Novel L-bis-Prolinamides from meso-1,2-Diphenylethylendiamine as Organocatalysts in the Asymmetric Intermolecular Aldol Reaction Under Wet Conditions

Introduction: Novel homochiral L-bis-prolinamides 1 and 2 were synthesized from meso-1,2-diphenylethylenediamine. They were evaluated as organocatalysts in the asymmetric in-termolecular aldolic reaction. The reaction was conducted between several ketones (20 equiv) and aromatic aldehydes (1 equiv), using chloroacetic acid (10 mol%), water (10 equiv), and a catalyst loading of 10 mol%, all under wet conditions at 0°C. The best results were obtained with L-bis-prolinamide 1, which yielded the aldolic product from cyclohexanone and 4-nitrobenzaldehyde in 86% yield, with a diastereomeric ratio of 95:5, and an enantioselectivity of 95%, favoring the anti-isomer as major product. Computational studies were performed to calculate the transition state (TS) structure, explaining the effects of water and the stereoselectivity of the major (R) isomer of the reaction between 4-nitrobenzaldehyde and acetone catalyzed by L-bis-prolinamide 1. All struc-tures were optimized and characterized with the Gaussian 16 program, using the M06-2X/6-31G(d,p) method. Gibbs free energy (ΔG) corrections were performed with the M06-2X/6-311++G(2d,2p) level of theory, at 298.15 K and 1 atm. Objective: The objective of this work is to synthesize chiral organocatalysts from meso-1,2-diphe-nylethylenediamine, which were evaluated as organocatalysts in the asymmetric intermolecular al-dol reaction. Methods: In this work, a synthetic route is reported where the reactions were carried out using the best conditions mentioned above (0 ˚C, 4 h) and 10 mol% of chloroacetic acid, in the presence of 10 equiv of water, under humid conditions. Results: L-Bis-prolinamides 1 and 2 were synthesized by an easy and efficient two-step route, from commercially available meso-1,2-diphenylethylenediamine obtained with good to excellent perfor-mance, with overall yields of 93% and 86%, respectively. Conclusion: Overall, this work demonstrates the efficiency of L-bis-prolinamide as an organocat-alyst in asymmetric aldol reactions.