Homochiral bifunctional L‐prolinamide‐ and L‐bis‐prolinamide‐catalyzed asymmetric aldol reactions performed in wet solvent‐free conditions

Abstract

In this study, the novel bifunctional homochiral thiourea-L-prolinamides 1-4, tertiary amino-L-prolinamide 5, and bis-L-prolinamides 6 and 7 were prepared from enantiomerically pure (11R,12R)-11,12-diamino-9,10-dihydro-9,10-ethanoanthracene 8 and (11S,12S)-11,12-diamino-9,10-dihydro-9,10-ethanoanthracene ent-8. Highly enantioselective and diastereoselective aldolic intermolecular reactions (up to 95% enantiomeric excess, 93:7 anti/syn) between aliphatic ketones (20 equiv) and a range of aromatic aldehydes (1 equiv) were successfully carried out in the presence of water (10 equiv) and monochloroacetic acid (10 mol%), solvent-free conditions, at room temperature over 24 h using organocatalysts 1-7 (5 mol%). Stereoselective induction using density functional theory-based methods was consistent with the experimental data.

Synthesis of Trans-4-Hydroxyprolineamide and 3-Ketoproline Ethyl Ester for Green Asymmetric Organocatalysts

“…This property raises the pKa value, placing proline ahead of other amino acids in terms of nucleophilicity [6]. The earliest discovery reported that proline is a "microaldolase", which is capable of activating the electrophile by its proton donor group, and also activating the nucleophile by its amine group [7]. This permits proline to take part in bifunctional asymmetric catalysis, which has been a successful laboratory strategy for enhancing chemical transformations [8].…”