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Directed Evolution of Artificial Metalloenzymes: A Universal Means to Tune the Selectivity of Transition Metal Catalysts?

Manfred T Reetz
Published in: Accounts of chemical research (2019)
Transition metal catalysts mediate a wide variety of chemo-, stereo-, and regioselective transformations, and therefore play a pivotal role in modern synthetic organic chemistry. Steric and electronic effects of ligands provide organic chemists with an exceedingly useful tool. More than four decades ago, chemists began to think about a different approach, namely, embedding achiral ligand/metal moieties covalently or noncovalently in protein hosts with formation of artificial metalloenzymes. While structurally fascinating, this approach led in each case only to a single (bio)catalyst, with its selectivity and activity being a matter of chance. In order to solve this fundamental problem, my group proposed in 2000-2002 the idea of directed evolution of artificial metalloenzymes. In earlier studies, we had already demonstrated that directed evolution of enzymes constitutes a viable method for enhancing and inverting the stereoselectivity of enzymes as catalysts in organic chemistry. We speculated that it should also be possible to manipulate selectivity and activity of artificial metalloenzymes, which would provide organic chemists with a tool for optimizing essentially any transition metal catalyzed reaction type. In order to put this vision into practice, we first turned to the Whitesides system for artificial metalloenzyme formation, comprising a biotinylated diphosphine/Rh moiety, which is anchored noncovalently to avidin or streptavidin. Following intensive optimization, proof of principle was finally demonstrated in 2006, which opened the door to a new research area. This personal Account critically assesses these early studies as well as subsequent efforts from my group focusing on different protein scaffolds, and includes briefly some of the most important current contributions of other groups. Two primary messages emerge: First, since organic chemists continue to be extremely good at designing and implementing man-made transition metal catalysts, often on a large scale, those scientists that are active in the equally intriguing field of directed evolution of artificial metalloenzymes should be moderate when generalizing claims. All factors required for a truly viable catalytic system need to be considered, especially activity and ease of upscaling. Second, the most exciting and thus far very rare cases of directed evolution of artificial metalloenzymes are those that focus on selective transformations that are not readily possible using state of the art transition metal catalysts.
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