Copper Complexes with Protein‐Based N‐Donor Ligands as cis‐Selective Nascent Cyclopropanases

In this study, we aimed to develop protein‐based metal ligands to catalyze cis‐selective cyclopropanation using the TM1459 cupin protein superfamily. Copper complexes with TM1459 mutants containing the 3‐His metal‐binding site exhibited excellent diastereoselectivity in cyclopropanation reactions with styrene and ethyl diazoacetate. Further mutations in the secondary coordination sphere increased the cis‐preference with t‐butyl diazoacetate as the substrate with up to 80 : 20 (cis:trans ratio) and high enantioselectivity (90 % ee). Stepwise repurposing of the first and second coordination spheres in cupin proteins yielded novel copper cupin complexes that could catalyze diastereo‐ and enantioselective cyclopropanation reactions via copper carbene species using ethyl diazoacetate. Even when employing t‐butyl diazoacetate which is too bulky to produce the cis‐cyclopropane, these nascent cyclopropanases exhibited thermodynamically unfavorable cis‐preference.