Computational Identification of Potential Organocatalysts (CIPOC) Reveals a 2-aminoDMAP/Urea Catalyst Superior to Its Thiourea Analogue

Date

2025-01-01

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Alsancak-Koca, Sezen
Çamlısoy, Yeşim
Bakırcı, İrem
Işık, Murat
Çelebi-Ölçüm, Nihan
Tanyeli, Cihangir

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Asymmetric organocatalysis by bifunctional acid- and base-type small organic molecules has emerged as a promising way to enhance stereoselective organic transformations since the beginning of this millennium. Takemoto’s tert-amine/thiourea catalyst, an archetype in these endeavors, has encouraged many to design new multifunctional alternatives. However, the discovery of efficient catalysts in a library of thousands of candidates containing the desired functionalities in their structures remains a great challenge both synthetically and computationally. We, toward these ends, developed a computational protocol (CIPOC─Computational Identification of POtential (Organo)Catalysts), which discovered a chiral 2-aminoDMAP/urea catalyst among 1600 multifunctional catalyst candidates enabling conjugate addition of malonates to trans-β-nitroalkenes rapidly (in a few hours) with exquisite selectivities and yields, producing superior results than that of Takemoto’s. The unique activity of this chiral 2-aminoDMAP/urea is attributed to the dual function of the 2-aminoDMAP unit (double H-bonding and π-stacking interactions) in addition to the exceptional performance of the urea unit compared to thiourea, as a result of a lower energetic penalty required to distort the catalyst to its active conformation to provide optimal catalytic interactions.

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https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=86000506369&origin=inward
https://hdl.handle.net/11511/113952

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Department of Chemistry, Article