, an automated tool that can identify potential catalyst candidates in a given pool for a target reaction could enormously facilitate an organocatalyst screening process.