Asymmetric Synthesis Of 3-substituted-3-fluoro-2-oxindoles And Its Preliminary Evaluation Of Inhibitory Activity On IDO2

Objective:Optically enriched 3,3–disubstituted oxindoles are widely present in natural products and bioactive molecules.In particular,oxindoles bearing a 3-fluorinated quaternary stereogenic center are structural motifs that have important applications in the pharmaceutical industry.Though various synthetic strategies have been devised to target this important molecular structure over the years,the scope of their substrates is limited.Asymmetric catalytic fluorination has been carried out with 3-functionalized oxindoles as substrates,and preliminary pharmacological activity evaluation of their products to inhibit IDO2 was performed in this work.Methods:The electrophilic fluorination reaction was carried out using 2-?1-methyl-2-oxindole-3-yl?acetonitrile as a model substrate.After comparing and screening the enantioselectivity of organic catalysts that have been reported to catalyze this type of reaction and have high-efficiency catalytic effects developed earlier in our laboratory,the reaction conditions including reaction media,inorganic bases,temperature,and catalyst loading were optimized,along with structural modification of the original catalyst design.The substrate scope of the catalytic protocol and its possible mechanism was then investigated.Finally,the inhibitory effect of representative compounds on IDO2 was evaluated.Results:Bifunctional urea catalyst containing bulking adamantyl side chains 11g provided the best catalytic effect.Asymmetric electrophilic fluorination at room temperature with Et OAc as the solvent and Na₂CO₃ as the base is the optimal condition.28 target products containing functional groups such as cyano,hydroxyl,and amide were successfully synthesized under the best reaction conditions.Preliminary activity studies showed that the IC₅₀ of product 13a was 16?mol,and its inhibiting effect on IDO2 was more prominent compared with the control group.Conclusion:An enantioselective fluorination of 3-functionalized oxindoles using electron-rich amino urea catalyst is described.Various protected and unprotected 3-functionalized3-fluoro-2-oxindoles were obtained in good yields and enantioselectivity.The resulting enantioenriched 3-methylene nitrile 3-fluoro-2-oxindole product was found to inhibit indoleamine 2,3-dioxygenase considerably.