Merging photoredox with metalloenzymatic catalysis for enantioselective decarboxylative C(sp3)‒N3 and C(sp3)‒SCN bond formation

The scope of nature’s catalytic abilities has been expanded by recent advancements in biocatalysis to include synthetic transformations with no biological equivalent. However, these newly introduced catalytic functions represent only a small fraction of reactions utilized in synthetic catalysis. Here we present a biocatalytic platform that combines photoredox and metalloenzymatic catalysis for enantioselective radical transformations. Under green light irradiation, the eosin Y photocatalyst enables 4-hydroxyphenylpyruvate dioxygenases to catalyse enantioselective decarboxylative azidation and thiocyanation of N-hydroxyphthalimide esters. The final optimized variant obtained through directed evolution can afford diverse chiral organic azide and thiocyanate compounds with up to 77% yield, 385 total turnovers and 94% enantiomeric excess. Mechanistic studies show that the eosin Y catalyst mediates the generation of both C(sp3) radical and Fe(III)‒N3/Fe(III)‒NCS intermediate, leading to efficient enantioselective C‒N3 and C‒SCN bond formation in the enzyme active site. These findings establish an adaptable biocatalytic platform for introducing abiological metallophotoredox catalysis into biology. Decarboxylative azidation is a valuable transformation in organic chemistry, but a biocatalytic equivalent remained elusive. Now merging photoredox with metalloenzymatic catalysis enables the enantioselective decarboxylative radical azidation and thiocyanation of N-hydroxyphthalimide esters.