Chiral Phosphoric Acid Catalyzed Asymmetric Conjugate Addition Reactions Of Isoxazolinones With Alkynyl Imine Esters And 6-indolylmethanols

Isoxazolinones are a kind of widely existing five-membered heterocyclic compounds,which have important application value in many aspects such as medical science.Due to their unique structure,they can not only be used as nucleophiles for regioselective N-or C-alkylation,but also as Michael receptors.Now they have been recognized as multifunctional synthetic raw material in pharmaceutical chemistry.So far,there are few reports on the stereoselective reactions of isoxazolinones,especially for the catalytic N-selective reactions of isoxazolinones.The main reason is that isoxazolinones have multiple reaction sites,so it is difficult to control their regional selectivity when participating in the reaction.Therefore,there is a great challenge for the synthesis of high regional selective isoxazolinone derivatives.In this context,it is very necessary to study the synthetic methods of isoxazolinone derivatives.Based on the previous research on asymmetric synthesis,our research group actively explored the enantioselective reaction of isoxazolinone derivatives with different electrophiles catalyzed by chiral phosphoric acid,which not only realized the asymmetric conjugate addition reaction of selective C-/N-functionalization of isoxazolinones,but also realized the remote stereocontrolled synthesis of chiral isoxazolinones compounds.Part Ⅰ: In this part,we used chiral phosphoric acid(CPA)as catalyst to realize high regioselectivity C-functionalization of isoxazolinones compounds and high regioselectivity of alkynyl imine esters γ-addition reaction.After determining the subject,in order to achieve the best results of the target product(yield,ee and dr),we optimized the reaction conditions,mainly including the type of catalyst and solvent.Finally,we obtained the standard conditions most suitable for the template reaction through a large number of screening.With the established the optimized conditions in hand,we then examined the scope of the chiral phosphoric acid catalyzed region-and enantioselective reactions between alkynyl imine esters and isoxazolinones.All kinds of substituted substrates can react smoothly furnishing the corresponding axial chiral tetrasubstituted allenes in good yields(31-96%)with high enantioselectivities(32-94% ee)and excellent diastereoselectivities(15:1->20:1 dr).Through this synthesis strategy,we successfully realized the selective C-functionalized asymmetric 1,4-conjugate addition reaction of isoxazolinones.Importantly,we obtained a series of axially chiral tetrasubstituted allenes.Part Ⅱ: In this part,we used chiral phosphoric acid(CPA)as catalyst to realize high regioselectivity N-functionalization of isoxazolinones compounds.After determining the subject,in order to achieve the best results of the target product(yield and ee),we optimized the reaction conditions,mainly including the type of catalyst and solvent.Finally,we obtained the standard conditions most suitable for the template reaction through a large number of screening.With the established the optimized conditions in hand,we then examined the scope of the chiral phosphoric acid catalyzed region-and enantioselective reactions between 6-indolylmethanols and isoxazolinones.All kinds of substituted substrates can react smoothly furnishing the corresponding isoxazolones containing nitrogen heterotrisubstituted carbon atom centers in good yields(70-83%)with high enantioselectivities(61-96% ee).Through this synthesis strategy,we successfully realized remote stereocontrolled asymmetric 1,8-conjugate addition reaction of isoxazolinones compounds.