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Publication Abstract from PubMed

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 non-covalent 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. Second, by controlling the geometry of attack of the olefin on the carbene via steric occlusion, attractive van der Waals forces and protein-mediated pi-pi interactions with the olefin substrate. These insights could be leveraged to expand the substrate scope of the myoglobin-based cyclopropanation catalyst toward non-activated olefins and to increase its cyclopropanation activity in the presence of a bulky alpha-diazo-ester. This work sheds first light into 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.

Origin of high stereocontrol in olefin cyclopropanation catalyzed by an engineered carbene transferase.,Tinoco A, Wei Y, Bacik JP, Carminati DM, Moore EJ, Ando N, Zhang Y, Fasan R ACS Catal. 2019 Feb 1;9(2):1514-1524. doi: 10.1021/acscatal.8b04073. Epub 2018, Dec 28. PMID:31134138^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.