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Title: Beyond Iron: Iridium-Containing P450 Enzymes for Selective Cyclopropanations of Structurally Diverse Alkenes

Abstract

Enzymes catalyze organic transformations with exquisite levels of selectivity, including chemoselectivity, stereoselectivity, and substrate selectivity, but the types of reactions catalyzed by enzymes are more limited than those of chemical catalysts. Thus, the convergence of chemical catalysis and biocatalysis can enable enzymatic systems to catalyze abiological reactions with high selectivity. Recently, we disclosed artificial enzymes constructed from the apo form of heme proteins and iridium porphyrins that catalyze the insertion of carbenes into a C-H bond. Here, we postulated that the same type of Ir(Me)-PIX enzymes could catalyze the cyclopropanation of a broad range of alkenes with control of multiple modes of selectivity. Here, we report the evolution of artificial enzymes that are highly active and highly stereoselective for the addition of carbenes to a wide range of alkenes. These enzymes catalyze the cyclopropanation of terminal and internal, activated and unactivated, electron-rich and electron-deficient, conjugated and nonconjugated alkenes. In particular, Ir(Me)-PIX enzymes derived from CYP119 catalyze highly enantio- and diastereoselective cyclopropanations of styrene with ±98% ee, > 70:1 dr, > 75% yield, and ~10,000 turnovers (TON), as well as 1,2-disubstituted styrenes with up to 99% ee, 35:1 dr, and 54% yield. Moreover, Ir(Me)-PIX enzymes catalyze cyclopropanation of internal, unactivated alkenesmore » with up to 99% stereoselectivity, 76% yield, and 1300 TON. They also catalyze cyclopropanation of natural products with diastereoselectivities that are complementary to those attained with standard transition metal catalysts. Finally, Ir(Me)-PIX P450 variants react with substrate selectivity that is reminiscent of natural enzymes; they react preferentially with less reactive internal alkenes in the presence of more reactive terminal alkenes. Altogether, the studies reveal the suitability of Ir-containing P450s to combine the broad reactivity and substrate scope of transition metal catalysts with the exquisite selectivity of enzymes, generating catalysts that enable reactions to occur with levels and modes of activity and selectivity previously unattainable with natural enzymes or transition metal complexes alone.« less

