Artificial Metalloenzymes as Catalysts in Stereoselective Diels–Alder Reactions

Numerous enzymes are useful catalysts in synthetic organic chemistry, but they cannot catalyze the myriad transition-metal-mediated transformations customary in daily chemical work. For this reason the concept of directed evolution of hybrid catalysts was proposed some time ago. A synthetic ligand/transition-metal moiety is anchored covalently or non-covalently to a host protein, thereby generating a single artificial metalloenzyme which can then be optimized by molecular biological methods. In the quest to construct an appropriate experimental platform for asymmetric Diels-Alder reactions amenable to this Darwinian approach to catalysis, specifically those not currently possible using traditional chiral transition-metal catalysts, two strategies have been developed which are reviewed here. One concerns the supramolecular anchoring of a Cu(II)-phthalocyanine complex to serum albumins; the other is based on the design of a Cu(II)-specific binding site in a thermostable protein host (tHisF), leading to 46-98% ee in a model Diels-Alder reaction. This sets the stage for genetic fine-tuning using the methods of directed evolution.