Chiral Sulfinamide Phosphine(Sadphos) And Derivatives:Application In Asymmetric Catalytic Reactions

Chiral phosphine compounds play an important role in asymmetric catalytic reactions,which have also become a research hotspot in the field of organic synthesis over the past decades.On one hand,chiral phosphine compounds can be employed as small molecular organocatalysts to realize the asymmetric reactions such as Michael addition;on the other hand,they can also be used as chiral ligands to realize the transition-metal catalyzed asymmetric reactions,such as gold,copper and palladium.Recently,our group has developed various series of structurally novel chiral sulfinamide phosphines(Sadphos),which can be divided into two categories.The first is ?-aminophosphine catalysts,such as Xiao-Phos,Wei-Phos,Peng-Phos and Le-Phos;the second is chiral monophosphine ligands,such as Ming-Phos,PC-Phos,XiangPhos,Xu-Phos and TY-Phos.Dedicated to continuously enrich our “Sadphos” catalysts and ligands,simultaneously based on our previous research work,this thesis is aimed to futher expand the application of these chiral phosphine compounds in asymmetric catalytic reactions.The main contents include the following several parts: 1.Design,synthesis and application of Na-Phos in asymmetric catalytic reactionsA chiral sulfinimide based on indole skeleton was obtained from commercially available 2-methylindole-3-carboxaldehyde and tert-butylsulfinamide under the employment of a condensation agent.The diphenylmethylenephosphine was introduced to the indole skeleton via LHMDS.Finally,the nucleophilic addition of series of Grignard reagents and lithium reagents furnished a new type of chiral tertiary phosphine catalyst(Na-Phos)based on a novel indole ring framework in moderate to high yields with good diastereoselectivity,which can be employed as small molecular organocatalysts in asymmetric organic catalytic reactions,such as the intermolecular asymmetric Rauhut-Currier reaction and cycloaddition of allenoates with activated enones.2.?-amino tertiary phosphine catalyzed intermolecular asymmetric RauhutCurrier reaction between enones and ?-perfluoroalkyl substituted enonesSeries of chiral N-acyl-?-amino phosphine catalysts were obtained through the modification of traditional Xiao-Phos,via introducing different acyl protecting groups after removing t-butylsulfinyl group,which can greatly improve the hydrogen bonding ability of N-H bond in the chiral phosphine catalyst.The novel multifunctional tertiary phosphine organocatalyst successfully realized the asymmetric intermolecular RauhutCurrier(R-C)reaction between ?-perfluoroalkyl substituted enones and alkyl/aryl vinyl ketones.Further investigation demonstrated that P3.4 was preferred to be the optimal catalyst in asymmetric intermolecular R-C reactions involving alkyl vinyl ketones,while P3.6 showed excellent catalytic activity and enantioselectivity control in asymmetric intermolecular R-C reactions involving aryl vinyl ketones.This catalytic system led to a broad substrate scope of chiral perfluoroalkyl substituted polycarbonyl functional compounds,up to 88% yield with 95% ee value.3.?-amino tertiary phosphine catalyzed intermolecular asymmetric aza-MoritaBaylis-Hillman reaction between enones and trifluoromethylated cyclic ketiminesBased on our well-developed research on the novel chiral sulfinamide ?-amino phosphine catalysts,we have successfully realized the enantioselective intermolecular aza-Morita-Baylis-Hillman(aza-MBH)reaction between trifluoromethylated cyclic ketimines and alkyl/aryl vinyl ketones,which could lead to a series of trifluoromethyl substituted fused heterocyclic compounds.Further investigation demonstrated that P4.9 was preferred to be the most suitable catalyst in asymmetric intermolecular aza-MBH reactions involving alkyl vinyl ketones.Chiral trifluoromethyl compounds via the primary addition could be obtained up to 80% yield and 95% ee value.However,the asymmetric intermolecular aza-MBH reactions involving aryl vinyl ketones could not effectively inhibit the self dimerization of ketene.As a result,the reactivity and enantioselectivity of the aza-MBH reaction involving the dimerization product were poor.4.Modification of chiral diadamantyl phosphine ligand Xiang-PhosThe synthesis of traditional Xiang-Phos poses considerable drawbacks,especially long synthetic routes and low synthetic efficiency.In order to further expand the scope of Sadphos chiral ligands,we have successfully developed a “one-pot” synthetic approach to the fast synthesis of chiral diadamantyl phosphine ligands.The modification of Xiang-Phos is simple and efficient,especially introducing substituents on the benzene skeleton.We synthesized several new type of N-Me-Xiang-Phos by introducing tetramethyltetrahydronaphthalene skeleton into the traditional Xiang-Phos,which not only increased the steric hindrance on the benzene ring,but also enhanced the electricity richness on phosphorus of the ligand.So that it can be attempted for more enantioselectivity control in asymmetric catalytic reactions.5.Pd/N-Me-Xiang-Phos catalyzed asymmetric carboheterofunctionalizations of norborneneBased on our developed Sadphos,we have successfully realized the highly enantioselective palladium catalyzed asymmetric carboheterofunctionalization between norbornene and 2-bromoanilline or 2-bromophenol.Further investigation demonstrated that N-Me-Xiang-Phos based on tetramethyltetrahydronaphthalene skeleton showed excellent catalytic activity and enantioselectivity control whether in carbonamination or in carboetherification reactions,producing the corresponding optically active polycyclic indolines and 2,3-dihydrobenzofurans,up to 98% yield with 99% ee value.6.Pd/N-Me-Xiang-Phos catalyzed asymmetric carboheterofunctionalizations of 2,3-dihydrofuransEmploying N-Me-Xiang-Phos based on tetramethyltetrahydronaphthalene skeleton as chiral ligands,we have successfully realized a highly efficient asymmetric palladium catalyzed carboheterofunctionalization of 2,3-dihydrofurans with a broader range of substrates.A series of chiral tetrahydrofurobenzofused heterocyclic compounds was constructed with a yield up to 97% and 99% ee value.At the same time,we have also realized the carboamination and carboetherification of substituted 2,3-dihydrofurans,leading to various of tricyclic moleculars with poly substituents and multi-stereocenters.Notably,the chiral diadamantylphosphine ligands N-Me-X7/8 have shown excellent catalytic activity in the asymmetric carboheterofunctionalizations of 2,3-dihydrofurans,by which the reaction still can be conducted smoothly at room temperature.