The Application Of Chiral Squaramide Catalysts In Asymmetric Michael Addition Reaction

Asymmetric synthesis is a process using the chiral materials to trigger theprochiral compounds as substrates to construct one or several stereocenters, which isan effective method to get chiral compounds in place of chiral resolution. Generally,the method, which has a wide range of application and a thriving prospect in thesynthesis of chiral compounds, only uses a small amount of chiral catalysts and canobtain lots of chiral products with high yield and enantioselectivity.Over the past decade, the use of small organic molecules as catalysts inasymmetric reactions has been developing rapidly and consequently it has become anew hot spot in asymmetric catalytic research field. Among these organic molecules,chiral squaramides based on the research of thioureas have become such a neweffective kind of chiral catalysts that more and more attention has been paid to it forthe asymmetric synthesis of chiral compounds recently.In this paper, three kinds of chiral catalysts6、18、4with different structureshave been successfully synthesized through cinchona alkaloid,1,2-diaminocyclohexane,(trifluoromethyl) aniline and2,3-dimethoxy-3-cyclobutene-1-dione as substrates respectively. The intermediate34derived fromthe transformation of the hydroxyl to amino group of cinchona alkaloid; theintermediate36was synthesized by the reaction of trifluoromethyl aniline and2,3-dimethoxy-3-cylobutene-1-dione; then, using34and36, the chiral squaramidecatalyst6, a cinchona alkaloid derivate was finally obtained. Catalyst36wassuccessfully synthesized by taking (1S,2S)-diaminocyclohexane and intermediate4as substrates. Following a methylation step of the amino group on37gets thecatalyst18.(1S,2S)-2-piperidine-1-cyclohexylamine, synthesized by a condensationreaction of (1S,2S)-diaminocyclohexane and glutataldehye followed by sodiumtriacetoxyborohydride reduction.(1S,2S)-2-piperidine-1-cyclohexylamine acts as anuclephile to go through a substitution reaction with intermediate36to get the chiralcatalyst4.The paper involves the study of the synthesis process of36in regard to the feeding sequence, the reaction temperature and the ratio of substrates. As a result, theyield is increased by approximately30%. Meanwhile, crafts such as the solvent,temperature, the ration of substrates were optimized and the reaction time wasshortened half by the optimum of in the synthesis of intermediate36. In thenucleophilic substitution to the aliphatic amine, the solvent, reaction time, reactiontemperature and the ratio of substrates were optimized to obtain optimal reactioncondition for the synthesis of catalyst6,18,4.The three catalytic chiral catalysts with different structures were studied in anasymmetric Michael addition reaction of2-hydroxy naphthoquinone to1,2-dicyano-2-phenyl ethylene. Relatively, little difference of enantioselectivity wasobserved between them. However, catalyst6a seemed to manifest best with25.5%enantioseclection.The enantioselective reaction of2-hydroxy naphthoquinone with1,2-dicyano-2-(substituted) phenyl ethylene catalyzed by the chiral squaramide catalyst6a wasconducted with catalyst (20mol%), in CH2Cl2at the temperature of zero degree in24hours. It could get a good yield (34.8%～65.6%) yet with an unsatisfactoryenantioselectivity (13.4%～25.5%). It was found by experiment that the character(electronegativity, steric hindrance) of the substituted groups on the benzene ring didnot influence the stereoselectivity practically.