Flavin-dependent 'ene'-reductases (ERED) can generate stabilized alkyl radicals when irradiated with visible light, however, they are not known to form unstabilized radicals. Here, we report an enantioselective radical cyclization using alkyl iodides as precursors to unstabilized nucleophilic radicals. Evidence suggests this species is accessed by photoexcitation of a charge-transfer complex that forms between flavin and substrate within the protein active site. Stereoselective delivery of a hydrogen atom from the flavin semiquinone to the prochiral radical formed after cyclization provides high levels of enantioselectivity across a variety of substrates. Overall, this transformation demonstrates that photoenzymatic catalysis can address long-standing selectivity challenges in the radical literature.
Non-natural photoenzymatic reactions
reported to date have depended
on the excitation of electron donor–acceptor complexes formed
between substrates and cofactors within protein active sites to facilitate
electron transfer. While this mechanism has unlocked new reactivity,
it limits the types of substrates that can be involved in this area
of catalysis. Here we demonstrate that direct excitation of flavin
hydroquinone within “ene”-reductase active sites enables
new substrates to participate in photoenzymatic reactions. We found
that by using photoexcitation these enzymes gain the ability to reduce
acrylamides through a single electron transfer mechanism.
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