Abstract
Artificial metalloenzymes (ArMs) formed by incorporating synthetic metal catalysts into protein scaffolds have the potential to impart to chemical reactions selectivity that would be difficult to achieve using metal catalysts alone. In this work, we covalently link an alkyne-substituted dirhodium catalyst to a prolyl oligopeptidase containing a genetically encoded L-4-azidophenylalanine residue to create an ArM that catalyses olefin cyclopropanation. Scaffold mutagenesis is then used to improve the enantioselectivity of this reaction, and cyclopropanation of a range of styrenes and donor–acceptor carbene precursors were accepted. The ArM reduces the formation of byproducts, including those resulting from the reaction of dirhodium–carbene intermediates with water. This shows that an ArM can improve the substrate specificity of a catalyst and, for the first time, the water tolerance of a metal-catalysed reaction. Given the diversity of reactions catalysed by dirhodium complexes, we anticipate that dirhodium ArMs will provide many unique opportunities for selective catalysis.
Highlights
Artificial metalloenzymes (ArMs) formed by incorporating synthetic metal catalysts into protein scaffolds have the potential to impart to chemical reactions selectivity that would be difficult to achieve using metal catalysts alone
To exploit the substrate-binding and activation capabilities of enzymes for reactions and catalysts not found in nature, researchers have developed a range of methods to link synthetic catalysts and protein scaffolds to create artificial metalloenzymes (ArMs)[1,7]
The majority of successful optimization efforts exploit the binding of biotinylated metal cofactors toavidin[10]; the development of new scaffolds capable of imparting high levels of selectivity metal catalysts could significantly expand the scope of ArM catalysis[9]
Summary
Artificial metalloenzymes (ArMs) formed by incorporating synthetic metal catalysts into protein scaffolds have the potential to impart to chemical reactions selectivity that would be difficult to achieve using metal catalysts alone. To exploit the substrate-binding and activation capabilities of enzymes for reactions and catalysts not found in nature, researchers have developed a range of methods to link synthetic catalysts and protein scaffolds to create artificial metalloenzymes (ArMs)[1,7] These efforts have culminated in ArMs for enantioselective, regioselective and chemoselective reactions, but, despite several notable examples[8,9,10,11,12,13], engineering scaffolds to further improve these parameters remains challenging[14]. Genetic optimization of these ArMs led to high levels of enantioselectivity and reduced levels of byproducts resulting from the reaction of catalytic intermediates with water
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