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Engineering a dirhodium artificial metalloenzyme for selective olefin cyclopropanation.

Srivastava P, Yang H, Ellis-Guardiola K, Lewis JC - Nat Commun (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Coskata Inc. 4575 Weaver Parkway, Warrenville, IL 60555, USA.

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.

No MeSH data available.


ArM formation and reactivity.(a) ArM formation using the SPAAC reaction. (b) Structure of cofactor 1. (c) Representative reactions catalysed by dirhodium complexes.
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f1: ArM formation and reactivity.(a) ArM formation using the SPAAC reaction. (b) Structure of cofactor 1. (c) Representative reactions catalysed by dirhodium complexes.

Mentions: We recently developed a new method for ArM formation via strain-promoted azide–alkyne cycloaddition (SPAAC) of bicyclo[6.1.0]nonyne (BCN)-substituted cofactors and scaffold proteins containing a genetically encoded L-4-azidophenylalanine (Z) residue (Fig. 1a)15. Unlike non-covalent methods for ArM formation, this approach allows the use of any desired protein as a scaffold, and, unlike most covalent methods, the bioorthogonality of SPAAC eliminates the need to remove residues (for example, cysteine) in the scaffold that might react with electrophiles used in conventional bioconjugation methods (for example, maleimides)7. ArM formation from various cofactors, including the Esp-based16 dirhodium cofactor 1 (Fig. 1b), was demonstrated with a range of protein scaffolds, but no selectivity was observed in reactions catalysed by these systems. We attributed this lack of selectivity to the inability of the protein scaffolds selected for bioconjugation method development to fully encapsulate the cofactors selected for catalysis. Given the broad range of reactions catalysed by dirhodium complexes (Fig. 1c), including cyclopropanation and X–H insertion (X=C, N, O, and so on)17, and the selectivity challenges that persist for many of these reactions18, we sought to identify a scaffold protein that could impart selectivity to 1. This would validate our hypothesis regarding the poor selectivity of our initial ArM designs, illustrate the importance of scaffold selection in ArM design and provide a platform for the development of future ArMs using different metal cofactors.


Engineering a dirhodium artificial metalloenzyme for selective olefin cyclopropanation.

Srivastava P, Yang H, Ellis-Guardiola K, Lewis JC - Nat Commun (2015)

ArM formation and reactivity.(a) ArM formation using the SPAAC reaction. (b) Structure of cofactor 1. (c) Representative reactions catalysed by dirhodium complexes.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525152&req=5

f1: ArM formation and reactivity.(a) ArM formation using the SPAAC reaction. (b) Structure of cofactor 1. (c) Representative reactions catalysed by dirhodium complexes.
Mentions: We recently developed a new method for ArM formation via strain-promoted azide–alkyne cycloaddition (SPAAC) of bicyclo[6.1.0]nonyne (BCN)-substituted cofactors and scaffold proteins containing a genetically encoded L-4-azidophenylalanine (Z) residue (Fig. 1a)15. Unlike non-covalent methods for ArM formation, this approach allows the use of any desired protein as a scaffold, and, unlike most covalent methods, the bioorthogonality of SPAAC eliminates the need to remove residues (for example, cysteine) in the scaffold that might react with electrophiles used in conventional bioconjugation methods (for example, maleimides)7. ArM formation from various cofactors, including the Esp-based16 dirhodium cofactor 1 (Fig. 1b), was demonstrated with a range of protein scaffolds, but no selectivity was observed in reactions catalysed by these systems. We attributed this lack of selectivity to the inability of the protein scaffolds selected for bioconjugation method development to fully encapsulate the cofactors selected for catalysis. Given the broad range of reactions catalysed by dirhodium complexes (Fig. 1c), including cyclopropanation and X–H insertion (X=C, N, O, and so on)17, and the selectivity challenges that persist for many of these reactions18, we sought to identify a scaffold protein that could impart selectivity to 1. This would validate our hypothesis regarding the poor selectivity of our initial ArM designs, illustrate the importance of scaffold selection in ArM design and provide a platform for the development of future ArMs using different metal cofactors.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Coskata Inc. 4575 Weaver Parkway, Warrenville, IL 60555, USA.

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.

No MeSH data available.