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

Antonio Tinoco, Yang Wei, John Paul Bacik, Daniela M. Carminati, Eric J. Moore, Nozomi Ando, Yong Zhang, Rudi Fasan

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1514-1524
Number of pages11
JournalACS Catalysis
Volume9
Issue number2
DOIs
StatePublished - 1 Feb 2019

Keywords

  • Density Functional Theory
  • biocatalytic carbene transfer
  • enantioselective cyclopropanation
  • heme carbenes
  • myoglobin
  • olefin cyclopropanation

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