Asymmetric Three-Component Radical Cascade Reactions Enabled by Synergistic Photoredox/Brønsted Acid Catalysis: Access to α‑Amino Acid Derivatives

Multicomponent reactions (MCRs), highly sought-after
methods to
produce atom-, step-, and energy-economic organic syntheses, have
been developed extensively. However, catalytic asymmetric MCRs, especially
those involving radical species, remain largely unexplored owing to
the difficulty in stereoselectively regulating the extraordinarily
high reactivity of open-shell radical species. Herein, we report a
conceptually novel catalytic asymmetric three-component radical cascade
reaction of readily accessible glycine esters, α-bromo carbonyl
compounds and 2-vinylcyclopropyl ketones via synergistic photoredox/Brønsted
acid catalysis, in which three sequential C–C (σ/π/σ)
bond-forming events occurred through a radical addition/ring-opening/radical–radical
coupling protocol, affording an array of valuable enantioenriched
unnatural α-amino acid derivatives bearing two contiguous stereogenic
centers and an alkene moiety in moderate to good yield with high diastereoselectivity,
excellent enantioselectivity and good E-dominated
geometry under mild reaction conditions. The radical relay cascade
process, especially a unique proton-coupled electron transfer (PCET)-promoted
radical–radical coupling, is supported by mechanistic investigations
and quantum mechanics calculations and should garner broad interest
and further inspire the development of asymmetric multicomponent radical
reactions.