Design And Synthesis Of Thiosquaramide Organicatalysts And Their Applications In Asymmetric Catalytic Synthesis Toward Bioactive Framework Structure

Objective:Asymmetric catalysis,as a key method for chiral proliferation and expansion,is important in the synthesis of compounds containing chiral bioactive framework structures.In this paper,a series of thiosquaramide and squaramide catalysts were designed and synthesized,and they were applied to the asymmetric catalysis study of the bioactive skeleton structure containing cyclopentene,cyclopentanol,butenolide,sulfonyl hydrazide and barbituric acid etc.It is desirable to obtain products of having higher enantiomeric purity.Methods:（1）Squaric acid,cyclopentanol,Lawesson’s reagent,benzylamine,3,5-bis（trifluoromethyl）aniline,（1R,2R）-N,N’-Dimethyl-1,2-cyclohexanediamine,and natural source of cinchona alkaloids were used as the starting material,to synthesize thiosquaramide and squaramide catalysts.（2）The synthesized catalysts were applied to the asymmetric catalytic study of the bioactive framework structure containing cyclopentene.The target compounds with high enantiomeric purity were obtained by screening catalysts and optimizing the reaction conditions.And the absolute configuration of products were confirmed by single-crystal X-ray structure analysis and electrostatic circular dichroism（ECD）.（3）The target catalysts were applied to the asymmetric catalytic study of the bioactive framework structure containing cyclopentanol,in order to obtain compounds with high diastereoselectivity and enantioselectivity.（4）The synthetic catalysts were used in the asymmetric catalytic study of bioactive framework structure containing butenolide.By screening the catalysts and optimizing the reaction conditions,the target products with high dr and ee values were obtained,and the absolute configuration of products were determined via the single crystal X-ray structure analysis.（5）The synthesized catalysts were used in the asymmetric catalytic study of the bioactive framework structure containing sulfonyl hydrazide or barbituric acid.Through a series of optimization of conditions,the target products with enantiomeric purity were expected to be obtained.Results:（1）12 Thiosquaramide and squaramide catalysts were synthesized and their structures were determined by ¹H NMR,¹³C NMR,IR,MS,HR-MS and specific rotation（[α]）.The catalysts 1a-1d,1f were not reported in the literature.（2）In the asymmetric catalytic study of the bioactive framework structure containing cyclopentene,using catalyst 1c,the target compounds were obtained with high dr（up to>99:1）and ee（up to95%）.（3）The catalysts were synergistic with TBAF to obtain the target compounds with high dr value in the asymmetric catalytic study of the bioactive framework structure containing cyclopentanol,but the ee values were not ideal.（4）Using catalyst 1f,a series ofα,γdouble Michael adducts of butenolide were obtained by up to 99:1 dr value and 95%ee value in the study of asymmetric catalysis of bioactive skeleton structure containing butenolide.（5）Compounds with the bioactive skeleton structure containing sulfonyl hydrazide cannot be obtained by the current method,and the bioactive framework structure’s compounds containing barbituric acid cannot be further judged whether or not contain good ee values by the current liquid phase conditions.Conclusion:（1）12 Thiosquaramide and squaramide catalysts were obtained.（2）The thiosquaramide catalyst 1c can be successfully used in the asymmetric catalytic study of the bioactive framework structure containing cyclopentene,and the target products were obtained with good results.（3）Catalysts and catalysts in combination with TBAF were not efficient for the asymmetric catalytic study of the bioactive framework structure containing cyclopentanol,albeit with high diastereoselectivity.（4）The thiosquaramide catalyst 1f can be successfully used in the asymmetric catalytic study of the bioactive framework structure containing butenolide to obtain target compounds with higher enantiomeric purity.（5）Catalysts have not been successfully used in the asymmetric catalytic study of the bioactive framework structure containing sulfonyl hydrazide,and the reaction conditions need to be further optimized;the bioactive framework structure’s compounds containing barbituric acid cannot be further structurally judged.