Design And Synthesis Of Prolinamide-Thiourea Organic Catalysts And Their Applications In Asymmetric Catalytic Reaction

In the field of asymmetric organic catalysis,amides and thiourea catalysts are one of the research hotspots,and play an important role in the formation of C-C bonds and carbon-heteroatom bonds.In the catalyst design,the amide bond has the advantages of being robust,easy to form,and modifying the structure to adjust the catalytic performance;at the same time,the thiourea provides a unique double hydrogen bond.According to the characteristics of amide and thiourea,we combined L-valine amide with 4-position thiourea unit to design a novel organic catalyst.In this paper,we designed and synthesized several L-prolinamide-thiourea small organic catalysts from 4-hydroxy-L-proline,and studied their applications in asymmetric Aldol reaction and Henry reaction.Mainly divided into the following three parts:1.The low-cost trans-4-hydroxy-L-proline was used as the starting material to synthesize 4-hydroxyprolinamide by amidation reaction,followed by hydroxyl/amino conversion reaction to synthesize 4-aminoprolinamide.Finally,the prolinamide-thiourea catalyst was synthesized by reaction with cyanosulfonate.The whole catalyst synthesis process was carried out in 8 steps,and the total yield was 20-29%.2.The asymmetric Aldol reaction of p-nitrobenzaldehyde and cyclohexanone was used as a model reaction.The application of prolinamide-thiourea catalysts were investigated.The multiple reaction conditions such as catalyst screening,catalyst concentration,reaction temperature and solvent were investigated.Optimization,the best reaction conditions were determined.Finally,when 0 ? of saturated brine is used as a solvent and 5 mol% of prolinamide-thiourea catalyst(7c or 7d)is used as acatalyst,most of the other substrates can be obtained except for the yield of individual substrates of <10%.Good yield and stereoselectivity,yield 60-96%,dr value61:39->99:1 and ee value 48->99%.It is particularly worth mentioning that,compared with other proline catalysts,the synthesized catalyst has a better substrate application range,and when the benzaldehyde derivative containing an electron withdrawing group is used as a substrate,the catalytic reaction can obtain an excellent pair.Mapping selectivity and non-corresponding selectivity.Moreover,it has been found in the solvent optimization experiment that the use of water or brine instead of the organic solvent not only reduces the contamination of the product and the environment by the solvent,but also effectively increases the yield and stereoselectivity of the product.Therefore,this kind of efficient and environmentally friendly catalytic system has a certain promotion effect in the wide application of synthetic chemistry.3.The asymmetric Henry reaction of thiobenzaldehyde and nitromethane is a model reaction.The application of prolinamine-thiourea catalysts were investigated.The optimal optimization of the reaction conditions such as catalyst screening,catalyst concentration and solvent was determined.Good reaction conditions.Finally,at 25 ? without the addition of acid,only 1 mol% of the prolinamide-thiourea catalyst 7c was required,and the catalytic product obtained moderate yield and excellent corresponding selectivity(77->99% ee).While the non-thiobenzaldehyde derivative is used as a substrate,the catalytic product obtains very poor enantioselectivity.This asymmetric Henry reaction is carried out at room temperature,and is simple and scalable,and has important research significance.