Authors:
 [1]; ORCiD logo [1];  [2];  [2];  [2];  [2];  [3]; ORCiD logo [1]
  1. Department of Chemistry, University of California, Berkeley, California 94720, United States, Chemical Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, United States
  2. Department of Chemistry, University of California, Berkeley, California 94720, United States
  3. Department of Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, United States, Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, United States
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1349533
Alternate Identifier(s):
OSTI ID: 1411658
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Published Article
Journal Name:
ACS Central Science
Additional Journal Information:
Journal Name: ACS Central Science Journal Volume: 3 Journal Issue: 4; Journal ID: ISSN 2374-7943
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Key, Hanna M., Dydio, Paweł, Liu, Zhennan, Rha, Jennifer Y. -E., Nazarenko, Andrew, Seyedkazemi, Vida, Clark, Douglas S., and Hartwig, John F. Beyond Iron: Iridium-Containing P450 Enzymes for Selective Cyclopropanations of Structurally Diverse Alkenes. United States: N. p., 2017. Web. doi:10.1021/acscentsci.6b00391.
Key, Hanna M., Dydio, Paweł, Liu, Zhennan, Rha, Jennifer Y. -E., Nazarenko, Andrew, Seyedkazemi, Vida, Clark, Douglas S., & Hartwig, John F. Beyond Iron: Iridium-Containing P450 Enzymes for Selective Cyclopropanations of Structurally Diverse Alkenes. United States. doi:10.1021/acscentsci.6b00391.
Key, Hanna M., Dydio, Paweł, Liu, Zhennan, Rha, Jennifer Y. -E., Nazarenko, Andrew, Seyedkazemi, Vida, Clark, Douglas S., and Hartwig, John F. Tue . "Beyond Iron: Iridium-Containing P450 Enzymes for Selective Cyclopropanations of Structurally Diverse Alkenes". United States. doi:10.1021/acscentsci.6b00391.
@article{osti_1349533,
title = {Beyond Iron: Iridium-Containing P450 Enzymes for Selective Cyclopropanations of Structurally Diverse Alkenes},
author = {Key, Hanna M. and Dydio, Paweł and Liu, Zhennan and Rha, Jennifer Y. -E. and Nazarenko, Andrew and Seyedkazemi, Vida and Clark, Douglas S. and Hartwig, John F.},
abstractNote = {Enzymes catalyze organic transformations with exquisite levels of selectivity, including chemoselectivity, stereoselectivity, and substrate selectivity, but the types of reactions catalyzed by enzymes are more limited than those of chemical catalysts. Thus, the convergence of chemical catalysis and biocatalysis can enable enzymatic systems to catalyze abiological reactions with high selectivity. Recently, we disclosed artificial enzymes constructed from the apo form of heme proteins and iridium porphyrins that catalyze the insertion of carbenes into a C-H bond. Here, we postulated that the same type of Ir(Me)-PIX enzymes could catalyze the cyclopropanation of a broad range of alkenes with control of multiple modes of selectivity. Here, we report the evolution of artificial enzymes that are highly active and highly stereoselective for the addition of carbenes to a wide range of alkenes. These enzymes catalyze the cyclopropanation of terminal and internal, activated and unactivated, electron-rich and electron-deficient, conjugated and nonconjugated alkenes. In particular, Ir(Me)-PIX enzymes derived from CYP119 catalyze highly enantio- and diastereoselective cyclopropanations of styrene with ±98% ee, > 70:1 dr, > 75% yield, and ~10,000 turnovers (TON), as well as 1,2-disubstituted styrenes with up to 99% ee, 35:1 dr, and 54% yield. Moreover, Ir(Me)-PIX enzymes catalyze cyclopropanation of internal, unactivated alkenes with up to 99% stereoselectivity, 76% yield, and 1300 TON. They also catalyze cyclopropanation of natural products with diastereoselectivities that are complementary to those attained with standard transition metal catalysts. Finally, Ir(Me)-PIX P450 variants react with substrate selectivity that is reminiscent of natural enzymes; they react preferentially with less reactive internal alkenes in the presence of more reactive terminal alkenes. Altogether, the studies reveal the suitability of Ir-containing P450s to combine the broad reactivity and substrate scope of transition metal catalysts with the exquisite selectivity of enzymes, generating catalysts that enable reactions to occur with levels and modes of activity and selectivity previously unattainable with natural enzymes or transition metal complexes alone.},
doi = {10.1021/acscentsci.6b00391},
journal = {ACS Central Science},
number = 4,
volume = 3,
place = {United States},
year = {2017},
month = {4}
}

Journal Article:
Free Publicly Available Full Text
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DOI: 10.1021/acscentsci.6b00391

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Cited by: 9 works
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Works referencing / citing this record:

Highly Diastereo- and Enantioselective Synthesis of Nitrile-Substituted Cyclopropanes by Myoglobin-Mediated Carbene Transfer Catalysis
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Highly Diastereo- and Enantioselective Synthesis of Nitrile-Substituted Cyclopropanes by Myoglobin-Mediated Carbene Transfer Catalysis
journal, November 2018

  • Chandgude, Ajay L.; Fasan, Rudi
  • Angewandte Chemie International Edition, Vol. 57, Issue 48
  • DOI: 10.1002/anie.201810059

Near-Infrared Phosphorescent Supramolecular Alkyl/Aryl-Iridium Porphyrin Assemblies by Axial Coordination
journal, September 2018

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Iridium porphyrin complexes with μ-nitrido, hydroxo, hydrosulfido and alkynyl ligands
journal, January 2019

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An Artificial Heme Enzyme for Cyclopropanation Reactions
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Site‐Selective Functionalization of (sp 3 )C−H Bonds Catalyzed by Artificial Metalloenzymes Containing an Iridium‐Porphyrin Cofactor
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