Origin of High Stereocontrol in Olefin Cyclopropanation Catalyzed by an Engineered Carbene Transferase

Recent advances in metalloprotein engineering have led to the development of a myoglobin-based catalyst, Mb­(H64V,V68A), capable of promoting the cyclopropanation of vinylarenes with high efficiency and high diastereo- and enantioselectivity. Whereas many enzymes evolved in nature often exhibit cata...

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Published in:ACS catalysis 2019-02, Vol.9 (2), p.1514-1524
Main Authors: Tinoco, Antonio, Wei, Yang, Bacik, John-Paul, Carminati, Daniela M, Moore, Eric J, Ando, Nozomi, Zhang, Yong, Fasan, Rudi
Format: Article
Language:English
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Summary:Recent advances in metalloprotein engineering have led to the development of a myoglobin-based catalyst, Mb­(H64V,V68A), capable of promoting the cyclopropanation of vinylarenes with high efficiency and high diastereo- and enantioselectivity. Whereas many enzymes evolved in nature often exhibit catalytic proficiency and exquisite stereoselectivity, how these features are achieved for a non-natural reaction has remained unclear. In this work, the structural determinants responsible for chiral induction and high stereocontrol in Mb­(H64V,V68A)-catalyzed cyclopropanation were investigated via a combination of crystallographic, computational (DFT), and structure–activity analyses. Our results show the importance of steric complementarity and noncovalent interactions involving first-sphere active site residues, heme–carbene, and the olefin substrate in dictating the stereochemical outcome of the cyclopropanation reaction. High stereocontrol is achieved through two major mechanisms: first, by enforcing a specific conformation of the heme-bound carbene within the active site, and second, by controlling the geometry of attack of the olefin on the carbene via steric occlusion, attractive van der Waals forces, and protein-mediated π–π interactions with the olefin substrate. These insights could be leveraged to expand the substrate scope of the myoglobin-based cyclopropanation catalyst toward nonactivated olefins and to increase its cyclopropanation activity in the presence of a bulky α-diazo-ester. This work sheds light on the origin of enzyme-catalyzed enantioselective cyclopropanation, furnishing a mechanistic framework for both understanding the reactivity of current systems and guiding the future development of biological catalysts for this class of synthetically important, abiotic transformations.
ISSN:2155-5435
2155-5435
DOI:10.1021/acscatal.8b04073