Development Of High-Performance Non-Covalent Bonding Organocatalysts Based On Asymmetric Coversion Of Imines

Hydrogen bonding catalysis and ion-pairing catalysis based on non-covalent bond interactions have achieved remarkable advance in the acquisition of chiral compounds benefit from the wide range of reaction types.However,non-covalent bond catalysis is based on the weak intermolecular interactions for activation and enantiocontrol.Thus,it is difficult to deal with complex multi-component reactions with non-covalent bonding catalysts.In addition,it is well known that the drawback of organocatalysis is the high catalyst loading,and it is also a roadblock for organocatalysis towards industrial application.How to achieve high-selectivity conversion（including chemical selectivity and stereoselectivity）in complex reaction systems and how to achieve transformation with low catalyst loading have become two scientific propositions of non-covalent bond catalysis.The development of novel chiral catalyst is the true way to deal with these problems.Imines are important intermediates.Various types of chemical transformations have been achieved with imines by which diverse nitrogen-containing compounds have been constructed.The imine-based reactions were selected as the research object in this dissertation.Through the screening and modification of chiral phosphoric acid,the catalytic enantioselective four-component Ugi reaction was realized.At the same time,theσ-hole interaction was introduced into the field of asymmetric catalysis.A novel pnictogen bonding catalyst has been developed for the non-covalent bonding catalysis with a low loading.The results provide an effective way to solve the problem of high-catalyst loading of non-covalent bond catalysis.The specific content is as follows:Targeting the difficulty in enantiocontrol of four-component Ugi reaction,a series of new chiral phosphoric acid catalysts were designed and synthesized.Then three typies of asymmetric Ugi reaction systems were developed with novel chiral phosphoric acids.Besides,the catalytic mechanism was investigated.Carboxylic acid-participated Ugi reaction and water-participated Ugi reaction were explored in this thesis.The optimal conditions of asymmetric Ugi reaction for different substrates were established through the screening and modification of catalysts,the screening of reaction solvents,and the screening of reaction temperature.For aliphatic aldehydes,the best catalyst was SPINOL-derived phosphoric acid substituted with 2,4,6-tricyclohexylphenyl groups,and the best solvent was CH₂Cl₂.The optimal temperatures for the reaction were-20℃ and-30℃.For aromatic aldehydes,the best catalyst was Br-SPINOL-derived phosphoric acid substituted with 2,4,6-triisopropyl phenyl groups,and the best solvent was cyclohexane.The optimal temperature for the reaction was 20℃.86 enantioenrichedα-amidoamide derivatives were prepared in 43%-96%yield and 75%-99%ee via carboxylic acid-participated asymmetric Ugi reaction.28 chiralα-aminoamide derivatives were synthesized in 62-99%yields and 81-99%enantioselectivities via water-participated asymmetric Ugi reaction.The synthesis of（R）-Lacosamide was accomplished in four steps with asymmetric Ugi reaction as key step.The total yield was 44%,and optical purity of product reached to 99.9%.Through the calculation of the pan-density function theory,the possible reaction pathways of the four-component Ugi reaction catalyzed by phosphoric acid were explored,and the contribution of the aggregation of chiral phosphoric acid and carboxylic acid to activation was verified.The intermolecular non-covalent bond between the groups on the catalysts and the aryl group of the substrate was found to account for the enantioselectivity origin of the reaction.The catalytic asymmetric four-component Ugi reaction was realized for the first time,which provides an efficient synthetic route for the synthesis of chiralα-amidoamide derivatives.Targeting the problem of high catalyst loading of non-covalent bond catalysis,a chiral pnictogen bonding catalyst based onσ-hole interaction was synthesized,and the catalytic application of the catalyst in hydrogenation of imines was explored.The chiral pnictogen catalyst was a antimony cation/anion pair,combined with a tetraaryl antimony cation and a hexacoordinated antimony anion,and mandelic acid incorporated as the chiral ligand.With a catalyst loading of 0.05 mol%,the nictogen bonding catalyst promoted the reduction of imines with high yields（93-99%）and high enantioselectivities（83-98%）to obtain chiral benzoxazines derivatives.Through ¹H NMR and mass spectrometry analysis,the ligand exchange behavior of the chiral catalyst was studied.The homochiral antimony was tand to undergo ligand exchange,while the heterochiral antimony ion pair was not.Besides,heterochiral antimony ion pair was found more active than homochiral antimony ion pair according to the negative non-linear effect.The catalytic activity of the pnictogen bonding was verified with control experiments such as conversion-time curve.This is the first example of pnictogen bonding catalysis which provides a new route for the application ofσ-hole donors in the field of catalysis.