Asymmetric Catalytic 1,3-Dipolar Cycloaddition In The Preparation Of Pyrrolidine Derivatives With Quaternary Stereogenic Centers

Highly substituted pyrrolidine skeleton is widely found in natural products and pharmaceutical intermediates.The asymmetric 1,3-dipolar cycloaddition of imine ylides with electron deficient olefins is one of the most efficient methods for the construction of pyrrolidine skeleton with multiple substitutions and stereogenic centers.Considerable advancements have been achieved in this area thus far,however,methods of asymmetric catalytic 1,3-dipolar cycloaddition that are capable of producing quaternary carbon centers remain scarce.In this thesis,the first asymmetric catalytic 1,3-dipolar cycloaddition of imine ylides with methacrylonitrile catalyzed by CuBF₄/L2 has been realized,affording nitrile-substituted pyrrolidine derivatives with one quaternary stereogenic centers with excellent diastereo-and enantioselectivies?up to 99:1 d.r.,99%ee?;and an asymmetric catalytic 1,3-dipolar cycloaddition of imine ylides with trisubstituted nitroethylene catalyzed by CuBF₄/L1 has been developed,producing nitro-substituted pyrrolidine derivatives containing two quaternary stereogenic centers with up to 34:1 dr and 98%ee value.Using the newly developed methodology,an enantioelective synthesis of an antitumor agent with a pivotal nitrile pharmacophore has been conducted.