A unified and desymmetric approach to axially chiral atropisomers

Given the widespread applications of axially chiral atropisomers, the development of catalytic asymmetric transformations toward their preparation has been an important goal in organic synthesis and is under intensive investigation. However, the majority of precedented methods focused on only one specific type of chiral X-Y axis, while the implementation of a unified approach that is capable of accessing diverse types of stereogenic X-Y axes has largely lagged, remaining an unmet synthetic challenge. Herein, we report a modular platform for constructing axially chiral atropisomers, for which four structurally distinct types of frameworks bearing either a C-C, C-N, N-N, or C-O axis are generated in high yields with high enantioselectivities. The success of this study lies in the development of an efficient silver-catalyzed desymmetric Schöllkopf reaction of prochiral dicarboxylic esters with isocyanoacetates. Mechanistic studies indicate that for the C-C, C-N, and C-O atropisomers, the origin of enantioselectivity comes solely from the desymmetrization process, while for the N-N atropisomers the subsequent kinetic resolution contributes synergistically. Density functional theory (DFT) calculations further elucidate that this stereocontrol is dictated by ligand-substrate steric repulsion during the rate-determining nucleophilic addition step.