Effect of Additives on L-Proline Catalyzed Direct Asymmetric Aldol Reactions

Abstract

The direct asymmetric aldol reaction of aromatic aldehydes with acetone catalyzed by L-proline was accelerated by the addition of diols or diphenols. The use of additives decrease the amount of L-proline needed and allowed the use of solvent free conditions. Catechol with two adjacent hydroxy groups on aromatic ring was the most efficient additive. Under the optimized conditions, 5 mol% L-proline with 1 mol% catechol gave excellent chiral selectivity (80% ee value) with > 90% yield, which was higher than that obtained using 30 mol% L-proline without an additive. Computations indicated that the additive promoted the reaction by an intermolecular hydrogen bond between the hydrogen of the hydroxyl group and the oxygen of the carbonyl group, which activated the carbonyl group of the aldehyde. Catechol with two adjacent hydroxyl groups on the aromatic ring can form two hydrogen bonds with the oxygen of the carbonyl group on the corresponding aldehyde. Therefore, the combination of L-proline and catechol was very efficient in catalyzing the direct asymmetric aldol reaction and gave a high yield in a short time. 在 L-脯氨酸催化的芳香醛与丙酮直接不对称 aldol 反应体系中添加二醇或二酚类助剂可有效提高反应活性. 助剂的使用降低了该反应体系中 L-脯氨酸的用量. 特别是以邻苯二酚为助剂时, 最佳反应条件下, 仅用 5 mol% L-脯氨酸与 1 mol% 助剂催化 2-硝基苯甲醛与丙酮直接不对称 aldol 反应, aldol 产物产率高达 90%, 对映选择性为 80%. 该反应产率比未加助剂条件下, L-脯氨酸用量为 30 mol% 时的反应产率高. 采用量子化学计算研究了助剂对该反应的促进作用. 结果表明, 助剂可与芳香醛的醛基形成氢键, 从而活化醛基, 提高反应效率. 邻苯二酚结构中相邻的羟基能与底物芳香醛羰基的氧原子形成双氢键, 大大活化了底物芳香醛的羰基. 因此, 该助剂可有效促进 L-脯氨酸催化剂的直接不对称 aldol 反应. Cheap catechol promoted the L-proline catalyzed aldol reaction efficiently through hydrogen-bonds interaction, which decreased the amount of L-proline and increased the yield of aldol products.