Synthesis Of Novel Small Organic Molecules Derived From Proline And Their Application In The Catalytic Asymmetric Construction Of Carbon-Carbon Bond

Organocatalysis have received great attention in asymmetric synthesis for its enzyme mimic, metal-free, atomatically economic and low toxic characters. In this thesis, a series of 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 prolinamides as organocatalysts to mimic typeⅠaldolase on direct asymmetric aldol reaction, and that of sulfonamide-prolinols on the enantioselective addition of diethylzinc to benzaldehyde were investigated.Ⅰ. Synthesis of novel 4-long alkoxyl-L-prolines and their application in catalytic asymmetric direct aldol reaction.1. Two novel proline derivatives with long alkyl chain 1a and 1b were synthesized according to the following procedure. Their chemical structures were characterized through IR, ~1HNMR, ~13CNMR and HRMS.2. The catalytic effects of 1a and 1b on the intermolecular direct asymmetric aldol reaction were evaluated in organic solvents and in water respectively. The activity of 1a was higher than that of 1b. 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 1a was used to catalyze the reaction at 0℃to 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 1a 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 1a. While acetone was used as substrate, the configuration of aldol product was related to the amount of water.3. The catalytic mechanism was investigated. The existence of long chain alkyl group in L-proline increased the solubility of 1a 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 1a 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.Ⅱ. Synthesis of novel prolinamides and their application in catalytic asymmetric direct aldol reaction.1. Six novel prolinamides 7a-f were synthesized though the reaction sequence of protection, condensation, and deprotection. Their chemical structures were characterized by IR, ~1HNMR, ~13CNMR and HRMS, and the single-crystal structure of 7a was analyzed. 2. The catalytic effects of 7a-f on the intermolecular direct asymmetric aldol reaction of aldehydes with acetone, cyclohexanone or other ketones were investigated. The catalytic efficiency of 7a was the best when acetone was used as Aldol donor, and the Aldol products were obtained with up to 78% ee in the presence of 10 mol% 7a. The aldol reaction of cyclohexanone with aromatic aldehydes catalyzed by 7a-d led to the formation of anti aldol product with high yields (up to 99%), excellent diastereoselectivity (anti/syn ratio up to 98/2) and enantioselectivity (up to 96%ee) both in neat ketone and in water.3. The catalytic mechanism of prolinamide phenol on the direct aldol reaction was studied using quantum mechanics theory. The best transition structure is corresponding to the channel with the lowest active energy and leading to R-aldol product. Both the amide and the hydroxyl groups are hydrogen-bonded with the aldehyde. This has a great agreement with the experimental results, and indicates the proposed mechanism is reasonable.Ⅲ. Synthesis of novel sulfonamide-prolinols and their application on the asymmetric addition of diethylzinc to benzaldehyde.1. Five novel sulfonamide-prolinols 16a-e were designed and synthesized using simple methods. Their chemical structures were characterized by IR, ~1HNMR, ~13CNMR and HRMS, and the single-crystal structure of 16b was analyzed.2. The catalytic effects of 16a-e on the asymmetric addition of diethylzinc to benzaldehyde were evaluated, and it was found that they could promote the reaction with up to 63% yield and 27% ee.