We report the reprogramming of nonheme iron enzymes to catalyze an abiological C(sp3)‒H azidation reaction through iron-catalyzed radical relay. This biocatalytic transformation uses amidyl radicals as hydrogen atom abstractors and Fe(III)‒N3intermediates as radical trapping agents. We established a high-throughput screening platform based on click chemistry for rapid evolution of the catalytic performance of identified enzymes. The final optimized variants deliver a range of azidation products with up to 10,600 total turnovers and 93% enantiomeric excess. Given the prevalence of radical relay reactions in organic synthesis and the diversity of nonheme iron enzymes, we envision that this discovery will stimulate future development of metalloenzyme catalysts for synthetically useful transformations unexplored by natural evolution.
Carbohydrates,
one of the three primary macromolecules of living
organisms, play significant roles in various biological processes
such as intercellular communication, cell recognition, and immune
activity. While the majority of established methods for the installation
of carbohydrates through the anomeric carbon rely on nucleophilic
displacement, anomeric radicals represent an attractive alternative
because of their functional group compatibility and high anomeric
selectivities. Herein, we demonstrate that anomeric nucleophiles such
as C1 stannanes can be converted into anomeric radicals by merging
Cu(I) catalysis with blue light irradiation to achieve highly stereoselective
C(sp3)–S cross-coupling reactions. Mechanistic studies
and DFT calculations revealed that the C–S bond-forming step
occurs via the transfer of the anomeric radical directly to a sulfur
electrophile bound to Cu(II) species. This pathway complements a radical
chain observed for photochemical metal-free conditions where a disulfide
initiator can be activated by a Lewis base additive. Both strategies
utilize anomeric nucleophiles as efficient radical donors and achieve
a switch from an ionic to a radical pathway. Taken together, the stability
of glycosyl nucleophiles, a broad substrate scope, and high anomeric
selectivities observed for the thermal and photochemical protocols
make this novel C–S cross coupling a practical tool for late-stage
glycodiversification of bioactive natural products and drug candidates.
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