Novel organic molecules containing an l-proline amide moiety and a terminal hydroxyl for catalyzing direct asymmetric aldol reactions of aldehydes in neat acetone are designed and prepared. Catalyst 3d, prepared from l-proline and (1S,2S)-diphenyl-2-aminoethanol, exhibits high enantioselectivities of up to 93% ee for aromatic aldehydes and up to >99% ee for aliphatic aldehydes. A theoretical study of transition structures demonstrates the important role of the terminal hydroxyl group in the catalyst in the stereodiscrimination. Our results suggest a new strategy in the design of new organic catalysts for direct asymmetric aldol reactions and related transformations because plentiful chiral resources containing multi-hydrogen bond donors, for example, peptides, might be adopted in the design.

L-proline amides derived from various chiral beta-amino alcohols that bear substituents with various electron natures at their stereogenic centers are prepared and evaluated for catalyzing the direct Aldol reaction of 4-nitrobenzaldehyde with acetone. Catalysts with strong electron-withdrawing groups are found to exhibit higher catalytic activity and enantioselectivity than their analogues with electron-donating groups. The presence of 2 mol % catalyst 4g significantly catalyzes the direct Aldol reactions of a wide range of aldehydes with acetone and butanone, to give the beta-hydroxy ketones with very high enantioselectivities ranging from 96% to >99% ee. High diastereoselectivity of 95/5 was observed for the anti Aldol product from the reaction of cyclohexanone, and excellent enantioselectivity of 93% ee was provided for anti Aldol product from the reaction of cyclopentanone.

L-Prolinamides 2, prepared from L-proline and simple aliphatic and aromatic amines, have been found to be active catalysts for the direct aldol reaction of 4-nitrobenzaldehyde with neat acetone at room temperature. They give moderate enantioselectivities of up to 46% enantiomeric excess (ee). The enantioselectivity increases as the amide NOH becomes a better hydrogen bond donor. L-Prolinamides 3, derived from the reaction of L-proline with ␣,␤-hydroxyamines such that there is a terminal hydroxyl group, show more efficient catalysis and higher enantioselectivities. In particular, catalyst 3h, prepared from L-proline and (1S,2S)-diphenyl-2-aminoethanol, exhibits high enantioselectivities of up to 93% ee for aromatic aldehydes and up to >99% ee for aliphatic aldehydes under ؊25°C. Model reactions of benzaldehyde with three enamines derived from the condensation of prolinamides with acetone have been studied by quantum mechanics calculations. The calculations reveal that the amide NOH and the terminal hydroxyl groups form hydrogen bonds with the benzaldehyde substrate. These hydrogen bonds reduce the activation energy and cause high enantioselectivity. Our results suggest a new strategy in the design of new organic catalysts for direct asymmetric aldol reactions and related transformations. The asymmetric aldol reaction is one of the most powerful methods for the construction of complex chiral polyol architectures (1). The great synthetic usefulness of the aldol reaction in organic synthesis has powered a rapid evolution of numerous highly enantioselective chiral catalysts (2). In general, asymmetric catalytic aldol reactions are classified into two main categories. One type of aldol reaction requires the preconversion of ketone or ester to a more active aldol donor, such as an enol ether or a ketene acetal by the use of a chiral Lewis acid (2) or Lewis base (3, 4) as the catalyst. The other type is called a direct aldol reaction, which is highly atomically economic (5). The development of efficient catalysts for asymmetric catalytic direct aldol reactions is a worthwhile endeavor. The first example of the asymmetric direct aldol reaction catalyzed by heterobimetallic complexes was reported by Shibasaki and coworkers (6, 7). Trost and coworkers (8, 9) have designed a zinc complex for the direct catalytic asymmetric aldol reaction with high enantioselectivities. Since the pioneering finding by List, Barbas, and their coworkers (10, 11) that L-proline could act as a catalyst in intermolecular direct aldol reaction, the concept of small organic molecules as catalysts has received increasing attention (12-32). However, efficient organic catalysts other than chiral amino acids for asymmetric direct aldol reactions are scarce (33,34). We seek to design small organic molecules with structural diversity for catalyzing organic transformations with high stereoselectivity and broad substrates. Here, we report on a class of organic catalysts, (S)-pyrrolidine-2-carboxamides (L-prolinamides), that efficiently catalyze the direct ...