Enantioselective artificial metalloenzymes by creation of a novel active site at the protein dimer interface.

Natural metalloenzymes are a continuing source of inspiration for the design of bio-inspired catalyst. Key to their high catalytic efficiencies and excellent (enantio)selectivities are the second coordination sphere interactions provided by the protein scaffold. The emerging concept of hybrid catalysis is an effort to impart enzyme-like characteristics to homogeneous transition-metal catalysts by embedding catalytically active transition-metal complexes in a biomolecular scaffold, resulting in an artificial metalloenzyme. Several elegant examples of artificial metalloenzymes, some of which are capable of performing highly enantioselective reactions, have been reported. However, the majority of these examples rely on a limited number of protein scaffolds that have a binding pocket that is large enough to bind the catalyst and still leave space for the substrates. Examples include scaffolds, such as avidin, streptavidin, bovine serum albumin (BSA), and apomyoglobin. An alternative approach to the design of artificial metalloenzymes involves creation of a new active site at an appropriate position in a protein scaffold, which is not necessarily an existing active site or binding pocket. Herein we present a novel concept for the creation of artificial metalloenzymes, which involves the creation of an active site on the dimer interface of the transcription factor LmrR. With this artificial metalloenzyme up to 97% ee was achieved in the benchmark copper(II)-catalyzed Diels–Alder reaction (Figure 1a). Dimerization of proteins is an important phenomenon in nature and is used as a convenient way to increase the complexity of the protein structure and to control activity. Indeed, quite regularly, active sites of dimeric proteins are