Asymmetric Relay Catalysis Enables Unreactive Allylic Alcohols to Participate in 1,3-Dipolar Cycloaddition of Azomethine Ylides

Current synthetic transformations occur readily with starting materials that possess both innate reactivity and steric accessibility or functional-group-oriented reactivity. However, achieving reactions with inactive feedstock substrates remains significantly challenging and normally requires cumbersome prior functional group manipulations. Herein, we report an unprecedented example of catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with nonactivated alkenes enabled by copper/ruthenium relay catalysis. Key to the success is the temporary activation strategy initiated by oxidative dehydrogenation of inert allylic alcohols into electron-demanding reversed highly reactive enones, which triggers the ensuing Cu-catalyzed asymmetric 1,3-dipolar cycloaddition followed by reductive hydrogenation to deliver highly functionalized chiral pyrrolidines with the construction of two C-C bonds and four well-defined stereogenic centers in an atom-/step-economical and redox-neutral manner. This method features mild reaction conditions, operational simplicity, and broad substrate scope and is also characterized by formal dynamic kinetic resolution. Mechanistic studies and control experiments supported a typical borrowing-hydrogen cascade orthogonally merged with 1,3-dipolar cycloaddition and revealed that the superiority and reliability of relay catalysis are enabled by the controlled release of highly reactive but unstable enones to impede the undesired polymerization. It should be noted that up to four stereoisomers of the challenging and otherwise inaccessible pyrrolidines and cyclobutanes could be readily prepared through concise late-stage elaborations.