Metal-organic Bifunctional Chiral Catalysts:Synthesis And Application In Asymmetric Henry Reaction

Metal-organic bifunctional catalytic strategy has attracted much attention due to its dual advantages of both metal catalysis and organic catalysis.In the past decades,this catalytic model has been used by chemists in several asymmetric catalytic reactions,showing excellent catalytic performance.Especially in some challenging substrates,metal-organic bifunctional catalysis has shown its unique advantages.There are numerous reported examples about asymmetric Henry reaction,but there are few reports on the extension of different types of nitroalkanes to different aldehydes.For example,asymmetric Henry reaction with 2-nitropropane as substrate,the product of which is an important synthetic intermediate of cardiovascular drugs,has not yet been reported in the literature.In this thesis,five new Schiff base ligands derived from amino acids can be obtained from readily available amino acids.In addition,new thiourea-Salen ligand was synthesized from cyclohexanediamine.Six new ligands were coordinated with anhydrous copper acetate to form catalysts for asymmetric Henry reaction,and excellent catalytic results were obtained.The main contents of this paper include:1.Five new chiral Schiff base ligands 70,71,72,73 and 74 were synthesized by using five different amino acids as raw materials,through amino Boc protection,amidation,Boc deprotection,carbonyl reduction,and condensation with 3,5-di-tert-butyl salicylaldehyde.The structures were characterized by ¹H NMR,¹³C NMR and H RMS.The optimal ligand73 was further determined by X-ray single crystal diffraction.Using cyclohexanediamine as starting material,diamine was bonded to two different Schiff bases by condensation reaction,and then concentrated to a thiourea group to form new thiourea-Salen ligand 85.Its structure was characterized by ¹H NMR,¹³C NMR and H RMS.2.After complexing the synthesized ligands with Cu?OAc?₂,the catalytic performance of novel ligands in asymmetric Henry reaction of aldehydes with nitroalkanes was investigated.The optimum catalytic condition of copper?II?/Schiff base 73 complex was obtained through deep study and reasonable screening.The results show that the catalytic system is more applicable than the reported catalytic methods.It not only has excellent catalytic effect on usual nitromethane and nitroethane,but also has good catalytic performance on less reported substrates such as 1-nitropropane and 2-nitropropane.117chiral?-nitroalcohols,with up to 99%ee and 96%yield,can be obtained.Substrate aldehydes were also expanded in detail,involving aromatic rings,heterocycles,fused rings,fused heterocycles,aliphatic aldehydes and cinnamaldehydes.3.We have also made a preliminary study on the transition state model of the reaction.The coordination mode between the ligand 73 and copper?II?has been inferred by X-ray single crystal diffraction of the ligand 73 and related literatures.A preliminary control experiment,NMR titration and high resolution mass spectrometry have been carried out to verify the coordination mode,and the plausible catalytic transition state has been reasonably speculated.Furthermore,the chiral?-nitroalcohol 90a obtained from our catalytic system was converted into very important pharmaceutical intermediates and fine chemical raw materials 92 by reduction and cyclization.The results show that the chiral catalysts derived from amino acids designed and synthesized by us can catalyze asymmetric Henry reaction efficiently and highly enantioselectively.The raw materials are cheap and easy to obtain;the synthesis of catalysts is simple and convenient for purification and industrialization;the catalyst dosage is low;the catalytic efficiency is high;the catalytic system is friendly and mild;the applicability of substrates is extremely wide;and the chiral products synthesized have important practical value.The catalytic system provides a new idea for the development of metal-organic bifunctional catalysis and a new catalytic strategy for asymmetric Henry reaction,which has very scientific value and significance.