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

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 -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 -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.