Enantiodivergent synthesis of isoindolones catalysed by a Rh(III)-based artificial metalloenzyme

Combining enzyme and transition-metal catalysis within artificial metalloenzymes has broadened the scope of new-to-nature reactions and efficiently solved several problems in asymmetric organometallic catalysis through compartmentalization of the catalytic centre within a protein active site and by providing easy access to cooperative catalysis and unparalleled selectivity via protein engineering. Streptavidin, a homotetrameric protein, along with a biotinylated metal complex is a promising artificial metalloenzyme for its application in diverse non-natural reactions. However, the use of engineered streptavidin-based artificial metalloenzymes for the synthesis of enantioenriched isoindolones has remained elusive. Here we report a streptavidin–biotin–Rh(III) system to synthesize chiral isoindolones from N-(pivaloyloxy)benzamides and aromatic diazoesters with up to 95:5 e.r. This hybrid catalytic platform can accommodate a diverse range of diazoesters and yields chiral isoindolones with several useful functionalities such as biphenyl, thioether, selenoether, amine, olefin and alkyne. Mechanistic studies reveal that the process involves a directed inner-sphere C–H activation followed by diazo insertion. A high-resolution crystal structure of streptavidin with the biotinylated Rh(III) cofactor allowed us to rationally engineer mutants at the N49 position for enantiodivergence. Biocatalytic methods for the synthesis of isoindolones, via C–H activation, have remained elusive. Now, an enantiodivergent artificial-metalloenzyme-catalysed method for the synthesis of chiral isoindolones is reported, using a streptavidin–biotin–Rh(III) catalyst system. Crystallographic analysis reveals the key residues that control stereoselectivity in streptavidin.