exo′-Selective Construction of Spirobipyrrolidines by the Silver-catalyzed Asymmetric [3+2] Cycloaddition of Imino Esters with 4-Benzylidene-2,3-dioxopyrrolidines

An unprecedented Ag-catalyzed exo '-selective [3+2] cycloaddition of imino esters with 4-benzylidene-2,3-dioxopyrrolidines is described. The reaction was efficiently catalyzed by Ag/(R, S-p)-ThioClickFerrophos (TCF) leading to the construction of the corresponding spirobipyrrolidine scaffolds in excellent enantio- and diastereoselectivities. This reaction is the first example of a silver-catalyzed exo '-selective asymmetric [3+2] cycloaddition, as well as the first exo '-selective spirobipyrrolidine construction via a [3+2] cycloaddition process using imino esters. The wide substrate scope of this reaction enabled the preparation of structurally diverse spirobipyrrolidine derivatives, which are attracting attention as targets for drug discovery. Mechanistic studies suggested that the unusual exo '-selectivity of this reaction is not due to epimerization following the common exo- or endo-selective cycloaddition, but instead is due to a stepwise Michael addition/Mannich sequence with bond rotation.

Automated summary

This study describes an unprecedented Ag-catalyzed exo'-selective [3+2] cycloaddition reaction between imino esters and 4-benzylidene-2,3-dioxopyrrolidines. The reaction, efficiently catalyzed by Ag/(R, S-p)-ThioClickFerrophos (TCF), allows for the construction of spirobipyrrolidine scaffolds with excellent enantio- and diastereoselectivities. It is the first example of a silver-catalyzed exo'-selective asymmetric [3+2] cycloaddition and the first exo'-selective spirobipyrrolidine construction process using imino esters. The broad substrate scope of this reaction enables the synthesis of diverse spirobipyrrolidine derivatives, which are of interest for drug discovery. Mechanistic studies suggest that the unusual exo'-selectivity of this reaction is due to a stepwise Michael addition/Mannich sequence with bond rotation, rather than epimerization following the common exo- or endo-selective cycloaddition.