Nickel-Catalyzed Hydrocarboxylation-Asymmetric Transfer Hydrogenation Tandem Reaction For The Synthesis Of Chiral Carboxylic Acid Drugs

Chiral carboxylic acids are widely found in natural products and medicines,and are also important intermediates for organic synthesis.In recent years,the market demand for chiral carboxylic acids such as ibuprofen and naproxen has been increasing,and their efficient synthesis methods have received great attention from organic synthesizers and pharmaceutical companies.At present,most domestic pharmaceutical companies still use the traditional racemate chemical resolution method to obtain optically pure chiral carboxylic acids,which is cumbersome,low yield,large consumption of organic solvents and serious emission of three wastes.But the atomically more economical and environmentally friendly asymmetric hydrogenation method relies excessively on rare and precious metal catalysts,flammable and explosive hydrogen and high-pressure resistant devices.Therefore,it is an important development trend in the field of chiral catalysis that develop more efficient,cheapper metal catalysts and safer,milder asymmetric transfer hydrogenation reactions.Tandem reaction is an attractive synthetic strategy which be used to construct multiple chemical bonds,rings or functional groups in one step,avoiding the tedious separation process caused by multi-step reactions and reducing production costs and pollution emissions effectively.Asymmetric tandem reactions catalyzed by cheap metal catalysis have promising applications in the green synthesis of chiral medicines and pesticides.In this thesis,nicke-catalyzed asymmetric transfer hydrogenation ofα-substituted acrylic acid was firstly investigated,and obtained excellent yields and enantioselectivities.Then this reaction was coupled with the raw material synthesis step to form a asymmetric tandem reaction which convert simple alkyne to chiral carboxylic acid in one step,and developed an efficient and green tandem reaction.The thesis contains two parts:（1）Nickel-catalyzed asymmetric transfer hydrogenation ofα-substituted acrylic acidUsing a nickel complex,which was in situ generated from Ni（OAc）₂·4H₂O and chiral bisphosphine ligand（R,R）-Benz P^*as catalysts,and formic acid as a hydrogen source,we successfully achieved the asymmetric transfer hydrogenation ofα-substituted acrylic acids.The system had a wide scope of substrates,α-aryl-substituted acrylic acids,benzoheterocyclic acrylic acids and aliphatic long-chain substituted acrylic acids,which all afforded excellent yields and enantioselectivities,the highest ee value could reach up to 99.3%.When the reaction was scaled up to the gram scale,the yield and ee value did not decrease significantly,showing a good potential for industrial scale production.（2）Nickel-catalyzed hydrocarboxylation-asymmetric transfer hydrogenation tandem reaction of alkynesUsing a Ni（OAc）₂·4H₂O/（R,R）-Benz P^*as catalyst,we successfully catalyzed the hydrocarboxylation-asymmetric transfer hydrogenation tandem reaction of alkynes and synthesized chiral carboxylic acid from simple alkynes in one pot for the first time.The system had wide substrate applicability,most of the aryl and alkyl alkynes could form the target products in excellent yields and ee values.Using this tandem reaction as the core step,Ibuprofen,naproxen,flurbiprofen and a chiral AZD2716 fragment were synthesized by simple halogenated aromatic hydrocarbons in only two steps.Kinetic experiments and deuteration experiments combined with theoretical calculations demonstrated that the Ni/Benz P^*complexes initiated two steps of hydrocarboxylation and hydrogenation in different forms and valence states.The reaction of these two steps occured successively and the rate was almost synchronous.In addition,the high regioselectivity of the carboxylation and the high stereoselectivity of the hydrogenation process were satisfied at the same time.In summary,the first nickel-catalyzed asymmetric transfer hydrogenation of unsaturated carboxylic acids was achieved under mild reaction conditions using Ni（OAc）₂·4H₂O/（R,R）-Benz P^*complexes as catalysts and formic acid as hydrogen source;Then,the transfer hydrogenation was coupled with a hydrocarboxylation to form a asymmetric tandem reaction which convert simple alkyne to chiral carboxylic acid in one step.This novel tandem reaction provides a more concise and green process route for the industrial production of chiral carboxylic acids.