Readily Tunable and Bifunctional l-Prolinamide Derivatives:  Design and Application in the Direct Enantioselective Aldol Reactions

Abstract

[reaction: see text] Readily tunable and bifunctional L-prolinamides as novel organocatalysts have been developed, and their catalytic activities were evaluated in the direct asymmetric Aldol reactions of various aromatic aldehydes and cyclohexanone. High isolated yields (up to 94%), enantioselectivities (up to 99% ee), and anti-diastereoselectivities (up to 99:1) were obtained under the optimal conditions.

Asymmetric Direct Aldol Reaction Catalysed by L‐Prolinethioamides

“…Though proline itself is a very attractive catalyst, its catalytic activity can be fine-tuned only by changing the reaction conditions. Since then, several proline-derived catalysts have been prepared, [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] in most cases with the carboxylic acid functionality having been modified. Unfortunately, none of them is a universal catalyst for aldol reactions of various ketones with all types of aldehydes.…”

“…Unfortunately, none of them is a universal catalyst for aldol reactions of various ketones with all types of aldehydes. Recently, the use of -prolineamides derived from -proline and different amines [14] -including diamines [26,27] and amines with strongly electron-withdrawing groups [14c] -has appeared promising for catalyst design.…”

Asymmetric Organocatalysis

“…Xiao and co-workers prepared the catalysts 4a and 4b that provided high stereoselectivity for the direct asymmetric aldol reaction of aromatic aldehydes with cyclohexanone and its structural analogous [15,16]. Xiao also prepared an organocatalyst 5 by incorporation of cinchona alkaloid to proline, which delivered a highly stereoselective direct aldol reaction of acetone and 2-butanone with a wide range of aromatic and heteroaromatic aldehydes [17].…”

Synthesis of D-pantolactone via Combined a Novel Organocatalyst Catalyzed Asymmetric Aldol Reaction and Hydrogenation Catalyzed by Cu-/SiO<sub>2</sub>

“…The precursor of D-pantolactone is mainly synthesized by aldol reaction as a key step that has promoted a rapid development of numerous highly enantioselective chiral catalysts [8][9][10]. In nature, small organic molecules, in particular amino acids [11][12][13] and their derivatives [14][15][16][17], are rich chiral sources, which are used as the catalysts, but with recycling problems, such as extensive work-up procedures with the corresponding waste generation or more time to recover the catalyst between two cycles [18][19][20]. However ionic liquids (ILs) have been widely used as environmentally benign solvents to replace common organic media [21] with advantages of reusable, strong design ability, low pollution, low toxicity, and excellent miscibility with organic compounds [22][23][24].…”