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Stereoselective Enzymatic Synthesis of Heteroatom-Substituted Cyclopropanes

Brandenberg, Oliver F. and Prier, Christopher K. and Chen, Kai and Knight, Anders M. and Wu, Zachary and Arnold, Frances H. (2018) Stereoselective Enzymatic Synthesis of Heteroatom-Substituted Cyclopropanes. ACS Catalysis, 8 (4). pp. 2629-2634. ISSN 2155-5435. http://resolver.caltech.edu/CaltechAUTHORS:20180312-085606768

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Abstract

The repurposing of hemoproteins for non-natural carbene transfer activities has generated enzymes for functions previously accessible only to chemical catalysts. With activities constrained to specific substrate classes, however, the synthetic utility of these new biocatalysts has been limited. To expand the capabilities of non-natural carbene transfer biocatalysis, we engineered variants of Cytochrome P450_(BM3) that catalyze the cyclopropanation of heteroatom-bearing alkenes, providing valuable nitrogen-, oxygen-, and sulfur-substituted cyclopropanes. Four or five active-site mutations converted a single parent enzyme into selective catalysts for the synthesis of both cis and trans heteroatom-substituted cyclopropanes, with high diastereoselectivities and enantioselectivities and up to 40 000 total turnovers. This work highlights the ease of tuning hemoproteins by directed evolution for efficient cyclopropanation of new substrate classes and expands the catalytic functions of iron heme proteins.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/acscatal.7b04423DOIArticle
https://pubs.acs.org/doi/10.1021/acscatal.7b04423PublisherArticle
https://pubs.acs.org/doi/suppl/10.1021/acscatal.7b04423PublisherSupporting Information
ORCID:
AuthorORCID
Brandenberg, Oliver F.0000-0001-5662-1234
Chen, Kai0000-0002-3325-3536
Knight, Anders M.0000-0001-9665-8197
Arnold, Frances H.0000-0002-4027-364X
Additional Information:© 2018 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Received: December 23, 2017; Revised: February 7, 2018; Publication Date (Web): February 24, 2018. We thank Dr. Stephan Hammer for help with chiral separations of cyclopropylamines and all members of the Arnold Laboratory for stimulating comments and discussions. We thank Dr. David Rozzell for suggestions on cyclopropanation substrate scope. Author Contributions: The manuscript was written with contributions of all authors. All authors have given approval to the final version of the manuscript. This work was supported in part by the National Science Foundation, Division of Molecular and Cellular Biosciences (Grant No. MCB-1513007) and the Defense Advanced Research Projects Agency Biological Robustness in Complex Settings Contract HR0011-15-C-0093. O.F.B. acknowledges support from the Deutsche Forschungsgemeinschaft (DFG Grant No. BR 5238/1-1) and the Swiss National Science Foundation (SNF Grant No. P300PA-171225). C.K.P. thanks the Resnick Sustainability Institute for a postdoctoral fellowship. A.M.K. and Z.W. acknowledge support from the NSF Graduate Research Fellowship (Grant No. 1745301), and A.M.K. acknowledges support from Caltech’s Center for Environmental Microbial Interactions. The authors declare no competing financial interest.
Group:Resnick Sustainability Institute, Caltech Center for Environmental Microbial Interactions (CEMI)
Funders:
Funding AgencyGrant Number
NSFMCB-1513007
Defense Advanced Research Projects Agency (DARPA)HR0011-15-C-0093
Deutsche Forschungsgemeinschaft (DFG)BR 5238/1-1
Swiss National Science Foundation (SNSF)P300PA-171225
Resnick Sustainability InstituteUNSPECIFIED
NSF Graduate Research FellowshipDGE-1745301
Caltech Center for Environmental Microbial Interactions (CEMI)UNSPECIFIED
Subject Keywords:biocatalysis; carbene transfer; cyclopropanes; Cytochrome P450
Record Number:CaltechAUTHORS:20180312-085606768
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20180312-085606768
Official Citation:Stereoselective Enzymatic Synthesis of Heteroatom-Substituted Cyclopropanes. Oliver F. Brandenberg, Christopher K. Prier, Kai Chen, Anders M. Knight, Zachary Wu, and Frances H. Arnold. ACS Catalysis 2018 8 (4), 2629-2634. DOI: 10.1021/acscatal.7b04423
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:85240
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:12 Mar 2018 17:24
Last Modified:25 Apr 2018 17:29

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