An unprecedented enantioselective protonation reaction enabled by photoredox catalytic radical coupling is developed. Under cooperative dicynopyrazine-derived chromophore (DPZ) as a photosensitizer and a chiral phosphoric acid catalyst, and Hantzsch ester as a sacrificial reductant, the transformations between α-substituted enones and cyanoazaarenes or 2-(chloromethyl)azaaren-1-iums can proceed a tandem reduction, radical coupling, and enantioselective protonation process efficiently. Two classes of pharmaceutically important enantioenriched azaarene variants, which contain a synthetically versatile ketone-substituted tertiary carbon stereocenter at the ß- or γ-position of the azaarenes, are synthesized with high yields and ees.
A novel enantioselective protonation protocol that is triggered by reductive cross coupling of olefins is reported. When under cooperative photoredox and chiral hydrogen-bonding catalytic conditions and using a terminal reductant, various α-branched vinylketones with diverse vinylazaarenes could provide important enantioenriched azaarene derivatives containing tertiary stereocenters at their remote δ-position with high yields and enantioselectivities. This reaction system is also suitable for α-branched vinylazaarenes, thus successfully assembling elusive 1,4-stereocenters. The convenient late-stage modifications of products, especially the formation of remote ε-tertiary and ε-heteroquaternary carbon stereocenters, further highlight the important synthetic value of this method. Control experiments and density functional theory (DFT) calculations were conducted to elucidate the plausible reaction mechanism and origins of regioselectivity and stereoselectivity.
Classic nucleophilic substitution reactions (SN1 and SN2) are not generally amenable to the enantioselective variants that use simple and racemic alkyl halide electrophiles. The merging of transition metal catalysis and radical chemistry with organometallic nucleophiles is a versatile method for addressing this limitation. Here, we report that visible light-driven catalytic asymmetric photoredox radical coupling can act as a complementary and generic strategy for the enantioconvergent formal substitution of alkyl haldies with readily available and bench-stable organic molecules. Single-electron reductive debrominations of racemic α-bromoketones generate achiral alkyl radicals that can participate in asymmetric Csp3-Csp3 bonds forming cross-coupling reactions with α-amino radicals derived from N-aryl amino acids. A wide range of valuable enantiomerically pure ß2- and ß2,2-amino ketones were obtained in satisfactory yields with good-to-excellent enantioselectivities by using chiral phosphoric acid catalysts to control the stereochemistry and chemoselectivity. Fluoro-hetero-quaternary and full-carbon quaternary stereocenters that are challenging to prepare were successfully constructed.
