Study On Novel Chiral Cinchona Alkaloid Oxazoline Ligands In Palladium-catalyzed Asymmetric Reactions

How to efficiently synthesize chiral drugs has become one of the major research hotspots in the field of medicine and health.The asymmetric catalysis with transition metal complexes is undoubtedly an effective way to solve this problem.The design and application of novel high-efficiency chiral ligands is the core of this kind of asymmetric catalysis.From the perspectives of the catalytic mechanism of these reactions,the organic ligands with dominant framework structures will affect the steric hindrance and electronic effects of metal catalysts,and further improve the reactivity,regioselectivity and enantioselection by reducing the occurrence of side reactions.Therefore,the design and application of novel chiral ligand skeletons are very important for transition metal asymmetric catalysis.The asymmetric reactions catalyzed by Pd and oxazoline ligands complexes have been rapidly developed recently.Up to date,many kinds of asymmetric synthesis catalysts have been reported.However,it still has some shortcomings such as low activity for some reaction catalysts,large catalytic loading,more complex catalytic system and lower chiral control effect on some specific substrates.Therefore,it is especially important to study the application of novel chiral oxazoline ligands in palladium-catalyzed asymmetric reactions.In this thesis,the "dominant chiral framework" cinchona alkaloids and oxazoline were combined to develop a series of novel chiral ligands and applied to Pd-catalyzed asymmetric reactions.The aim is to further regulate and influence transition metal catalysts in terms of steric hindrance effect and electronic properties,and to achieve the purpose of high-efficiency and selectivity of the catalytic reactions.This thesis mainly includes the following parts:1.Synthesis of four kinds of chiral oxazoline ligands(60a,60 b,67a,67b)based on cinchona alkaloids,and the structures of the compounds were confirmed by sprectrum data.2.Starting from o-iodoaniline,nineteen kinds of aromatic nitrogen-containing diene aza-Wacker substrates(74a-74s)were synthesized by allylic double substitution,Grignard reaction,amino reduction and amidation,and four of them were new compounds(74p-74s).The structures of these compounds were confirmed by 1H NMR,13 C NMR,HRMS and IR.3.The novel cinchona alkaloid oxazoline ligands were applied to the palladium-catalyzed asymmetric aza-Wacker-type oxidation tandem cyclization reaction.The screening of ligands,solvents and catalysts were carried out.Asymmetric oxidative cyclization of nitrogen-containing diene substrates with substituent structure were achieved in moderate yield:(up to 83%)and good enantioselectivity(up to 97% ee).In addition,the efficiency of the cinchona oxazoline was further verified by comparison of other chiral ligands and the amplification of the reaction.4.Starting from the nitrile compounds,nine kinds of amino olefin substrates(88a-88i)were synthesized by diarylation,allyl substitution,cyano reduction and amino protection,and their structures were confirmed by sprectrum data.In addition,two substrates(88j,88k)were synthesized.We have applied chiral cinchona alkaloid oxazoline ligands to Pd-catalyzed asymmetric amination acetylation.By preliminary screening of the reaction conditions,a catalytic system suitable for the reaction is obtained.For the substrates extension,the corresponding chiral acetoxypyrrolidine products were obtained with good regioselectivities(up to 6.3:1)and desirable enantioselectivities(up to 98% ee).