Catalytic Enantioselective Smiles Rearrangement Enabled by the Directed Evolution of P450 Radical Aryl Migratases

Despite its synthetic potential, catalytic enantioselective Smiles rearrangement has remained elusive. Through the directed evolution of P450 radical aryl migratases (P450_Smiles's), we describe the first example of catalytic enantioselective Smiles rearrangement. A range of racemic <i>N</i>-arylsulfonyl-α-chloroamides could be transformed by P450_Smiles in an enantioconvergent manner, affording acyclic amide products possessing an all-carbon quaternary stereocenter with excellent chemo- and enantioselectivity. Both electron-rich and electron-deficient substituents were compatible with the migrating aryl group, demonstrating this P450-catalyzed Smiles rearrangement is insensitive to the electronic properties of the migrating group. Importantly, our evolved P450 variants were capable of overriding the innate cyclization activity of the <i>N</i>-alkyl amidyl radical intermediate, allowing the chemoselective reductive formation of acyclic products. Classical molecular dynamics (MD) simulations revealed this unusual enzyme-controlled chemoselectivity stems from the restricted conformation of the amidyl radical within the enzyme active site, disfavoring the cyclization pathway. This new-to-nature biocatalytic asymmetric Smiles rearrangement showcases the synthetic potential of enzymatic chemo- and enantioselectivity control over highly reactive radical intermediates eluding small-molecule catalysts.