Study On Asymmetric Synthesis Of Potential Biologically Active Containing Trifluoromethyl Pyrrolidine Spiropyrazolone Compounds

Pyrrolidine is an important class of nitrogen-containing heterocycles,which widely existing in molecular drugs.Trifluoromethyl is the most commonly used fluoro group,which is often used in the design of new drug synthesis to improve the physical chemical properties of drugs.There are not many methods for introduced trifluoromethyl into pyrrolidine,therefore the construction of contain trifluorome-thylpyrolidine skeleton has a broad research prospect.Pyrazolones exist in most natural products,and especially spiropyridones because of their important biological properties have attracted the attention of organic synthetic chemists.Therefore,how to develop and construct such core structures has always been one of the themes in the drug research fields.Based on the idea of molecular hybridization,it's very challenging jobs to perfectly combine trifluoromethyl,pyrrolidine and pyrazolone to synthesize optically active compounds containing trifluoromethylpyrrolidine spiropyrazolone.Through the analysis of this structure,we can find that[3+2]cycloaddition is an effective method to construct this structure.Based on this idea,we imagine whether it was possible to synthesize our target product by using a trifluoroethylamine derived ketimine as a dipole performed a 1,3-dipolar cycloaddition reaction with unsaturated pyrazolone.Therefore,under the catalysis of chiral amine,we selected 4-enylpyrazolone substituted with 5-position benzene and trifleoroethylamine derived ketimine undergoes 1,3-dipolar cycloaddition reaction to construct a pyrrolidine spiropyra-zolone hybrid.In this synthesis process,we optimized its catalyst,solvent,and reaction temperature,and selected the best reaction conditions.That the disubstituted trifluoromethyl cinchonine thiourea was used as a catalyst,and chloroform was used as a solvent.At-78?,an?-CF₃ pyrrolidine spiropyrazolone derivative with three adjacent stereocenters was synthesized efficiently and asymmetrically.It has excellent stereoselectivity?>20:1 dr,99%ee value?and good yield?86%?.It provided a new synthetic method and research value for the construction of?-CF₃ pyrrolidine skeleton.Through the activity study of the compound,it can be seen that the compound is not toxic to cells,which provides the possibility for the application of the compound in other pharmaceutical research.