Long-chain Alkyl Proline Derivatives And Their Direct Catalytic Asymmetric Aldol Reaction

Organocatalysis have received great attention in asymmetric synthesis for its enzyme mimic, metal-free, atomatically economic and low toxic characters. In this thesis, three proline-derived small molecules were synthesized using L-proline and trans-4-hydroxyl-L-proline as main materials. The catalytic effects of 4-long alkoxyl-L-prolines and (S)-N-(5-dodecyl-2-hydroxyphenyl)pyrrolidine-2-carboxamide as organocatalysts to catalyze the direct asymmetric aldol reaction were evaluated.I. Synthesis of novel long alkoxyl-L-proline derivatives and their application incatalytic asymmetric direct aldol reaction.1. Three novel proline derivatives with long alkyl chain 1a, 1b and 7 weresynthesized according to the following procedure. Their chemical structures were characterized through IR, ¹H NMR, ¹³C NMR and HRMS.2. The catalytic effects of la and lb on the intermolecular direct asymmetric aldol reaction were evaluated in organic solvents and in water respectively. The activity of la was higher than that of lb. When the reaction proceeded in organic solvents, the catalytic activity and stereoselectivity in neat ketone were better than that in other solvents. When 5 mol% of la was used to catalyze the reaction at 0°C or room temperature, the aldol products were obtained with up to 96% ee, which were comparable to the effect with 30 mol% of L-proline as catalyst. Additionally, ketone is more convenient to treat after reaction.The catalytic effects of la on the direct aldol reaction in water were much better than that of 1b. When cyclohexanone was used as substrate, the anti-aldol products were obtained with high yields, excellent diastereoselectivity and enantioselectivity for most of the aromatic aldehydes in the presence of 5 mol% of la. While acetone was used as substrate, the configuration of aldol product was related to the amount of water.3. The catalytic effects of 7 with additives on the direct asymmetric aldol reactions in water were evaluated. The stereoselectivity of the Aldol reaction improved a lot when the catalyst 7 was loaded with the salts, especially,when the SnCl₂ was loaded with we got the best results. We found that the catalytic effect was sensitive to the position of the substitute. The reactivitiy of the catalysts improved a lot when the organic acids were loaded as the promoter.4. The catalytic mechanism was investigated. The existence of long chain alkyl group in L-proline increased the solubility of la in organic solvent and remains the catalytic center, hence, the solvents used were extended and the loading of catalyst decreased without sacrificing the yields and enantioselectivities. Amphiphilic la could assemble with reactants in water through hydrophobic interactions and sequester the transition state from water. Therefore, the reaction proceeded efficiently in the aggregated organic phase to afford the aldol products with higher enantioselectivity through a transition state similar to that of the reaction in organic solvent. We conclude that the mechanism of salts and 7 catalyzing the asymmetric direct aldol reaction efficiently is that the salts could coordinate with 7.