Study On α-regioselective Asymmetric [3+2] Cycloaddition Reaction Of Isatin-derived MBH Carbonate Catalyzed By Chiral Tertiary Amine

Part I:Chapter 1:Study on the Asymmetric[3+2]Cycloaddition Reaction of Isatin-derived MBH Carbonates with 3- MethyleneoxindolesObjective:To develop a highly regio-and stereoselective synthetic method and achieve the asymmetric synthesis of 3,3’-cyclopentenyldispirooxindole derivatives incorporating two adjacent quaternary spirostereocenters,and to provide a more efficient strategy for the construction of complex double spirocyclic oxindole.Methods:Using isatin-derived MBH carbonates and 3-methyleneoxindoles as starting materials,an asymmetric[3+2]cycloaddition reaction system withα-regional selectivity and high stereoselectivity was obtained by screening of the key factors such as chiral Lewis bases and solvent.By investigating the compatibility of the substituted MBH-carbonates and the 3-methyleneoxindoles,a series of chiral 3,3’-cyclopentenyldispirooxindole derivatives incorporating two adjacent quaternary spirostereocenters were constructed.On the basis of NMR,HRMS and X-ray single crystal diffraction datas of the products,the reaction process was verified by control experiments design.Results:（1）29 examples of chiral 3,3’-cyclopentenyldispirooxindole derivatives incorporating two adjacent quaternary spirostereocenters were synthesized.The isolated yield of the products was high to 91%,and the enantioselectivity and diastereoselectivity were high to>99%and>99:1,respectively.（2）When the reaction was amplified to the gram scale,the model product was obtained in 70%yield with 97%ee and>99:1 dr.The results were not significantly different from the small amount reaction.（3）Through the hydrogenation reduction experiment,a more diverse double spirocyclic oxindole molecule with multi-chiral centers was obtained.（4）By designing the deuterated control experiments,the key 1,3-hydrogen migration step that have an important influence on the product structure during the reaction process were verified.Conclusion:A highly regio-and stereoselective[3+2]cycloaddition reaction has been developed in this study.The chiral 3,3’-cyclopentenyldispirooxindole derivatives incorporating two adjacent quaternary spirostereocenters were firstly constructed via a chiral amine catalyzedα-regioselective asymmetric cycloaddition process of isatin-derived MBH carbonates and 3-methyleneoxindoles.This study provides an efficient strategy for the synthesis of chiral double spirocyclic oxindoles in a relatively crowded space.Part II:Study on the Asymmetric[3+2]Cycloaddition Reaction of Isatin-derived MBH Carbonates withβ,γ-Unsaturatedα-Keto EstersObjective:To expand the asymmetric[3+2]cycloaddition reaction of the isatin-derived MBH carbonates as a C3 synthons and expand the asymmetric construction of the chiral spirocyclopentene-oxindole compounds.Methods:With the isatin-derived MBH-carbonates andβ,γ-unsaturatedα-ketoesters as the starting materials,an asymmetric[3+2]cycloaddition reaction system with regional selectivity and high stereoselectivity were established by screening of the factors such as chiral Lewis bases and substituent of substrates.A series of chiral spirocyclopentene-oxindole compounds were constructed by investigating the compatibility of the isatin-derived MBH-carbonates andβ,γ-unsaturatedα-ketoesters.Results:The optimalα-regioselective asymmetric[3+2]cycloaddition reaction system was established as follows:β-ICD（10 mol%）,isatin-derived MBH carbonates（1.5 equiv.）,β,γ-unsaturatedα-ketoesters（1.0 equiv.）,CH₂Cl₂/ClCH₂CH₂Cl（2 mL）,25°C/0°C.（2）28 examples of structurally diverse spirocyclopentene-oxindole compounds were synthesized,and the isolated yield of the products was high to 91%.The enantioselectivity and diastereoselectivity were high to>99%and>99:1,respectively.（3）When the reaction was amplified to the gram scale,the target product was obtained in 86%yield with 91%ee and>99:1 dr.After a simple one-step recrystallization,the ee was increased to>99%.（4）The product 3k was subjected to Suzuki coupling reaction to give an oxidative dehydrogenated spirocyclopentadiene-oxindole in 62%yield with 97%ee.Conclusion:An asymmetric[3+2]cycloaddition reaction withα-regioselectivity and stereoselectivity has been developed in this study that further extended the asymmetric synthetic methodology of isatin-derived MBH-carbonates as a synthon.This study provides an efficient method for the construction of chiral spirocyclopentene-oxindole compounds.