Biocatalytic Synthesis of N-Protected α-Amino Acids through 1,3-Nitrogen Migration by Nonheme Iron Enzymes

Nonheme iron enzymes rank among nature's most versatile catalysts for molecular functionalization. Their flexible coordination environments provide a unique platform for expanding the scope of new-to-nature metalloenzymatic catalysis. Leveraging this feature, we herein present a novel biocatalytic strategy for synthesizing N-protected α-amino acids via 1,3-nitrogen migration. Specifically, we demonstrate that the nonheme iron enzyme isopenicillin N synthase (IPNS) from Aspergillus nidulans generates an iron-nitrene intermediate capable of aminating benzylic and allylic α-C-H bonds of carboxylic acids. Directed evolution has been performed to optimize the IPNS variant to accommodate a broad range of azanyl esters, yielding α-amino acids (24 examples) with up to 92% yield, 1477 total turnover number (TTN), and 99% enantiomeric excess (ee).