High-Efficiency Asymmetric Synthesis And In Vitro Activity Of Difluoromethylpyrrolidine Compounds

The synthesis of pyrrole-contained compounds is very important for pharmaceutical research,because pyrrolidine is one of the most frequently occurring heterocyclic motif in small-molecule drugs.The combination of fluorine atoms or fluorine-containing groups on the heterocyclic ring may improve the lipid solubility and metabolism of the corresponding molecules,and adjust the acidity and basicity of the N atom.More importantly,fluorine can also improve the drug-target affinity and selectivity by the conformation affection of the substituted pyrrolidine.Due to the strong electronegativity of the fluorine atom,-CF₂H has a special properties act as a hydrogen bond donor.So,it is of great significance for drug research to construct CF₂H-containing pyrrolidine skeleton.However,there is a lack of research reports on the construction of difluoromethylpyrrolidine in existing reports.After analyzing the structure of difluoromethylpyrrolidine,we found that the[3+2]cycloaddition reaction is one of the most commonly methods in the construction five-membered N-heterocyclic compounds.In this paper,we have developed a asymmetric method in the synthesis of CF₂H-containing pyrrolidine compounds.In the presence of a bifunctional organic catalyst,the cycloaddition reaction of difluorothioisatinimine developed by our group with electron-deficient olefins under mild conditions performed smoothly.Under the optimal conditions:Cinchonidine thiourea substituted with bistrifluoromethyl as a catalyst,xylene as a solvent,at 10℃,a series of difluoromethylpyrrolidine compounds with diverse substituents have been obtained with excellent stereoselectivity（94%）and good yield（80%）.The product was reduced by Na BH₄,and yield a product with five chiral centers.After the identification of all the new compounds obtained,all compounds were assigned to evaluate the in vitro antibacterial and antitumor bioactivity.The results showed that these compounds have some antitumor activity.The anti-tumor activity exhibited by the reduced product 4a suggests that this type of compound still has great probabilities in the biological activity research.