Ni(?)-Catalyzed Asymmetric Addition Reaction Of Carboxylic Acid Derivatives With Acyclic Oxycarbonium Ions

a-Substituted chiral acyclic ether is a kind of dominant structure with potential pharmacological activity widely existing in biologically active small molecules and natural products.Exploring how to efficiently and conveniently synthesize a-substituted chiral acyclic ethers is an important research topic for organic chemists all over the world.A large number of traditional methods for synthesizing ?-substituted chiral ethers have been reported,which have the advantages of high yield,high selectivity,but the substrates are relatively limited,mainly focusing on ?-substituted chiral cyclic ethers.However,there are relatively few studies on the synthesis of a-substituted chiral acyclic ethers.Therefore,it is necessary to develop a method with high yield and high enantioselectivity to synthesize ?-substituted chiral acyclic ethers.In the traditional method of substrate control chirality,the reaction can be roughly divided into three steps.Before the reaction,chiral auxiliary is pre-installed in the reaction substrate;in the reaction,chiral auxiliary induces the enantioselectivity of the product through chiral transfer method;after the reaction,chiral auxiliary is removed from the reaction product.This method has specific advantages in total synthesis of natural products,but its disadvantages are also obvious.The reaction requires an equivalent chiral auxiliary,which does not have atom economy and step economy.Oxycarbonium ions are widely used in the construction of C-C bonds as a key intermediate in chemical reactions.The asymmetric addition reaction of nucleophilic with latent electrophilic chiral acyclic Oxycarbonium ions is a significant method to synthesize ?-substituted acyclic ethers.The previous researchers mainly focused on cyclic Oxycarbonium ions intermediates,but there are relatively few studies on acyclic Oxycarbonium ions intermediates.Compared with the cyclic Oxycarbonium ions,the acyclic Oxycarbonium ions lacks the dominant spatial conformation.Therefore,it is difficult to control the enantioselectivity of the reaction.Based on the understanding of chiral auxiliary and oxycarbonium ions,this paper mainly discusses the asymmetric addition reaction of carboxylic acid derivative to acyclic acetal with the catalysis of nickel(?).Our design ideas are as follows:acyclic acetals generate latent chiral acyclic oxonium ions in situ under the activation of lewis acid;Carboxylic acid derivative complexed with chiral nickel salt and isomerized to enolate;Asymmetric addition of enolate with acyclic oxycarbonium ions to synthesis of ?-substituted acyclic ethers.Firstly,2-Phenyl-1-(2-thiooxazolidin-3-yl)ethan-l-one and(dimethoxymethyl)-benzene were selected as substrates.Conditional optimizing on lewis acid,lewis base,metals,chiral ligands,solvents and material ratio were conducted and then the optical condition was determined.Secondly,the substrate scope of carboxylic acid derivatives and acetals were examined respectively after the optimal reaction conditions determination.When the substituent at the ?-position of the carbonyl group of the carboxylic acid derivative is replaced by alkyl,alkenyl or aryl,and substituents of acetals' side chain is replaced by aryl or alkenyl,the reaction can still be carried out with high enantioselectivity and high yield.When the substituent is the aryl group,the substitution effect and the electrical effect of aromatic ring was examined separately.The results show that,the substituted groups at different positions had almost no effect on the reaction,and the electron with-drawing group and the electron-donating group had little effect on the reaction.However,it's worth mentioning that,the target product was hardly obtained when chiral auxiliary was changed to oxazolidin-2-one.Finally,a variety of structural derivation of the reaction products were implemented.Possible reaction mechanism was proposed based on the known literature and experimental results.Gram-scale amplification of the reaction was performed and the results shows that enantioselectivity and yield of the reaction are at an excellent level.The absolute configuration of marjor product and minor product were determined by X-ray single crystal diffraction.In summary,the asymmetric addition strategy of nucleophilic to latent chiral acyclic oxycarbonium ions was applied to achieve the synthesis of ?-substituted chiral acyclic ethers.The reaction has advantages of wide substrate scope,good enantioselective,and high yields.It may provide a new method to synthesizing ?-substituted chiral acyclic ethers.