Stereoselective intermolecular radical cascade reactions of tryptophans or &x264;-alkenyl-α-amino acids with acrylamides via photoredox catalysis

Photocatalytic radical cascade reactions enable the facile construction of diverse cyclic compounds, though they rely on templated precursors. In this paper, the authors report on stereoselective intermolecular radical cascade reaction between tryptophan or & x264;-alkenyl substituted amino acids and acrylamides to synthesise multi-substituted trans-fused hexahydrocarbazoles or 1,3,5-trisubstituted cyclohexanes. The radical cascade reaction is considered as one of the most powerful methods to build molecular complexity. However, highly stereoselective intermolecular radical cascade reactions that can produce complex cyclic compounds bearing multiple stereocenters via visible-light-induced photocatalysis have been challenging yet desirable. Herein we report a facile and efficient synthesis of multi-substituted trans-fused hexahydrocarbazoles via a stereoselective intermolecular radical cascade reaction of readily available tryptophans and acrylamides enabled by visible-light-induced photoredox catalysis. The trans-fused hexahydrocarbazoles with up to five stereocenters including two quaternary ones can be accessed in up to 82% yield, >20/1 diastereoselectivity, and 96% ee. Interestingly, the tetrahydrocarbazoles are favorably formed when the reaction is performed under air. Moreover, by simply switching the starting material from tryptophans to & x264;-alkenyl substituted alpha-amino acids, this protocol can be further applied to the stereoselective syntheses of 1,3,5-trisubstituted cyclohexanes which are otherwise challenging to access. Preliminary mechanistic studies suggest that the reaction goes through radical addition cascade and radical-polar crossover processes.

Automated summary

This study demonstrates a facile and efficient synthesis of multi-substituted cyclic compounds with high stereoselectivity using photocatalytic radical cascade reactions. The results show that this method is a promising strategy for the synthesis of complex organic molecules.