Enantioselective direct aldol reactions catalyzed by L-prolinamide derivatives.
Enantioselective direct aldol reactions catalyzed by L-prolinamide derivatives.
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DOI：
10.1073/pnas.0307176101
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发表时间：
2004-04
影响因子：
11.1
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中科院分区：
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由L-脯氨酸与简单的脂肪胺和芳香胺反应制得的L-脯氨酸酰胺2，在室温下对4-硝基苯甲醛与丙酮的直接羟醛缩合反应具有催化活性。它们给出高达46%对映体过量（ee）的中等对映体选择性。随着酰胺N-H成为更好的氢键供体，对映选择性增加。由L-脯氨酸与α，β-羟胺反应得到的具有末端羟基的L-脯氨酸酰胺3显示出更有效的催化作用和更高的对映选择性。特别地，由1-脯氨酸和（1S，2S）-二苯基-2-氨基乙醇制备的催化剂3h在-25 ℃下表现出对芳香醛高达93%ee和对脂肪醛高达> 99%ee的高对映选择性。用量子力学方法研究了脯氨酰胺与丙酮缩合生成的三种烯胺与苯甲醛的模型反应。计算表明，酰胺N-H和末端羟基与苯甲醛底物形成氢键。这些氢键降低了活化能，导致高的对映选择性。我们的研究结果表明，在设计新的有机催化剂的直接不对称羟醛缩合反应和相关的转变的新策略。
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 N-H becomes a better hydrogen bond donor. l-Prolinamides 3, derived from the reaction of l-proline with alpha,beta-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 degrees 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 N-H 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.