Asimetrik sentez için hesaplamalı anlayış ile kinkona tabanlı katalizörler geliştirilmesi

The reaction of 3-substituted 2-oxindoles with nitrosobenzene has an attractive product distribution. It is possible to obtain two different products with different biological activities in this reaction. However, controlling the regioselectivity and enantioselectivity of these products is challenging due to high reactivity of nitrosoarenes and the unknown factors influencing O- and N- selectivity. In this work, we employ for the first time a computational approach developed in our group, called CIPOC (Computational Identification of Potential (Organo)Catalysts) to gain insights into the factors that govern the activity and selectivity of the target reaction and guide experiments by uncovering novel catalytic structures not yet explored. CIPOC uses quantum mechanically optimized transition state models (theozymes) to determine optimal catalytic groups and their 3D arrangements around the substrates, and screens these catalytic elements in the conformer libraries of an organocatalyst database, consisting of 1586 candidates, using pharmacophore query tools commonly used for drug design. Calculations identified hydroxyamination as the major reaction pathway that proceeds via a concerted addition-proton transfer mechanism. No catalysts in our database could be determined to steer the product distribution towards the aminoxylation products. A total of nine new catalysts, predicted to give promising efficiencies and selectivities, were proposed for experimental testing as efficient and selective catalysts for hydroxyamination reaction. Among the proposed compounds, four of them were synthesized and tested for activity for the first time for the target reaction. The effect of reaction time, temperature, reactant ratio, solvent were studied to optimize the reaction conditions. Characterization of the products pointed out to a facile decomposition pathway for the aminoxylation product, which was further justified by computations showing a significant weakening of the N-O bond upon protonation. The decomposition product is of particular interest to access C3-hydroxy-bearing stereogenic center, a motif common in therapeutic compounds. The highest enantioselectivity for the decompositon and accordingly the aminoxylation product was achieved as 98.4% by the urea-based cinchona catalyst at 0°C.