Biomimetic combination of photoactivation and relay catalysis for an asymmetric cascade reaction

Abstract Asymmetric ketene cycloaddition is a powerful tool for chiral heterocycle synthesis, stimulating the development of innovative catalytic strategies to achieve a high level of efficiency and stereocontrol. Herein, we disclose an asymmetric cascade reaction between enynamides and α-diazoketones inspired by natural photosynthesis. The biomimic combination of visible-light photoactivation and relay gold and N-oxide catalysis allowed the facile generation and controlled assembly of two reactive intermediates, ketene and aza-o-quinone methide. This produced chiral bicyclic lactams bearing chiral all-carbon quaternary stereocenters with high efficiency and selectivity. Density functional theory calculations revealed a stepwise [4+2] cycloaddition mechanism, with the stereochemistry controlled by the amide group of the catalyst. Notably, this study presents the first example of chiral N-oxides as catalysts for asymmetric ketene cycloaddition, and demonstrates that a biomimetic cascade strategy is a promising approach to access important chiral heterocyclic scaffolds.